WO2019094625A1

WO2019094625A1 - Methods and compositions for parenteral administration of cannabidiol in the treatment of convulsive disorders

Info

Publication number: WO2019094625A1
Application number: PCT/US2018/059871
Authority: WO
Inventors: Alexander M. WASYL; Jeremy R. REEH
Original assignee: Nexien Biopharma, Inc.
Priority date: 2017-11-09
Filing date: 2018-11-08
Publication date: 2019-05-16

Abstract

The present disclosure provides pharmaceutical compositions, parenteral delivery methods and methods for the manufacture of a cannabidiol drug delivery system. The system comprises pharmaceutical compositions having therapeutically active amounts of cannabidiol in a nanoparticle formulation for delivery of an API to a mammal, preferably a human in the treatment of seizures and epilepsy. Also described herein are devices for their delivery such as an auto-injector device for rapid and safe delivery of cannabidiol as an auto-injector rescue. Other delivery devices are described for in a long-term treatment regimen for epilepsy. The platform has clinical applications in the treatment of subjects suffering from epilepsy or epileptic-induced seizures.

Description

Title: Methods and Compositions for Parenteral Administration of Cannabidiol in the Treatment of Convulsive Disorders

Cross-Reference to Related Applications

This application claims benefit of and priority to U.S. Provisional Patent Application Nos. 62/583535, filed November 09, 2017; 62/617193, filed January 13, 2018; and 62/638194, filed March 04, 2018 and where permissible is incorporated by reference in its entirety.

Background of the Invention Field of the Invention

The invention relates to the use of cannabinoids in the treatment of epilepsy, in particular the parenteral administration of cannabidiol (CBD) formulations to treat epileptic induced generalized or partial seizures. The invention further considers the therapeutic use of the cannabidiol formulations alone or in combination with other anti-epileptic drugs as a co- medication or adjuvant therapy.

Description of Related Art

Epilepsy is a chronic neurological disorder having the hallmark of which is the recurrent, unprovoked seizures. A person is diagnosed with epilepsy if they have two or more unprovoked seizures that were not caused by some known or reversible medical condition like alcohol withdrawal or extremely low blood sugar. Epilepsy affects approximately 1% of the population worldwide. There is a need to provide a fast-acting rescue that is also save, non-psychoactive, without the tolerance or habit-forming characteristics seen in the current standard of care as seen, for example, with benzodiazepine withdrawal. Of the people affected in this population 30% are unable to control their seizures with treatment using existing anti-epileptic drugs (AED) available. There is also an issue with the abuse of benzodiazepine drugs and the exacerbation of seizures and even death during improper withdrawal. Accordingly, there is still an unmet need to provide safe, cost-effective control and treatment of epilepsy and other convulsive disorders.

Seizures in epilepsy may be related to a brain injury or connected through family history, but often the cause is completely unknown. Some patients with epilepsy have more than one type of seizure. The main symptom of epilepsy is the repeated seizures. They often begin as a focal seizure preceded by an aura, perceptual disturbance experience or prodrome which can manifest as a strange light, an unpleasant smell or confusing thoughts. The focal or partial seizure is limited to a specific region in the brain, but may extend to a more generalized seizure. Patient suffering from repeated seizures will generally know when they are about to experience a seizure.

The use of cannabinoids to treat medical illnesses has become an area of significant interest within the medical community, including in treating brain or neurological disorders. Illnesses such as AIDS and cancer are often accompanied with a lack of appetite. Patients receiving cancer chemotherapy often experience nausea and vomiting side-effects. Chronic pain such as neuropathic pain, malignant tumors and neurodegenerative disease have been considered additional therapeutic targets for cannabinoid therapy. There is a significant amount of interest in assessing the ability of cannabinoid therapy in treating specific epileptic disorders such as Dravet syndrome in children. The capability to control these problems would greatly increase the quality of life for these individuals. Delivery methods for cannabinoids include oral ingestion into the GI tract, edibles, tinctures and soft gel caps. There is also an intraoral delivery into the oral mucosa via sprays and drops, emulsion compositions and chewing gums. Further, there are inhalation delivery methods of smoking and vaporization which do not provide a reliable dosage as a medical delivery system. Oral delivery methods of extracts, infusions and edibles forms have a delay in the onset of their actions, making the correct dosage difficult to assess. Typically, there is a 6% bioavailability in the circulation after extensive first pass liver metabolism.

Cannabinoid, including CBD, in oral dosage forms must overcome several obstacles in order to achieve a therapeutically-effective systemic concentration. First because CBD is highly lipophilic, their limited water solubility restricts the amount of CBD available for absorption in the gastrointestinal tract. Second, CBD undergoes substantial first-pass metabolism when absorbed from the human gastrointestinal tract. Finally, the oral bioavailability of any CBD product is further diminished when a patient is unable to swallow a pill because he or she is having a seizure or is aware of an impending episode. Cannabinoids such as CBD when taken orally have low oral bioavailability, resulting in more than 90% of the ingested dose being removed during the first pass (Grotenhermen, F. (2003) Pharmacokinetics and Pharmacodynamics of Cannabinoids. Clinical Pharmacokinetics, 42, 327-360). Several factors account for the low oral bioavailability including variable absorption, degradation of CBD in the stomach, and significant first-pass metabolism. First pass metabolism is caused by the actions of enzymes of the gastrointestinal lumen, gut wall enzymes, bacterial enzymes, and hepatic enzymes before CBD reaches the circulation. Further, CBD is acted on by CYP450 mixed function oxidases in the liver, all contributing to the significant reduction in CBD reaching the site of action. There are also epigenetic variances in the first-pass effect that result in significant differences in CBD blood levels. Low and fluctuating bioavailability results in the increased amount of CBD required for oral delivery and an increase cost for therapeutic administration. Other routes that avoid the first pass affect are fraught with problems. Suppositories are subject to hygiene and patient compliance restrictions. Formulations intended for administration to the nasal mucosae may cause pain or reflex sneezing, and in extreme cases cause irritation and damage to the nasal mucosae. Sublingual formulations may stimulate the flow of saliva and it is difficult for patients to avoid swallowing when substantial amounts of saliva are produced.

