Note: Descriptions are shown in the official language in which they were submitted.
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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.
?'v
......::.-f., c .oi ........,ti.
........ ..ti,, , . ,..
= t `
.,,. ,,..
$va"~
M:.
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
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2
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
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3
require complex packaging and actuation technology. