Exhibit 1007
`
`Coalition For Affordable Drugs XI LLC
`Exhibit 1007
`Coalition For Affordable Drugs XI LLC v Insys Pharma, Inc.
`IPR2015-01799
`
`

`
`(12) United States Patent
`Whittle
`
`(10) Patent N0.:
`(45) Date of Patent:
`
`US 6,946,150 B2
`Sep. 20, 2005
`
`US006946l50B2
`
`(54) PHARMACEUTICAL FORNIULATION
`
`6,713,048 B2 ’*
`2002/0136752 A1 *
`
`................. .. 424/45
`3/2004 Peart et al.
`9/2002 Whittle et al.
`............ .. 424/435
`
`(75)
`
`Inventor: Brian Whittle, East Yorkshire (GB)
`
`FOREIGN PATENT DOCUMENTS
`
`(73) Assignee: GW Pharma Limited, Wiltshire (GB)
`
`(313
`WO
`
`2361869
`WO—200232420
`
`4 11/2001
`*
`4/2002
`
`( * ) Notice:
`
`Subject to any disclaimer, the term of this
`patent is extended or adjusted under 35
`U'S'C' 154(b) by 2 days:
`
`(21) Appl. No.: 10/218,989
`
`*
`
`.
`. d b
`Y exammer
`Cue
`Primary Exczminer—A ton Pryor
`(74) Attorney, Agent, or Firm—Wolf, Greenfield & Sacks,
`RC,
`
`(22) Filed:
`
`Aug. 14, 2002
`
`(57)
`
`ABSTRACT
`
`(.65)
`
`Prior Publication Data
`Us 2004/10034108/(1 Feb. 19, 2004
`
`Int Cl-7 ....................... .. A01N 55/00; A61K 35/78
`(51)
`(52) U.S. Cl.
`...................................... .. 424/725; 424/435
`(58) Field of Search ............................... .. 424/725, 435,
`424/434, 449, 443, 447
`
`(56)
`
`References Cited
`U.S. PATENT DOCUMENTS
`
`The invention relates to pharmaceutical formulations, and
`more particularly to formulations containing cannabinoids
`for administration via a pump action spray. In particular, the
`invention relates to pharmaceutical formulations, for use in
`administration of lipophilic medicaments via mucosal
`surfaces, comprising: at least one lipophilic medicament, a
`solvent and a co-solvent, wherein the total amount of solvent
`and co-solvent present in the formulation is greater than
`55% Wt/Wt of the formulation and the formulation is absent
`of a self emulsifying agent and/or a fluorinated propellant.
`
`0,503,532 B1 *
`
`1/2003 Murty et al.
`
`.............. .. 424/449
`
`26 Claims, 9 Drawing Sheets
`
`

`
`U.S. Patent
`
`Sep. 20, 2005
`
`Sheet 1 of 9
`
`US 6,946,150 B2
`
`GWPD9901: Mean Canobinuid Concumutians,
`CEME High THC
`
`-0-CED -I-THC -o-11-Hydmy THC
`
`CBMEHighCBD
`GWPO9901: Mean Canabinoid Concen!rah'ons,
`
`Fi3.‘Q
`
`F (9 . ‘L
`
`‘
`
`'
`
`LI
`
`1.51.4J11 _
`
`I
`
`0.:
`
`0.0
`
`n_4
`12
`
`0
`
`0
`
`1%
`
`I
`
`1
`
`700
`
`III
`
`-0-030 -D—‘I'Hc—o-114-OydmzyTHC
`
`100
`
`am
`
`4M
`
`SM
`
`600
`
`

`
`U.S. Patent
`
`Sep. 20, 2005
`
`Sheet 2 of 9
`
`US 6,946,150 B2
`
`GWPDSQO1: Mean Canabinoid Concentrations
`
`CBME THC:CflJ. 131 P455
`
`(ng.mr')OCNIdE(IQHD
`Conoonlrotion
`
`GWPDSBO1: Mean Canabinoid Concentrations,
`
`Placebo
`
`
`
`.°:3C
`
`
`
`Concanhhbn(ng.mr‘}.9.6o3BB
`
`

`
`U.S. Patent
`
`Sep. 20, 2005
`
`Sheet 3 of 9
`
`US 6,946,150 B2
`
`
`
`.5950mzm._>._oEe.
`
`o.‘
`
`C C
`
`D
`<1-
`
`amaW...
`
`..._u.013
`
`1:.mm
`3WSSds
`
`
`
`
`
`..m_EE._s._oz<Ema..z..5950wzudEom._
`
`
`
`.\.2,9.5......omo._m<“.0«mm...._<zo_.5ma«menu
`
`
`
`
`
`

