BUPRENORPHINE-CONTAINING NON-PRESSURISED SPRAY COMPOSITION
FOR TRANSMUCOSAL ADMINISTRATION
This invention relates to compositions of buprenorphine especially pump spray compositions
suitable for transmucosal, particularly sublingual, delivery.
Buprenorphine, with structure shown below, is a partial agonist of opiate receptors which is
widely used for the treatment of moderate to severe pain or in the treatment of opiate
dependence.

Buprenorphine is often described as a partial agonist (receptor stimulator)/antagonist (prevents
receptor stimulation). It has important actions on two types of opiate receptors in the brain.
Many of the most common opioid effects, such as euphoria, respiratory effects and reduced
pain sensation, are caused by stimulation of the mu receptor. Buprenorphine stimulates this
receptor, albeit at lower intensity than other opiates such as heroin or methadone. This lower
level of stimulation is of benefit clinically in people with respiratory compromise but require
opioid medication, such as the elderly.
Buprenorphine is also an antagonist of the kappa opioid receptor, which is associated with
some of the negative effects experienced in withdrawal, particularly depression. As
buprenorphine inhibits stimulation of this receptor it may produce feelings of well-being. Finally,
its disassociation from these receptors is slow, leading to a long duration of action, allowing
once daily dosing and sometimes dosing every two days, making buprenorphine a versatile
treatment option in treatment of drug addiction.
A number of presentations of buprenorphine are currently available. Low-dose sub-lingual
tablets, containing 0.2-0.4 mg of the drug as hydrochloride, are sold under the brand name
Temgesic and are normally used for analgesic purposes. Temgesic brand of buprenorphine
hydrochloride is also available as ampoules for intramuscular or slow intravenous injection. The

most common formulation of buprenorphine used for the treatment of opiate dependence is
sublingual tablets containing 0.4, 2 and 8 mg buprenorphine hydrochloride and available under
the brand name Subutex. Using a combination of tablets, doses of up to 32 mg may be
administered. These tablets are specifically intended for the treatment of problem drug use in
patients who are being maintained in medically assisted treatment; in the case of patients
undergoing withdrawal treatment, they are administered in a gradually reducing dose. Low-dose
sublingual tablets are sometimes used for the treatment of opiate dependence, in which case
multiple tablets are prescribed in order to achieve the desired dose.
A liquid formulation for sub-lingual administration is described in GB2100985 (Todd).
Specifically, this document describes formulations containing buprenorphine or a non-toxic salt
thereof, but especially buprenorphine hydrochloride, dissolved in 20-30% v/v ethanol in water
buffered to a pH of between 4.5-5.5 with 0.05-0.2 molar concentration of a buffering agent
selected from citric acid/disodium hydrogen phosphate, sodium citrate/hydrochloric acid, lactic
acid/disodium hydrogen phosphate, lactic acid/sodium lactate, sodium citrate/citric acid and
sodium acetate/acetic acid, the concentration of buprenorphine being between 0.8 and 10
mg/ml (i.e. around 0.08-1.0% w/v) of the composition. The Examples relate to buprenorphine
hydrochloride solutions containing various different concentrations of ethanol and a variety of
buffers. The compositions do not appear to be sprays as the document refers to the volume of
liquid that a patient can hold sublingually for a reasonable amount of time.
It is well known that the application of carefully chosen medicaments to mucosa, for example
the sublingual mucosa, offers a route of administration which is capable of resulting in very rapid
transmission of medicament to the bloodstream with consequent fast onset of effect. Other
mucosa to which medicaments may be administered include the nasal mucosa and buccal
mucosa. A number of ways of administering compositions sublingually are known. For
example, tablets or liquids may be held under the tongue prior to swallowing. Another method is
spray delivery. Of these various types of sublingual administration, spray delivery is preferred as
it does not involve holding the composition under the tongue for an extended period of time as,
for example, with a lozenge and it reduces the amount of material which is swallowed (and may
enter the blood stream in a delayed manner via the gastrointestinal tract). However it is not
considered desirable to spray large volumes of liquid (eg greater than around 500 uL) to the
sublingual cavity.
WO01/97780 (Ross) describes a pharmaceutical composition comprising a solution of an opioid
analgesic (especially fentanyl, although buprenorphine is referred to) and a propellant, for
sublingual aerosol administration. The example formulations are pressurized and therefore

require complex packaging and actuation technology. Also they employ halogenated
propel Iants which may not be environmentally friendly.
Weinberg et al (1988) Clin Pharmacol Ther 44, 335-342 discusses the adsorption of various
opioids including buprenorphine (presented in an aqueous phosphate buffer at pH 6.5) when
administered by pipette in liquid form to the sublingual cavity.
WO01/89476 (Pinney et al) discloses buffered compositons for transmucosal delivery.
Buprenorphine is mentioned in a very long list of possible active agents and is not exemplified.
Presently there are no spray compositions containing buprenorphine which have been made
available commercially.
Thus an object of the present invention is to provide a spray composition containing
buprenorphine for transmucosal, particularly sublingual, administration. Further objects of the
invention are to provide a spray composition containing buprenorphine for transmucosal (eg
sublingual) administration with good physical properties, especially good stability and low
environmental impact, and good biological properties, especially rapid onset of activity and
efficacy at relatively low doses. Such a composition would mitigate many of the disadvantages
of prior art compositions containing buprenorphine.
Thus according to a first aspect of the invention there is provided a non-pressurised
pharmaceutical liquid solution spray composition comprising:
(i) buprenorphine; and
(ii) a solvent comprising ethanol;
characterised in that the composition is substantially free of chloride.
The composition is non-pressurised i.e. is substantially free of any propellant. Exemplary
propellants to be substantially avoided include volatile substances which develop significant
vapour pressure at ambient temperature and pressure such as lower alkanes (eg propane,
butane and the like) and halogenated hydrocarbons such as CFCs (P12 etc) and
hydrofluorocarbons (P134a, P227 etc) as well as other propellants commonly used in aerosol
presentations. Use of P11 is also preferably substantially avoided. By "substantially free" or
"substantially avoided" is meant that an amount of less than 5% w/w based on weight of
composition is employed, suitably less than 2% eg less than 0.1% w/w. Preferably propellants
are avoided altogether.

The concentration of the buprenorphine in the composition may typically vary between 0.05 and
12% w/v, more suitably 0.1-10% w/v, eg 0.1-4% w/v or especially 2-8% w/v, for example 4-8%
w/v eg 4% or 8% w/v (all figures being based on weight of buprenorphine base relative to total
weight of composition).
By "substantially free of chloride" is meant that the formulation has a substantial absence of
chloride in ionised (i.e. such that CI" is formed in solution) or unionised form. The reason for the
substantial absence of chloride is to avoid the precipitation of buprenorphine hydrochloride
which is not highly soluble in aqueous or ethanolic solvents. Thus the amount of chloride in the
composition is suitably less than 3% w/w based on weight of buprenorphine eg less than 1%
w/w, eg less than 0.5% w/w for example less than 0.1% w/w, especially when the pH of the
composition is less than 7.
Preferably the buprenorphine is employed as base or as citrate, particularly as base.
An advantage of the invention, and in particular of use of buprenorphine in a formulation which
is substantially free of chloride, is that relatively concentrated compositions can be prepared
which allows for administration of high doses of buprenorphine without using excessively large
metering volumes. For example, as will be explained below, we have successfully prepared
solutions of concentration 4 and 8% w/v, whereas buprenorphine hydrochloride has not proved
soluble in water or ethanol at these concentrations. These higher concentrations of
buprenorphine are achieved by using a solvent containing a significant amount of ethanol and
the highest concentrations are achieved by lowering the pH with citric acid.
Some sprayable non-pressurised analgesic compositions are taught in the art, for example in
WO02/094234 (Rabinowitz), WO 03/080022 (Birch) and WO 2004/071491 (Blondino).
WO02/094234 relates to an opioid-containing aerosol formulation for administration by
inhalation. The formulations are all aqueous solutions with no other solvent being suggested.
WO 03/080022 relates to aqueous solutions comprising an analgesic for intranasal
administration. The analgesic may be buprenorphine or a salt thereof but there is no teaching
that the composition should not contain chloride and indeed the examples all relate to
compositions comprising buprenorphine hydrochloride. There is no suggestion that ethanol
could be included in the solvent. WO 2004/071491 relates to liquid aerosol formulations in
which the solvent may contain ethanol. There is no suggestion that it would be advantageous to
provide a chloride-free composition and all of the examples relate to formulations containing
buprenorphine hydrochloride.

