CA2952335A1 - Therapeutic delivery formulations and systems comprising cannabinoids and terpenes - Google Patents

Abstract

A formulation of at least one cannabinoid and at least one terpene wherein the at least one terpene is present in at least one of: i) a cannabinoid dispersion enhancing amount; and ii) a cannabinoid membrane adsorption amount.

Description

TITLE: THERAPEUTIC DELIVERY FORMULATIONS AND SYSTEMS COMPRISING
CANNABINOIDS AND TERPENES
INVENTOR: SIMON HOWARD WALLIS

I

Field of the Invention [0001] This invention relates to the enhanced formulations for the delivery of cannabinoids and terpenes Background of the Invention

[0002] Oral ingestion is currently the most popular route of administering drugs, and supplements such as vitamins, minerals, enzymes, probiotics, botanical materials, and other substances having beneficial dietary or therapeutic value. However, this mode of administration may be disadvantageous in certain cases, leading to an erratic absorption and reduced bioavailability of the dosed active ingredients.

[0003] The normal physiological conditions that prevail in the gastro-intestinal (GI) tract are evolved to promote digestion of ingested materials, and act as a barrier to the systemic access of ingested toxins and pathogenic micro-organisms. Thus, orally administered medications are subjected to potential degradation by acidic gastric fluid, digestive enzymes, bile, regional pH variations, and food interactions. On absorption across the mucosal epithelia of the GI tract further metabolic inactivation may occur, due to biotransformation, prior to their entering the systemic circulation. Once they have gained initial systemic access they enter the liver and may be subjected to further significant biotransformation to inactive metabolites (the hepatic first pass metabolism effect) prior to continuing systemic circulation around the body. All of these mechanisms of degradation and inactivation may significantly reduce the bioavailability of a wide range of medicinal and supplemental substances. This is often compensated for by increasing the dosage level of administered materials, whilst balancing this against their possible toxic side effects, so that a sufficient concentration and quantity reach the target sites of action. Whilst representing a pragmatic approach, it is, essentially, a wasteful process in terms of active agent input, may lead to potential formulation difficulties, and represents an increased marketing cost for such products. In addition to the above, certain orally administered substances may be irritant to the stomach, potentially causing micro-bleeding and gastric ulceration, and possibly exacerbating pre-existing duodenal ulcers. Oral administration may not be appropriate for certain individuals who are not inclined or able to swallow solid dosage units, those suffering from nausea and vomiting (e.g. patients undergoing cancer chemotherapy, those having fevers, people suffering from infections), and unconscious individuals.

[0004] There is a pressing need for improved formulations and utilisation of routes of administration that facilitate enhanced, consistent, and effective delivery of lipophilic cannabinoid and terpenoid ingredients, thereby augmenting the bioavailability of these active ingredients at potentially lower doses of the active ingredients and reduction of unwanted side effects. In addition, attendant production process and cost efficiencies are of benefit to the manufacturer.

[0005] This specific need for improved formulations is marked in the area of cannabinoid and terpene delivery. The therapeutic use of cannabinoids dated back at least 4,000 years to the ancient dynasties of China and includes applications for various illnesses ranging from lack of appetite, emesis, cramps, menstrual pain, spasticity to rheumatism. The long history of medicinal use of cannabinoids has led to the development of several modern pharmaceutical drugs. For example, MARINOLTM (generic name dronabinol) and CESAMETTm (generic name nabilone), two synthetic cannabinoids based on THC, are prescribed as anti-emetics and for enhancement of appetite. In addition to their clinical use as an antiemetic, potential therapeutic uses of nonselective cannabinoid receptor agonists include the management of multiple sclerosis, spinal cord injury, pain, inflammatory disorders, glaucoma, bronchial asthma, vasodilatation that accompanies advanced cirrhosis, and cancer.

[0006] Given the therapeutic benefit, it would be advantageous to develop a composition in which lipophilic cannabinoids and or terpenes are delivered systemically to achieve a therapeutically effective dose. As noted above, the cannabinoids undergo substantial first-pass metabolism when absorbed from the human gut after oral administration, which suggests alternate forms of dosage and/or gutprotected delivery systems.

[0007] It is an object of the present invention to obviate or mitigate the above noted disadvantages.
[0001] 1Y. Cheng and S. A. Hitchcock, Targeting Cannabinoid Agonists for Inflammatory and Neuropathic Pain, Expert Opin. Investig. Drugs 16(7): 951-965(2007); B. G. Ramiirez, et al., Prevention of Alzheimer's Disease Pathology by Cannabinoids: Neuroprotection Mediated by Blockade of Microglial Activation, J.
Neurosci. 25(8): 1904-1913 (2005) [0002]

I

Summary of the Invention

[0008] It is an object of the present invention to provide superior formulations, (delivery systems), for enhancing the bioavailability of a cannabinoids, by the addition of terpenes to cannabis extracts or to isolate pure cannabinoids.

[0009] The present invention comprises a composition of at least one cannabinoid and a dispersion-enhancing amount of at least one terpene.

[0010] The present invention comprises a composition of at least one cannabinoid and a membrane absorption-enhancing amount of at least one terpene.

[0011] The present invention comprises a solid dispersion of at least one cannabinoid and a dispersion-enhancing amount of at least one terpene.

[0012] The present invention comprises a solid dispersion of at least one cannabinoid and a membrane adsorption-enhancing amount of at least one terpene.

[0013] The present invention comprises a solid solution of at least one cannabinoid and a dispersion-enhancing amount of at least one terpene.

[0014] The present invention comprises a solid solution of at least one cannabinoid and a membrane adsorption-enhancing amount of at least one terpene.

[0015] The present invention comprises an emulsion with at least one cannabinoid and a dispersion-enhancing amount of at least one terpene.

[0016] The present invention comprises an emulsion with at least one cannabinoid and a membrane adsorption-enhancing amount of at least one terpene.

[0017] The present invention comprises a dosage from selected from the group consisting of rectal suppository, vaginal suppository, enema and oral solid dosage capsules, said dosage form comprising with at least one cannabinoid and a dispersion-enhancing amount of at least one terpene.

[0018] The present invention comprises a dosage from selected from the group consisting of rectal suppository, vaginal suppository, enema and oral solid dosage capsules, said dosage form comprising with at least one cannabinoid and a membrane adsorption-enhancing amount of at least one terpene.

[0019] It has been found surprisingly that cannabinoids and terpenes can be formulated successfully into specific formulations in lipophilic and hydrophilic matrices and delivery systems, including solid dosage matrices (solid solutions), insoluble or partially soluble dispersions and emulsions (biphasic delivery systems), which each provide improved absorption and therapeutically relevant and effective plasma levels of the cannabinoids and terpenes active ingredients.

[0020] In the compositions of this invention, the formulated active ingredients are present as molecular solutions in the solid dosage matrices (solid solutions), insoluble or partially soluble dispersions of the active ingredients in the matrices (solid dispersions), or a combination of both types. These formulations may be delivered in the form of rectal and vaginal suppositories, enemas and oral solid dosage capsules. Within the scope of the invention, active ingredients are prepared in oil-water (o/w) liquid emulsion dosage forms (for example, sublingual, buccal, gingival, palatal, rectal enema, and oral ingestion delivery systems), wherein such emulsions comprise an oil (lipid) phase and an aqueous (water) phase, and are prepared asmolecular solutions and/or insoluble dispersions in the dispersed oil phase, or a combination of both and potentially with some solubility in the aqueous continuous phase.

[0021] According to one aspect of the present invention there is provided a formulation for the rectal delivery of cannabinoids and terpenes. According to another aspect of the present invention there is provided a formulation for the vaginal delivery of cannabinoids and terpenes.
According to another aspect of the present invention there is provided a formulation for the gingival delivery of cannabinoids and terpenes. According to another aspect of the present I

invention there is provided a formulation for the sublingual delivery of cannabinoids and terpenes. According to another aspect of the present invention there is provided a formulation for the buccal delivery of cannabinoids and terpenes. According to another aspect of the present invention there is provided a formulation for the palatal delivery of cannabinoids and terpenes.
According to another aspect of the present invention there is provided a formulation for the solid oral dosage form delivery of cannabinoids and terpenes.

[0022] In one embodiment, the present invention includes formulations which comprise a pharmaceutically effective amount of a cannabinoid and terpene for delivery of the cannabinoid and terpene to the bloodstream of a user.

[0023] Finally, the instant invention includes methods for treating a patient suffering from a condition such as pain, nausea and emesis, convulsions, muscle spasm, inflammation, depression, and cachexia, comprising administering a formulation of the instant invention.

[0024] It is an object of the present invention, in one aspect, to provide suppository and emulsion formulations, incorporating cannabinoids and terpenes in lipophilic and hydrophilic matrices, having facile solubility, dispersion and dissolution characteristics in aqueous media and body fluids.

[0025] As noted in the background section, oral formulations of synthetic cannabinoids are available commercially. For instance, Nabilone is a synthetic cannabinoid marketed as Cesamet in Canada the United States, the United Kingdom and Mexico. Nabilone is formulated as capsules suitable for oral administration. Cesamete is approved for use as an antiemetic and analgesic for neuropathic pain. Sativex , is a mouth spray containing tetrahydrocannabinol (THC) and cannabidiol (CBD). It is approved for the treatment of spasticity due to multiple sclerosis.. These known oral formulations have disadvantages.

[0026] Among other issues, of poor absorption and poor bioavailability, oral formulations have the additional disadvantage that they require several administrations a day, making them inconvenient for patients who have difficulty swallowing. Accordingly, there is an urgent need in the art for oral formulations of cannabinoids with improved dissolution and enhanced bioavailability and absorption, while at the same decreasing gastrointestinal irritation. In regards to the solid dosage form of the invention, these problems are addressed and overcome.

[0027] Certain other formulations and dosage forms that are the subject of this invention will be administered by "non-swallowing means". These include administration via rectal (inferior and middle regions), vaginal, and specific oral (sub-lingual ¨ under the tongue, buccal ¨ cheeks, gingival ¨ gums, and palatal ¨ roof of mouth) routes of administration, thus avoiding the above disadvantages, and in particular essentially avoiding the hepatic first pass metabolism effect. All of these regions are richly provided with blood supplies, via their extensive systemic capillary networks, and are capable of rapid and significant absorption of active ingredients in contact with the mucosal epithelia.

[0028] The "swallow" dosage forms of the present invention, intended for normal ingestion by directly swallowing comprise oral emulsions (for example, conventional and micro-emulsion systems) and solid self-emulsifying dosage forms (hard-shell and softshell capsules).
While these swallow dosage forms do not avoid the above-noted hepatic first pass metabolism effect, they are specifically designed to possess superior dispersion and dissolution characteristics, they demonstrate lower GI tract irritancy tendencies, and are at least partially protected from gastric fluid acidity and regional pH variations.

[0029] The compositions of the present invention are designed to deliver active ingredient(s) in an optimal form for local activity and systemic absorption by virtue of the following design characteristics: increased surface area exposure at the target sites of action (by micellization, micro-emulsion formation, self-emulsification properties), enhanced solubility in the various formulation matrices (emulsification, micellization, the use of co-solvents, solid solutions and dispersions), improved dispersibility and dissolution in physiological fluids (emulsification, micellization, the use of co-solvents, solid solutions and dispersions), enhanced penetration and permeability across mucosa! membranes (surface active wetting and permeability promotion, penetration/permeability enhancers). There has been found to be a surprising effect in the formulations of the invention, in facilitating absorption and dispersion of cannabinoids. While some terpenes are present in the cannabis plant and cannabis extracts, the effects achieved within the scope of the invention are not found, without supplementation of higher levels of terpenes than naturally occurring. Furthermore, when terpenes are added to purified cannabinoids, the same beneficial effects on dissolution and dispersion are achieved.

[0030] The inventive compositions are suitable for medical, pharmaceutical and nutraceutical applications. I

[0031] The foregoing general description and following brief description of the drawings and the detailed description are exemplary and explanatory and are intended to provide further explanation of the invention as claimed. Other objects, advantages, and novel features will be readily apparent to those skilled in the art from the following detailed description of the invention.
Description of the Figures

[0032] The following figures set forth embodiments in which like reference numerals denote like parts. Embodiments are illustrated by way of example and not by way of limitation in all of the accompanying figures wherein:
Figure 1 is a table showing the main classes of natural cannabinoids and their structures; and Figure 2 is a table showing the main classes of terpenes and their structures.
Preferred Embodiments of the Invention

[0033] A detailed description of one or more embodiments of the invention is provided below along with accompanying figures that illustrate the principles of the invention. The invention is described in connection with such embodiments, but the invention is not limited to any embodiment. The scope of the invention is limited only by the claims and the invention encompasses numerous alternatives, modifications and equivalents. Numerous specific details are set forth in the following description in order to provide a thorough understanding of the invention. These details are provided for the purpose of example and the invention may be practiced according to the claims without some or all of these specific details. For the purpose of clarity, technical material that is known in the technical fields related to the invention has not been described in detail so that the invention is not unnecessarily obscured.
This description of preferred embodiments is to be read in connection with the accompanying figures, which are part of the entire written description of this invention.