`
`U.S. Patent
`
`Sep. 20, 2005
`
`Sheet 4 of 9
`
`US 6,946,150 B2
`
`
`
`
`
` ._oo>._um_,_m._>._oE2>.\.88
`
`
`
`._oo>.6mzm._>..om._nozo:.ozE<2Emooms
`
`
`
`._oz<:h..:oo>._amzm..>.__oE2.Empzoo
`
`mm.=:.x_=
`
`(spuooas ug mug um)
`
`LLISOOSIA anmnau
`
`
`
`
`

`
`U.S. Patent
`
`Sep. 20, 2005
`
`Sheet 5 of 9
`
`US 6,946,150 B2
`
`
`mumaiz._oz<=.Ea._mo".
`
`
`
`
`t_ooom_>2,«mm...._<zo_Smm«memom::._._._omo¢u<
`
`
`
`
`
`
`
`Emoom_>u>:<._m¢
`
`'1VNO|.LO3S S8083 3|NlTld
`
`
`
`

`
`U.S. Patent
`
`Sep. 20, 2005
`
`Sheet 6 of 9
`
`US 6,946,150 B2
`
`

`
`U.S. Patent
`
`Sep. 20, 2005
`
`Sheet 7 of 9
`
`US 6,946,150 B2
`
`

`
`U.S. Patent
`
`Sep. 20, 2005
`
`Sheet 8 of 9
`
`US 6,946,150 B2
`
`

`
`U.S. Patent
`
`Sep. 20, 2005
`
`Sheet 9 of 9
`
`US 6,946,150 B2
`
`
`
`.zo_._.<n<moma._<u_:u:
`
`993.02
`
`080 %
`
`

