WO2019082171A1

WO2019082171A1 - Oral cannabinoid compositions with improved bioavailability

Info

Publication number: WO2019082171A1
Application number: PCT/IB2018/058452
Authority: WO
Inventors: Yoram Sela
Original assignee: Alvit Pharma
Priority date: 2017-10-27
Filing date: 2018-10-29
Publication date: 2019-05-02

Abstract

The instant invention provides cannabinoid compositions for oral administration with high colonic delivery comprising at least one cannabinoid active ingredient selected from the group comprising THC, CBD and other minor cannabinoids and optionally at least one additional active selected from the group comprising budesonide, nicotine, mesalamine, analgesics, anti-inflammatories, anti-Parkinson drugs and combinations thereof. The improved bioavailability is achieved in one embodiment by releasing a first pulse of the actives in the upper part of the small intestine and a second pulse of the actives in the colon. Said compositions are formulated in the form of tablet or capsule.

Description

ORAL CANNABINOID COMPOSITIONS WITH IMPROVED BIOAVAILABILITY

Field Of The Invention

The present invention relates to pharmaceutical compositions for the administration of cannabinoid active ingredients. More particularly, the present invention relates to pharmaceutical compositions for the oral administration and colonic release of cannabinoid compositions having improved bioavailability.

Background Of The Invention

Cannabinoids are a class of natural or synthetic chemical compounds which act on cannabinoid receptors in cells that repress neurotransmitter release in the brain. Two of the most important cannabinoids are tetrahydrocannabinol (THC) and cannabidiol (CBD) .

THC

One of the best known commercial cannabinoids is Marinol®, sold on the US markets as Marinol® capsules. The active ingredient in Marinol® is dronabinol (synthetic delta-9- tetrahydrocannabinol (Δ-9-THC) or THC) which is the primary psychoactive cannabinoid component of the Cannabis sativa L. plant (marijuana) . Dronabinol is a cannabinoid designated chemically as ( 6aR-trans) 6a, 7, 8, 10a-tetrahydro-6, 6, 9- trimethyl-3-pentyl- 6H-dibenzo [b, d] pyran-l-ol . Dronabinol is a light yellow resinous oil that is sticky at room temperature and hardens upon refrigeration. It is insoluble in water and is formulated in sesame oil. It has a pKa of 10.6 and an octanol-water partition coefficient: 6,000:1 at pH 7. THC PHARMACOLOGY:

Dronabinol is an orally active cannabinoid which, like other cannabinoids , has complex effects on the central nervous system (CNS), including central sympathomimetic activity.

PHARMACOKINETICS

Absorption and Distribution:

Dronabinol in Marinol® Capsules is almost completely absorbed (90 to 95%) after single oral doses. However, due to the combined effects of first pass hepatic metabolism and high lipid solubility, only 10 to 20% of the administered dose reaches the systemic circulation. Dronabinol has a large apparent volume of distribution, approximately 10 L/kg, because of its lipid solubility. The plasma protein binding of dronabinol and its metabolites is approximately 97%. The elimination phase of dronabinol can be described using a two compartment model with an initial (alpha) half-life of about 4 hours and a terminal (beta) half-life of 25 to 36 hours.

Because of its large volume of distribution, dronabinol and its metabolites may be excreted at low levels for prolonged periods of time.

Metabolism:

Undergoes extensive first-pass hepatic metabolism, primarily by microsomal hydroxylation, yielding both active and inactive metabolites. Dronabinol and its principal active metabolite, ΙΙ-ΟΗ-Δ-9-THC, are present in approximately equal

concentrations in plasma. Concentrations of both parent drug and metabolite peak at approximately 0.5 to 4 hours after oral dosing and decline over several days. Values for clearance average about 0.2 L/kg-hr, but are highly variable due to the complexity of cannabinoid distribution.

Dronabinol and its biotransformation products are excreted in both feces and urine. Biliary excretion is the major route of elimination with about half of a radio-labeled oral dose being recovered from the feces within 72 hours as contrasted with 10 to 15% recovered from urine. Less than 5% of an oral dose is recovered unchanged in the feces. Following single dose administration, low levels of dronabinol metabolites have been detected for more than 5 weeks in the urine and feces. After oral administration, dronabinol has an onset of action of approximately 0.5 to 1 hours and peak effect at 2 to 4 hours. Duration of action for psychoactive effects is 4 to 6 hours, but the appetite stimulant effect of dronabinol may continue for 24 hours or longer after administration. Marinol® capsules (2.5-10 mg) are dosed twice daily, and it is clear from the pharmacokinetic data that the current

commercial formulation provides only very low dissolution. Marinol' s PK is problematic, limits its uses and decreases the ability to take full advantage of dronabinol's vast potential applications.