Buccal formulations may be subject to the same limitations. Both sublingual and buccal formulations depend on the efficient transfer of CBD from a hydrophilic vehicle to the mucous membrane of the sublingual or buccal mucosae. Transfer of CBD through the interstices between or through epithelial cells is governed by the lipid solubility of the CBD. There are therefore physical and biological limitations on the therapeutic usefulness of lipophilic medications given by mouth.

Avoiding the absorption and first pass effects or an oral route and the problems associated with other routes of administration provides the rationale for a sterile parental route having rapid, immediate, and consistent blood levels for the treatment of epileptic seizures.

The present invention relates to the use of CBD for the treatment of seizures through the parenteral administration of CBD. One formulation disclosed is for the safe, stable, and rapid treatment of CBD as an auto-injectable rescue medication that is non-psychoactive, and non- habit forming. An auto-injection rescue treatment as described herein enables emergency health care professionals or individuals themselves to quickly and effectively administer a

therapeutically effective dose of CBD to attenuate or suppress an epileptic seizure at the point- of-care (POC). Another formulation disclosed herein is a non-psychoactive, non-habit forming slow-release intramuscular CBD depot formulation to manage or reduce the incidence of convulsive episodes in a subject predisposed to these events. Both formulations have

applications in healthcare for the treatment of focal, general, or refractory epilepsy.

Therefore, in view of the foregoing and given the therapeutic benefits of CBD in the treatment of epilepsy, it would be desirable to develop a stable formulation in which CBD is delivered parentally to achieve rapid therapeutically effective plasma concentrations in a patient.

Summary of the Invention

The present invention overcomes the problems associated with existing drug delivery systems used in the treatment of epileptic patients by delivering CBD parenterally either as a short-term rescue or as a long-term dosing treatment regimen. Preferably, the CBD is delivered via a nano- sized lipid matrix system such as solid-lipid nanoparticles (SLN) to avoid inefficient oral delivery routes encountered through gastrointestinal (first-pass) metabolism of CBD by the patient.

One embodiment of the present invention includes formulated compositions having a SLN with a solid or solid-lipid core containing CBD as an Active Pharmaceutical Ingredient (API) that has long-term stability and is safe for clinical use. The formulation is optionally coated with Polyethylene glycol (PEG) or N-(2-hydroxypropyl)methacrylamide (HPMA) for additional stability or, more generally to include any polymer technology providing similar stabilizing characteristics when used as a coating. Other embodiments incorporate the formulations disclosed herein in treatment methods for individuals or subjects suffering from epilepsy and the resultant seizure episodes with a therapeutically effective amount of CBD. The method utilizes parenteral administration of a therapeutically effective amount of CBD that rapidly obtains stable CBD levels in the blood circulation. The present disclosure also considers delivery devices for short-term, rapid administration such as an auto-injector for immediate rescue from an epileptic seizure or vial, syringe or preOloaded syringe options for long-term administration to maintain therapeutically effective blood levels of CBD in a treatment regimen where the long treatment is provided with less frequent injections in a depot formulation or with the use of an implant. Still further embodiments of the invention provide manufacturing processes for the preparations and use of the formulated compositions disclosed herein. The process comprises the steps of extracting CBD from a cannabinoid plant as a highly CBD-enriched extract relative to other cannabinoids, incorporating the CBD extract into a stable nanoparticle such as SLN as the API, and packaging the formulation for long-term storage and stability.

The present invention establishes a platform for administration of a therapeutically effective amount of CBD in a subject diagnosed with epilepsy in a safe, rapid and stable means. The use of this platform provides the ability to consistently deliver a known, clinically-acceptable, amount of CBD in the treatment of epilepsy or epileptic-induced seizures and solves a significant healthcare need.

Brief Description of the Drawings

Figure 1: Shows the chemical structure of cannabidiol (CBD).

Figure 2: (a) Results of TLC analysis of clone 202 extract. 1 microliter of the extract was run on TLC, CBD= Cannabidol, CBDA=Cannabidiolic acid, (b) GD/MS chromatograms of an extract from Cannabis clone 202 showing the full chromatogram (c) Magnification of weaker signals. Number keys: 1- Cannabidivarol (CBDV), 2- Cannabidiol (CBD), 3- Cannbichromene (CBC), 4- delta⁹-Tetrahydrocannabinol (THC), 5-Cannbigerol (CBG), 6-Cannabinol (CBN), IS.- Internal Standard (Tetracosane). [Gallily, et. al., 2015]

Figure 3: Representation of a SNL particle showing a solidified lipid as the hydrophobic core with a non-spherical shaped particle.

Figure 4: Solid lipid nanoparticle preparation by hot homogenization.

Figure 5: Solid lipid nanoparticle preparation by cold homogenization.

Detailed Description of the Invention

This present invention is capable of being embodied in various forms. The description below of several embodiments is made with the understanding that the present disclosure is to be considered as an exemplification of the claimed subject matter, and is not intended to limit the attached claims to the specific embodiments illustrated. The headings used throughout this disclosure are provided for convenience only and are not to be construed to limit the claims in any way. Embodiments illustrated under any heading may be combined with embodiments illustrated under any other heading.

The disclosure relates, in part, to methods for relieving seizures associated with epilepsy in a subject. Subjects who can benefit from the methods include, for example, mammals, such as humans, particularly humans requiring long term relief from seizures alone or as an adjunct with other anti-epileptic agents or humans requiring immediate and rapid treatment of epileptic seizures at the point-of-care.

"Active Pharmaceutical Ingredient" (API) is the therapeutically effective component in a formulation designed for administration to a subject. Suitable API's in the present invention include synthesized CBD, purified CBD, CBD extracts, their analogs, and derivatives thereof.