`
`US 6,946,150 B2
`
`1
`PHARMACEUTICAL FORMULATION
`
`FIELD OF THE INVENTION
`
`invention relates to pharmaceutical
`The present
`formulations, and more particularly to formulations contain-
`ing cannabinoids for administration via a pump action spray.
`BACKGROUND OF THE INVENTION
`
`It has long been known to introduce drugs into the
`systemic circulation system via a contiguous mucous mem-
`brane to increase onset of activity, potency etc.
`For example, U.S. Pat. No. 3,560,625 disclose aerosol
`formulations for introducing an alkoxybenzamide into the
`systemic circulatory system. Two different types of aerosol
`formulations are disclosed:
`
`a) fluorinated hydrocarbon type comprising 2% by weight
`alkoxybenzamide, 18% ethanol, and 80% propellant; and
`b) nebuliser
`type comprising 0.5% by weight
`alkoxybenzamide, a mixed solvent system comprising
`10.3% ethanol and 31.4% propylene glycol and 57.8%
`deionised water.
`
`U.S. Pat. No. 3,560,625 identifies a problem in finding a
`suitable solvent system to produce an aerosol spray for
`inhalation of thc ortho-cthoxybcnzamidc, due to the fact that
`whilst ethanol was undoubtedly the best solvent, a mixture
`containing more than 18% of ethanol by weight produced an
`unpleasant oral reaction which more than counterbalanced
`the efficacy of the oral route.
`to produce spray
`When the present applicant set out
`formulations for a botanical drug substance comprising one
`or more cannabinoids they were aware that
`the highly
`lipophylic nature of the cannabinoids could present prob-
`lems in formulating the active component(s).
`The present applicant first sought to develop a formula-
`tion for oromucosal, preferably sublingual, delivery in a
`pressurised aerosol or spray form, as disclosed in interna-
`tional patent application PCT/GB01/01027. Their initial
`focus was on propellant driven systems with HFC-123a and
`HFC-227 but these proved to be unsuitable as solvents for
`the cannabinoids. The formulations comprised synthetic
`A9-THC in amounts from 0.164 to 0.7% wt/wt, with ethanol
`as the primary solvent in amounts up to 20.51% by weight.
`One particular composition comprised 0.164% synthetic
`A9-THC, 4.992% ethanol, 4.992% propylene glycol and
`89.582% p134a (propellant).
`The applicant found that even at ethanol levels of 20% by
`volume of the total formulation volume they were unable to
`dissolve sufficient levels of A9-THC in a standard spray dose
`to meet clinical needs, because of the cannabinoids poor
`solubility in the propellant. They also found that the ethanol
`level could not be increased, as the delivery characteristics
`of the device nozzle altered substantially when the lower
`volatility solvents were increased above a critical ratio. The
`HFC-123a and HFC-227 propellant sprays delivered a maxi-
`mum of 7 mg/ml, whereas initial clinical studies suggested
`the formulations would be required to contain up to 50 mg
`cannabinoids/ml.
`Thus, the present applicants focussed on self-emulsifying
`drug delivery systems, as are discussed in detail in a review
`article European Journal of Pharmaceutics and Biopl1arn1a-
`ceutics 50 (2000) 179-188, which concluded that the poor
`aqueous solubility of many chemical entities represents a
`real challenge for the design of appropriate formulations
`aimed at enhancing oral bioavailability.
`In their co-pending International application PCT/GB02/
`00620 the applicant discloses a wide range of cannabinoid-