CBD

Cannabidiol (CBD), the major non-psychotropic cannabinoid compound derived from Cannabis sativa, was first isolated in 1940, and its structure and stereochemistry elucidated in

1963. Interest in exploiting CBD therapeutically was initially focused on its interactions with A9-THC, its sedative and antiepileptic effects, and later its antipsychotic and

anxiolytic actions and utility in treating movement disorders. More recently the discovery of its antioxidative, anti^¬ inflammatory and neuroprotective effects, effects that occur for the most part independent of the cannabinoid CBl and CB2 receptors has sparked renewed interest and research. The endocannabinoid system plays a role in a variety of

physiological processes including appetite, pain sensation, and mood and CBD is proving to have potentially therapeutic utility in a number of conditions involving both inflammation and oxidative stress, including Parkinson disease, diabetes, rheumatoid arthritis, Alzheimer disease, and ischemia- reperfusion injury. Both CBland CB2 are expressed by cells of the immune system and are upregulated in the activation state.

Since CBD's pharmacokinetic characteristics are similar to THC, similar limitations and requirements exist regarding the limited potential use of the existing formulations.

Oral Drug Delivery Versus Self-Emulsifying Drug Delivery

Systems (SEDDS)

Oral drug delivery that relies on simple aqueous

solubilization and gastrointestinal absorption is a highly preferred mode of administration for a large number of medical indications. For such drugs, the absorption rate from the gastrointestinal tract is mainly governed by dissolution, hence improvement in solubility is expected to lead to

enhanced bioavailability. Unfortunately, 30% to 40% of drugs possess low aqueous solubility and therefore low

bioavailability, resulting in higher dosage requirements to counter high intra- and inter-sub ect variability and lack of dose proportionality. Technologies such as complex formation with cyclodextrins , solid dispersion, liposome formation, co- precipitation, micronization, salt formation, use of micelles, co-grinding and emulsification have been used for improving the dissolution profile of drugs with low solubility, thereby improving therapeutic efficacy, at lower doses, of these drugs. However, when the main reason for poor bioavailability of orally delivered substances is the body' s pre-systemic metabolism, commonly referred to as "the first pass effect", better solubilization does not necessarily provide a sufficient solution and alternative routes need to be

considered .

One example for an alternative to aqueous-solubility based oral delivery is the lymphatic route which appears to provide a viable alternative to oral delivery, substantially avoiding the first pass effect. SEDDS have been developed to enhance the solubility of drugs and enable improved lymphatic

delivery, mainly by the body' s chylomicrons created when fat is digested in the small intestine. SEDDS are defined as isotropic mixtures of natural or synthetic oils, solid or liquid surfactants or alternatively, one or more hydrophilic solvents and co-solvents/cosurfactants .

SEDDS are able to self-emulsify rapidly in the gastro- intestinal fluids and under the influence of gentle agitation provided by peristaltic and other movements of the gastro^¬ intestinal tract, forming a fine oil in water emulsion. SEDDS can effectively incorporate hydrophobic drugs within the oil surfactant mixture. They can be used for liquid as well as solid dosage forms and they permit the use of lower doses of active ingredient as compared with respect to the same active ingredient in conventional aqueous solubility dependent dosage forms .

Additional characteristics associated with SEDDS include: 1. Protection of sensitive drug substances from the harsh environment of the GI tract;

2. Selective targeting of the drug toward a specific

absorption window in the GI tract, mainly the upper part of the small intestine; 3. Enhanced oral bioavailability; 4. Consistent drug absorption profile;

5. Better control of drug delivery profiles;

6. Ability to provide dosage forms as liquids or solids; and, 7. Predictable therapy due to reduced variability including food effects.