"Cannabidiol" as used herein, refers to cannabidiol and cannabidiol derivatives. As used in this application, cannabidiol is obtained from naturally from plant extracts or synthetically from any method known in the art. The IUPAC nomenclature to 2-((l S,6S)-3-methyl-6-(prop-l-en-2- yl)-hex-2-enyl)-5-pentylbenzene-l-,3-diol) as well as to pharmaceutically acceptable salts, solvates, metabolites and metabolic precursors of 2-((l S,6S)-3-methyl-6-(prop-l-en-2-yl)-hex-2- enyl)-5-pentylbenzene-l-,3-diol). The present invention provides pharmaceutical compositions comprising cannabidiol (CBD) having the molecular formula C21H30O2 and derivatives thereof which are administered parenterally through the use of targeted nanoparticles, avoiding the problems associated with other delivery routes such as oral administration. "Cannabinoid" as used herein refers to any compound that interacts with a cannabinoid receptor and other cannabinoid mimetics, their salts, solvates, metabolites, and metabolic precursors. They may act on cells in the brain, or other organs and modulate endocannabinoid activity. They include the plant cannabinoids found in cannabis, hempseed oil, other plants and synthetic cannabinoids manufactured artificially. "Comprise" as used herein is non-limiting to mean those items following the word, but items not specifically mentioned are not excluded.

"Parenteral administration" as used herein means administration by any method other than through the digestive tract or non-invasive topical routes. For example, parenteral administration may include administration to a subject intravenously intradermally, intraperitoneally, intrapleurally, intratracheally, intraossiously, intracerebrally, intrathecally, intramuscularly, subcutaneously, by injection and by infusion. The present invention further considers the use of long term implants for improved patient convenience from not using an injection device.

"Pharmaceutically acceptable", as used herein, refers to compounds, material, compositions, and/or dosage forms that are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans or animals without excessive toxicity, irritation, allergic response, or other problems or complications commensurate with a reasonable benefit/risk ratio, in accordance with the guidelines of agencies such as the U.S. Food and Drug Administration. A "pharmaceutically acceptable carrier" refers to all components of a pharmaceutical formulation that facilitate the delivery of the composition in vivo. Pharmaceutically acceptable carriers include, but not limited to, diluents, preservatives, binders, lubricants, disintegrators, swelling agents, fillers, stabilizers, and combinations thereof.

"Sufficient" or "effective", as used interchangeably herein, refer to an amount, such as mass, volume, dosage, concentration, and/or time period, needed to achieve one or more desired result(s).

"Therapeutically effective amount" is at least the minimum concentration required to effect a measurable improvement or prevention of at least one symptom or a particular condition or disorder, to effect a measurable enhancement of life expectance, or to generally improve a subject's quality of life. Active Pharmaceutical Ingredient

The present invention relates, in part, to a pure or substantially pure form of cannabidiol CBD which can be obtained from any method known in the art.

CBD is a CB-1 receptor antagonist, while THC is a CB-1 receptor agonist. CBD is considered to have a wider scope of medical applications compared to THC. A synthetic form of CBD is considered in the present invention which is made by any method known in the art. These synthetic forms result in a single, known chemical CBD as the Active Pharmaceutical Ingredient (API) without other cannabinoids mixed in.

Several synthesis methods are well known. For example, CBD has been synthesized from p- menthadienol by the Petrzilka procedure (T. Petrzilka, W. Haefliger, C. Sikemeier,G. Ohloff, and A. Eschenmoser, Helv. Chim. Acts, 50, 719 (1967); T. Petrzilka, W. Haefliger, and C. Sikemeier, Helv. Chim. Acta, 52, 1102 (1969) or by a modification of Petrzilka's procedure (R.K. Razdan, H.C. Dalzell, and G.R. Handrick, J.Am.Chem. Soc, 96, 5860 (1974). Other methods for the synthesis of CBD has been described by Handrick et al. (G.R. Handrick, R.K. Razdan, D.B. Uliss, and H.C. Daizell, J. Org. Chem. 42, 2563 (1977). Synthetic CBD has the same chemical structure as the naturally occurring CBD as shown in Figure 1, Panel A. While both the synthetic CBD and a substantially pure CBD extract from plants are considered in the present invention, there is evidence to suggest that the plant form containing a highly enriched CBD component provides for a more effective pharmaceutical agent and thus a more effective API. Pure CBD has a very limited dosage range in the treatment of certain disorders where the effectiveness of CBD begins to decline at higher dosages.

Accordingly, another embodiment of the present invention utilizes CBD as a substantially pure cannabinoid from a purification process that results in the purification of CBD. CBD is a major cannabinoid found in plants, accounting for up to 40% of the cannabinoid plant extract. A substantially pure preparation of CBD is a preparation having a chromatographic purity of greater than 95% or more preferably greater than 98% as determined by an HPLC profile. A typical purification process is disclosed in US2005/0266108; US6,403, 126 and

WO2002/0032420.

Extracts from plant materials encompass a plant or part of a plant (leaves, stems, roots, flowers fruits, seeds, or berries) as well as exudates. The cannabis plant includes wild type Cannabis sativa and variants thereof, including cannabis chemovars which naturally contain different amounts of individual cannabinoids. Plants can also include plants which are the result of genetic crosses, self-crosses or hybrids thereof.

Cannabinoids are isolated from cannabis plants in the genus Cannabis sativa, Cannabis ruderalis, and Cannabis indica which are natural sources of cannabinoids. Cannabinoid extracts have recently been found useful in treating several diseases, including severe spasticity in multiple sclerosis (Syed, Y.Y., McKeage, K. and Scott, L.J. (2014) Delta-9- Tetrahydrocannabinol/Cannabidiol (Sativex®): A Review of Its Use in Patients with Moderate to Severe Spasticity Due to Multiple Sclerosis. Drugs, 74, 563-578) and cancer-related anorexia- cachexia syndrome as well as for nausea and vomiting (Greydanus, D.E., Hawver, E.K., Greydanus, M.M. and Merrick, J. (2013) Marijuana: Current Concepts. Frontiers in Public Health, 1, 42). In all these preparations, the major disadvantage of CBD as a phytomedicine is its psychoactive effects due the presence of delta⁹-Tetrahydrocannabinol (THC). Accordingly, any means to enrich or purify CBD from THC where the psychoactive effects are less than or equal to DEA guidelines. One embodiment considers an isolated form of CBD from cannabis which is devoice of THC and thus not potentiating the negative side effects associated with THC psychoactivity.

The beneficial anti-inflammatory effects of purified CBD, particularly as it relates to pain, migraines, cluster headaches, etc. in rheumatoid arthritis, diabetes type 1 inflammatory bowel disease, and multiple sclerosis show that pure CBD administration gives a bell-shaped dose- response curve, resulting in a very limited dose range. For example, a maximum inhibition of inflammation in a zymosan-induced inflammation mouse model occurs with an oral dose of 5 mg/kg CBD which is reduced by 20% to 25% at 25 mg/kg and further reduced by 14% to 28% at 50 mg/kg. One explanation for a more beneficial CBD from plants may be that the Cannabis plant contains hundreds of different chemicals with about 85 chemicals known as cannabinoids (Gallily, R. et al. (2015) Overcoming the Bell-Shaped Dose-Response of Cannabidiol by using Cannabis Extract Enriched in Cannabidiol, Pharm. & Pharmacy, 6:75-85; Brenneisen, R. (2007) Chemistry and Analysis of Phytocannabinoids and Other Cannabis Constituents. Marijuana and the Cannabinoids, Chapter 2, 17-49), each needed to obtain the pharmacokinetic profile of an effective agent when used as an API. One example for preferentially extracting an enriched form of CBD and minimizing other cannabinoids to control the psychoactive effects is shown in Example 1. Example 1 discloses one method for extracting an enriched CBD as a suitable API.

Example 1 :

CBD is extracted from Cannabis sativa L. flowers from clone 202 which is rich in CBD while low in any psychotropic constituents (Gallily et al., "Overcoming the Bell-Shaped Dose- Response of Cannabidiol by Using Cannabis Extract Enriched In Cannabidiol", Pharmacology & Pharmacy, 2015, 6, 75-85). The Cannabis clone 202 is grown under controlled temperature and light conditions. The flowers are processed by chopping and extracting with 100% ethanol to dry the flowers. Following filtration, CBD is extracted by evaporation. The extract is then dried and emulsified in a suitable vehicle. Analysis of clone 202 extract by TLC and GC/MS showed CBD and Cannabidiolic acid as the major components in the extract with approximately 1% or trace amounts each of

Cannabidivarol, Cannabichromeme, THC, Cannabigerol, and Cannabinol (Figure 2).

The resulting extract is then available for incorporation into nanoparticles as provided below. Nanosize CBD Carriers

Target nano-sized lipid carriers have been described in drugs where their use improves the pharmacokinetic properties of drugs, thus increasing the drug's safety and maximizing therapeutic effects. These delivery systems are designed as sterically stabilized nanoparticles. They are prepared, in part, by modifying their surface with hydrophilic polymers in order to increase the blood circulation time of an incorporated active pharmaceutical ingredient (API) which in the present invention includes a form of CBD.

The present invention considers incorporating an API within a target nano-sized lipid matrix thereby providing for a delivery system that will prolong the half-life of the API in the circulation, reduce non-specific uptake of the API, and improve accumulation of the API at the sites of action (i.e. brain or peripheral nervous system). One embodiment incorporates nano- sized lipid matrix formulations to encapsulate API molecules, while targeting specific transport processes in the brain vasculature, thus enhancing the effect through the biood-brain harrier in convulsive disorders and targeting relevant regions in the brain.

One embodiment for these nano-sized lipid matrix systems includes nanoparticle vesicles. Nanoparticles are composed of lipids and stabilizers. They may also contain surfactants, co- surfactants and coating materials. For example, Poly(ethylene)glycol derivatives or PEG- derivatives such as but not limited to, PEG 400 are used to obtain the steric stabilization of the nanoparticles, thus further reducing their uptake or absorption in the surrounding tissue. PEG400 can also be used as a co-surfactant with propylene glycol. Antioxidants, electrolytes, preservatives such as benzyl alcohol, viscosity enhancing agents, adhesives, absorption enhancers, and other excipients can also be used. Most of these formulation ingredients are safe and under the Generally Recognized as Safe (GRAS) status issued by the Food and Drug Administration. One embodiment incorporates nanoparticle-based solid lipids (SLNs). SLNs are used as a drug delivery system because they combine the benefits of liquid lipid-based colloidal systems such as emulsions and liposomes, and solid systems. They have very good tissue

biocompatibility, biodegradability, composition flexibility and small size with formulations remaining stable for up to three years, making them ideal for a variety of applications. SLN are colloidal particles composed of a biocompatible/biodegradable lipid matrix containing an immobilized form of the target API. SLNs are a solid at room temperature with a size range of approximately 50 nm to 1 um which can be stabilized using non-toxic surfactants, polymers, or both. Figure 3 shows a representation of a SNL particle (5) having a solid lipid core (10), and surfactant monolayer (15). SNL with a hydrophobic core of solidified lipid often forms a non- spherical shaped particle due to the solidification/crystallization of the lipid.

SLNs are particulate in nature and are amendable to hydrophilic and hydrophobic drugs as an API. They have the ability to prevent chemical, photochemical, or oxidative degradation of the API. Large-scale production can be performed in a cost-effective and relatively easy process using hot or cold high-pressure homogenization (HPH) techniques. HPH is associated with three different forces leading to particulation. These include high differences in speed in the liquid causing shear force, large pressure drop at the opening of the nozzle causing cavitation, and the spray against the end fixture causing high impact. Other possible preparation methods, such as emulsificati on-solvent evaporation, solvent injection, solvent emulsification-diffusion and ultrasonication/high speed homogenization (probe ultrasonication or bath ultrasonication forming acoustic cavitation and subsequent nanoparticle formation) are also considered. In addition, methods such as supercritical fluid, micro-emulsion based, spray drying, double emulsion, precipitation techniques, and film-ultrasound dispersion are considered.

For parenteral application, SNL's have good physical stability, protection of incorporated API from degradation and controlled API release, either fast or sustained, depending on the design, good tolerability and site-specific targeting. SLNs can be easily scaled-up and manufactured at a low cost compared with other phospholipid and biodegradable polymers. Drug loading capacity of SLNs is approximately 25% by volume of the lipid matrix based on the solubility of the API in the lipid melt, the structure of the lipid matrix and the polymorphic state of the lipid matrix. One example incorporating SLNs as a drug delivery system targeting the brain is with doxorubicin as an API. The pharmacokinetics of doxorubicin in SLNs has been shown to have blood concentrations that are markedly higher than the commercial drug alone with a

significantly different drug distribution. Moreover, the drug was found to be present in the brain in significant amounts (Zara GP, Cavalli R., Fundaro A., Bargoni A., Caputo O., Gasco MR,

Pharmacokinetics of doxorubicin incorporated in solid lipid nanoparticles (SLN). Pharmacol Res 1999: 40: 281-286.)