[0034] The term "invention" and the like mean "the one or more inventions disclosed in this application", unless expressly specified otherwise.

[0035] The terms "an aspect", "an embodiment", "embodiment", "embodiments", "the embodiment", "the embodiments", "one or more embodiments", "some embodiments", "certain embodiments", "one embodiment", "another embodiment" and the like mean "one or more (but not all) embodiments of the disclosed invention(s)", unless expressly specified otherwise.

[0036] The term "variation" of an invention means an embodiment of the invention, unless expressly specified otherwise. A reference to "another embodiment" or "another aspect"
in describing an embodiment does not imply that the referenced embodiment is mutually exclusive with another embodiment (e.g., an embodiment described before the referenced embodiment), unless expressly specified otherwise.

[0037] In this specification, the terms "comprise, comprises, comprised and comprising"
and the terms "include, includes, included and including" are deemed to be totally interchangeable and should be afforded the widest possible Interpretation.

[0038] The articles "a" and "an" are used herein to refer to one or to more than one (i.e., to at least one) of the grammatical object of the article. By way of example, "an element" means one element or more than one element.

[0039] The term "or" as used herein should be understood to mean "and/or", unless the context clearly indicates otherwise.

[0040] The term "plurality" means "two or more", unless expressly specified otherwise.

[0041] The term "herein" means "in the present application, including anything which may be incorporated by reference", unless expressly specified otherwise.

[0042] The term "whereby" is used herein only to precede a clause or other set of words that express only the intended result, objective or consequence of something that is previously and explicitly recited. Thus, when the term "whereby" is used in a claim, the clause or other words that the term "whereby" modifies do not establish specific further limitations of the claim or otherwise restricts the meaning or scope of the claim.

[0043] The term "e.g." and like terms mean "for example", and thus does not limit the term or phrase it explains. For example, in a sentence "the image of an item is captured by an image capture device, for example a camera, the term "for example" explains that " camera" is an example of "an image capture device" through which one aspect of the data collection of this invention operates.

[0044] The term "respective" and like terms mean "taken individually".
Thus, if two or more things have "respective" characteristics, then each such thing has its own characteristic, and these characteristics can be different from each other but need not be.

[0045] The term "i.e." and like terms mean "that is", and thus limits the term or phrase it explains.

[0046] As used herein, unless specifically indicated otherwise, the word "or" is used in the "inclusive" sense of "and/or" and not the "exclusive" sense of "either/or."

[0047] As used herein, a "user", "patient," "subject," or "host" to be treated by the subject method may mean either a human or non-human animal, such as primates, mammals, and vertebrates.

[0048] The phrase "therapeutically effective amount" or even "effective amount" is an art-recognized term. The effective amount of the therapeutic agent may vary depending on such factors as the type and severity of disease being treated, its advancement, the particular formulation of active ingredient being administered, the active agent and/or the size/age/gender of the subject. One of ordinary skill in the art may empirically determine the effective amount of a particular therapeutic agent without necessitating undue experimentation.

[0049] The term "treating" is art-recognized and includes treating the disease or condition by ameliorating at least one symptom of the particular disease or condition, even if the underlying pathophysiology is not affected.

[0050] As used herein, the term "active ingredient" means the full description of cannabinoids and terpenes disclosed herein in preferred combinations. More specifically, in regards to terpenes, this refers to the supplementation of cannabinoids (whether in pure form or as cannabis extract) with a higher than "in plant" or "in nature" amount of terpenes, preferably specific targeted terpenes, in order to achieve formulation and therapeutic benefits.

[0051] As used herein, the term "membrane adsorption-enhancing" or "membrane adsorption-enhancing amount of..." means, in regards to terpenes (one or more), an amount sufficient to increase the bioavailability of cannabinoids (whether in pure form or as cannabis extracts). This includes, but is not limited to enhanced adsorption across the human blood-brain barrier membrane.

[0052] As used herein, the term "dispersion-enhancing" or "dispersion-enhancing amount of..." means, in regards to terpenes (one or more), an amount sufficient to increase the dispersion of cannabinoids (whether in pure form or as cannabis extracts) in a slected delivery vehicle..

[0053] As used herein, the term "biocompatible" means characterized by not causing a toxic, injurious or immunological response when brought into contact with living tissue, particularly human or other mammalian tissue.

[0054] As used herein, the term "hydrophobic" means having lower affinity for an aqueous solvent than an organic solvent.

[0055] As used herein, the term "hydrophilic" means having lower affinity for an organic solvent than an aqueous solvent.

[0056] As used herein, the term a "biphasic delivery system" means a pharmaceutical composition comprising two phases of which one phase contains the dissolved, dispersed, solubilised or dissoluted active ingredient (one or more cannabinoids, one or more terpenes or any combination thereof) and the other phase provides the carrier for the composition, for example the outer (surrounding) water phase in an emulsion system. Biphasic delivery systems may be in the form of emulsion systems, such as an oil-in-water (0/W) emulsion, aqueous systems containing a solubilising or dispersing agent.

[0057] As used herein, the recitation of a numerical range for a variable is intended to convey that the invention may be practiced with the variable equal to any of the values within that range. Thus, for a variable which is inherently discrete, the variable can be equal to any integer value within the numerical range, including the end-points of the range. Similarly, for a variable which is inherently continuous, the variable can be equal to any real value within the numerical range, including the end-points of the range. As an example, and without limitation, a variable which is described as having values between 0 and 2 can take the values 0, 1 or 2 if the variable is inherently discrete, and can take the values 0.0, 0.1, 0.01, 0.001, or any other real values if the variable is inherently continuous.

[0058] Diseases treatable with and/or clinical conditions that may benefit from the formulations of this invention are diverse, and comprise diseases and disorders selected from intractable cancer pain, neuropathic and chronic pain, postoperative pain, rheumatoid arthritis, multiple sclerosis and spasticity; acne, addiction, Alzheimer's Disease, acute schizophrenia anxiety, appetite stimulation in chemotherapy patients, bronchodilation, cancers of various types (e.g. breast cancer), chronic pain relief (e.g. fibromyalgia, cancer patients), dementia, depression, epilepsy of various types, fevers, fungal, and bacterial infections (including methicillin-resistant Staphyloccocus aureus), gastro-intestinal disorders (e.g. colitis, Crohn's Disease, Inflammatory Bowel Syndrome), Huntington's Disease, inflammatory conditions, insomnia and other sleep disorders, jaundice, metabolic syndrome, muscle relaxant (e.g. in multiple sclerosis patients), Parkinson's Disease, post-traumatic stress disorder, pruritis, psoriasis, sedation, Tourette's Syndrome, certain viral infections. 234

[0059] The term "treatment" or any lingual variation thereof is used herein to denote treating the above noted disease, disorder or condition, or ameliorating, alleviating, reducing, or suppressing symptoms of the disease, or slowing or stopping the progress of the disease.

[0060] In still another one of its aspects, the present invention provides the use of the formulations/delivery systems of the invention in combination with other therapeutic modalities.

[0061] As used herein, the terms "therapeutic modalities", generally refers to any therapeutic agent, treatment or protocol/method that can be used in the treatment or alleviation of a disease or disorder or at least one symptom thereof.

[0062] In some embodiments, the therapeutic modality is selected from chemotherapy, hormonal therapy, radiation therapy, surgery, biological therapy and immunotherapy.

[0063] In some embodiments, the therapeutic modality is a non-drug therapy.

[0064] The present invention provides stable formulations of cannabinoids (and analogs) and terpenes in both lipophilic and hydrophilic matrices, having facile solubility, dispersion and dissolution characteristics in aqueous media (and body fluids).
The

[0065]
2.1. Nat. Prod; 1996, 59, pages 49-51; Ross, S.A. and ElSohly, M. A.
("The Volatile Oil Composition of Fresh and Air-Dried Buds of Cannabis sativa").
3Haworth Integrative Healing Press, 2001, pages 103-132; McPartland, J. M. and Russo, E. B.
("Cannabis and Cannabis Extracts: Greater Than The Sum of Their Parts?").
4Bioresource Hemp 2000, Wolfseburg 13 ¨ 16 September 2000; McPartland, J.
("Advantages of Polypharmaceutical Herbal Cannabis Compared to Single-Ingredient Synthetic Tetrahydrocannabinol").

The preferred formulations of this invention are in the form of rectal and vaginal suppositories, rectal enemas, oral capsule dosage forms, and emulsion formulations for human use, incorporating cannabinoids and terpenes in lipophilic and hydrophilic matrices, having facile solubility in the dosage forms, improved dispersion and dissolution characteristics of the dosage forms in aqueous media and body fluids, and enhanced bioavailability.
Specifically, rectal and vaginal suppositories (pessaries); rectal enemas; conventional emulsions and micro-emulsions;
which may be formulated as solid dosage units, including those of the self-emulsifying type, and as liquid dosage presentations.

[0066] The invention provides solid dispersions, solid solutions and emulsions comprising one or more cannabinoids and one or more terpenes.. Preferably, the cannabinoids in the inventive suspensions are natural compounds, synthetic compounds, semi-synthetic compounds, or mixtures thereof. Illustrative of such compounds are cannabinol, cannabidiol, .DELTA.-9-tetrahydrocannabinol, .DELTA.-8-tetrahydrocannabinol, 11-hydroxy-tetrahydrocannabinol, 11-hydroxy-.DELTA.-9-tetrahydrocannabinol, DELTA.-11-tetrahydrocannabinol, tetrahydrocannabivarin, a combination two or more such compounds, or a mixture of a natural cannabinoid and a synthetic analogue of a cannabinoid.
The final maximum concentration of cannabinoids in the inventive formulations range from generally from 1-500mg per dosage unit. New patients generally start with microdosing up to 5 mg per dosage unit.
After such titration, generally dosages increase. 500mg would generally be for more serious clinical conditions . The concentration of the terpene in the inventive formulations ranges 0.1 to 10% w/w of the final formulation.

[0067] Particular advantages of the various solid dosage formulations (rectal and vaginal suppositories, oral capsules) are based upon enhancing the solubility of active ingredients in the delivery systems (solid solutions and solid dispersions formation), their subsequent self-emulsification/micellization when in contact with aqueous physiological fluids, and, thus, enhanced properties of dispersion and dissolution of the active ingredients for availability at target absorption sites. The aforementioned advantages also apply to liquid dosage forms (emulsions and enemas), but in this case the active ingredients would be present in the dispersed lipid phase liquid droplets. The combined effect of these formulation design parameters would lead to an improved bioavailability of the active ingredients, and a potentially more efficient usage at lower dosage levels to achieve the desired therapeutic effects.

Active Ingredients

[0068] Cannabinoids are a class of diverse chemical compounds that act on cannabinoid receptors in cells that repress neurotransmitter release in the brain, and also act at receptor sites peripheral to the central nervous system (brain and spinal cord). These are compounds derived from Cannabis sativa, an annual plant in the Cannabaceae family;
Cannabis indica, Cannabis hybrids and Hemp species. Ligands for these receptor proteins include the endocannabinoids (produced naturally in the body by humans and animals), the phytocannabinoids (found in cannabis and some other plants), and synthetic cannabinoids (manufactured artificially). The most notable cannabinoid is the phytocannabinoid tetrahydrocannabinol (THC), the primary psychoactive compound of cannabis.
Cannabidiol (CBD) is another major constituent of the plant. There are at least 85 different cannabinoids isolated from cannabis, exhibiting varied effects. Illustrative of the cannabinoids are those represented in Figure 1.

[0069] These cannabinoid receptors are common in animals, and have been found in mammals, birds, fish, and reptiles. At present, there are two known types of cannabinoid receptors, termed CB1 and CB2, with mounting evidence of more. CB1 receptors are found primarily in the brain, more specifically in the basal ganglia and in the limbic system, including the hippocampus. They are also found in the cerebellum and in both male and female reproductive systems. CB1 receptors are absent in the medulla oblongata, the part of the brain stem responsible for respiratory and cardiovascular functions. CB2 receptors are predominantly found in the immune system, or immune-derived cells, with the greatest density in the spleen.
While found only in the peripheral nervous system, a report does indicate that CB2 is expressed by a subpopulation of microglia in the human cerebellum. CB2 receptors appear to be responsible for the anti-inflammatory and possibly other therapeutic effects of cannabis seen in animal models.