Generally speaking it will be desired to employ the least amount of solvent necessary (or a
modest excess over that necessary) to adequately solubilise the buprenorphine such that the
buprenorphine remains in solution under the conditions of likely usage or exposure.
Typically the solvent is selected from ethanol and ethanol/water mixtures. In a first embodiment
of the invention ethanol is substantially the only solvent. For example the concentration of
ethanol in the solvent is greater than 90% w/w eg greater than 95% w/w particularly greater than
98% w/w, for example around 100% w/w (i.e. the solvent is ethanol, the presence of any water
as contaminant from the atmosphere being ignored). In this first embodiment of the invention
use of water as solvent is substantially avoided, for example the water concentration is less than
10% w/w eg less than 5% w/w particularly less than 98% w/w, for example around 0% w/w (i.e.
the composition is substantially free of water). As noted below, avoidance of water can be
advantageous especially in formulations of buprenorphine containing citrate since we have
observed that such formulations have a tendency to turn pink on storage.
In a second embodiment of the invention the solvent comprises water as well as ethanol. For
example the solvent consists of a water/ethanol mixture in which the concentration of ethanol is
approximately 30-90% w/w (the balance being water) for example approximately 40-70%> w/w
eg around 50% w/w.
Preferably water when employed as solvent meets the USP (US Pharmacopoeia), EP
(European Pharmacopoeia) "Purified Water" standards.
The pH of the solution may typically be between around 4 and 9.5 however will preferably be
between around 4.5 and 9. In a first embodiment of the invention the pH is between 4 and 6 eg
between around 4.5 and 6 eg around 5 or between around 4 and 5 eg around 4.5. In a second
embodiment of the invention, the pH is greater than 7 for instance between around 8 and 9.5 eg
between around 8 and 9 eg around 8.5. It is envisaged that compositions at this higher pH
will be more efficacious and/or have more rapid activity. Without being limited by theory it is
envisaged by the inventors that buprenorphine will be more rapidly or efficiently adsorbed
through the mucosa, especially the sublingual mucosa, at a pH close to the pKa of
buprenorphine, which is 8.5 (Pharmaceutical Codex). Compositions of pH above 7 have not
thus far been described in concrete terms, presumably due to the predominant use of
buprenorphine hydrochloride and the problems of solubility of the active at higher pH. Such
problems are substantially overcome by use of compositions of the invention.
By "pH" is meant the pH reading that would be obtained using a conventional pH meter eg
model pH 211 manufactured by Hanna Instruments Ltd and Orion 420A manufactured by

Thermo Electron Corporation (i.e. in water free systems the word "pH" would be construed to
mean "apparent pH").
In order to adjust the pH buffer salts can be employed, however we have found that careful
attention must be paid to the concentration of these due to the insolubility of many organic and
inorganic salts in substantially ethanolic solvents. When buffers are employed, the preferred
buffer system for lower pH ranges is citrate (eg sodium citrate)/citric acid which does have
adequate solubility in ethanolic solvents. However citrate/citric acid is itself problematic since
we have found that compositions of the invention containing citrate/citric acid and water have a
tendency to turn pink on storage especially at elevated temperature. Accordingly use of buffer
salts and even citrate/citric acid is preferably avoided.
Suitably the use of phosphate containing buffers (eg phosphate and protonated derivatives such
as hydrogen and dihydrogen phosphate) is also avoided. Thus the amount of phosphate in the
composition (eg as phosphate per se or as a protonated derivative such as hydrogen or
dihydrogen phosphate) is suitably less than 3% w/w based on weight of buprenorphine eg less
than 1% w/w, eg less than 0.5% w/w for example less than 0.1 % w/w especially when the pH of
the composition is less than 7.
We have found nevertheless that citric acid is useful to enhance the solubility of buprenorphine
base in ethanolic solvents (eg to concentrations of 4% w/v or higher eg 4-8% w/w (based on
total weight of composition) particularly 5-8% w/w). In such compositions the solvent may (most
suitably) be essentially ethanol (eg 100% ethanol) or may (alternatively) contain water (eg
ethanol/water 1:1). In order to achieve these higher concentrations typically citric acid may be
employed at a concentration of around 0.1-10% w/w eg 0.2-5% w/v eg 0.2-2% w/w.
In order to address the issue of pH adjustment of buprenorphine solutions and in particular
without use of conventional buffer salts or use of chloride (eg as HCI) the inventors have
appreciated that it may be possible to achieve this by the use of other organic formulation
components. Accordingly we undertook a careful assessment of the impact on pH on
buprenorphine solutions by addition of saccharin or sodium saccharin optionally together with
certain other formulation components such as menthol (eg L-menthol) or peppermint oil.
As a result of our investigations we discovered that the pH of buprenorphine base in ethanol is
not significantly affected by buprenorphine concentration. However we surprisingly discovered
that saccharin may be effectively employed to lower the pH of buprenorphine base
compositions, and is particularly useful in achieving a pH in the range 4-6, particularly 4.5-6 eg
around 5. The pH lowering effect of saccharin lessens with increased buprenorphine