Based on the water solubility of their components, SEDDS can be classified as follows (A) Non-water-soluble Component Systems

These systems are isotropic mixtures of lipids and lipophilic surfactants having HLB value of less than 12 that self- emulsify to form fine oil in water emulsions in aqueous medium. Self-emulsification is generally obtained at a surfactant level above 25% w/w. But at a surfactant level of 50-60% w/w the emulsification process may be compromised by formation of viscous liquid crystalline gels at the oil/water interface. This system is also known as Type-II SEDDS

according to the lipid formulation classification system (LFCS) .

Poorly water-soluble drugs can be incorporated in SEDDS and filled in capsules (hard or soft gelatin) to produce

convenient single unit dosage forms. These systems offer important advantages: they are able to generate large

interfacial areas which cause efficient partitioning of drug between oil droplets and the aqueous phase.

(B) Water soluble component system:

These systems are formulated by using hydrophilic surfactants with a HLB value of more than 12 and co-solvents such as ethanol, propylene glycol and polyethylene glycols. Type III SEDDS are commonly known as self micro-emulsifying drug delivery systems (SMEDDS) . Type III formulations can be further divided into type III A & Type III B formulations in order to identify more hydrophilic forms. In Type IIIB, the content of hydrophilic surfactants and co-solvents is increased and lipid content is reduced.

The distinction between SEDDS and SMEDDS formulation is commonly based on particle size and optical clarity of the resultant dispersion. Thus, SEDDS formulations typically provide opaque dispersions with particle size greater than 100 nm while SMEDDS disperse to give small droplets with particle size less than 100 nm and provide optically clear or slightly opalescent dispersions. SEDDS and SMEDDS have played an important role in the improvement of solubility as well as bioavailability of drugs with poor aqueous solubility.

An example of a marketed SMEDDS formulation is Neoral®

cyclosporine formulation in which corn oil, derived mono, di and triglycerides were used as lipid phase, Cremophor RH 40 as surfactant, propylene glycol & ethanol as co-solvent along with tocopheryl as an antioxidant. Neoral® spontaneously forms a transparent and thermodynamically stable dispersion with droplet size below 100 nm when introduced into an aqueous medium. SEDDS may be solid or liquid and they may be

formulated into tablets, capsules, pellets, solid dispersions, microspheres, nanoparticles or dry emulsions. SUMMARY OF THE INVENTION Colonic Delivery of Drugs:

The oral route is considered to be most convenient for the administration of drugs to patients. That is where drug normally dissolves in the gastrointestinal (GI) fluids and is absorbed from these regions of the GIT, and both processes depend upon the physicochemical properties of the drug. Oral delivery of drugs to the colon is valuable in the treatment of diseases of colon such as colon cancer, ulcerative colitis, Crohn's disease and inflammatory bowel disease whereby high local concentration can be achieved while minimizing side effects and also used in treatment of asthma, angina and rheumatoid arthritis and for delivery of steroids, which are absorbable in the colon. Colon specific drug delivery systems (CDDS) should be capable of releasing the drug in to the colon i.e. drug release and absorption should not occur in the stomach nor preferably the small intestine, and neither should the bioactive agent be degraded in either of those sites but only released and absorbed once it reaches the colon. Because the colon has a long residence time of 72 hours and high water content in it favors absorption of poorly absorbed drug molecules thereby improving bioavailability, CDDS has been employed to achieve following objectives: [] Sustained delivery to reduce dosing frequency

Q Delayed delivery of drug to achieve high concentrations in treatment of disease of distal gut to delay delivery to a time appropriate to treat acute phase of disease

[] Deliver the drug to a region that is less hostile

metabolically, for drug which are acid and enzyme labile such as proteins.

Benefits of colon targeted drug delivery systems (CDDS)

Q Reducing the adverse effects in the treatment of colonic diseases (ulcerative colitis, colorectal cancer, Crohn's disease etc . )

[] By producing a friendlier' environment for peptides and proteins as compared to the upper gastrointestinal tract

[] Minimizing extensive first pass metabolism of steroids. [] Preventing the gastric irritation produced by oral

administration of NSAIDS.

Q Delayed release of drugs to treat angina, asthma and

rheumatoid arthritis.

Limitations of colon targeted DDS [] Difficulty to access colon.

Q Successful delivery requires the drug to be in solution before it arrives in the colon, but the fluid content in the colon is lower and more viscous

Need for colon targeting drug delivery

□ to ensure direct treatment at the disease site (local delivery) , at lower dosing and fewer systemic side effects . [] would allow oral administration of peptide and protein drugs ; Q to prolong the drug delivery . to be particularly beneficial in the treatment of colon diseases both local or systemic drug delivery could be achieved the typical treatment of inflammatory bowel disease, e.g. ulcerative colitis or Crohn' s disease is with

glucocorticoids and sulphasalazine other serious diseases of the colon, e.g. colorectal cancer, might be treated more effectively if drugs were targeted to the colon.

[] highly suitable for delivery of drugs which are polar

and/or susceptible to chemical and enzymatic degradation in the upper GI tract, or highly affected by hepatic metabolism, in particular, therapeutic proteins and peptides .

The instant invention provides oral cannabinoid compositions with improved bioavailability comprising at least one

cannabinoid selected from the group comprising THC, CBD and other minor cannabinoids and optionally at least one

additional active selected from the group comprising

budesonide, nicotine, mesalamine, analgesics, anti^¬ inflammatories and combinations thereof.

The improved bioavailability is achieved by releasing a first pulse of the actives in the upper part of the small intestine and a later second pulse of the actives in the colon. Said compositions are formulated in the form of tablet or capsule. The compositions comprise two components, first component formulated as a self-emulsifying drug delivery system (SEDDS) to be released in the upper part of the intestine, and the second component formulated to release the actives in the colon and wherein the release mechanism is based on pH- dependent polymers like Eudragit S, pH-independent polymers like HPMC, different natural or synthetic gums and their combinations .

DETAILED DESCRIPTION OF THE INVENTION

Cannabinoid drugs like THC or CBD are poorly soluble

molecules, which are well absorbed but due to significant first pass effect and their oily characteristics suffer from low (10-20%) systemic bioavailability, in addition to erratic and unpredictable release into the systemic circulation due to their lipidic molecular characteristics.

As a result of these poor and problematic pharmacokinetic characteristics the potential use of these molecules is only partially achieved, and the current use is limited to

indications which do not require high and predictable

bioavailability .

This problem becomes significant with the dronabinol (Δ9-ΤΗ0) , where in addition to the poor bioavailability the main

metabolite (11-OH-THC) appears in amounts equal to the parent drug but is twice more psychoactive and has a longer half- life.

In order to overcome the above described drawbacks and provide an optimal solution to the oral administration with colonic delivery of cannabinoids with emphasis on THC and CBD, a delivery platform is taught herein which combines both self- emulsifying and colonic delivery characteristics in one dosage form thereby enabling relatively quick and predictable onset of the drug, together with improved bioavailability enabling once daily dosing and expanding the THC use to additional indications, such as pain.

One exemplary embodiment of the delivery platform of this invention comprises pulse release of the active ingredients in two release areas. The release of the first pulse starts after the composition passes the stomach, in the upper part of the small intestine and lasting for up to about 1 hr, and preferably as little as 45 or 30 minutes. The second pulse delivery starts at the colon and releases its content as pulsatile or in a controlled manner in the colon, in either the simple colonic formulation or using a self-emulsified formulation .

In both release areas the cannabinoids might be released as such, self-emulsified or both. In this unique dosage form the ratios between the drug released in the small intestine or the colon are varied in broad ranges, for example can be mainly 99% released in the small intestine and one percent in the colon, or 99% in the colon and 1% in the intestine, any ratio in between or alternatively can be only colonic.

The advantage of releasing a self-emulsified portion in the upper small intestine is the relatively quick onset of the drug, enabling improved absorption and more predictable, less variable absorption, together with reduced first pass effect due to faster and more significant absorption. The portion formulated for colonic release enables release of the

cannabinoids in that portion of the GI tract having less enzymatic and first pass activity combined with extended time presence long stay in the colon. The combination of these factors enable improved bioavailability with lower enzymatic degradation. These advantages can be highly clinically

significant, and especially so with regard to dronabinol, for which decreased metabolism means less of the main active metabolite, the 11-OH THC which has longer half-life and higher psychoactive activity than its parent drug the

dronabinol. Providing a two peaks release profile separated by about 4-5 hrs, enables once daily administration of the drug with less side effects and better compliance. It should be understood that the colonic release part of the formulation discussed herein may be formulated as immediate release or controlled release.