Further, SLNs have been used to target the central nervous system using other API's such as antipsychotics, anti-Parkinson, and antibiotics for brain targeting. Surface-modified SLN have been demonstrated in the treatment of brain disease such as cerebral malaria.

When using hot or cold HPH, the lipid is heated to approximately 5°C to 10°C above its melting point, then the API is dissolved in the melt. For the hot HPH technique (see Figure 3) the API containing molten lipid is placed into a hot aqueous surfactant solution and stirred to obtain a good dispersion. The pre-emulsion is homogenized using a piston-gap homogenizer and the hot nanoemulsion is then cooled down to room temperature so that the lipid can crystalize again forming SLN particles or further disrupting droplets to form cavitations which allow for incorporation of the API. Crystallization can also be initiated at lower temperatures or by lyophilization. Cold homogenization techniques (see Figure 4) are employed with highly temperature-sensitive API's or very hydrophilic API's. Both hot and cold HPH exclude the use of organic solvents, which could deactivate the API or produce undesired effects in the body.

Still another preparation of SLNs is by a microemulsion technique. Here, a mixture of water, surfactant (phospholipids) and co-surfactant (short-chain fatty acids) is heated to the lipid melting temperature and added under gentle stirring to the lipid melt. The compounds must be mixed in the correct ratio to provide a clear stable system for microemulsion formation. The microemulation is then dispersed in a cold aqueous medium about 2°C to 3°C under mild mechanical mixing, resulting in precipitated spherical particles having diameters of 70 to 200 nm.

SLNs can be further modified to achieve long circulation times. SLNs surface can be modified by hydrophilic polymers or copolymers. In one non-limiting example, polyethylene glycol (PEG) is used as a non-biodegradable, non-ionic surfactant. PEG is also useful as an excipient and/or as a nonionic surfactant, or anionic surfactant. Other non-ionic surfactants include alkyl ethers and alkyl esters. SNLs, loaded with resveratrol and modified by PEG2000 exhibited high drug loading, steady nanoparticle size distributions, photostability and sustained release compared to SNLs lacking PEG2000 Because of their prolonged circulation time and good biocompatibility with blood components and other tissues and high toxicological acceptance, a parenteral formulation that incorporates SLNs which is capable of targeting the brain or sites in the peripheral nervous system with an API containing CBD and with the potential of successful regulatory clearance provides for a sustainable platform in treating epilepsy and other convulsive disorders in a subject. Example 2: Preparation of SLNs

Two forms of SLNs are considered in the present invention. SLN containing a coating of PEG and an SLNs without the protective agent.

In one embodiment, SLNs are prepared from a warm oil-in-water (o/w) microemulsion containing stearic acid (0.70mM), Epikuron 200 (0.20mM) as a surfactant, taurocholate sodium salt as a co-surfactant (0.68mM), and filtered water (11 l . lOmM) as a continuous phase. An optimal amount of API is then added. A molar ratio of Hexadecylphosphate is used as a counter ion. SLNs are obtained by dispersing the warm microemulsion (about 70°C) in cold distilled water at an optimum ratio of microemulsion to cold, distilled water under mechanical stirring. The dispersion is washed three times with distilled water and then concentrated to an optimum ratio by diaultrafiltration with a TCF2 system (Amicon, Danvers, USA).

To prepare SLNs with a protective coating, stearic acid-PEG such as, but not limited to, PEG 2000 is added to melted stearic acid in an optimal amount (approximately 0.15% of the complete microemulsion).

The SLNs can then be characterized by photon correlation spectroscopy to determine the average diameters and poly dispersity indices using an N4 MD instrument (Coulter) at a fixed angle of 90° and a temperature of 25°C. The amount of API incorporated into an SLN is determined by spectrophotometry using a Lambda 2 spectrophotometer (Perkin Elmer). Stability of SLN nanoparticles is generally more than 1 year Another embodiment of the present invention and a more recent formulation utilizes nanostructured lipid carriers ( LC) in the formulation of API's. LCs are designed to improve certain characteristics found with using SLNs such as increasing the payload and preventing drug expulsion. Accordingly, one embodiment incorporates the use of spatially different lipids such as, but not limited to, a mixture of glycerides composed of different fatty acids to create large distances between fatty acid chains of the glycerides and general imperfections in the crystal and thus improving the room for a higher API load. The higher API loads are achieved by mixing solid lipids with small amounts of liquid (oils).

A further embodiment of the present invention is the addition of even higher amounts of oil mixed with the solid-lipid to produce a different type of nanostructure with the target API. Here, the solubility of the oil molecules in the solid lipid leads to phase separation and the formation of oily nanocompartments within the solid-lipid matrix. API's with a higher solubility in oils than in solid-lipids can be dissolved in the oil and still be protected from degradation by the surrounding solid-lipids. The particles are solid with many of the problems associated with crystallization upon cooling avoided.

A still further embodiment of the present invention is the utilization of a Lipid Drug

Conjugate (LDC). While SLNs are useful for the incorporation of most lipophilic APIs due to partitioning effects during the production process, only highly potent hydrophilic APIs which are effective in low concentrations can be firmly incorporated in the solid-lipid matrix. In order to overcome this limitation, LDC nanoparticles with approximately 33% loading capacities have been developed. An insoluble API-lipid conjugate bulk is prepared either by salt formation with a fatty acid or by covalent linking to esters or ethers. For salt formation, the free API base and fatty acid are dissolved in a suitable solvent. The solvent is then evaporated under reduced pressure. For the covalent linking, the API and a fatty alcohol react in the presence of a catalyst and the LDC bulk is then purified by recrystallization. The obtained LDC bulk is then processed with an aqueous surfactant solution to a nanoparticle formulation using high pressure

homogenization (HPH).