concentration. Addition of menthol (eg L-menthol) or peppermint oil has relatively little impact
on pH when in conjunction with saccharin.
We also discovered that saccharin sodium as well as menthol (eg L-menthol) and peppermint oil
all have a modest but potentially useful effect on raising the pH of buprenorphine base
compositions in ethanol, and is particularly useful in achieving a pH in the range between about
8 and 9.5 eg between around 8 and 9 eg around 8.5.
The above mentioned results are illustrated in Figures 1 and 2.
As well as their above mentioned useful properties in modifying the pH of the compositions,
saccharin and saccharin sodium are useful as sweeteners which improve patient acceptability.
As well as their above mentioned useful properties in modifying the pH of the compositions,
menthol (eg L-menthol) and/or peppermint oil are useful as flavourings and moisturing agents
which may have penetration enhancing activity.
The properties of the claimed compositions may be further improved by including therein a
number of additional formulation components.
It may be desirable to include one or more of the following components in the composition
- sweeteners such as saccharin, saccharin sodium, sucrose, flavouring or taste-masking agents
(to improve patient acceptability),
-moisturising agents (to improve patient comfort and overcome the drying tendency of ethanol
and other polar organic solvents) for example peppermint oil, menthol (eg L-menthol) pineapple
extract, lanolin, polypropylene glycol, polyethylene glycol.
-mucoadherents (in order to increase residency time on the mucosa) for example carboxyvinyl
polymers, chitosans, polyacrylic acid, gelatin, polyvinyl pyrrolidone.
-preservatives (to improve long term resistance to microbial contamination) for example sodium
metabisulphite, benzalkonium, Nipas.
-antioxidants for example alkyl gallates, butylated hydroxyanisole butylated hydroxytoluene,
nordihydroguaiaretic acid, tocopherols, Ascorbic acid, sodium metabisulphite
-anionic surfactants for example magnesium stearate, sodium cetostearyl sulphate, sodium
lauryl sulphate, sodium oleate, sodium stearyl fumarate, sodium tetradecyl sulphate
-nonionic surfactants for example glyceryl monostearate, Macrogol cetostearyl ethers,
Poloxamers, polyoxyl stearates, Polysorbates, sorbitan esters, sucrose esters, Tyloxapol,
propylene glycol monostearate, Quillaia, polyoxyl, caster oils, nonoxinols, lecithins and
derivatives, oleic acid and derivatives, oleyl alcohol and derivatives

-foaming agents for example alginic acid and salts, propylene glycol alginate, sodium lauryl
sulphate, sodium cetostearyl sulphate, carbomers, hydroxyethylcellulose
Amongst the above mentioned possible additional components, it may be remarked that a
preservative should not normally be necessary in view of the ethanol content of the
compositions.
In accordance with best pharmaceutical principles, additional components will be avoided if not
necessary.
We have observed that compositions according to the invention which are of higher strength (eg
4 % w/v or above), especially those containing saccharin, have a tendency to yellow on storage,
especially at higher temperatures. Accordingly a stabiliser selected from anti-oxidants (eg
ascorbic acid/ascorbate) and/or a chelating agent (eg EDTA/sodium edetate) may suitably be
employed.
Some of the components proposed above may already be included in the composition of the
present invention for other purposes. Suitable moisturising agents include, for example, the
polar organic solvents such as glycols, especially propylene glycol, and the liquid polyethylene
glycols, glycerol, methylcellulose, hypromellose, hydroxypropylcellulose, and many other
substituted celluloses.
As mentioned above, a versatile component, which improves the acceptability and other
properties of the composition, is menthol especially L-menthol. Menthol (eg L-menthol), as well
as flavouring the composition, has moisturising effect. It may also have effect as a penetration
enhancer. Preferably menthol (eg L-menthol) is employed in a concentration range of 0.1% to
0.75% w/w eg around 0.2% w/w.
Peppermint oil is an alternative component which may be used in place of menthol. Peppermint
is known to have incompatibilities with certain actives (eg fentanyl) however it appears to be
compatible with buprenorphine. Suitably peppermint oil is employed in a concentration range of
0.1 % to 0.75% w/w eg around 0.5% w/w.
In preferred embodiments of the invention, the composition contains a sweetener. In one
embodiment of the invention, the sweetener is saccharin sodium. Suitably the concentration of
saccharin sodium is around 0.1-0.9% w/w eg around 0.45% w/w.