The compositions described in this invention may comprise cannabinoids only or fixed dose combinations (FDC) of a cannabinoid selected from THC, CBD and minor cannabinoids with at least one additional active selected from the group

comprising budesonide, nicotine, mesalamine, analgesics, anti- inflammatories, anti-Parkinson drugs and combinations thereof.

In an embodiment, there are provided oral compositions

comprising at least one cannabinoid selected from the group comprising THC, CBD and other minor cannabinoids and

optionally at least one additional active selected from the group comprising budesonide, nicotine, mesalamine, analgesics, anti-inflammatories , anti-Parkinson drugs and combinations thereof. The actives of the composition are formulated in two components, the first component releasing a first pulse in the upper part of the small intestine and the second component releasing a second pulse in the colon as immediate release or controlled release and the composition is formulated in the form of tablet or capsule. The above first component is formulated to release the actives in the upper part of the small intestine as a self-emulsifying drug delivery system (SEDDS) . The second component of the compositions is

formulated to release the actives in the colon and the colonic release mechanism is based on pH-dependent polymers like

Eudragit S, pH-independent polymers like HPMC, different natural or synthetic gums and their combinations and the actives release pattern in the colon is immediate or

controlled release. In another embodiment the self-emulsifying component is enteric coated.

In an embodiment, the compositions of this invention may further comprise Vitamin E TPGS with the combined role of emulsifier, stabilizer, enhancer and solubilizer.

The emulsifier in the above compositions is lecithin,

polysorbate, Cremophor or any other surface-active material suitable for the preparation of such systems. A mineral or vegetable oil assisting the self-emulsification process may be added to the self-emulsifying component.

In an embodiment, the compositions may further comprise a stabilizer or antioxidant selected from the group comprising BHT, BHA, disodium EDTA, methylparaben, propylparaben or their mixtures . In another embodiment, the colonic second component and the enteric coated component are formulated either as separate coated minitabs or beads or as multilayered beads, minitabs or tablets .

In another embodiment, there are provided oral compositions comprising at least one cannabinoid selected from the group comprising THC, CBD and other minor cannabinoids and

optionally at least one additional active selected from the group comprising , analgesics, anti-inflammatories , anti- Parkinson drugs and combinations thereof, wherein the actives of the composition are released in the colon and the colonic release mechanism is based on pH-dependent polymers like

controlled release. In yet another embodiment, there is provided a method of treatment of inflammation, by administration to a patient in need thereof a composition of this invention, comprising therapeutically effective doses of actives selected from THC, CBD, mesalamine, budesonide, anti-inflammatory drugs and their combinations .

There is provided a method of treatment of pain, including neuropathic pain, by administration to a patient in need thereof therapeutically effective doses of a composition of this invention.

In an embodiment, there is provided a method of treatment of epilepsy, CNS-related diseases or inflammation, by

administration to a patient in need thereof a therapeutically effective dose of the compositions of this invention, wherein the at least one cannabinoid is CBD.

In another embodiment, there is provided a method of treatment of Parkinson disease by administration to a patient in need thereof a therapeutically effective dose of the compositions of this invention, wherein the at least one cannabinoid is THC.

Similarly, there is provided a method of treatment of cancer pain by administration to a patient in need thereof of a therapeutically effective dose of the compositions of this invention, wherein the at least one cannabinoid is THC or a combination of THC with CBD.

In an embodiment, there is provided a method of treatment of a medical condition by administration to a patient in need thereof of a therapeutically effective dose of a composition of this invention. Examples 1-5 below provide guidance about the preparation of the compositions of this invention.

EXAMPLES

The following examples illustrate certain embodiments of the invention but are not meant to limit the scope of the claims in any way. The following examples are put forth so as to provide those of ordinary skill in the art with a complete disclosure and description of how to make and use the

described invention, and are not intended to limit the scope of what the inventors regard as their invention nor are they intended to represent that the experiments below are all or the only experiments performed. Efforts have been made to ensure accuracy with respect to numbers used (e.g. amounts, temperature, etc.) but some experimental errors and deviations should be accounted for. Unless indicated otherwise, parts are parts by weight, molecular weight is weight average molecular weight, temperature is in degrees Centigrade, and pressure is at or near atmospheric.