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`least one self-
`containing formulations containing at
`least one self-
`emulsifying agent. The inclusion of at
`emulsifying agent was thought necessary to get
`the
`formulation to adhere to the mucosal surface in order to
`achieve sufficient absorption of the cannabinoids. One par-
`ticular formulation comprised 2% by wt glycerol mono-
`oleate, 5% CBME of G1 cannabis to give THC, 5% CBME
`of G5 cannabis to give CBD, 44% ethanol BP and 44%
`propylene glycol.
`
`SUMMARY OF THE INVENTION
`
`Surprisingly, the applicant has found that they do not
`absolutely require the presence of a self-emulsifying agent
`in a liquid formulation to achieve a satisfactory dosage level
`by oromucosal, and specifically sub-lingual or buccal, appli-
`cation.
`
`Indeed, contrary to the teachings of U.S. Pat. No. 3,560,
`625 and the European Journal of Pharmaceutics and Biop-
`harmaceutics 50 (2000) 179-188, they have been able to
`produce a simple and effective vehicle for delivering a
`lipophilic medicament in a liquid spray.
`According to a specific aspect of the present invention
`there is provided a pharmaceutical formulation consisting
`essentially of one or more cannabinoids, ethanol and pro-
`pylene glycol.
`Preferably the one or more cannabinoids are present in the
`form of at least one extract from at least one cannabis plant.
`The cannabis plant(s) preferably include at least one can-
`nabis chemovar. Most preferably the plant extract will be a
`botanical drug substance (BDS), as defined herein.
`Optionally,
`the formulation may additionally contain a
`flavour, such as, for example, peppermint oil.
`The formulation may also contain, in addition to the
`cannabinoid(s), a further active agent, which is preferably an
`opiate, for example morphine. Thus, it is contemplated to
`provide a formulation consisting essentially of one or more
`cannabinoids, ethanol, propylene glycol and an opiate, pref-
`erably morphine.
`A typical liquid pharmaceutical formulation according to
`this specific aspect of the invention, given by way of
`example and not intended to be limiting to the invention,
`may contain in a 1 ml vol: THC 25-50 mg/ml, preferably 25
`mg/ml (based on amount of cannabinoid in a botanical drug
`substance), CBD 25-50 mg/ml, preferably 25 mg/ml (based
`on amount of cannabinoid in a botanical drug substance),
`propylene glycol 05 ml/ml, peppermint oil 0.0005 ml/ml,
`and ethanol (anhydrous) qs to 1 ml.
`Other preferred formulations include a “high THC” for-
`mulation comprising in a 1 ml vol: THC 25 mg/ml (based on
`amount of cannabinoid in a botanical drug substance),
`propylene glycol 0.5 ml/ml, peppermint oil 0.0005 ml/ml,
`and ethanol (anhydrous) qs to 1 ml; and a “high CBD”
`formulation comprising in a 1 ml vol: CBD 25 mg/ml (based
`on amount of cannabinoid in a botanical drug substance),
`propylene glycol 05 ml/ml, peppermint oil 0.0005 ml/ml,
`and ethanol (anhydrous) qs to 1 ml.
`In these formulations the cannabinoids are added as
`botanical drug substances derived from cannabis plants,
`quoted amounts of cannabinoids correspond to total amount
`(weight) of cannabinoid present in 1 ml of the final formu-
`lation. The skilled reader will appreciate that
`the total
`amount of BDS which must be added in order to achieve the
`desired amount of cannabinoid in the final formulation will
`be dependent on the concentration of cannabinoid present in
`the BDS, which will vary between different batches of BDS.
`
`