In another embodiment of the invention, the composition contains saccharin. Suitably the
concentration of saccharin is around 0.025-0.75% w/w, for example around 0.05-0.4% w/w eg
around 0.05-0.1% w/w. As pointed out above the concentration of saccharin may be varied
depending on the eventual pH desired (see Figure 2).
A number of compositions of the invention are considered to be especially suitable.
A suitable example composition comprises (or consists essentially of (eg consists of)):
-buprenorphine as base;
-a solvent selected from ethanol and ethanol/water mixtures;
wherein the composition is substantially free of chloride; and
wherein the pH of the composition is greater than 7.
The pH of the composition may, for instance, be between around 8 and 9.5 eg between around
8 and 9 eg around 8.5.
The solvent may suitably be ethanol.
Optionally (and advantageously) such compositions comprise saccharin sodium.
Optionally (and advantageously) such compositions comprise a flavouring agent selected from
menthol (eg L-menthol), peppermint oil and mixtures thereof.
Optionally such compositions comprise a chelating agent (eg EDTA or sodium edetate).
Optionally such compositions comprise an anti-oxidant.
Optionally hydroxide (eg NaOH, KOH) may be used to raise the pH if needed.
Suitably the concentration of buprenorphine base is 0.1-4% w/v.
Another suitable example composition comprises (or consist essentially of (eg consist of)):
-buprenorphine as base;
-a solvent selected from ethanol and ethanol/water mixtures;
-saccharin;
wherein the composition is substantially free of chloride; and wherein the pH of the composition
is between around 4 and 6 eg between around 4.5 and 6 eg around 5.
The solvent may suitably be ethanol.
Optionally (and advantageously) such compositions comprise a flavouring agent selected from
menthol (eg L-menthol), peppermint oil and mixtures thereof.
Optionally such compositions comprise a chelating agent (eg EDTA or sodium edetate).
Optionally such compositions comprise an anti-oxidant.
Suitably the concentration of buprenorphine base is 0.1-4% w/v.
Another suitable example composition comprises (or consist essentially of (eg consist of)):
-buprenorphine as base at a concentration of 4% w/v or more;

-a solvent selected from ethanol and ethanol/water mixtures;
-citric acid;
wherein the composition is substantially free of chloride; and wherein the pH of the composition
is between around 4 and 6 eg between around 4 and 5 eg around 4.5.
The solvent may suitably be ethanol.
Optionally (and advantageously) such compositions comprise a flavouring agent selected from
menthol (eg L-menthol), peppermint oil and mixtures thereof.
Optionally (and advantageously) such compositions comprise saccharin.
Optionally such compositions comprise a chelating agent (eg EDTA or sodium edetate).
Optionally such compositions comprise an anti-oxidant.
Suitably the concentration of buprenorphine base is 4-8% w/v.
A process for preparation of compositions of the invention comprises:
(a) taking buprenorphine as base and a solvent comprising ethanol optionally containing the
other formulation ingredients (eg saccharin, saccharin sodium, menthol, peppermint oil etc) and
dissolving the buprenorphine in the solvent; or
(b) taking buprenorphine as base and a solvent comprising ethanol and dissolving the
buprenorphine in the solvent, then adding the other formulation ingredients (eg saccharin,
saccharin sodium, menthol, peppermint oil etc); or
(c) the process of (a) or (b) in which the pH of the solvent is adjusted (eg with citric acid) once
all the other formulation ingredients are mixed together.
Amongst the advantages of the claimed compositions is the fact that by being non-pressurised
they avoid the issues associated with using propellant, such as their manufacturing
disadvantages and their potential environmental impact (many propellants are "greenhouse
gasses"). The solution compositions of the invention are homogenous and have limited or no
susceptibility to dose-to-dose variation. Furthermore compositions of the present invention are
characterised by good long-term physical and chemical stability.
The compositions of the invention are preferably administered transmucosally (particularly
sublingually) as a spray. The compositions are expected to be well tolerated when administered
to the sensitive sublingual mucosa and the sublingual spray administration will result in rapid
onset of the therapeutic effect of the buprenorphine.
Thus according to a second aspect of the invention there is provided a metered dose dispensing
system comprising a sealed container containing a composition of the invention fitted with a
metering pump, an actuator and a channelling device. The metered dose dispensing system is
preferably adapted for transmucosal (particularly sublingual) administration.