[0070] Cannabinoids are lipophilic and potentially acid-labile compounds.
Due to their hydrophobic nature, cannabinoids are poorly absorbed systemically from oral dosage forms because of the poor dissolution of cannabinoids in the aqueous environment of gastrointestinal tract. Oral formulations of cannabinoids, therefore, exhibit low bioavailability.

[0071] Tetrahydrocannabinol (THC) is the primary psychoactive component of the Cannabis plant. Delta-9-tetrahydrocannabinol (A9-THC, THC) and delta-8-tetrahydrocannabinol (A8-THC), mimic the action of anandamide, a neurotransmitter produced naturally in the body.
These two cannabinoids produce the effects associated with cannabis by binding to the CB1 cannabinoid receptors in the brain. THC appears to ease moderate pain (analgesic) and to be neuroprotective in animal models, while also offering the potential to reduce neuroinflammation and to stimulate neurogenesis. THC has also shown antitumor activity in animal studies where it killed cancer cells. THC has approximately equal affinity for the CB1 and CB2 receptors.

[0072] Cannabidiol (CBD) is non-psychotropic. Recent evidence shows that the compound counteracts cognitive impairment associated with the use of cannabis.
Cannabidiol acts as an indirect antagonist of cannabinoid agonists. It was found to be an antagonist at the putative new cannabinoid receptor, GPR55, a GPCR expressed in the caudate nucleus and putamen. Cannabidiol has also been shown to act as a 5-HT1A receptor agonist.
It appears to relieve convulsion, inflammation, anxiety, and nausea. In animal studies CBD
has shown antitumor activity on human breast carcinoma by inhibiting cancer cell growth.
At slightly higher concentrations it is cytotoxic to normal cells. CBD has a greater affinity for the CB2 receptor than for the CB1 receptor.

[0073] CBD shares a precursor with THC and is the main cannabinoid in low-THC
Cannabis strains. CBD has been shown to play a role in preventing the short-term memory loss associated with THC. Cannabinol (CBN) is the primary product of THC
degradation, and there is usually little of it in a fresh plant. CBN content increases as THC degrades in storage, and with exposure to light and air. It is only mildly psychoactive. Its affinity to the CB2 receptor is higher than for the CB1 receptor.

[0074] Cannabigerol(CBG) is non-psychotomimetic but still affects the overall effects of Cannabis. CBG has been shown to promote apoptosis in cancer cells and inhibit tumor growth in mice. It acts as an a2-adrenergic receptor agonist, 5-HT1A receptor antagonist, and CB1 receptor antagonist. It also binds to the CB2 receptor.

[0075] Tetrahydrocannabivarin(THCV) is prevalent in certain central Asian and southern African strains of Cannabis. It is an antagonist of THC at CB1 receptors and attenuates the psychoactive effects of THC.

[0076] Cannabidivarin(CBDV) is usually a minor constituent of the cannabinoid profile, however enhanced levels of CBDV have been reported in feral cannabis plants from the northwest Himalayas, and in hashish from Nepal.

[0077] Cannabichromene (CBC) is non-psychoactive and does not affect the psychoactivity of THC. CBC has shown antitumor effects in breast cancer xenoplants in mice.
More common in tropical cannabis varieties.

[0078] The cannabinoids (phytocannabinoids) comprising the compositions of this invention are derived from Cannabis species, including Cannabis sativa and Cannabis indica, and their various strains (genotypes/phenotypes), or may be obtained from Hemp species.
The cannabinoids may be present in the acidic forms (carboxylated) and non-acidic (decarboxylated) forms, and preferably are selected from: Delta-9 Tetrahydrocannabinol, Delta-9 Tetrahydrocannabinol Acid, Cannabidiol, Cann abidiolic Acid, Cannabigerol, Cannabigerolic Acid, Cannabichromene, Cannabichromenic Acid, Delta-9-Tetrahydrocannabivarin, Cannabidivarin and Cannabinol. The cannabinoids for use as active ingredients may be in the form of pharmaceutically acceptable derivatives. A suitable ester, for example, is THC-hemisuccinate.5678 5.). Nat. Prod; 1996, 59, pages 49-51; Ross, S.A. and ElSohly, M. A.
("The Volatile Oil Composition of Fresh and Air-Dried Buds of Cannabis sativa").
66Haworth Integrative Healing Press, 2001, pages 103-132; McPartland, J. M.
and Russo, E. B.
("Cannabis and Cannabis Extracts: Greater Than The Sum of Their Parts?").
'British Journal of Pharmacology, 2011, 163, pages 1344-1363; Russo, E. B.
("Taming THC: Potential Cannabis Synergy and Phytocannabinoid-Terpenoid Entourage Effects").
8Forensic Science and Medicine: Marijuana and the Cannabinoids, 2007, 1st Edition, Edited by ElSohly, M.A;
(Chapter 2, "Chemistry and Analysis of Phytocannabinoids and Other Cannabis Constituents", Brenneisen, R).

[0079] These active ingredients may be in the form of extracts or isolated compositions from fresh or dried plant materials, or as purified single substances. All of these forms may be incorporated into the formulations of the invention as single ingredients, or as various combinations thereof, with or without added terpenes. Cannabinoids are small molecular weight (within the range 300 to 350 Daltons) lipophilic molecules, making them ideal candidates for delivery via the presently disclosed delivery vehicles and formulations.

[0080] Natural cannabinoid compounds used herein are readily obtained from plant tissue, for example, trichomes of the C. sativa plant, by suspending the tissue in an appropriate solvent to extract cannabinoid compounds and other tissue components.
Analytical purification of such an extract provides pharmaceutical grade cannabinoid compounds.
Alternatively, cannabinoid compounds are extracted from plant tissue under supercritical- or sub-critical extraction conditions. Solvents used for supercritical- and sub-critical extraction of cannabinoids include without limitation carbon dioxide, or other gases in isolation or combination with or without solvent modifiers, selected from ethanol, propanol, butanol, hexane, chloroform, dichloromethane, acetone, or any organic solvent capable of extracting cannabinoids, and alcohol-water mixtures, for instance water-ethanol or water-butanol mixtures.

[0081] In addition to natural cannabinoids, the formulations of the present invention may comprise synthetic cannabinoid compounds as well as cannabinoids and their analogs that are obtained using semi-synthetic protocols. The manufacture of cannabinoid compounds and their analogs using semi-synthetic means may involve contacting an appropriate substrate with one of the cannabinoid synthase enzymes. For instance, tetrahydrocannabinolic acid (THCA) or its analogs can be manufactured semi-synthetically by contacting cannabigerolic acid (CBGA) or an appropriately substituted derivative of CBGA with THC synthase to obtain the corresponding THC or THCA analog respectively. The inventive compositions may also contain natural or synthetically modified cannabinoids.

[0082] In the context of this invention terpenes (terpenoids) are classified as molecular compounds based upon single or multiple isoprene [(C5H8)n] units: for example monoterpenes, such as D-Limonene, Terpineol, and Myrcene, are composed of two isoprene units, sesquiterpenes, such as alpha-Caryophyllene, are comprised of three isoprene units. Terpene molecular structures may be either acyclic or cyclic, and substituted or unsubstituted. Figure 2 refers to preferred terpenes, in accordance with the invention.

[0083] To date over 200 terpene compounds have been identified in Cannabis plants, and such terpenes may be incorporated into the formulations of the invention.
These include, but not limited to: L-Borneol, delta-3-Carene, alpha-Caryophyllene (alpha-Humulene), beta-Caryophyllene, Caryophyllene Oxide, 1,8-Cineole (Eucalyptol), para-Cymene, D-Limonene, beta-Linalool, beta-Myrcene, trans-Nerolidol, beta-Linalool, Unalyl acetate, alpha-Pinene, beta-Pinene, Pulegone, alpha-Terpineol, Terpineol-4-ol, and Terpinol.Of particular interest are beta-Caryophyllene, Caryophyllene Oxide, 1,8- Cineole (Eucalyptol), D-Limonene, beta-Linalool, Unalyl acetate, beta-Myrcene, trans-Nerolidol, alpha-Pinene, Pulegone, and Phyto1.91oil

[0084] The above terpenes are generally lipophilic in nature, one exception being 1,8-Cineole (reported to be partially hydrophilic), of molecular weights under 300 Da!tons, octanol /water partition coefficients (Log Kow values) within the range 1 to 8, and have good solubility characteristics for the lipophilic cannabinoids. They possess characteristic aromas, and have limited or poor solubility in water and aqueous media (such as physiological fluids of the human body).

[0085] The distinctive fragrances of many plant species are due in part to their terpenes content, and many of these substances can elicit various physiological and sensory effects in mammals, as in, for example, aromatherapy, but may also possess their own spectra of pharmacological activities. In addition to this they may also beneficially modify the pharmacological activities of co-administered cannabinoids (the so-called entourage effect).
'British Journal of Pharmacology, 2011, 163, pages 1344-1363; Russo, E. B.
("Taming THC: Potential Cannabis Synergy and Phytocannabinoid-Terpenoid Entourage Effects") 1 Bioresource Hemp 2000, Wolfseburg 13 ¨ 16 September 2000; McPartland, J.
("Advantages of Polypharmaceutical Herbal Cannabis Compared to Single-Ingredient Synthetic Tetrahydrocannabinol") 'Cannabinoids, 2014, 9(1), January 19, pages 1-8; Ujvary, I. and Grotenherman, F.
("Mini-Review: 11-Nor-9-carboxy-delta-9-tetrahydrocannabinol ¨ a Ubiquitous Yet Under-researched Cannabinoid:
A Review of the Literature")

[0086] As noted above, fresh Cannabis and Hemp plants contain a wide variety of terpenes, but at relatively low concentrations. The compositional spectrum of the various terpenes significantly varies depending upon the species, e.g. sativa versus indica, hybrids, and cultivars (strains). Amongst other properties, the terpenes are responsible for the aromas of the various strains currently offered to consumers. The terpenes profiles (type and concentration) are not uniformly distributed throughout the aerial parts of the plants: the more volatile and aromatic monoterpenes, (high vapour pressure, e.g. D-Limonene, beta-Linalool, beta-Myrcene) are particularly rich in the buds, to discourage attack by flying and crawling insects, whilst the less volatile and more bitter sequiterpenes (lower vapour pressure, e.g. alpha-and beta-Caryophyllene) are generally present at higher concentrations in the leaves, as a deterrent to foliar browsing animals.

[0087] In addition to this natural and cultivated variation the terpenes profile is also affected by processing of the plant, e.g. by drying (which tends to preferentially deplete the monoterpenes due to their lower boiling points and higher vapour pressures), extraction (which tends to concentrate the terpenes generally), and thermal decarboxylation to prepare concentrated extracts (which, again, tends to preferentially deplete the monoterpenes).

[0088] It is also critical to note that purification of individual cannabinoids, such as Cannabidiol (CBD), to produce high potency isolates also removes the majority, if not all, of the terpenes content. Since the compositions described and claimed hereinmay also utilise whole plant extracts, and isolated purified single cannabinoids such as Cannabidiol (CBD), the terpene contents of these forms are subject to all of the above variables. Hence, to achieve the formulation benefits described herein, it is necessary and desirable to add back individual terpenes, at levels that are sufficiently high to contribute to the desired pharmacological effect(s) and formulation performance characteristics of the selected dosage forms provided herein. As such, within the compositions and formulations of the invention, concentrations of terpenes is much higher than would be found in either the native plants or extracts/isolates prepared therefrom. Furthermore the pharmacological effect(s) and formulation performance characteristics achieved with the compositions and formulations of the invention, could not be expected or achieved without such targeted terpene enhancement, as provided herein.

[0089] Many terpenes possess their own in vivo pharmacological and physiological properties, independent of the cannabinoids or their entourage effect interactions, when administered at a sufficiently high dose. For example, certain terpenes are inhibitors of acetylcholinesterase, the enzyme responsible for hydrolysing and inactivating the parasympathetic nervous system neurotransmitter acetylcholine following normal nerve activity in mammalian peripheral and central nervous systems (e.g. 1,8-Cineole, Pulegone, and, in particular, alpha-Pinene). Beta-Caryophyllene is an endocannabinoid system CB2 receptor agonist and down regulates (reduces) the release of the neurotransmitter dopamine in the central nervous system; excess levels of dopamine are associated, amongst other activities, with an increase in addictive potential. Myrcene, specifically p-myrcene, is a monoterpene and the most common terpene produced by cannabis. Myrcene has some very special medicinal properties, and has been shown to increase the maximum saturation level of the CB1 receptor, allowing for a greater maximum psychoactive effect. Myrcene is a potent analgesic, anti-inflammatory, antibiotic and antimutagenic. Beta-Myrcene enhances saturation at the endocannabinoid system CB1 receptor, thereby facilitating the activity of CBI
receptor agonist compounds. Pinene is a bicyclic monoterpenoid. As its name suggests, pinene has distinctive aromas of pine and fir. There are two structural isomers of pinene found in nature: a-pinene and 3-pinene. It tends to react with other chemicals, forming a variety of other terpenes (like limonene) and other compounds. Limonene is a monocyclic monoterpenoid and one of two major compounds formed from pinene. As the name suggests, varieties high in limonene have strong citrusy smells like oranges, lemons and limes. Strains high in limonene promote a general uplift in mood and attitude. This citrusy terpene is the major constituent in citrus fruit rinds, rosemary, juniper and peppermint, as well as in several pine needle oils.

[0090] Linalool is a non-cyclic monoterpenoid and has been described as having floral and lavender undertones. Varieties high in linalool promote calming, relaxing effects. Linalool has been used for centuries as a sleep aid. Linalool lessens the anxious emotions provoked by pure THC, thus making it helpful in the treatment of both psychosis and anxiety. Linalool boosts the immune system; can significantly reduce lung inflammation; and can restore cognitive and emotional function (making it useful in the treatment of Alzheimer's disease).
system as it directly activates immune cells through specific receptors and/or pathways.

[0091] Whole plant Cannabis extracts generally consist of waxy or resinous semi-solids or solids. When treated to reduce the content of plant waxes, and subsequently thermally decarboxylated to convert the cannabinoids from their native acid forms to the free non-acid forms, they tend to present as viscous sticky liquids, which are difficult to handle and process into final dosage delivery systems. Terpenes, preferably D-Limonene, are good solvents for such cannabinoid extracts, and single isolated and purified cannabinoids such as CBD, and their incorporation into the compositions herein greatly facilitates handling and subsequent homogeneous incorporation into the various dosage forms of the invention. In addition, of the terpenes that are effective and efficient cell membrane penetration enhancers, facilitating the in vivo absorption of the cannabinoids (and themselves) into the systemic circulation thereby enhancing bioavailability, and potentially allowing for lower dosages to be used for achieving effective clinical responses (preferably, D-Limonene, beta-Myrcene, 1,8-Cineole, and trans-Nerolidol).

[0092] It will thus be seen and appreciated that incorporation of selected terpenes into the compositions of this patent application offers manifold benefits, both in terms of manufacturing processibility and effective in vivo pharmacological efficacy.
Formulations/Delivery Systems

[0093] The present invention, at the core, addresses known delivery and formulation challenges for phytocannabinoids, including THC and CBD which are typically poorly water-soluble, amorphous, highly viscous, and unstable in acidic solutions and when exposed to heat, air and light. The basic advantageous formulation parameters that reside in the invention are, in part, achieved by the addition or supplementation of cannabinoids with terpenes, with resultant solvent and membrane penetration enhancement. It is not intended that any one mechanism of action or result be claimed herein, but it has been found that the formulations, provided herein, exhibit, in their totality, the full range of desirable properties.

[0094] The added or supplemented terpenes operate as beneficial agents contributing to the physicochemical characteristics of the various dosage forms, but also possess their own particular pharmacological properties that add to the overall in vivo effectiveness of the formulations, for example, D-Limonene is known to have an uplifting effect on users. Beta-Linalool is also a solvent and possesses a tranquilising effect (anti-anxiolytic, good for daytime use). Beta-Myrcene is a solvent also possesses a sedative effect (useful for combating night-time insomnia).

[0095] Since cannabinoids and terpenes are primarily lipophilic (hydrophobic) in nature they would be essentially present in the oil phase of biphasic oil/water dosage forms, such as preformed ex-vivo emulsions/micro-emulsions/nano-emulsions for oral administration, and the emulsions/micro-emulsions/nano-emulsions that form in vivo when suppositories and oral capsules are in contact with physiological fluids.

[0096] Research in the field of drug absorption has focused on ways to increase drug efficacy by increasing drug absorption. To this end, methods have been used to increase drug absorption using liposomes as carriers and by designing more lipophilic drugs.
However, these methods have not been successful in circumventing liver biotransformation and biliary secretion of drugs. Thus, when a medication is orally administered, its bioavailability generally decreases due to incomplete absorption and first-pass metabolism and also may vary from patient to patient. Bioavailability is one of the essential tools in pharmacokinetics, as it must be considered when calculating dosages for none intravenous routes of administration.

[0097] In some aspects of the invention, formulations comprise rectal and vaginal suppositories, rectal enemas, oral capsule dosage forms, and emulsion formulations for human use, said formulations comprising therapeutically effective amounts of cannabinoids and terpenes in lipophilic and hydrophilic matrices, having facile solubility in the dosage forms, improved dispersion and dissolution characteristics of the dosage forms in aqueous media and body fluids, and enhanced bioavailability. Specifically, rectal and vaginal suppositories (pessaries); rectal enemas; conventional emulsions and micro-emulsions; which may be formulated as solid dosage units, including those of the self-emulsifying type, and as liquid dosage presentations.

[0098] In the compositions of this invention, the formulated active ingredients are, in some aspects, present as molecular solutions in the solid dosage matrices (solid solutions), insoluble or partially soluble dispersions of the active ingredients in the matrices (solid dispersions), or a combination of both types. This would apply to rectal and vaginal suppositories and oral solid dosage capsules. Active ingredients in the o/w liquid emulsion type dosage forms (sublingual, buccal, gingival, palatal, rectal enema, and oral ingestion delivery systems) would be present as molecular solutions or insoluble dispersions in the dispersed lipid phase, or a combination of both, possibly with some solubility in the aqueous continuous phase.

[0099] Particular advantages of the various solid dosage formulations (rectal and vaginal suppositories, oral capsules) are based upon enhancing the solubility of active ingredients in the delivery systems (solid solutions and solid dispersions formation), their subsequent self-emulsification/micellization when in contact with aqueous physiological fluids, and, thus, enhanced properties of dispersion and dissolution of the active ingredients for availability at target absorption sites. The aforementioned advantages also apply to liquid dosage forms (emulsions and enemas), but in this case the active ingredients would be present in the dispersed lipid phase liquid droplets. The combined effect of these formulation design parameters would lead to an improved bioavailability of the active ingredients, and a potentially more efficient usage at lower dosage levels to achieve the desired therapeutic effects.
Emulsions

[00100] Emulsions are finely divided or colloidal dispersions comprising two immiscible phases, e.g. fatty (oil or "o") and aqueous (water or "w"), one of which (the internal or discontinuous phase) is dispersed as droplets within the other (external or continuous phase).
Thus, an oil-in-water emulsion consists of oil as the internal phase, dispersed water as the external phase, the water-in-oil emulsion being the opposite. So, an oil in water (o/w) type provides that the oil dispersed phase is present as small droplets in the aqueous continuous phase and in the water in oil (w/o) type, the dispersed phase is water and the continuous phase is oil. The preferred emulsions of this invention are o/w emulsion compositions.

[00101] A wide variety of emulsified systems may be formed which comprise the composition of the present invention including standard emulsions, micro-emulsions and those which are self-emulsifying (emulsify on exposure to agitated aqueous fluids such as gastric or intestinal fluids).Generally, emulsions may include oil and water phases, emulsifiers, emulsion stabilizers and optionally preservatives, flavouring agents, pH adjusters and buffers, chelating agents, antifoam agents, tonicity adjusters, colouring agents, and anti-oxidants. Energy input is required to create adequate dispersions, and additional ingredients (surfactants or emulsifying agents, viscosity enhancers, etc) are required to stabilise the formed emulsions and produce a dosage form having adequate long-term stability.

[00102] Emulsions are finely divided or colloidal dispersions comprising two immiscible phases, e.g. oil and water, one of which (the internal or discontinuous phase) is dispersed as droplets within the other (external or discontinuous phase). Thus an oil-in-water emulsion consists of oil as the internal phase, dispersed water as the external phase, the water-in-oil emulsion being the opposite.

[00103] A wide variety of emulsified systems may be formed which comprise the composition of the present invention including standard emulsions, microemulsions and those which are self-emulsifying (emulsify on exposure to agitated aqueous fluids such as gastric or intestinal fluids).

[00104] Generally, emulsions may include oil and water phases, emulsifiers, emulsion stabilizers and optionally preservatives, flavouring agents, pH adjusters and buffers, chelating agents, antifoam agents, tonicity adjusters and anti-oxidants. Suitable emulsifiers (wherein bracketed numerals refer to the preferred HLB values) include: anionic surfactants such as alcohol ether sulfates, alkyl sulfates (30-40), soaps (12-20) and sulfosuccinates; cationic surfactants such as quaternary ammonium compounds; zwitterionic surfactants such as alkyl betaine derivatives; amphoteric surfactants such as fatty amine sulfates, difatty alkyl triethanolamine derivatives (16-17); and nonionic surfactants such as the polyglycol ether derivatives of aliphatic or cycloaliphatic alcohols, saturated fatty acids and alkyphenols, water-soluble polyethyleneoxy adducts onto polypropylene glycol and alkyl polypropylene glycol, nonyl phenol polyethoxyethanols, castor oil polyglycol ethers, polypropylene/polyethylene oxide adducts, tributylphenoxy-polyethoxyethanol, polyethylene glycol, octylphenoxy-polyethcmethanol, lanolin alcohols, polyoxyethylated (POE) alkyl phenols, POE
fatty amides, POE fatty alcohol ethers, POE fatty amines, POE fatty esters, poloxamers (7-19), POE glycol monoethers (13-16), polysorbates and sorbitan esters. This list is not intended to be exhaustive as other emulsifiers are equally suitable. Appropriate emulsion stabilizers include, but are not limited to, lyophilic colloids such as polysaccharides (e.g. acacia, agar, alginic acid, carrageenin, guar gum, karaya gum, tragacanth xanthan gum), amphoterics (e.g. gelatin) and synthetic or semi-synthetic polymers (e.g. carbomer resins, cellulose ethers, carboxymethyl chitin, polyethylene glycol-n (ethylene oxide polymer H(OCH2CH2)n0H); finely divided solids including clays (e.g. attapulgite, bentonite, hectorite, kaolin, magnesium aluminum silicate and

[00105] Emulsions of this invention may be classified as conventional (dispersed phase droplet diameters generally ranging from around 200nm to 1urn or higher, with a wide droplet diameter distribution that may often be multi-modal) and micro-emulsions (dispersed phase droplet diameters typically ranging from lOnm to 200nm, with a narrow droplet diameter distribution that tends to be significantly unimodal). Conventional emulsions require a relatively high energy input, using high-energy mixers or homogenisers, and heating of the aqueous and oil phases (generally 60 to 70C) prior to mixing, to uniformly distribute the dispersed phase in the continuous phase, and generally have an opaque appearance. Micro-emulsions require only a low energy input to form a homogeneously dispersed system, for example the degree of agitation and mixing that is typically found in the stomach, may be formed at ambient or body temperatures, and are generally transparent to slightly opalescent in appearance. Thus, they are a preferred type of delivery system that can be manufactured more economically than conventional emulsions. They may be prepared as liquid formulations for oral administration, or as self-emulsifying solid dosage forms, such as hard-shell and softshell capsules, which spontaneously form micro-emulsions when brought into contact with the gastric fluid under normal physiological conditions of stomach agitation and mixing.

[00106] In order to increase the efficacy (systemic bioavailability) of the emulsion and micro-emulsion compositions intended for specific oral (sub-lingual ¨ under the tongue, buccal ¨
cheeks, gingival ¨ gums, and palatal ¨ roof of mouth) routes of administration, the formulation may be swished around the oral cavity for a period of time (for example, 1-2 minutes) prior to swallowing.

[00107] An oil-in-water emulsion can be prepared using a combination of a pharmaceutically acceptable oil and emulsifier. The active ingredient(s) is dissolved in the oil phase plus a surfactant, which is then mixed with an aqueous phase typically containing a second surfactant and other formulation ingredients under vigorous mixing, milling or homogenisation. Such emulsification methods (which are incorporated herein by reference) are well described by Idson12.

[00108] Typical oils are vegetable oils such as soybean oil, olive oil, cotton seed oil, peanut oil, sesame oil and castor oil. Vitamin E (tocopherol) can also be used as an oil phase.
This material is also an antioxidant and can help to stabilise the chosen cannabinoids which tend to be prone to oxidation.