SLNs, NLCs and LDCs can all be optimized as a carrier system for CBD to allow a high loading capacity of APIs as well as long-term stability and incorporation. Table 1 shows several drugs in different pharmacological groups as examples of API's incorporated into SLNs for parenteral application. SLNs delivery of API's with neurologic targets are shown in Table 2. With a particle size below Ι μιη, SLN formulations are useful in systemic delivery with minimal risk of blood clotting and aggregation leading to embolism. SLNs provide a sustained release depot of API when administered subcutaneously. The API is then gradually released by erosion or enzyme degradation or by diffusion from the particles. The particle size of an intravenously administered API must be below 5μιη to avoid blocking of fine capillaries leading to an embolism.

Table 1

Pharmacological Group Drugs

Anticancer Drugs Camptothecin; Etoposide; Paclitaxel;

Docetaxel; Vinorelbine; Vinpocetine;

Doxorubicin; Idarubicin; Adriamycin;

Mitoxantrone; Methotrexate, 5-Fluorouracil; Oxaliplatin, Tamoxifen, Ubidecarenone; Cholesteruyl Butyrate; Chlorambucil;

Temozolomide; B-elements; Podephyllotoxin; All transretinoic acid

Cardiovascular Drugs Verapamil; Nifedipine, Nitrendipine;

Hormonal Drugs Hydrocortisone; Cortisone; Prednisolone;

Deoxycorticosterone; Progesterone; Estradiol; Mifepristone; Betamethasone; Sildenafil Citrate; Insulin

Vitamins Vitamin- A; Vitamin-B; Vitamin-K; Ascorbyl

Palmitate, Retinol

NSAIDS Ibuprofen; Flurbiprofen; Diclofenacl;

Nimesulide; Naproxen; Ketorolac

Antifungal Drugs Ketoconazole; Miconazole; Itraconazole;

Econazole; Terbinafine; Amphotericin

Antibacterial Drugs Ciprofloxacin; Tobramycin; Clotrimazole

Antiviral Drugs Aciclovir; saquinavir; Penciclovir; Adefocir;

Dipivoxil; Thymopentin; 3-Azida-3- deoxyruidine; Oxymetrine; Quinine;

Choloroquine

Table 2

Drugs acting on the Nervous System Drugs

Anxiety and Epilepsy Diazepam; Oxazepam; Carbamazepine

Antipsychotic Drugs Clozapin; Olanzapin

Parkinson's disease Drugs Piribedil

Immunosupressant Drugs Cuclosporin; Tacrolimus

 The present invention considers the use of nanoemulsions as a parenteral delivery means of CBD. Nanoemulsions are kinetically stable liquid-in-liquid dispersions with droplet sizes, approximately lOnm to lOOnm. A nanoemulsion is an emulsion which is formed by the application of shear to a mixture of oil, water and surfactant. They are thermodynamically stable systems in which two immiscible liquids (water and oil) are mixed to form a single phase by using the appropriate surfactant.

Nanoemulsions have the benefit of appearing translucent/transparent as a result of their small size. Also, nanoemulsions have the benefit of having a high interfacial area to volume ratio which can aid in the dissolution of a poorly soluble API and aid the rapid digestion of the emulsion by faster rates of lipolysis. Furthermore, nanoemulsions retain their structure (small size) upon dilution and/or acidification. This may have the added benefit of aiding active adsorption as it is currently thought that emulsions below lOOnm have a greater ability to penetrate epithelial layers such as the skin and oral mucosa.

The nature of the oil contained within the nanoemulsion is also important. It is advantageous to have an oil that is a triglyceride as they present a lower toxicological and/or irrigational profile to humans than synthetic or hydrocarbon oils. There are three classes of triglycerides, short chain triglycerides (less than 6 carbons in fatty acid chain), medium chain triglycerides (6 to 12 carbons in fatty acid chain) and long chain triglycerides (greater than 12 carbons in fatty acid chain). It is advantageous if the triglyceride oil within a nanoemulsion is of a long chain format, with preferably some degree of unsaturation as these oils have been shown to provide positive nutritional benefits.

The creation of nanoemulsions using medium chain triglycerides, especially miglyol, is known. Medium chain triglycerides are used as their smaller molecular bulk and higher solubility in water aids their ability to form nanoemulsions. There are two types of nanoemulsions useful in parenteral delivery. Oil-in-water is a nanoemulsion wherein oil droplets are dispersed in the continuous aqueous phase while water-in- oil nanoemulsions have water droplets dispersed in the continuous oil phase. In both, the interface is stabilized by an appropriate combination of surfactants and co-surfactants.

17 Parenteral delivery of API's using nanoemulsions have been used in nutrition with the delivery of fats, carbohydrates, or vitamins. Because of their fine particle size they are cleared more slowly than more coarse particles and therefore have longer time periods in the body.

A parenteral formulation of an API using a nanoemulsion is considered in the present invention and provides another platform for the administration of CBD in epilepsy.

A still further embodiment of the present invention considers the use of nonionic surfactant vesicular systems such as, but not limited to, niosomes. Niosomes are nonionic surfactant vesicular drug delivery systems which have a concentric bilayer of amphiphilic molecules surrounding an aqueous compartment. They are useful for drug delivery of both hydrophobic drugs, which associate with the lipid bilayer and hydrophilic drugs which are encapsulated in the interior aqueous compartment. When the composition of the concentric bilayer is optimized for CBD, niosomes are applicable, in part, in co-medication of convulsive disorders where CBD is used in conjunction with an anti-epileptic drug as described herein.

Niosomes are vesicles made of nonionic surfactants (such as alkyl ethers and alkyl esters) and cholesterol. They are used to improve the solubility of poorly soluble drugs, like CBD. These vesicles have a low toxicity. There physical properties are determined by the manufacturing parameters, nature of the surfactant, temperature at which the lipids are hydrated and the critical packing parameters all of which allow sustained and controlled CBD delivery for prolonged periods of time. Syringes and Rescue Injectors

Parenteral injection by syringe, auto-injector, ampule, pre-filled syringe, etc. offers multiple administration routes available in a clinical setting, such as intravenous, subcutaneous or intramuscular administration. A syringe or other parenteral injection means containing the formulation is used in a format typically accepted by the medical community, which is carried out by trained medical personnel. In certain instances, the subject requiring an injection can be trained in the use of the syringe to allow for self-injection. In addition, API's can be formulated in pre-filled syringes for direct administration by the subject or professional medical personnel which avoids the need for the subject or medical personnel to fill the syringe.