`
`US 6,946,150 B2
`
`3
`The finding that such a simple combination of one or more
`cannabinoids, ethanol and propylene glycol can be used
`effectively in a pump action spray was unexpected.
`The applicant has found that, where the solvent/co-
`solvent system is ethanol/propylene glycol and the lipophilic
`medicament comprises one or more cannabinoids in the
`form of a botanical drug substance (BDS), the limits in
`which the solvent/co-solvent will work effectively are quite
`narrow, as discussed below.
`More broadly speaking, and according to a general aspect
`of the invention, there is provided a liquid pharmaceutical
`formulation, for use in administration of a lipophilic medi-
`cament via a mucosal surface, comprising at
`least one
`lipophilic medicament, a solvent and a co-solvent, wherein
`the total amount of solvent and co-solvent present in the
`formulation is greater than 55% wt/wt of the formulation
`and the formulation is absent of a self-emulsifying agent
`and/or a fluorinated propellant.
`Preferably the amount of solvent/co-solvent is greater
`than 80%, more preferably in the order 90-98%.
`Preferably the formulation has a water content of less than
`5%.
`
`Preferably the formulation does not contain any type of
`propellant.
`The formulation also lacks any self-emulsifying agent.
`Self-emulsifying agents are defined herein as an agent which
`will form an emulsion when presented with an alternate
`phase with a minimum energy requirement. In contrast, an
`emulsifying agent, as opposed to a self-emulsifying agent, is
`one requiring additional energy to form an emulsion. Gen-
`erally a self-emulsifying agent will be a soluble soap, a salt
`or a sulphated alcohol, especially a non-ionic surfactant or
`a quaternary compound. Exemplary self-emulsifying agents
`include, but are not limited to, glyceryl mono oleate (esp. SE
`grade), glyceryl monostearate (esp. SE grade), macrogols
`(polyethylene glycols), and polyoxyhydrogenated castor oils
`e.g. cremophor.
`The formulation may additionally comprise a flavouring.
`The preferred flavouring is peppermint oil, preferably in an
`amount by volume of up to 0.1%, typically 0.05% v/v.
`Preferably the solvent is selected from C1-C4 alcohols.
`The preferred solvent is ethanol.
`Preferably the co-solvent is a solvent which allows a
`lower amount of the “primary” solvent
`to be used. In
`combination with the “primary” solvent it should solubilise
`the lipophylic medicament sufficiently that a medically
`useful amount of the lipophylic medicament is solubilised.
`A medically useful amount will vary with the medicament,
`but for cannabinoids will be an amount of at least 1.0 mg/0.1
`ml of solvent/co-solvent.
`
`Preferred co-solvents are selected from glycols, sugar
`alcohols, carbonate esters and chlorinated hydrocarbons.
`The glycols are preferably selected from propylene glycol
`and glycerol, with propylene glycol being most preferred.
`The carbonate ester is preferably propylene carbonate.
`The most preferred combination is ethanol as the solvent
`and propylene glycol as the co-solvent.
`The preparation of liquid formulations for oropharangeal
`delivery of cannabinoids poses a number of problems. First,
`it is necessary to deliver at least 1.0 mg, more preferably at
`least 2.5 mg and even more preferably at least 5 mg of
`cannabinoids per 0.1 ml of liquid formulation to achieve a
`therapeutic effect in a unit dose. In this regard a patient may
`require up to 120 mg cannabinoid/day, on average around 40
`mg/day to be taken in a maximum of six doses.
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`4
`In the case of a sublingual or buccal delivery, this means
`delivering this quantity of the active ingredient in an amount
`of formulation which will not be swallowed by the patient,
`if the active ingredient is to be absorbed transmucosally.
`Whilst such amounts can be achieved by dissolving the
`cannabinoid in ethanol as the solvent, high concentrations of
`ethanol provoke a stinging sensation and are beyond the
`limit of tolerability.
`There is thus a need to use a co-solvent in order to reduce
`the amount of ethanol, whilst still enabling suflicient quan-
`tities of cannabinoid to be solubilised.
`
`The applicant has discovered that the choice of co-solvent
`is limited. Preferred co-solvents should have a solubilizing
`effect suflicient to allow enough cannabinoid to be solubi-
`lised in a unit dose, namely at
`least 1.0 mg/0.1 ml of
`formulation, and which allows the amount of solvent present
`to be reduced to a level which is within the limits of patient
`tolerability. Particularly suitable co-solvents which fulfil
`these criteria are propylene glycol and glycerol.
`In a preferred embodiment the total amount of solvent and
`co-solvent present in the formulation, is greater than about
`65% w/w, more preferably greater than about 70% w/w,
`more preferably greater than about 75% w/w, more prefer-
`ably greater than about 80% w/w, more preferably greater
`than about 85% w/w of the formulation. Most preferably the
`total amount of solvent and co-solvent present in the for-
`mulation is in the range from about 80% w/w to about 98%
`w/w of the formulation.
`
`In a preferred embodiment the formulations according to
`the invention are liquid formulation administered via a
`pump-action spray. Pump-action sprays are characterised in
`requiring the application of external pressure for actuation,
`for example external manual, mechanical or electrically
`initiated pressure. This is in contrast to pressurized systems,
`e.g. propellant-driven aerosol sprays, where actuation is
`typically achieved by controlled release of pressure e.g. by
`controlled opening of a valve.
`Pump-action sprays are found to be particularly beneficial
`when it comes to delivering cannabinoids. Indeed, previ-
`ously people have focussed their attention on solvent sys-
`tems including a propellant.
`Whilst it has been recognised that there are disadvantages
`with such systems, including the speed of delivery, those
`skilled in the art have tried to address this by slowing the
`propellant or by altering the nozzle. The applicants have
`found that by using a pump spray with their formulations
`they are able to produce a spray in which the particles have
`a mean aerodynamic particle size of between 15 and 45
`microns, more particularly between 20 and 40 microns and
`an average of about 33 microns. These contrast with par-
`ticles having a mean aerodynamic particle size of between 5
`and 10 microns when delivered using a pressurised system.
`In fact, comparative tests by the applicant have shown
`such a pump-action spray system to have advantages in
`being able to deliver the active components to a larger
`surface area within the target area. This is illustrated with
`reference to the accompanying Example 3.
`The variation in particle distribution and sprayed area has
`been demonstrated by direct experiment. A formulation as
`described in the accompanying Example 4 was filled into a
`pump action spray assembly (Valois vial
`type VP7100
`actuated). The same formulation was filled into a pressurised
`container powered by HFA 134a.
`Roth containers were discharged at a distance of 50 mm
`from a sheet of thin paper held at right angles to the direction
`
`

`
`US 6,946,150 B2
`
`5
`of travel of the jet. The pattern of spray produced in both
`cases by discharge of 100 yl was then visualised against the
`light. In both cases the pattern of discharge was circular and
`measurements were as follows:
`
`Pump Action Spray
`Pressurised Spray
`
`Mean Diameter (mm)
`23
`16
`
`Mean Area (mmz)
`425.5
`201.1
`
`The pressurised spray produced pooling of liquid at the
`centre of the area. The pump action spray gave a more even
`spray pattern and less “bounce back”. There was also a
`significantly greater area covered by the pump action spray.
`The conditions under which this test was carried out are
`relevant to the in-practice use of the device. Awider area of
`buccal mucosa can be reached by the pump action spray
`compared with the pressurised spray.
`For pump spray applications the solvent/co-solvent com-
`bination must have a viscosity within the viscosity range
`defined by the preferred solvent/co-solvent combination.
`Thus it should be a viscosity ranging between that for an
`ethanol/propylene glycol combination where the ethanol/
`propylene glycol are present in the relative proportions by
`Volume of 60/40 and 40/60, more preferably still 55/45 to
`45/55 and most preferably about 50/50.
`The viscosity of the resulting formulation when packaged
`for delivery by pump action through a mechanical pump
`such as, for example, a VP7 actuator valve (Valois), allows
`the resulting aerosol
`to deliver a spray having a mean
`aerodynamic particle size of from 20-40 microns, more
`preferably 25-35 and most preferably with an average
`particle size of from 30-35 microns. This maximises contact
`with the target mucosal membrane for sublingual/buccal
`delivery.
`Preferably the formulations according to the general and
`specific aspects of the invention comprises as the lipophilic
`medicament one or more cannabinoids.
`
`least one
`is at
`Preferably the lipophilic medicament
`extract from at least one cannabis plant. The cannabis
`plant(s) preferably include at least one cannabis chemovar.
`Most preferably the plant extract will be a botanical drug
`substance (BDS), as defined herein.
`A “plant extract” is an extract from a plant material as
`defined in the Guidance for Industry Botanical Drug Prod-
`ucts Draft Guidance, August 2000, US Department of Health
`and Human Services, Food and Drug Administration Center
`for Drug Evaluation and Research.
`“Plant material” is defined as a plant or plant part (e.g.
`bark, wood,
`leaves, stems, roots, flowers,
`fruits, seeds,
`berries or parts thereof) as well as exudates.
`The term “Cannabis plant(s)” encompasses wild type
`Cannabis saliva and also variants thereof, including can-
`nabis chemovars which naturally contain diiferent amounts
`of the individual cannabinoids, Cannabis sativa subspecies
`indica including the variants var.
`indica and var.
`kafiristanica, Cannabis indica and also plants which are the
`result of genetic crosses, self-crosses or hybrids thereof. The
`tcrm “Cannabis plant matcrial” is to bc intcrprctcd accord-
`ingly as encompassing plant material derived from one or
`more cannabis plants. For the avoidance of doubt
`it
`is
`hereby stated that “cannabis plant material” includes dried
`cannabis biomass.
`
`In the context of this application the terms “cannabis
`cxtract” or “extract from a cannabis plant”, which are uscd
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`interchangeably, encompass “Botanical Drug Substances”
`derived from cannabis plant material. A Botanical Drug
`Substance is defined in the Guidance for Industry Botanical
`Drug Products Draft Guidance, August 2000, US Depart-
`ment of Health and Human Services, Food and Drug Admin-
`istration Center for Drug Evaluation and Research as: “A
`drug substance derived from one or more plants, algae, or
`macroscopic fungi. It is prepared from botanical raw mate-
`rials by one or more of the following processes:
`pulverisation, decoction, expression, aqueous extraction,
`ethanolic extraction, or other similar processes.” Abotanical
`drug substance does not include a highly purified or chemi-
`cally modified substance derived from natural sources. Thus,
`in the case of cannabis, “botanical drug substances” derived
`from cannabis plants do not include highly purified, Phar-
`macopocial grade cannabinoids.
`“Cannabis based medicine extracts (CBMEs)”, such as
`the CBMEs prepared using processes described in the
`accompanying examples, are classified as “botanical drug
`substances”, according to the definition given in the Guid-
`ance for Industry Botanical Drug Products Draft Guidance,
`August 2000, US Department of Health and Human
`Services, Food and Drug Administration Center for Drug
`Evaluation and Research.
`
`“Botanical drug substances” derived from cannabis plants
`include primary extracts prepared by such processes as, for
`example, maceration, percolation, extraction with solvents
`such as C1 to C5 alcohols (e.g. ethanol), Norflurane
`(HFA134a), HFA227 and liquid carbon dioxide under sub-
`critical or super-critical conditions. The primary extract may
`be further purified for example by super-critical or sub-
`critical solvent extraction, vaporisation or chromatography.
`Whcn solvents such as those listed above are uscd,
`the
`resultant extract contains non-specific lipid-soluble material.
`This can be removed by a variety of processes including
`“winterisation”, which involves chilling to —20° C. followed
`by filtration to remove waxy ballast, extraction with liquid
`carbon dioxide and by distillation.
`In the case where the cannabinoids are provided as a BDS,
`the BDS is preferably obtained by C02 extraction, under
`sub-critical or super-critical conditions, followed by a sec-
`ondary extraction, e.g. an ethanolic precipitation, to remove
`a substantial proportion of waxes and other ballast. This is
`because the ballast
`includes wax esters and glycerides,
`unsatutrated fatty acid residues,
`terpenes, carotenes, and
`flavenoids which are not very soluble in the chosen solvent/
`co-solvent, particularly the preferred co-solvent, propylene
`glycol, and will precipitate out. Most preferably the BDS is
`produced by a process comprising decarboxylation, extrac-
`tion with liquid carbon dioxide and then a further extraction
`to remove significant amounts of ballast. Most preferably
`the ballast is substantially removed by an ethanolic precipi-
`tation.
`
`Most preferably, cannabis plant material is heated to a
`defined temperature for a defined period of time in order to
`decarboxylate cannabinoid acids to free cannabinoids prior
`to extraction of the BDS.
`
`Preferred “botanical drug substances” include those
`which are obtainable by using any of the methods or
`processes specifically disclosed herein for preparing extracts
`from cannabis plant material. The extracts are preferably
`substantially free of waxes and other non-specific lipid
`soluble material but preferably contain substantially all of
`the cannabinoids naturally present in the plant, most pref-
`erably in substantially the same ratios in which they occur in
`the intact cannabis plant.
`
`