[00109] For example, the oily phase of the oil-in-water emulsion formulation comprises an oil, which may be a vegetable oil such as but not limited to soya bean oil. In an embodiment, the oil comprises, consists essentially of or consists of soya bean oil.
Optionally, the oil comprises one or more medium chain triglyceride (MCT) oils (i.e. a triglyceride oil in which the carbohydrate chain has 8-12 carbons) or combinations of an MCT oil and a vegetable oil.

[00110] The oil-in-water emulsion formulations of the present disclosure may also comprise an emulsifier. Suitable emulsifiers include a phospholipid or a mixture of phospholipids. For example, purified egg yolk phospholipids, soybean or sunflower oil phospholipids or other purified phospholipid mixtures may be useful emulsifiers. Phospholipids may be either natural or hydrogenated.

[00111] Additionally, the oil-in-water emulsion formulations of the present invention comprises a surfactant. For example, the surfactant can be a non-ionic alkylene oxide condensate of an organic compound which contains one or more hydroxyl groups.
12Idson, Pharmaceutical Emulsions, Ch. 6, Pharmaceutical Dosage Forms, Disperse Systems. Vol.1. Ed. Lieberman et al. Dekker, New York, 1988

[00112] The aqueous component of the oil-and-water emulsion formulations of the present disclosure is the continuous phase of the emulsion and may be water, saline or any other suitable aqueous solution which can, for example, yield an isotonic and pH controlled preparation. The oil-in-water emulsion formulations of the present disclosure, for example used in the compositions of cannabinoids may comprise from 0.5 to 50% oil, from 0.1 to 10%
emulsifier and from 0.1 to 10% surfactant. The concentration of the non-aqueous phase can be manipulated to achieve a desired viscosity. For more viscous formulations this concentration is increased.

[00113] Suitable anti-oxidants for use in the formation of emulsions include: chelating agents such as citric acid, EDTA, tartaric acid and tryptophane;
preferentially oxidized compounds such as ascorbic acid, sodium bisulfite and sodium sulfite; water soluble chain terminators such as thiols and lipid soluble chain terminators such as alkyl gallates, ascorbyl palmitate, t-butyl hydroquinone, butylated hydroxyanisole, butylated hydroxytoluene, hydroquinone, and alpha-tocopherol.

[00114] The term Vitamin E (tocopherol) it is intended to encompass the a-, p--, y- and ö-forms of tocopherol that differ by the number and position of methyl groups on the chromanol ring as well as the various isomers of these compounds. Pharmaceutically acceptable derivatives of tocopherol are also included, such as the esters of tocopherol, e.g. the linoleate, nicotinate, acetate or acid succinate ester. The United States Pharmacopoeia describes Vitamin E as a form of a-tocopherol. This includes d- or d, 1-a-tocopherol, d- or d, 1-a-tocopherol acetate and d- or d, 1-a-tocopherol succinate. The term Vitamin E is also used as a generic description for all tocopherol and tocotrienol derivatives that exhibit Vitamin E activity. Thus, the term tocopherols is synonymous with Vitamin E, but also for methyl tocols. One useful Vitamin E
composition for use in the emulsions of the present invention is a-tocopherol as described in the United States Pharmacopoeia, Volume 23, 1995 which is also known as all-rac-a-tocopherol.

[00115] The chosen emulsifier will be one that confers good stability to the emulsion and is pharmaceutically acceptable.One preferred emulsifier is a block copolymer containing a polyoxyethylene block, i.e. a block made up of repeating ethylene oxide moieties. A suitable emulsifier of this type is Poloxamer, i.e. a polyoxyethylene-polyoxypropylene block copolymer, such as Poloxamer 188. See the Handbook of Pharmaceutical Excipients, p.352, 2nd Edn.

Pharmaceutical Press, London, 1994, Eds, Wade and Weller.Another preferred emulsifier is a phospholipid emulsifier. This can be any pharmaceutically acceptable material derived from soybeans, sunflower seeds, or eggs, e.g. soy or egg lecithins.

[00116] The quantity of oil in the emulsion can be from 10 to 50% on a w/v basis, preferably from 15 to 40 % w/v and more preferably from 20 to 35 % w/v.

[00117] The general preparation of emulsions is as follows: the two phases (oil and water) are separately heated to an appropriate temperature (the same in both cases, generally 5- 10 C above the melting point of the highest melting ingredients in the case of a solid or semi-solid oil, or where the oil phase is liquid, a suitable temperature as determined by routine experimentation). Water-soluble components are dissolved in the aqueous (water) phase and oil-soluble components (including but not limited to active ingredients, cannabinoids, whether extracts or pure compounds and also, terpenes) are dissolved in the oil phase.
To create an oil-in water emulsion, the oil phase is vigorously mixed into the aqueous phase to create a suitable dispersion and the product is allowed to cool at a controlled rate with stirring. A water-in-oil emulsion is formed in the opposite fashion i.e. the water phase is added to the oil phase. When hydrophillic colloids are a part of the system as emulsion stabilizers, a phase inversion technique may be employed whereby the colloid is mixed into the oil phase rather than the aqueous phase, prior to addition to the aqueous phase. In using the oil-based composition of the present invention, which is semi-solid to solid, it is preferred to add the composition to the oil phase accompanied by mild pre-heating to 30-40 C.

[00118] Microemulsions, characterized by a particle size at least an order of magnitude smaller (10-200 nm) than standard emulsions and defined as "a system of water, oil and amphiphile which is a single optically isotropic and thermodynamically stable liquid" (14), may also be formed comprising the composition of the present invention. In a preferred form, the micro-emulsion comprises a surfactant or surfactant mixture, a co- solvent (e.g. a short chain aliphatic alcohol) the oil-based composition of the present invention, water and optionally other additives.

[00119] This formulation has several advantages as a delivery system for the cannabinoids and terpenes or mixtures thereof having relatively high lipophilicity. Firstly, micro-emulsions tend to be created spontaneously, that is, without the degree of vigorous mixing required to form standard emulsions. From a commercial perspective, this simplifies the manufacturing process. Secondly, micro-emulsions are highly thermodynamically stable.
Thirdly, micro-emulsions possess high solubilizing power which is particularly important as they allow for an increased solubilization of the poorly hydrosoluble cannabinoids and terpenes.
Fourthly, micro-emulsions present a larger surface area of disperse phase droplets from which absorption of the active cannabinoid and terpenoid ingredients can occur.
Nano-emulsions are a sub-set of micro-emulsions, and generally possess dispersed phase droplet diameters towards the lower end of the micro-emulsion particle diameters distribution range.

[00120] Surfactant or surfactant mixtures which are suitable for use in the formation of micro-emulsions can be anionic, cationic, zwitterionic, non-ionic and preferably possess HLB
(hydrophile-lipophile balance) values within the range of 1-20, more preferably in the ranges 2-6 and 8-17. Especially preferred agents are non-ionic surfactants, selected from the group consisting of polyglycol ether derivatives of aliphatic or cycloaliphatic alcohols, saturated fatty acids and alkyphenols, water-soluble polyethyleneoxy adducts onto polypropylene glycol and alky polypropylene glycol, nonylphenol polyethoxyethanols, castor oil polyglycol ethers, polypropylene/polyethylene oxide adducts, tributylphenoxy-polyethoxyethanol, polyethylene glycol, octylphenoxy- polyethoxyethanol, lanolin alcohols, polyoxyethylated (POE) alkyl phenols, POE fatty amides, POE fatty alcohol ethers, POE fatty amines, POE fatty esters, poloxamers (7-19), POE glycol monoethers (13-16), polysorbates and sorbitan esters.

[00121] There are many methods known and used by those skilled in the art for making micro-emulsions. In a preferred method of forming micro-emulsions of the present invention, a surfactant, a co-surfactant/co-solvent and the cannabinoid and terpenes or mixtures thereof (pre-dissolved in a suitable proportion of an appropriate oil) is mixed and then titrated with water until a system of desired transparency is obtained.

[00122] Preferably, the emulsions and micro-emulsions of this invention, are of the o/w type, and may be pH adjusted within the range pH 4 to 7. Emulsions comprise at least the following basic components: a lipid (fatty/oil) dispersed phase, primary surfactant/emulsifier, secondary surfactant/emulsifier, aqueous continuous phase, other appropriate additives, and of course, the active ingredient(s).

[00123] Micro-emulsions are a sub-set of emulsions, which comprise at least the same basic ingredients, in modified amounts, and, in addition, a co-surfactant/cosolvent.

[00124] The following are preferred components/ingredient of an emulsion of the present invention and for delivery of cannabinoids and terpenes:
= Vegetable oils including but not limited to: corn oil, coconut oil and fractionated forms, cottonseed oil, grapeseed oil, hemp oil, olive oil, safflower oil, sunflower oil, soybean oil = Lipid ingredients including but not limited to: medium and long chain saturated (naturally occurring or synthetically hydrogenated) and unsaturated fatty acid monoglyceride, diglyceride or triglyceride esters, either singly or in admixture = Non-ionic surfactants/emulsifying agents including but not limited to:
- Polyethcmlated sorbitan fatty acid esters, with HLB Values within the range 10 to 18, including PEG-20 sorbitan monolaurate, PEG-4 monolaurate, PEG-20 sorbitan monopalmitate, PEG-20 sorbitan monostearate, PEG-4 sorbitan monostearate, PEG-20 sorbitan tristearate, PEG-20 sorbitan monooleate - Polyoxyethylated fatty acid ethers, with HLB Values within the range 9 to 18, including PEG-12 cetostearyl ether, PEG-20 cetostearyl ether, PEG-25 cetostearyl ether, PEG-9 lauryl ether, PEG-23 lauryl ether, PEG-20 oleyl ether - Polyoxyethylated fatty acid esters, with HLB Values within the range 9 to 18, including Lauroyl polyoxy1-32 glycerides, PEG-8 caprylic/capric glycerides, PEG-6 stearate, PEG-8 stearate, PEG-32 stearate, PEG-35 castor oil glycerides, PEG-40 stearate - Ethylene glycol palm itostearate, diethylene glycol palm itostearate = Non-ionic co-surfactants including but not limited to: sorbitan fatty acid esters, with HLB
Values within the range 1 to 9, including Sorbitan monopalmitate, Sorbitan monostearate, Sorbitan monooleate, Sorbitan isostearate = Lecithin, phospholipids (including phosphatidylcholine, phosphatidylserine, phosphatidylethanolamine, phosphatidylinositol) and their hydrogenated derivatives = Cosolvents including but not limited to: propylene glycol, diethylene glycol monoethyl ether, polyethylene glycols 400 and 600, ethanol, glycerol = Antioxidants including but not limited to: alpha-tocopherol and its acetate and succinate esters, ascorbic acid and its salts (e.g. calcium, magnesium, potassium, sodium ascorbates), ascorbyl palm itate, butylated hydroxyanisole, butylated hydroxytoluene, mixed natural tocopherols concentrate in vegetable oil, sodium metabisulfite = pH adjustment means and buffering agents including but not limited to, either singly (pH
adjustment) or in appropriate combination (buffer systems): acetic acid, citric acid, disodium hydrogen phosphate, hydrochloric acid, potassium dihydrogen phosphate, sodium acetate, sodium acid phosphate, sodium hydroxide, trisodium citrate = antimicrobial preservatives including but not limited to: para-hydroxybenzoate esters (methyl, butyl, ethyl, propyl), phemmethanol, potassium sorbate, sorbic acid, rosmarinic acid, sodium benzoate = Flavouring and taste masking agents as required: water soluble and oil soluble cornpositions = Viscosity enhancing agents including but not limited to: water-soluble cellulose derivatives such as hydroxypropyl cellulose; hydroxypropylmethyl cellulose;
methylcellulose; sodium carboxymethyl cellulose; carbomers, such as carbomer 974P, xanthan gum = Colouring agents as required: water soluble or water dispersible Table la denotes the preferred ranges of the various non-active composition ingredients.
Emulsions Ingredient Composition (%w/w) Preferred Most Especially Preferred Most Preferred LipidNegetable Oil Phase 40.0-50.0 30.0-40.0 20.0-30.0 Surfactants/Emulsifying Agents 10.0-20.0 5.0-10.0 0.5-5.0 Co-solvents (lipid/vegetable oil phase) 10.0-20.0 5.0-10.0 0.0-5.0 Anti-oxidants (lipid/vegetable oil phase) 1.0-5.0 0.5-1.0 0.1-0.5 Antimicrobial preservatives (aqueous 1.0-5.0 0.5-1.0 0.1-0.5 phase) pH Adjusters (buffers, aqueous phase) As required, pH As required, pH As required, adjustment to adjustment to pH
adjustment 5.5-7.0 4.5-5.5 to 4.0-4.5 Flavouring agents (aqueous phase) As required As required As required Viscosity Enhancing/Suspending Agents 5.0-10.0 2.0-5.0 0.0-2.0 (aqueous phase) Clouring Agents (aqueous phase) As required As required As required Purified Water (aqueous phase) As required As required As required The active ingredients (cannabinoids and/terpenes) dosages per suppository will be adjusted according to the therapeutic condition being treated, and will, therefore, have condition dependant variable dosages. As a general non-limiting guide this will be within the range 1mg to 500mg.
Table 2b denotes the preferred ranges of the various non-active composition ingredients.
Micro-emulsions/Nano-emulsions Ingredient Composition (%w/w) Preferred Most Especially Preferred Most Preferred Lipid/Vegetable Oil (as % of dispersed 40.0-80.0 40.0-80.0 40.0-80.0 phase) Surfactants/Emulsifying Agents (as 20.0-60.0 20.0-60.0 20.0-60.0 percent of dispersed phase) Co-surfactants/Cosolvents (as % of 10.0-40.0 10.0-40.0 10.0-40.0 dispersed phase) Anti-oxidants (as % of dispersed phase) 1.0-5.0 0.5-1.0 0.1-0.5 Antimicrobial preservatives (aqueous 1.0-5.0 0.5-1.0 0.1-0.5 phase) pH Adjusters (buffers, aqueous phase) As required, pH As required, pH As required, adjustment to adjustment to pH
adjustment 5.5-7.0 4.5-5.5 to 4.0-4.5 Flavouring agents (aqueous phase) As required As required As required Viscosity Enhancing/Suspending Agents 5.0-10.0 2.0-5.0 0.0-2.0 (aqueous phase) Colouring Agents (aqueous phase) As required As required As required Purified Water (aqueous phase) As required As required As required Micro-emulsions/nano-emulsions are a specialised sub-set of emulsions, and the specific compositional quantities of certain formulation components are critically dependant on the physicochemical properties of the individual ingredients chosen. As such, overall ranges of these critical components are stated in Figure 2b (lipid/vegetable oil phase, surfactants/emulsififing agents, co-surfactants/cosolvents).
The active ingredients (cannabinoids and terpenes) dosages per suppository will be adjusted according to the therapeutic condition being treated, and will, therefore, have condition dependant variable dosages. As a general non-limiting guide this will be within the range 1mg to 500mg.

[00125] ... Micro-emulsions/nano-emulsions are a specialised sub-set of emulsions, and the specific compositional quantities of certain formulation components are critically dependant on the physicochemical properties of the individual ingredients chosen. As such, overall ranges of these critical components are stated in Figure 2b (lipid/vegetable oil phase, surfactants/emulsifying agents, co-surfactants/co-solvents).

[00126] The active ingredients (cannabinoids and terpenes) dosages per suppository will be adjusted according to the therapeutic condition being treated, and will, therefore, have condition dependant variable dosages. As a general non-limiting guide this will be within the range 1mg to 500mg.

[00127] With specific respect to delta-9-Tetrahydrocannabinol (D9THC), the primary psychoactive molecule in cannabis plants, oral administration (by swallowing ingested dosage forms, thus subject to hepatic first pass metabolism), undergoes hepatic metabolism initially to 11-Hydroxy-delta-9-Tetrahydrocannabinol (11-0H-D9THC), which is reported to possess 4 times the psychoactive potency of its D9THC parent, followed by further metabolism to 11-Nor-9-carboxy-delta-9-Tetrahydrocannabinol (delta-9-THCA), which is non-psychoactive but is thought to possess analgesic and antioxidant activities. Continuing biotransformation reactions generate inactive glucuronide and other conjugates. It is theorized that administration via routes that avoid hepatic first pass metabolism would initially expose peripheral and central receptors of the endocannabinoid system (CB1, CB2, and others) to untransformed D9THC
molecules thereby partially or substantially blocking them from interacting with 11-0H-D9THC for a period of time, and thus reducing or eliminating the so-called "THC high" experienced by users.
Rectal and Vaginal Administration

[00128] There are many advantages to the rectal or vaginal administration of cannabinoids/terpenes not afforded by other routes. The active ingredient may still be administered even if the oral route is impaired (e.g., due to vomiting, an injured jaw or throat, or gastrointestinal difficulties) or disallowed due to the oral intake restrictions that are frequently required both before and after surgery. This administration is not affected by nausea and vomiting that may prevent effective oral administration, e.g. during infection or fevers, and for cancer chemotherapy patients. This administration overcomes the problem of gastric irritation caused by certain medicaments (e.g. gastric micro-bleeding, irritation of existing gastric and duodenal ulcers) and may be administered to unconscious patients.

[00129] Avoiding the oral-route gastrointestinal tract also prevents first-pass metabolism by the liver, which metabolizes many different molecules (including D9-tetrahydrocannabinol, otherwise known as THC), and allows the active constituents to reach the blood in much higher concentrations. Vaginal suppositories, and, if properly inserted, rectal suppositories offering this benefit of avoidance of the hepatic first pass metabolism is a significant benefit. Specifically, there is avoidance of potential degradation of medicament by the acidic gastric fluid, gastro-intestinal digestive enzymes, bile, and food interactions that may reduce the amount of medicament available for absorption, and enzymatic degradation of medicament during passage across the epithelial membranes of the digestive tract into the systemic blood circulation.

[00130] In the case of THC, hepatic first pass metabolism transforms a considerable amount of what is ingested into the significantly more psychoactive metabolite 11-Hydroxy-D9-tetrahydrocannabinol. While not harmful in and of itself and potentially of therapeutic benefit, this molecule causes much more intense cognitive effects than THC. Rectal administration not only avoids this effect, but also allows a much greater proportion of THC to eventually reach the blood stream. This increase in overall efficiency is also shown in the different levels of bioavailability that different administration routes afford. Rectal and often vaginal administration also allows for active ingredient to exert effects over localized ailments (e.g., hemorrhoidal tissue, inflammation of the rectum, cervical, uterine issues, or tumours in the rectal cavity, cervix or uterine areas). This form of use (especially rectal) also has a much faster uptake than oral administration and leads to more consistent blood concentrations of the active constituents. The speed and reliability of their uptake combined with their circumvention of many of the issues surrounding both ingestion and inhalation make these applications an excellent addition to both new and pre-existing therapeutic regimens.

[00131] Rectal suppositories are solid dosage units having a cylindrical or conical form, preferably with one flat end and tapering to a point at the other (insertion) end. Adult suppositories are typically 2grams to 2.8grams in weight, while pediatric suppositories would be approximately 1gram in weight. Adult vaginal suppositories are of various shapes, and typically 2grams to 5grams in weight; pediatric versions are typically half that weight.

[00132] The lipid-based (lipophilic, or fatty/oily) type are solid at typical ambient temperatures (30C or below), melt over a range (33 to 380) at body temperature (approximately 37C), to spread over the rectal or vaginal mucosal epithelia, and release their active medications for subsequent local effect or systemic absorption. It is desirable that suppositories melt within 15 minutes of administration, and spread their contents over as large an area as possible of the target mucosal epithelium within around 60 minutes.

[00133] Hydrophilic-base suppositories remain as solids over a wider ambient temperature range, and do not melt at body temperature, but dissolve in the rectal and vaginal fluids, releasing their active medication(s) for subsequent local effect or systemic absorption.
This type of formulation dissolves in physiological fluids to release its active ingredient(s) more slowly than the melting type, and tends to have a slower onset and more prolonged duration of action. Again, it is desirable for the suppository to dissolve within a few hours, and for the rectal or vaginal fluid containing solubilized active agent(s) to achieve good spreading properties over a significant area of mucosal epithelium.

[00134] In both cases, the composition of the formulation is critical in facilitating the dispersion, dissolution and absorption of the active ingredient(s) from the dosage form matrix, and thus their bioavailability. The choice of lipophilic or hydrophilic formulations is matched to the clinical condition to be treated, and duration of required activity. For example, a more prolonged duration of action would be desirable for the treatment of insomnia and other sleep disorders, whilst a more rapid onset of action is advantageous for pain relief and epileptic disorders.
Fatty Suppositories

[00135] Cocoa Butter (Theobroma Oil) is a "traditional lipid" (fatty) suppository base of natural origin, introduced in the 1850s, and still in some use today. It is a solid substance, which softens at around 300 and melts at approximately 32-34C (i.e. below the normal body temperature of 370), and comprises a mixture of triglyceride esters of palmitic, stearic, and oleic acids. This material can exist in a number of crystalline polymorphic forms (alpha, beta, beta1, and gamma), depending upon how it is processed when making suppositories. The degree of heating during melting and rate of solidification during cooling and setting are two of the key process parameters involved. These polymorphic forms are of the same chemical composition but differ in their crystalline habits and melting points: alpha melts at 220, beta melts at 34-35C, beta1 melts at 28C, and gamma melts at 18C. The beta polymorph is the most stable one, and the desired form for suppository formulations. The other three polymorphs are metastable, and tend to convert back to the more stable beta form over varying periods of time. Cocoa Butter possesses several disadvantageous properties including: it is of natural origin and may therefore vary in compositional consistency, sensitivity to processing conditions, its relatively low melting point range which may lead to problems in handling the suppositories due to softening and deformation, potentially inconsistent polymorphic composition in the final dosage form leading to stability problems, and lack of suitability for use in elevated climatic ternperatures.

[00136]
Coconut oil, another commonly-used fatty suppository base, is also subject to some of the same limitations as Cocoa Butter (it is of natural origin and may therefore vary in compositional consistency, sensitivity to processing conditions, its relatively low melting point range which may lead to problems in handling the suppositories due to softening and deformation, potentially inconsistent polymorphic composition in the final dosage form leading to stability problems, and lack of suitability for use in elevated climatic temperatures).
The formulations/suppositories of this invention do not use these materials and are specifically formulated to avoid their undesirable characteristics.Suppository formulations of this invention preferably comprise a lipid (fatty) matrix component comprising the main mass of the suppository, surfactant/emulsifying agents to facilitate dispersion and dissolution of active ingredient(s) from the dosage form into physiological fluids upon administration, co-solvents [for the active agent(s)] which may also act as epithelial penetration and permeability enhancers, an antioxidant to protect the lipid matrix component and active ingredients(s) from oxidative degradation during manufacturing and storage of the suppositories, the active ingredient(s).

[00137] Surfactants/emulsifying agents are molecules that contain both lipophilic and hydrophilic functionalities within their molecular structures (amphiphilic molecules). They may be either anionic (net negative charge in aqueous solutions), cationic (net positive charge in aqueous solutions), zwitterionic (equal positive and negative charges in aqueous solutions), or non-ionic (no charge in aqueous solutions). Non-ionic surfactants are preferred for the dosage forms of this invention, since they are considerably less irritant to mucosal membranes, and do not demonstrate potential ionic interactions with formulation ingredients thereby producing more =

stable compositions. The overall degree of lipophilicity and hydrophilicity of a given surfactant/emulsifying agent is typically represented using the Hydrophile-Lipophile Balance (HLB) value. Molecules with HLB Values less than 10 are overall lipophilic (lipid soluble) in nature, whilst those with HLB Values of 10 or above are overall hydrophilic (water soluble) in nature. It is critical to select members with appropriate HLB Values for the type of formulation required, thus for formulations which are designed to form o/w emulsion systems (self-emulsifying delivery systems) on exposure to aqueous physiological fluids HLB
Values of 10-18 are preferred. Note that surfactants / emulsifying agents of differing HLB
Values may also be mixed to give the final desired HLB Value of the blend, and this often leads to the formation of more physically stable emulsion systems. For example, a mixture of 0.5 parts of surfactant of HLB Value 7.8 plus 0.5 parts of a surfactant of HLB Value 13.4 will yield a mixed surfactant system having an additive HLB Value of 10.6 (0.5 x 7.8 = 3.9, 0.5 x 13.4 =
6.7, 3.0 + 6.7 = 10.6).
As described below, surfactants/emulsifying agents of HLB Values 10-18 would be the principal component, whilst those with HLB Values less than 10 would be the co-surfactant component.