Although in principle the container for the pharmaceutical liquid composition may contain a
single dose of buprenorphine (which may, nevertheless be a divided dose), preferably the
container will contain a plurality of doses (eg 20 to 200 doses) of buprenorphine.
Although the composition could be packaged in a suitable pharmaceutical grade, plastics
container, such a container would be relatively easy to open for abuse of the product. Therefore
a glass container would be more suitable. Glass would shatter if attempts were made to open
the pack, rendering the contents either lost or unusable due to glass fragments. Preferably the
glass container will be coated on the exterior with a suitable moulded film of plastic to protect
against shattering. For example the film may be of polypropylene. The material may be
coloured and contain a UV absorber. The container glass may be colourless or more suitably
may be provided with a UV protective colouring, for example amber colouring. Optionally, the
interior of the container can be coated to enhance stability of the product. Coatings include
polymers and lacquers but also silicone dioxide as an unreactive coating can be used to line the
inside of the container.
Since the composition is non-pressurised, it is suitably administered to the patient by pump
action. Thus the metering dose dispensing system suitably contains a metering pump permitting
a metered dose of the composition to be administered as a spray.
Suitable metering pumps include those adapted for dispensation with the container in the
upright or inverted orientation. Preferably the metering chamber is adapted for dispensation
with the container in the upright orientation since this facilitates administration under the tongue.
Accordingly the metering chamber will be in communication with the composition by means of a
dip-tube.
The metering pump is suitably a non-venting type. Suitable materials of construction include
polypropylene and polyethylene. Example metering pumps are those manufactured by Valois
(eg VP3, VP6, VP7 and VP7D) and for example those illustrated in International Patent
Application No. WO01/66089. Other conventional pumps include those from Rexam (eg
SP270) and Calmar (eg Accupump or Mistette Mk II).
Preferably the actuator will be designed to deliver a transmucosally (particularly a sublingually)
effective dose. The pump may suitably be manually actuated, although assisted actuation using
stored energy (eg spring or gas) may be contemplated.

For a secure seal, the pump is suitably crimped onto the container neck. Suitable sealing
materials eg thermo plastic crimp gaskets suitable for the purpose will be employed. In addition,
a suitable aluminium ferrule purposely designed for crimping on to glass containers may suitably
be employed. Suitable grade stainless steel springs will preferably be adopted.
The metering pump will administer a metered volume of composition. Suitable metering
volumes are 10-1000 uL, more suitably 50-250 uL, eg 100uL or 200 uL, particularly 200 uL.
A channelling device is provided to direct the liquid sprayed from the metered dose dispensing
area to the appropriate part of the mouth e.g. to the sublingual cavity or if desired to the nose.
Channelling devices are suitably fabricated from moulded plastics. A number of channelling
devices adapted to administer sprays to the mouth or nose are known to persons skilled in the
art eg


Compositions of the invention are useful in treatment or prevention of opiate dependency and
abuse, particularly in the treatment or prevention of dependency on opiates such as heroin and
for analgesic purposes eg for the treatment of moderate to severe pain. Thus in a further
aspect of the invention there is provided a method of treatment or prevention of opiate
dependency and abuse or pain which comprises administering to a subject in need thereof an
effective amount of a composition of the invention. In a further aspect of the invention, there is
provided the use of a composition according to the invention in the manufacture of a
medicament for the treatment or prevention of opiate dependency and abuse or pain. In a
further aspect, there is provided a composition of the invention for use in the treatment or
prevention of opiate dependency and abuse or pain.
In order to lessen the risk of abuse with the product, suitably the container or the dispensing
system may be provided with features to prevent tampering. In particular, the container or the
dispensing system may suitably be provided with features to prevent or discourage access to
the reservoir and/or to prevent administration of more than one dose of buprenorphine at one
time.
The dispensing system, in particular the actuator, may, for example, be provided with a lock-out
feature to prevent administration of a second dose within a specified time interval of the first.
Lock-out features are, for example, described in US2006191532, WO03097141 and
WO0232487.
Typically a patient is treated by administration transmucosally (eg sublingually) of 1 to 4
actuations eg 1 or 2 actuations from the spray pump. Another advantage of mucosal spray
delivery is the ability to easily titrate patients by 1 or 2 doses as required by a single actuation.
This is not the case with other forms of drug delivery (patches, lozenges, tablets, suppositories).
Pharmaceutical compositions of the invention are useful in the treatment of animals, particularly
non-human mammals (for example domestic or livestock animals) as well as humans.
Accordingly pharmaceutical uses, for example uses in the treatment of pain, may be extended
to veterinary uses. Dosages and methods of administration (eg the spray actuator design) will
be adapted for the intended recipient as would be known to a skilled person.