`
`US 6,946,150 B2
`
`7
`Botanical drug substances are formulated into “Botanical
`Drug Products” which are defined in the Guidance for
`Industry Botanical Drug Products Draft Guidance, August
`2000, US Department of Health and Human Services, Food
`and Drug Administration Center for Drug Evaluation and
`Research as: “A botanical product that is intended for use as
`a drug; a drug product that is prepared from a botanical drug
`substance.”
`
`“Cannabis plants” includes wild type Cannabis sativa
`and variants thereof, including cannabis chemovars which
`naturally contain different amounts of the individual can-
`nabinoids.
`
`The term “cannabinoids” also encompasses highly
`purified, Pharniacopoeial Grade substances, wl1icl1 may be
`obtained by purification from a natural source or via syn-
`thetic means. Thus, the formulations according to the inven-
`tion may be used for delivery of extracts of cannabis plants
`and also individual cannabinoids, or synthetic analogues
`thereof, whether or not derived from cannabis plants, and
`also combinations of cannabinoids.
`
`Preferred cannabinoids include, but are not limited to,
`tetrahydrocannabinoids, their precursors, alkyl (particularly
`propyl) analogues, cannabidiols,
`their precursors, alkyl
`(particularly propyl) analogues, and cannabinol. In a pre-
`ferred embodiment
`the formulations may comprise any
`cannabinoids selected from tetrahydrocannabinol,
`A9-tetrahydrocannabinol (THC), A8-tetrahydrocannabinol,
`A9-tetrahydrocannabinol propyl analogue (THCV), canna-
`bidiol (CBD), cannabidiol propyl analogue (CBDV), can-
`nabinol (CBN), cannabichromene, cannabichromene propyl
`analogue and cannabigerol, or any combination of two or
`more of these cannabinoids. THCV and CBDV (propyl
`analogues of THC and CBD, respectively) are known can-
`nabinoids which are predominantly expressed in particular
`Cannabis plant varieties and it has been found that THCV
`has qualitative advantageous properties compared with THC
`and CBD respectively. Subjects taking THCV report that the
`mood enhancement produced by THCV is less disturbing
`than that produced by THC. It also produces a less severe
`hangover.
`Most preferably the formulations will contain THC and/or
`CBD.
`
`In a preferred embodiment the formulations may contain
`spccific, prc-dcfincd ratios by weight of different
`cannbinoids, e.g. specific ratios of CBD to THC, or tetrahy-
`drocannabinovarin (THCV) to cannabidivarin (CBDV), or
`THCV to THC. Certain specific ratios of cannabinoids have
`been found to be clinically useful
`in the treatment or
`management of specific diseases or medical conditions. In
`particular, certain of such formulations have been found to
`be particularly useful in the field of pain relief and appetite
`stimulation.
`
`It has particularly been observed by the present applicant
`that combinations of specific cannabinoids are more benefi-
`cial
`than any one of the individual cannabinoids alone.
`Preferred embodiments are those formulations in which the
`
`amount of CBD is in a greater amount by weight than the
`amount of THC. Such formulations are designated as
`“reverse-ratio” formulations and are novel and unusual
`since, in the various varieties of medicinal and recreational
`Cannabis plant available world-wide, CBD is the minor
`cannabinoid component compared to THC. In other embodi-
`ments THC and CBD or THCV and CBDV are present in
`approximately equal amounts or THC or THCV are the
`major component and may be up to 95.5% of the total
`cannabinoids prcscnt.
`
`10
`
`15
`
`20
`
`25
`
`30
`
`35
`
`40
`
`45
`
`55
`
`60
`
`65
`
`8
`Preferred formulations contain THC and CBD in defined
`ratios by weight. The most preferred formulations contain
`THC and CBD in a ratio by weight in the range from 0.9:1.1
`to 1.1:0.9 THC:CBD, even more preferably the THC:CBD
`ratio is substantially 1:1. Other preferred formulations con-
`tain the following ratios by weight of THC and CBD: greater
`than or equal to 19:1 THC:CBD, greater than or equal to
`19:1 CBD:THC, 4.5:1 THC:CBD, 1:4 THC:CBD and 122.7
`TIIC:CBD. For formulations wherein the TI IC:CBD ratio is
`
`substantially 1:1 it is preferred that the formulation includes
`about 2.5 g/ml of each of THC and CBD.
`Cannabis has been used medicinally for many years, and
`in Victorian times was a widely used component of pre-
`scription medicines. It was used as a hypnotic sedative for
`the treatment of “hysteria, delirium, epilepsy, nervous
`insomnia, migraine, pain and dysmenorrhoea”. The use of
`cannabis continued until thc middlc of the twentieth century,
`and its usefulness as a prescription medicine is now being
`re-evaluated. The discovery of specific cannabinoid recep-
`tors and new methods of administration have made it
`
`possible to extend the use of cannabis-based medicines to
`historic and novel indications.
`
`The recreational use of cannabis prompted legislation
`which resulted in the prohibition of its use. Historically,
`cannabis was regarded by many physicians as unique;
`having the ability to counteract pain resistant
`to opioid
`analgesics, in conditions such as spinal cord injury, and other
`forms of neuropathic pain including pain and spasm in
`multiple sclerosis.
`In the United States and Caribbean, cannabis grown for
`recreational use has been selected so that it contains a high
`content of tetrahydrocannabinol (THC), at the expense of
`other cannabinoids. In the Merck Index (1996) other can-
`nabinoids known to occur in cannabis such as cannabidiol
`
`and cannabinol were regarded as inactive substances.
`Although cannabidiol was formerly regarded as an inactive
`constituent there is emerging evidence that it has pharma-
`cological activity, which is different from that of THC in
`several respects. The therapeutic effects of cannabis cannot
`bc satisfactorily cxplaincd just in tcrms of onc or the othcr
`“active” constituents.
`
`It has been shown that tetrahydrocannabinol (THC) alone
`produces a lower degree of pain relief than the same quantity
`of THC given as an extract of cannabis. The pharmacologi-
`cal basis underlying this phcnomcnon has bccn investigated.
`In some cases, THC and cannabidiol (CBD) have pharma-
`cological properties of opposite effect in the same preclinical
`tests, and the same effect in others. For example, in some
`clinical studies and from anecdotal reports there is a per-
`ception that CBD modifies the psychoactive effects of THC.
`This spectrum of activity of the two cannabinoids may help
`to explain some of the therapeutic benefits of cannabis
`grown in different regions of the world. It also points to
`useful effects arising from combinations of THC and CBD.
`These have been investigated by the applicant. Table 1
`below shows the dilference in pharmacological properties of
`the two cannabinoids.
`
`Effect
`
`THC THCV CBD CBDV Reference
`
`TABLE 1
`
`CB1 (Brain
`receptors)
`CB3 (Peripheral
`receptors)
`
`++
`
`+
`
`1
`
`—
`
`Pertwee et al, 1998
`
`