[00138] The fatty acid moieties of the lipid matrix ingredients are typically defined with respect to their aliphatic hydrocarbon chain length: short chain fatty acids contain up to 5 carbon atoms, medium chain fatty acids 6 to 12 carbon atoms (e.g. caprylic, capric, and lauric acids), and long chain fatty acids 13 to 21 carbon atoms (e.g. myristic, palmitic, stearic, and oleic acids). They may be saturated or unsaturated. These fatty moieties comprise one or more of:
= Lipid matrix ingredients including but not limited to: medium and long chain saturated (naturally occurring or synthetically hydrogenated) and unsaturated fatty acid monoglyceride, diglyceride or triglyceride esters, and polyglycolysed or polyoxyl glyceride derivatives of said, either singly or in admixture = Non-ionic surfactants/emulsifying agents including but not limited to:
- Polyethoxylated sorbitan fatty acid esters, with HLB Values within the range 10 to 18, including PEG-20 sorbitan monolaurate, PEG-4 monolaurate, PEG-20 sorbitan monopalmitate, PEG-20 sorbitan monostearate, PEG-4 sorbitan monostearate, PEG-20 sorbitan tristearate, PEG-20 sorbitan monooleate - Polyoxyethylated fatty acid ethers, with HLB Values within the range 9 to 18, including PEG-12 cetostearyl ether, PEG-20 cetostearyl ether, PEG-25 cetostearyl ether, PEG-9 lauryl ether, PEG-23 lauryl ether, PEG-20 ley! ether - Polyoxyethylated fatty acid esters, with HLB Values within the range 9 to 18, including Lauroyl polyoxy1-32 glycerides, PEG-8 caprylic/capric glycerides, PEG-6 stearate, PEG-8 stearate, PEG-32 stearate, PEG-35 castor oil glycerides, PEG-40 stearate - Ethylene glycol palm itostearate, diethylene glycol palm itostearate = Non-ionic co-surfactants including but not limited to:
- Sorbitan fatty acid esters, with HLB Values within the range 1 to 9, including Sorbitan monopalmitate, Sorbitan monostearate, Sorbitan monooleate, Sorbitan isostearate = Co-solvents including but not limited to:
- Propylene glycol - Diethylene glycol monoethyl ether - Polyethylene glycols 400 and 600 - Ethanol - Glycerol = Vegetable oils including but not limited to: corn oil, coconut oil and fractionated forms, cottonseed oil, grapeseed oil, hemp oil, olive oil, safflower oil, sunflower oil, soybean oil = Anti-oxidants including but not limited to:
- Mixed Natural Tocopherols (alpha-, beta-, delta-, and gamma-Tocopherols) Concentrate in vegetable oil - Alpha-Tocopherol, and its Acetate and Succinate esters - Ascorbyl palm itate - Butylated Hydroxyanisole (BHA) - Butylated Hydroxytoluene (BHT) = Penetration/Permeability Enhancers comprise Oleic Acid, Diethylene glycol monoethyl ether, Terpenes.

[00139] In addition, suspending agents, such as colloidal silica, may be added if the active agent is a solid powder that is not completely soluble in the formulation, to prevent sedimentation of solid particles during suppository setting.
Table 3 denotes the preferred ranges of the various non-active composition ingredients.
Lipophilic Base Suppositories Ingredient Composition (%w/w) Preferred Most Especially Preferred Most Preferred Lipid Matrix Ingredients To 100% To 100% To 100%
Surfactants/Co-surfactants/Emulsifying 5.0-10.0 2.0-5.0 0.0-2.0 Agents Co-solvents 5.0-10.0 3.0-5.0 0.0-3.0 Vegetable Oils 10.0-20.0 5.0-10.0 0.0-5.0 Anti-oxidants 0.5-1.0 0.1-0.5 0.01-0.1 Penetration/Permeability Enhancers 3.0-5.0 1.0-3.0 0.5-1.0 Suspending Agents 1.0-5.0 0.5-1.0 0.1-0.5 The active ingredients (cannabinoids and terpenes) dosages per suppository will be adjusted according to the therapeutic condition being treated, and will, therefore, have condition dependant variable dosages. As a general non-limiting guide this will be within the range 1mg to 500mg.
Hydrophilic Suppositories

[00140] The suppositories of this invention preferably comprise of a hydrophilic (water soluble) matrix component comprising the main mass of the suppository, surfactant/emulsifying agents to facilitate dispersion and dissolution of active ingredient(s) from the dosage form into 41.

physiological fluids upon administration, cosolvents [for the active agent(s)]
which may also act as epithelial penetration and permeability enhancers, an antioxidant to protect the active ingredients(s) from oxidative degradation during manufacturing and storage of the suppositories, the active ingredient(s).

[00141] Hydrophilic matrix ingredients comprise but are not limited to:
- Polyethylene glycols - PEGs, polymers of oxyethylene monomeric sub-units, of varying molecular weights indicated by the suffix number e.g. PEG 1000 has an average molecular weight of 1000 Daltons. As the molecular weight increases the water solubility tends to decrease, and the melting range increase. PEGs of this invention include liquid forms: PEGs 200, 400, and 600 (100% water soluble), and solid forms: PEGs 1000 (80% water soluble, melting range 37-40C), 1450 (72% water soluble, melting range 43-46C), 3350 (67% water soluble, melting range 54-58C), 4600 (65% water soluble, melting range 57-61C), and 8000 (63% water soluble, melting range 60-63C). The PEGs may be admixed in various proportions, to achieve the required physicochemical characteristics of a suppository formulation, and its duration of activity in vivo.
- Poloxamers are block copolymers composed of polyethylene oxide and polypropylene oxide monomeric sub-units, trade names include Pluronic. The Poloxamers of this invention include liquid forms: Poloxamer 124 (Pluronic L44), Pluronic L62, and Pluronic L62, and solid forms: Poloxamer 188 (Pluronic F68), Poloxamer 237 (Pluronic F87), Poloxamer 338 (Pluronic F108), and Poloxamer 407 (Pluronic F127. All Poloxamers are water soluble and also possess surfactant/emulsifying properties. The Poloxamers may be admixed in various proportions, to achieve the required physicochemical characteristics of a suppository formulation, and its duration of activity in vivo. They do not melt at body temperature, but dissolve in the rectal and vaginal fluids.

[00142] Non-ionic surfactants/emulsifying agents comprise but are not limited to:
- Polyethoxylated sorbitan fatty acid esters, with HLB Values within the range 10 to 18, including PEG-20 sorbitan monolaurate, PEG-4 monolaurate, PEG-20 sorbitan monopalmitate, PEG-20 sorbitan monostearate, PEG-4 sorbitan monostearate, PEG-20 sorbitan tristearate, PEG-20 sorbitan monooleate - Polyoxyethylated fatty acid ethers, with HLB Values within the range 9 to 18, including PEG-12 cetostearyl ether, PEG-20 cetostearyl ether, PEG-25 cetostearyl ether, PEG-9 lauryl ether, PEG-23 lauryl ether, PEG-20 oleyl ether - Polyoxyethylated fatty acid esters, with HLB Values within the range 9 to 18, including PEG-8 caprylic./capric glycerides, PEG-8 stearate, PEG-35 castor oil glycerides, PEG-40 stearate

[00143] Cosolvents comprise but are not limited to:
- Propylene glycol - Diethylene glycol monoethyl ether - Polyethylene glycols 400 and 600 - Ethanol - Glycerol

[00144] Anti-oxidants comprise but not limited to:
- Mixed Natural Tocopherols (alpha-, beta-, delta-, and gamma-Tocopherols) Concentrate in vegetable oil - Alpha-Tocopherol, and its Acetate and Succinate esters - Ascorbyl Palm itate - Butylated Hydroxyanisole (BHA) - Butylated Hydroxytoluene (BHT)

[00145] Optionally present are penetration/permeability enhancers: Lower carbon chain alcohols, Diethylene glycol monoethyl ether, Propylene glycol, polyethylene glycols 200/400/600.

[00146] In addition, suspending agents, such as colloidal silica, may be added if the active agent is a solid powder that is not completely soluble in the formulation, to prevent sedimentation of solid particles during suppository setting.

Table 4 denotes the preferred ranges of the various non-active composition ingredients.
Hydrophilic Base Suppositories Ingredient Composition (%wlw) Preferred Most Especially Preferred Most Preferred Hydrophilic Matrix Ingredients To 100% To 100% To 100%
Surfactants/Co-surfactants/Emulsifying 5.0-10.0 2.0-5.0 0.0-2.0 Agents Co-solvents 5.0-10.0 3.0-5.0 0.0-3.0 Anti-oxidants 0.5-1.0 0.1-0.5 0.01-0.1 Penetration/Permeability Enhancers 3.0-5.0 1.0-3.0 0.5-1.0 Suspending Agents 1.0-5.0 0.5-1.0 0.1-0.5

[00147] The active ingredients (cannabinoids and terpenes) dosages per suppository will be adjusted according to the therapeutic condition being treated, and will, therefore, have condition dependant variable dosages. As a general non-limiting guide this will be within the range 1mg to 500mg.
Suppository Dispersibility Testing

[00148] The suppository dispersibility characteristics were monitored in vitro using the following controlled test conditions:

[00149] 200mL distilled/deionised water were placed in a squat form 250mL
clear borosilicate glass beaker, heated to 37C+/-1C, and gently stirred using a 1.5 inch cylindrical Teflon coated magnetic stirbar. A test suppository was added and the following parameters visually observed over a timed period: whether the suppository sinks or floats, whether the suppository melts or dissolves, progressive surface erosion, opacity development in solution, presence or absence of undispersed solid fragments.

[00150] Various experimental batches of two different lipophilic base suppositories and one hydrophilic base suppository, formulated in accordance with compositions of this Application, were evaluated in the above test. Figure 5 indicates a generalised summary of test results, versus a simple lipophilic base suppository formulated with Coconut Oil as a comparator. A number of Coconut Oil based suppositories are available on the market, but lack the designed advantages of the compositions of this Application.

[00151] It is noted that the simple Coconut Oil suppository base, without the performance enhancement ingredients that are the subject of this Application, did not disperse under the conditions of the test, but simply melted and floated on the surface of the water in a small pool, whereas the test formulations that are the subject of this Application either progressively melted (lipophilic base) or dissolved (hydrophilic base) and uniformly dispersed throughout the bulk test liquid over time. This behaviour would be reflective of the in vivo dispersion characteristics of the dosage form.
Table 5 Suppository Type Dispersibility Characteristics Time to Complete Dispersion Lipophilic Base 1 Floats initially then partially submerges, 3-5 minutes (Suppocire Type) no fragmentation, uniform progressive surface erosion, uniform progressive dispersibility in test liquid (increasing development of solution opacity over time), visually uniform dispersion throughout bulk of test liquid, no solid fragments remain at end of test Lipophilic Base 2 Floats initially then partially submerges, 7-10 minutes (Witepsol Type) no fragmentation, uniform progressive surface erosion, uniform progressive dispersibility in test liquid (increasing development of solution opacity over time), visually uniform dispersion throughout bulk of test liquid, no solid fragments remain at end of test Hydrophilic Base 1 (PEGs Sinks, no fragmentation, uniform 10-20 Type) progressive surface erosion, uniform minutes progressive dispersibility in test liquid (increasing development of solution opacity over time), visually uniform dispersion throughout bulk of test liquid, no solid fragments remain at end of test Lipophilic Base 3 (Coconut Floats, no fragmentation, melts to form a 3-4 minutes Oil) small pool on the surface of the test liquid, does not disperse Physical Characteristics Monitoring

[00152] Various experimental batches of two different lipophilic base suppositories and one hydrophilic base suppository, formulated in accordance with compositions of this Application, were evaluated for the following characteristics:
= Surface smooth and uniform =
= Colour and Uniformity of Colour =
= Free from surface bloom (white powdery appearance) =
= Free from air bubbles/bubble craters =
= Free from cracks/fissures =
= Free from visible sedimentation =
= = Odour/Aroma ¨ free from rancidity, odour characteristic of the formulation (principally due to the specific terpene ingredients) =
= Ease of removal from suppository mold =

= Uniformity of Weight =
= Dispersibility Testing

[00153] All tests were consistently satisfactory, indicating well-defined reproducible manufacturing procedures and formulation physical characteristics.
Enemas (Rectal and Colonic)

[00154] The enemas of this invention comprise o/w emulsions and formulation ingredients are similar to those elaborated for emulsions and micro-emulsions/nano-emulsions.
The active ingredient(s) (cannabinoids and terpenes) is/are dissolved in the dispersed oil phase droplets. They may also be partially soluble in the aqueous continuous phase.

[00155] More preferably, the rectal and colonic enemas of this invention consist of liquid emulsion-type dosage forms (conventional emulsions and micro-emulsions/nano-emulsions), preferably micro-emulsions/nano-emulsions. They may be of varying administration volumes, generally from a few mL- microenemas - up to approximately 1 Litre, depending upon the regions of the rectum and colon to which active ingredient(s) are to be delivered. Colonic irrigation requires a larger enema volume than rectal irrigation.
Solid Oral Dosage Forms (Capsules)

[00156] Within the scope of the invention capsules may be of either the hardshell or softshell types, containing solid compositions fill. The fill is preferably introduced into the capsules in a heated liquid form, which subsequently sets to a solid at ambient temperatures below approximately 33C, Capsules would be sealed during this process.
Formulations would be of the self-emulsifying type, preferably the self-micro-emulsifying type.

[00157] The commercially-available capsule shell materials may be based on polymers of various types, including but not limited to bovine, porcine, or fish gelatins;
pullulan;
carageenans; starch-containing compositions; or cellulosic compositions, for example hydroxypropylmethylcellulose (hypromellose). Other formulation additives may be present, such as plasticizing agents, colouring agents, opacifying agents, pH-sensitive polymeric agents (e.g.
for enteric barrier protection, to prevent capsules from dissolving in the acidic gastric fluid of the stomach). Ingredients for the solid self-emulsifying compositions fill of the oral capsules formulations are selected from those listed under Fatty Suppositories.

[00158] These and other changes can be made to the present systems, methods and articles in light of the above description. In general, in the following claims, the terms used should not be construed to limit the invention to the specific embodiments disclosed in the specification and the claims, but should be construed to include all possible embodiments along with the full scope of equivalents to which such claims are entitled.
Accordingly, the invention is not limited by the disclosure, but instead its scope is to be determined entirely by the following claims.
EXAMPLES:

[00159] The following examples are provided for illustrative purposes only and are not intended to limit the scope of the invention.
Example 1 Preparation of Fatty Suppository 1:
A fatty base adult rectal suppository comprising a cannabis extract containing 2.5mg -5.0mg of decarboxylated Delta-9-Tetrahydrocannabinol THC and Cannabidiol CBD in a 1:1 w/w ratio (50% of each) per 1.8g-2.8g of total formulation, 1%w/w ultra-high purity D-Limonene (a terpene), 3%w/w Transcutol P (purified Diethylene glycol monoethyl ether), and Suppocire Asa (90-95%W/VV C10-C18 fatty acids glycerides, plus 5-10%w/w Polysorbate 65) to 100%w/w.
Example 2 Preparation of Fatty Suppository 2:
A fatty base adult rectal suppository comprising a cannabis extract containing 2.5mg -5mg of decarboxylated Delta-9-Tetrahydrocannabinol and Cannabidiol in a 1:1 w/w ratio (50% of each) per 1.8g-2.8g of total formulation, 1%w/w ultra-high purity D-Limonene (a terpene), 0.5% w/w beta-Caryophyllene (a terpene), 3%w/w Transcutol P (purified Diethylene glycol monoethyl ether), and Suppocire AS2X (90-95%W/VV C10-C18 fatty acids glycerides, plus 5-10%w/w Polysorbate 65) to 100%w/w.
Example 3 Preparation of Fatty Suppository 3:
A fatty base adult rectal suppository comprising a cannabis extract containing 10mg decarboxylated Delta-9-Tetrahydrocannabinol and 10mg decarboxylated Cannabidiol per 1.8g of total formulation, 1%w/w ultra-high purity D-Limonene (a terpene), 0.5%w/w beta-Linalool (a terpene), 3%w/w Transcuto10 P (purified Diethylene glycol monoethyl ether), 0.02%
Ascorbyl Palmitate, 0.04% Mixed Natural Tocopherols in Vegetable Oil, and Suppocire AS2X
(90-95%WAN C10-C18 fatty acids glycerides, plus 5-10%w/w Polysorbate 65) to 100%w/w.
Example 4 Preparation of Fatty Suppository 4:
A fatty base adult rectal suppository comprising comprising 2.5mg-3mg decarboxylated Cannabidiol and 25-30mg decarboxylated Delta-9-Tetrahydrocannabinol per 1.8g-2.8g of total formulation, 1%w/w ultra-high purity D-Limonene (a terpene), 0.5%w/w beta.
Myrcene (a terpene), 3%w/w Transcuto10 P (purified Diethylene glycol monoethyl ether), 0.02% Ascorbyl Palmitate, 0.04% Mixed Natural Tocopherols in Vegetable Oil, and Suppocire0 AS2X (90-95%W/W C10-C18 fatty acids glycerides, plus 5-10%w/w Polysorbate 65) to 100%w/w.
Example 5 Preparation of Fatty Suppository 5:
A fatty base adult rectal suppository comprising a fatty base adult rectal suppository comprising 5mg-200mg decarboxylated Cannabidiol per 1.8g-2.8g of total formulation, 1-5%w/w ultra-high purity D-Limonene (a terpene), 0.5-1%w/w beta-Caryophyllene (a terpene), 3-5%w/w Transcutol P (purified Diethylene glycol monoethyl ether), and Suppocire AS2X (90-95%W/VV C10-C18 fatty acids glycerides, plus 5-10%w/w Polysorbate 65) to 100%w/w.
Example 6 Preparation of Fatty Suppository 6:
A fatty base adult rectal suppository comprising a cannabis extract containing 5mg-200mg of decarboxylated Delta-9-Tetrahydrocannabinol and Cannabidiol in a 1:1 w/w ratio (50% of each) per 1.8g-2.8g of total formulation, 1-5%w/w ultra-high purity D-Limonene (a terpene), 5-10%w/w Hemp Seed Oil, and Witepsol H15 (hydrogenated coco fatty acids glycerides) to 100%w/w.
Example 7 Preparation of Fatty Suppository 7:
A fatty base adult rectal suppository comprising a cannabis extract containing 15mg of decarboxylated Delta-9-Tetrahydrocannabinol and 15mg of decarboxylated Cannabidiol per 1.8g-2.8g of total formulation, 1%w/w ultra-high purity D-Limonene (a terpene), 2-10%w/w Hemp Seed Oil, and Witepsol H15 (hydrogenated coco fatty acids glycerides) to 100%w/w.
Example 8 Preparation of Fatty Suppository 8:

A fatty base adult rectal suppository containing 5mg-200mg of decarboxylated Cannabidiol per 1.8g-2.8g of total formulation, 1%w/w ultra-high purity D-Limonene (a terpene), 2-10%w/w Hemp Seed Oil, and Witepsol0 H15 (hydrogenated coco fatty acids glycerides) to 100%w/w.
Example 9 Preparation of Fatty Suppository 9:
A fatty base adult rectal suppository containing 5mg-200mg of decarboxylated Cannabidiol per 1.8g-2.8g of total formulation, 1%w/w ultra-high purity D-Limonene (a terpene), 1-5%w/w beta-Caryophyllene (a terpene), 2-10%w/w Hemp Seed Oil, and Witepsol H15 (hydrogenated coco fatty acids glycerides) to 100%w/w.
Example 10 Preparation of Fatty Suppository 10:
A fatty base adult rectal suppository comprising a cannabis extract containing 5mg -200mg of decarboxylated Delta-9-Tetrahydrocannabinol and Cannabidiol in a 4:1 w/w ratio per 1.8g-2.8g of total formulation, 1% D-Limonene (a terpene), 2-10%w/w Transcutol P
(purified Diethylene glycol monoethyl ether), 10-20%w/w Suppocire0 AP (saturated polyglycolized fatty acids glycerides), and Gelucire0 44/14 (Lauryl Polyoxy1-32 glycerides) to 100%w/w.
Example 11 Preparation of Fatty Suppository 11:
A fatty base adult rectal suppository comprising a cannabis extract containing 5mg -200mg of decarboxylated Delta-9-Tetrahydrocannabinol and Cannabidiol in a 1:1 w/w ratio (50% of each) per 1.8g-2.8g of total formulation, 2-10%w/w Transcutole P (purified Diethylene glycol monoethyl ether), 0.5%w/w beta-Caryophyllene (a terpene), 10-20%w/w and Suppocire AP
(saturated polyglycolized fatty acids glycerides), and Gelucire0 44/14 (Lauryl Polyoxy1-32 glycerides) to 100%w/w.
Example 12 Preparation of Hydrophilic Suppository 1:
A hydrophilic base adult rectal suppository comprising a cannabis extract containing 5mg -200mg of decarboxylated Delta-9-Tetrahydrocannabinol and Cannabidiol in a 1:1 w/w ratio (50% of each) per 1.8g-2.8g of total formulation, 1-5%w/w Polysorbate 80, 20-50%w/w Polyethylene Glycol 400-600, and 45-75%w/w Polyethylene Glycol 3,350.
Example 13 Preparation of Hydrophilic Suppository 2:

I

A hydrophilic base adult rectal suppository containing 5mg-200mg of decarboxylated Cannabidiol per 1.8g-2.8g of total formulation, 1-5%w/w Polysorbate 80, 30-40%w/w Polyethylene Glycol 400, and Polyethylene Glycol 3,350 to 100%w/w.
Example 14 Preparation of Hydrophilic Suppository 3:
A hydrophilic base adult rectal suppository comprising a cannabis extract containing 15mg of decarboxylated Delta-9-Tetrahydrocannabinol and 15mg of decarboxylated Cannabidiol per 1.8g-2.8g of total formulation, 1%w/w Polysorbate 80, 30%w/w Polyethylene Glycol 400, and Polyethylene Glycol 3,350 to 100%w/w.
Example 15 Preparation of Hydrophilic Suppository 4:
A hydrophilic base adult rectal suppository containing 5mg-200mg of decarboxylated Cannabidiol per 1.8g-2.8g of total formulation, 1-5%w/w Polysorbate 80, 30%w/w Polyethylene Glycol 400, and Polyethylene Glycol 3,350 to 100%w/w.
Example 16 Preparation of Fatty Suppository 12:
A fatty base adult rectal suppository comprising a cannabis extract containing 5mg -200mg of decarboxylated Delta-9-Tetrahydrocannabinol and 5mg-100mg of decarboxylated Cannabidiol per 1.8g-2.8g of total formulation, 1%w/w ultra-high purity D-Limonene (a terpene), 3%w/w Transcutol P (purified Diethylene glycol monoethyl ether), and Suppocire AS2X
(90-95%W/VV C10-C18 fatty acids glycerides, plus 5-10%w/w Polysorbate 65) to 100%w/w.
Example 17 Preparation of Fatty Suppository 13:
A fatty base adult rectal suppository comprising a cannabis extract containing 5mg -200mg of decarboxylated Delta-9-Tetrahydrocannabinol and 5mg-100mg of decarboxylated Cannabidiol per 1.8g-2.8g of total formulation, 1%w/w ultra-high purity D-Limonene (a terpene), 0.5%w/w beta-Caryophyllene (a terpene), 3-10%w/w Transcutole P (purified Diethylene glycol monoethyl ether), and Suppocire AS2X (90-95%W/W C10-C18 fatty acids glycerides, plus 5-10%w/w Polysorbate 65) to 100%w/w.
Example 18 Preparation of Fatty Base Oral Capsule Dosage Form 1 A fatty base oral capsule comprising a cannabis extract containing 5mg -200mg of decarboxylated Delta-9-Tetrahydrocannabinol and Cannabidiol in a 1:1 w/w ratio (50% of each) per 1-1.5g of total formulation, 2-10%w/w Transcutole P (purified Diethylene glycol monoethyl ether), 10-20%w/w Suppocire0 AP (saturated polyglycolized fatty acids glycerides), ), 0.02%w/w Ascorbyl Palm itate, 0.04%w/w Mixed Natural Tocopherols in Vegetable oil, and Gelucire 44/14 (Lauryl Polyoxl,f1-32 glycerides) to 100%w/w.
Example 19 Preparation of Fatty Base Oral Capsule Dosage Form 2 A fatty base oral capsule comprising a cannabis extract containing 5mg -200mg of decarboxylated Delta-9-Tetrahydrocannabinol and Cannabidiol in a 1:1 w/w ratio (50% of each) per 1-1.5g of total formulation, 2-10%w/w Transcutol P (purified Diethylene glycol monoethyl ether), 1%w/w D-Limonene (a terpene), 10-20%w/w and Suppocire AP (saturated polyglycolized fatty acids glycerides), ), 0.02%w/w Ascorbyl Palmitate, 0.04%w/w Mixed Natural Tocopherols in Vegetable Oil, and Gelucire 44/14 (Lauryl Polyoxy1-32-Glycerides) to 100%w/w.
The embodiments described and shown in the figures were chosen and described in order to explain the principles of the invention, the practical application, and to enable others of ordinary skill in the art to understand the invention for various embodiments with various modifications as are suited to the particular uses contemplated. All references cited herein are incorporated in their entirety by reference.