EXAMPLE 1

Preparation of a Tablet Matrix containing THC

Mix 5 g synthetic THC together with 2 g Vitamin E TPGS, 3 g of sesame oil, 20 ml of ethanol absolute and mix all ingredients until completely dissolved. The mixture obtained was dried in vacuum oven. The dry mixture was added into a second mixture prepared from: PVP K 30 10 g, BHT and BHA 0.05+0.05 g,

Methylparaben 1.25 g, Starch 1500 5 g. EDTA disodium-0.25 g, and Phosphate buffer, pH 7, 0.5 g.

Lactose for direct compression-150 g Mannitol for direct compression-130 g

Sieve the obtained mixture with 1.4 mm sieve and mix 10 minutes in a planetary mixer. Add 1 g Magnesium stearate to the mixture and mix 2 minutes. Transfer the resulting powder into a type B rotary tableting machine with flat round shape 3 mm mini tablets punches and compress into 30 mg mini tablets containing 0.5 mg THC/tablet.

Preparation of a Tablet Matrix containing CBD

Mix 10 g synthetic CBD with 2 g Vitamin E TPGS, 3 gr of sesame oil, 20 ml of ethanol absolute, and mix all ingredients until completely dissolved. Dry the resulting mixture in vacuum oven. Add the dry mixture into a second mixture prepared from: PVP K 30 10 g, BHT and BHA 0.05g+0.05 g, Methylparaben 1.25 g, Starch 1500 5 g, EDTA disodium-0.25 g, Phosphate buffer, pH 7, 0.5 g.

Lactose for direct compression-150 g and/or Mannitol for direct compression-130 g. As a general matter, these

excipients might be used separately or together, for direct compression and for granulation. Sieve the obtained mixture with a 1.4 mm sieve and mix 10 minutes in a planetary mixer. Add 1 g magnesium stearate and mix 2 minutes. Transfer the resulting powder into a type B rotary tableting machine with flat round shape 3 mm mini tablets punches and compress into 30 mg mini tablets

containing 1 mg CBD/tablet.

Preparation Of Enteric Coated THC Or CBD Mini Tablets

Place minitablets containing 0.5 mg THC or 1 mg CBD per tab in a perforated coating pan and coat with Eudragit L 30D coating layer, 8% w/w. The enteric coated tablets comply with the USP enteric coated solid dosage forms characteristics. Preparation Of Colonic Delivery Mini Tablets Of THC Or CBD

Place minitablets containing 0.5 mg THC or 1 mg CBD per tab in a perforated coating pan and coat with Eudragit S 100 coating layer, 10% w/w. The coated tablets release their content at a pH above 7 which complies with the pH conditions in the terminal ileum and lower parts of the GI tract, the colon.

Preparation Of Colonic Delivery Extended Release Minitablets Of THC Or CBD

Place minitabs containing 0.5 mg THC or 1 mg CBD per tab in a perforated coating pan and coat first with extended release layer of ethyl cellulose 20 cp, 5% w/w layer, followed by a second coating layer of Eudragit S 100, 10% w/w. The coated tablets start releasing their content in pH above 7, and continue until fully released for 7 hrs . Mix together the enteric coated and colonic coated minitabs and fill into size 0 hard gelatin capsules containing 5 mg THC per capsule, in a ratio of 1 mg enteric coated THC to 4 mg colonic coated THC.

Mix together the enteric coated and colonic extended release coated minitabs and fill into size 0 hard gelatin capsules containing 5 mg THC per capsule, in a ratio of 1 mg enteric coated THC together with 4 mg colonic extended release coated THC.

Mix together the enteric coated and colonic coated minitabs together and fill into size 00 hard gelatin capsules contain 10 mg THC per capsule, in a ratio of 4 mg enteric coated CBD and 6 mg colonic coated CBD.

EXAMPLE 2 Fill 5 mg of the colonic THC minitabs prepared in Example 1 into size 0 capsules.

EXAMPLE 3 Fill the colonic CBD minitabs prepared in Example 1 into size 0 capsules containing 10 mg of colonic CBD minitabs

EXAMPLE 4

Mix the CBD colonic coated minitabs prepared as described in Example 1 with mesalamine colonic coated minitabs or beads and fill into size 0 gelatin capsules containing 10 mg CBD and 250 mg mesalamine.