`
`US 6,946,150 B2
`
`10
`The invention still further relates to pharmaceutical
`formulations, having all the essential features as defined
`above, which have specific ratios of THCV to THC. Such
`formulations have been found to be particularly useful in the
`field of pain relief and appetite stimulation.
`It has particularly been observed by the present applicants
`that the combinations of the specific cannabinoids are more
`beneficial than any one of the individual cannabinoids alone.
`Preferred embodiments are those formulations in which the
`amount of CBD is in a greater amount by weight than the
`amount of THC. Such formulations are designated as
`“reverse-ratio” formulations and are novel and unusual
`since, in the various varieties of medicinal and recreational
`Cannabis plant available world—wide, CBD is the minor
`cannabinoid component compared to THC. In other embodi-
`ments THC and CBD or THCV and CBDV are present in
`approximately equal amounts or THC or THCV are the
`major component and may be up to 95.5% of the total
`cannabinoids present.
`Particularly preferred ratios of cannabinoids and the target
`medical conditions for which they are suitable are shown in
`Table 2 below. Other preferred ratios of THC:CBD,
`THCV:CBDV and THC:TCHV and preferred therapeutic
`uses of such formulations are set out in the accompanying
`claims.
`
`TABLE 2
`
`Target Therapeutic Groups for Different Ratios of Cannabinoid
`
`Product group
`
`Ratio THC:CBD Target Therapeutic Area
`
`9
`
`TABLE 1-continued
`
`THC THCV CBD CBDV Reference
`
`——
`—
`—
`——
`++
`++
`++
`—
`+
`
`++
`+
`+