The compositions formed a clear colourless solution at 4, 25 and 40°C and remained so after 1
month storage at these temperatures.
Examples 5-8
Compositions were prepared as follows:

The compositions formed a clear colourless solution at 4, 25 and 40°C and remained so after 2
weeks storage (Example 8) or 1 month storage (Examples 5-7) at these temperatures.
Examples 9-12
Compositions were prepared as follows:


The compositions formed a clear colourless solution at 4, 25 and 40°C and remained so after 1
month storage at these temperatures.
Examples 13-16
Compositions were prepared as follows:

NM not measured
Example 13: the composition formed a clear colourless solution at 4, 25 and 40°C. and
remained so after 2 months storage at these temperatures.
Example 14: the composition formed a clear colourless solution at 4 and 25°C and a clear vei
light yellow solution at 40°C after 2 months storage at these temperatures.
Examples 15, 16: the compositions formed a clear colourless solution at 4 and 25°C and a
clear light yellow solution at 40°C after 3.5 months storage at these temperatures.
Examples 17-20
Compositions were prepared as follows:

NM not measured
Examples 17 and 18: the compositions formed a clear colourless solution at 4 and 25°C and a
dark yellow solution at 40°C after 3.5 months storage at these temperatures.

Example 19: the composition formed a clear light yellow solution at 4°C, a clear yellow solution
at 25°C and a clear dark yellow solution at 40°C after 3.5 months storage at these
temperatures.
Example 20: the composition formed a clear colourless solution at 4°C, a clear light yellow
solution at 25°C and a clear yellow solution at 40°C after 2 months storage at these
temperatures.
Examples 21-24
Compositions were prepared as follows:

Examples 21 and 22: the compositions formed a clear colourless solution at 4, a light yellow
solution at 25°C and a yellow solution at 40°C after 3 months storage at these temperatures.
Example 23: the composition formed a clear colourless solution at 4°C and 25°C and a clear
pink solution at 40°C after 3 months storage at these temperatures.
Example 24: the composition formed a clear colourless solution at 4°C and 25°C and a clear
light pink solution at 40°C after 3 months storage at these temperatures.
Example 25
The dependence of apparent pH on buprenorphine base concentration in ethanol solution was
investigated for various compositions. The results are shown in Figure 1.
The most striking observation is that saccharin has a significant effect on the composition
apparent pH, which decreases with buprenorphine base concentration. The overlapping profile;
at markedly lower pH was obtained from the 3 compositions containing (i) saccharin; (ii)
saccharin with peppermint oil; and (iii) saccharin with L-menthol.

Example 26
The dependence of apparent pH on saccharin concentration in buprenorphine base (0.2% w/v) /
ethanol solution was investigated for various compositions. The results are shown in Figure 2.
Throughout the specification and the claims which follow, unless the context requires otherwise,
the word 'comprise', and variations such as 'comprises' and 'comprising', will be understood to
imply the inclusion of a stated integer, step, group of integers or group of steps but not to the
exclusion of any other integer, step, group of integers or group of steps.
The application of which this description and claims forms part may be used as a basis for
priority in respect of any subsequent application. The claims of such subsequent application
may be directed to any feature or combination of features described herein. They may take the
form of product, composition, process, or use claims and may include, by way of example and
without limitation, the following claims:

Claims
1. A non-pressurised pharmaceutical liquid solution spray composition comprising:
(i) buprenorphine; and
(ii) a solvent comprising ethanol
characterised in that the composition is substantially free of chloride.
2. A composition according to claim 1 wherein the concentration of ethanol in the solvent is
greater than 90% w/w.
3. A composition according to claim 1 or claim 2 which is substantially free of water.
4. A composition according to claim 2 or claim 3 wherein the concentration of ethanol in the
solvent is around 100% w/w.
5. A composition according to claim 1 wherein the concentration of ethanol in the solvent is
approximately 30- 90% w/w, the balance being water.
6. A composition according to any one of claims 1-5 wherein the concentration of
buprenorphine in the composition is around 0.05-12% w/v.
7. A composition according to claim 6 wherein the concentration of buprenorphine in the
composition is around 2-8% w/v.
8. A composition according to any one of claims 1-7 wherein the pH of the composition is
between around 4 and 6.
9. A composition according to any one of claims 1 -7 wherein the pH of the composition is
between around 8 and 9.5.
10. A composition according to claim 8 which contains saccharin.
11. A composition according to claim 9 which contains saccharin sodium.
12. A composition according to any one of claims 1 to 11 which contains menthol.
13. A composition according to any one of claims 1 to 12 which contains peppermint oil.

14. A composition according to claim 1 comprising:
-buprenorphine as base;
-a solvent selected from ethanol and ethanol/water mixtures;
wherein the composition is substantially free of chloride; and
wherein the pH of the composition is greater than 7.
15. A composition according to claim 14 wherein the pH of the composition is between
around 8 and 9.
16. A composition according to claim 14 or claim 15 which comprises saccharin sodium.
17. A composition according to claim 1 which comprises
-buprenorphine as base;
-a solvent selected from ethanol and ethanol/water mixtures;
-saccharin;
wherein the composition is substantially free of chloride; and wherein the pH of the
composition is between around 4 and 6.
18. A composition according to any one of claims 14 to 17 wherein the concentration of
buprenorphine base is 0.1-4% w/v.
19. A composition according to claim 1 which comprises:
-buprenorphine as base at a concentration of 4% w/v or more;
-a solvent selected from ethanol and ethanol/water mixtures;
-citric acid;
wherein the composition is substantially free of chloride; and wherein the pH of the
composition is between around 4 and 6.
20. A composition according to claim 19 which comprises saccharin.
21. A composition according to any one of claims 14 to 20 wherein the solvent is ethanol.

22. A composition according to claim 19 or claim 20 wherein the solvent is an ethanol/water
mixture.
23. A composition according to any one of claims 14 to 22 which comprises a flavouring
agent selected from menthol, peppermint oil and mixtures thereof.

24. A composition according to any one of claims 14 to 23 which comprises a chelating
agent.
25. A composition according to any one of claims 14 to 24 which comprises an anti-oxidant.
26. A composition according to any one of the preceding claims for transmucosal
administration as a spray.
27. A composition according to claim 26 wherein the transmucosal administration is
sublingual administration.
28. A composition according to any one of the preceding claims, for use in the treatment or
prevention of opiate dependency or abuse or pain.
29. Use of a composition according to any one of claims 1 to 28 in the manufacture of a
medicament for the treatment or prevention of opiate dependency or abuse or pain.
30. A sealed container containing a plurality of doses of a composition according to any one
of claims 1 to 28.
31. A container according to claim 30 which is made out of glass.
32. A metered dose dispensing system comprising a sealed container according to claim 30
or claim 31 fitted with a metering pump, an actuator and a channelling device.
33. A metered dose dispensing system according to claim 32 containing a metering
chamber which is adapted for dispensation with the container in the upright orientation and
wherein the metering chamber is in communication with the composition by means of a dip-
tube.
34. A metered dose dispensing system according to claim 32 or claim 33 adapted for
transmucosal administration of the composition as a spray.
35. A metered dose dispensing system according to claim 34 wherein the transmucosal
administration is sublingual administration.

36. A process for preparation a composition according to any one of claims 1 to 28 which
comprises:
(a) taking buprenorphine as base and a solvent comprising ethanol optionally containing
the other formulation ingredients and dissolving the buprenorphine in the solvent; or
(b) taking buprenorphine as base and a solvent comprising ethanol and dissolving the
buprenorphine in the solvent, then adding the other formulation ingredients; or
(c) the process of (a) or (b) in which the pH of the solvent is adjusted once all the other
formulation ingredients are mixed together.

There is provided according to the invention a non-pressurised pharmaceutical liquid solution spray composition
comprising: (i) buprenorphine; and 5 (ii) a solvent comprising ethanol which composition is substantially free of chloride.