EXAMPLE 5 Stage 1 Compress the THC matrix described in Example 1 into about 500 mg tablets containing 8 mg THC. Coat the obtained tablets with 7% w/w Eudragit S.

Stage 2 Mix 5 g THC with 3 g Vitamin E TPGS (1:1), and 0.01 gr BHT, dissolve in ethanol and coat over the tablet obtained in stage 1, providing an additional THC layer containing 2 mg THC.

Stage 3 Further coat the THC coated tablets of stage 2 with a 6% w/w Eudragit L30D 55 layer to obtain enteric coated

tablets . The compositions prepared according to the above-described examples and description may be administered to patients for the treatment of many indications, and are particularly well- suited for treating indications involving the lower GI, such as Crohn's disease and Irritable Bowel Syndrome.

Claims

WHAT IS CLAIMED IS:

1. An oral composition for lower GI release comprising at least one cannabinoid as an active ingredient and colonic release excipients selected from the group comprising pH- dependent polymers, pH-independent polymers, different natural or synthetic gums and their combinations and wherein at least 25% of the active ingredient is released in the colon.

2. A composition according to claim 1 and optionally at

least one additional active selected from the group comprising analgesics, anti-inflammatories , anti- Parkinson drugs and combinations thereof.

3. A composition according to claim 1 wherein the pH- dependent polymer is Eudragit S.

4. Composition of claim 1 wherein the pH-independent polymer is HPMC.

5. An oral composition comprising at least one cannabinoid as an active ingredient, wherein the active ingredient is formulated in a first component and a second component, the first component formulated to release active

ingredient in the upper part of the small intestine and the second component formulated to release active

ingredient in the colon.

6. An oral composition according to claim 5, wherein the

first component is formulated as a self-emulsifying drug delivery system (SEDDS) .

7. An oral composition according to claim 5, wherein the

second component is formulated with at least one of pH- dependent polymers, pH-independent polymers, natural gums or synthetic gums, and combinations thereof, whereby the active ingredient in the second component is selectively released in the colon and the release pattern in the colon is immediate or controlled release.

8. The composition of claim 6 wherein the first component is enteric coated.

9. The composition of any of claims 5-9, further comprising Vitamin E TPGS functioning as emulsifier, stabilizer, enhancer and solubilizer.

10. The composition of any of claims 5-9, comprising at least one additional active selected from the group consisting of budesonide, nicotine, mesalamine,

analgesics, anti-inflammatories , and anti-Parkinson drugs .

11. The composition of claim 6 wherein the emulsifier is lecithin, polysorbate, Cremophor or any other surface active material suitable for the preparation of such systems .

12. The composition of claim 6 further comprising a

mineral oil or vegetable oil thereby assisting the self- emulsification process.

13. The composition of any of claims 5-12, further

comprising a stabilizer or antioxidant selected from the group consisting of BHT, BHA, disodium EDTA,

methylparaben, propylparaben, and their mixtures.

14. The composition of claim 5-12 wherein the colonic second component and the enteric coated component are formulated either as separate coated minitabs or beads or as multilayered beads, minitabs or tablets.

15. A method of treatment of inflammation, by administration to a patient in need thereof a composition of any of the preceding claims, comprising

therapeutically effective doses of actives selected from THC, CBD, mesalamine, budesonide, anti-inflammatory drugs and their combinations.

16. A method of treatment of pain, including neuropathic pain, by administration to a patient in need thereof therapeutically effective doses of a composition of any of the preceding claims.

17. A method of treatment of epilepsy, CNS-related

diseases or inflammation, by administration to a patient in need thereof a therapeutically effective dose of the composition of claim 114, wherein the at least one cannabinoid is CBD.

18. A method of treatment of Parkinson disease by

administration to a patient in need thereof a

therapeutically effective dose of the composition of claim 1-14, wherein the at least one cannabinoid is THC.

19. A method of treatment of cancer pain by

administration to a patient in need thereof of a

therapeutically effective dose of the composition of claim 1-14, wherein the at least one cannabinoid is THC or a combination of THC with CBD.

20. A method of treatment of Crohn's Disease or

Inflammatory Bowel Disease by administration to a patient in need thereof of a therapeutically effective dose of a composition of any of the preceding claims.