18 While the present invention considers all modes of parenteral administration known in the art, one embodiment which is useful as an auto-injector rescue at the point-of-care incorporates a parenteral administration through an auto-injector.

Automatic injection devices offer an alternative to a syringe for delivering a therapeutic agent. Automatic injection devices have been used, for example, to deliver medications under emergency conditions, such as the administration of epinephrine to counteract the effects of a severe allergic reaction. Automatic injection devices also have been described for use in administering antiarrhythmic medications and selective thrombolytic agents during a heart attack (US 3,910,260; 4,004,577; 4,689,042; 4,755,169 and 4,795,433). Various types of automatic injection devices also are described in, for example, US 3,941, 130; 4,261,358; 5,085,642;

5,092,843; 5, 102,393; 5,267,963; 6, 149,626; 6,270,479; and 6,371,939.

These automatic injection devices act to cause the needle of a syringe to move forward and project from a protective housing prior to actuation of the syringe to eject a dose of liquid through the needle. They are easily stored and available to immediate use. A stable formulation containing the API described herein allows for long term storage with immediate and rapid administration of a formulated API when needed.

Implant Delivery Systems

Another embodiment of the present invention considers a reservoir-based system for CBD delivery and provides a way to deliver the API formulation containing CBD to a subject using passive or active mechanisms. All dermal and implantable systems known in the art are considered in the present invention. Passive systems utilize diffusion, osmotic potential, or concentration gradients as their driving forces, while active systems include mechanical pumping, electrolysis, and other actuation methods.

Provided herein is a further means for delivering a formulated API containing CBD to its target tissue or brain in a subject. The method includes the step of implanting an implant in a target tissue and in a manner sufficient to deliver a therapeutically effective amount of API into the circulating blood, wherein the implanted implant includes the API in a therapeutically effective quantity with or without a nanoparticle formulation as disclosed herein. The subject must be diagnosed as having or being predisposed to having seizures or epilepsy. In certain

19 cases, the implanted tissue comprises breast, prostate, uterine, brain, skin, ovarian, gastrointestinal, bladder, muscle, liver, kidney or pancreatic tissue, but any appropriate tissue is considered which optimizes the blood levels of CBD for a sustained therapeutic effect.

This delivery method eliminates the need for repetitive administration of a CBD formulation in situations where a depot source of CBD is needed for therapeutically effective blood levels over an extended period.

Auto-Injection Rescue

The present invention considers the use of the disclosed formulation as an emergency treatment for a life-threatening epileptic seizure caused by an unknown trigger, along with mild and severe forms or where a seizure is actively occurring and a response is urgently required. The unknown trigger may be in the form of an aura which is followed by the seizure itself. Patients respond to the presence of the aura by using a self-injecting rescue or contacting emergency care personnel who will administer an auto-injection dose. A one-time, parenteral injection of a formulation that has a single, rapid release of a therapeutically effective amount of CBD into the circulation to reduce the immediate seizure episode and stabilize the individual for later medical care.

While all known formulations for the rapid release into the circulation are considered, one consideration is to formulate the nanoparticles to deliver a burst API release. The particle size affects API release rate. Composition of nanoparticle formulation such as surfactant/surfactant mixture, amount of drug incorporated, structural properties of lipid and drug, production methods and conditions such as time, production temperature, equipment, sterilization and lyophilization are all considered in designing the release profile of the API. Additionally, surface modifiers to reduce phagocytic uptake such as polyethylene oxide and PEG will change the particle size and dosage level. The release of the API from nanoparticles in a burst effect is inversely related to the partition coefficient. A burst release for SLN nanoparticles containing API has been reported to show up to 100% of tetracaine and etomidate released in less than 1 minute. By optimizing the surface area of the nanoparticles and lipid matrix, the release of the API can be modified to control the

20 burst. For example, any modification that increases the amount API in the shell as the nanoparticle core begins to solidify will improve the burst release of the API.

Intramuscular Depot

Similar to the auto-injector rescue, an intramuscular formulation for release can be used to prolong and maintain therapeutic CBD levels. A prolonged release can be achieved by optimizing the SLN nanoparticles, specifically their lipid matrix.

In contrast to the formulations for rapid release or having a burst effect in the auto-injection rescue, the design of the SLN nanoparticles can be modified to delay the release of the API and thereby maintain therapeutically effective blood circulation levels. Slow API release can be achieved when the API is homogenously dispersed in the lipid matrix. One approach for obtaining this release is to create an API-enriched core which occurs with a more rapid precipitation of the API than the lipid during cooling.

NLC nanoparticles are more easily optimized for controlled release than other types of nanoparticles as the oil content of the particles have a high loading capacity. The imperfect and amorphous nature of NLC nanoparticles provide much more flexibility to achieve the desire prolonged release.

CBD in Combination with Anti-Epileptic Drugs

The present invention further considers the use of formulated parenteral administration of CBD in combination with one or more other anti-epileptic drugs (AED). When used in combination with another AED, the CBD may be formulated for administration separately, sequentially or simultaneously with one or more AED or the combination may be provided in a single dose.

The combination of CBD co-administered in a pharmaceutical formulation with commonly used anti-epileptic drugs (AEDs) has been reported to result in the increase serum levels of several AEDs such as topiramate, rufinamide, and N-desmethylclobazam and decreases levels of clobazam with increasing levels of CBD dose. Increases in serum levels of zonisamide and eslicarbazepine with increasing CBD dose was also seen in adult patients. Other than clobazam and desmethylclobazam all were within the accepted therapeutic range.

21 Accordingly, the administration of CBD as disclosed herein should be monitored with any coadministration of AED.

The CBD formulation, method of use and manufacture as disclosed herein will have tremendous benefits for treating epilepsy and other convulsive disorders, reducing the cost of long-term treatment, providing an immediate rescue for seizure episodes, and offering a non- psychoactive alternative and/or as an adjunct therapy with current treatment regimens.

The methods, formulations, and manufacture illustrated herein may suitably be practiced in the absence of several element or elements, limitation or limitations, not specifically disclosed herein. The terms and expressions used herein have been used as terms of description and not of limitation, and there is no intention in the use of such terms of excluding any equivalents of the features shown and described or portions thereof. It is recognized that various modifications are possible within the scope of the invention claimed. Thus, it should be understood that although the present invention has been specifically disclosed by preferred embodiments and other features, modifications and variations of the invention embodied therein disclosed may be used by those skilled in the art, and that such modifications and variations are considered to be within the scope of the invention.

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Claims

1. A sterile parenteral formulation for treating a convulsive disorder comprising:

a. an API having at least cannabidiol as an active component in pharmaceutically acceptable salts or solvates; and

b. stable and adjustable nano-sized carrier containing a therapeutically effective amount of API wherein the parenteral delivery of the formulation is effective in treating epilepsy.

2. The formulation of claim 1 wherein the cannabidiol is a highly-enriched plant extract or synthetic compound.

3. The formulation in claim 1 wherein the cannabidiol is selected from a group consisting of a synthetic cannabidiol, an analog of cannabidiol, a derivative of cannabidiol, and

combinations thereof.

4. The formulation of claim 1 wherein the nano-sized carriers are nanoparticles.

5. The formulation of claim 4 wherein the nanoparticles are solid lipid nanoparticles.

6. The formulation of claim 1 wherein the solid lipid nanoparticles are coated with at least one polymer.

7. The formulation of claim 6 wherein the polymer is PEG or HPMA.

8. The formulation of claim 6 wherein the polymer is PEG 400 or PEG 2000.

9. The formulation of claim 6 wherein the solid lipid nanoparticles are coated with PEG 400 and propylene glycol as co-polymers.

10. The formulation of claim 1 wherein the nano-sized carriers are nanostructured lipid carriers.

11. The formulation of claim 10 wherein the nanostructured lipid carriers are coated with at least one polymer.

12. The formulation of claim 11 wherein the polymer is PEG or HPMA.

13. The formulation of claim 11 wherein the polymer is PEG 400 or PEG 2000.

14. The formulation of claim 11 wherein the nanostructured lipid carriers are coated with PEG 400 and propylene glycol as co-polymers.

15. The formulation of claim 1 wherein the nano-sized carriers are lipid drug conjugates.

16. The formulation of claim 15 wherein the lipid drug conjugates are coated with at least one polymer.

17. The formulation of claim 16 wherein the polymer is PEG or HPMA.

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18. The formulation of claim 16 wherein the polymer is PEG 400 or PEG 2000.

19. The formulation of claim 16 wherein the lipid drug conjugates are coated with PEG 400 and propylene glycol as co-polymers.

20. The formulation of claim 1 wherein the nano-sized carrier is a niosome.

21. The formulation of claim 1 wherein the convulsive disorder is epilepsy.

22. A method for treating a subject having a convulsive disorder comprising a parenteral

administration of a therapeutically effective formulation comprising

i. an API having at least cannabidiol as an active component in

pharmaceutically acceptable salts or solvates; and

ii. stable and adjustable nano-sized carriers containing a therapeutically

effective amount of API

wherein the therapeutically effective formulation reduces the seizure episodes in the epileptic subject.

23. The method of claim 22 wherein the cannabidiol is a highly-enriched plant extract or

synthetic compound.

24. The method of claim 22 wherein the cannabidiol is selected from a group consisting of a synthetic cannabidiol, an analog of cannabidiol, a derivative of cannabidiol, and

combinations thereof.

25. The method of claim 22 wherein the nano-sized carriers are solid lipid nanoparticles.

26. The method of claim 25 wherein the solid lipid nanoparticles are coated with at least one polymer.

27. The method of claim 26 wherein the polymer is PEG or HPMA.

28. The method of claim 27 wherein the polymer is PEG 400 or PEG 2000.

29. The method of claim 26 wherein the solid lipid nanoparticles are coated with PEG 400 and propylene glycol as co-polymers.

30. The method of claim 22 wherein the nano-sized carriers are nanostmctured lipid carriers.

31. The method of claim 30 wherein the nanostmctured lipid carriers are coated with at least one polymer.

32. The method of claim 31 wherein the polymer is PEG or HPMA.

33. The method of claim 31 wherein the polymer is PEG 400 or PEG 2000.

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34. The method of claim 31 wherein the nanostructured lipid carriers are coated with PEG 400 and propylene glycol as co-polymers.

35. The method of claim 22 wherein the nano-sized carriers are lipid drug conjugates.

36. The method of claim 32 wherein the lipid drug conjugates are coated with at least one

polymer.

37. The method of claim 33 wherein the polymer is PEG or HPMA.

38. The method of claim 33 wherein the polymer is PEG 400.

39. The method of claim 33 wherein the lipid drug conjugates are coated with PEG 400 and propylene glycol as co-polymers.

40. The method of claim 22 wherein the nano-sized carrier is a noisome.

41. The method of claim 22 wherein the convulsive disorder is epilepsy.

42. The method of claim 22 wherein the administration is intermuscular.

43. The method of claim 22 wherein the administration is an injection device.

44. The method of claim 43 wherein the injection device is an auto-injector.

45. The method of claim 22 wherein the administration is an implant delivery system.

46. The method of claim 45 wherein the implant delivery system is active.

47. The method of claim 45 wherein the implant delivery system is passive.

48. A method for the manufacture of a parenteral nanoparticle formulation containing

cannabidiol for use in treating epilepsy comprising:

a. obtaining an API having cannabidiol as at least one active component wherein the cannabidiol is a highly-enriched extract or synthetic compound in a therapeutically effective amount; and

b. forming a nanoparticle comprising:

i. adding the API in a melted lipid;

ii. combining (i) with a hot aqueous surfactant solution;

iii. stirring to obtain a good dispersion;

iv. homogenizing with a piston-gap homogenizer; and

v. cooling to room temperature wherein the cooling forms the nanoparticles.

49. The method of claim 48 wherein the nanoparticle is selected from a group consisting of SLN, NLC, and LDC.

50. The method of claim 49 further adding at least one polymer.

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51. The method of claim 50 where the polymer is PEG.

52. The method of claim 50 where the polymer is PEG 400 or PEG 2000.

53. The method of claim 50 where the polymers are PEG 400 and propylene glycol as copolymers

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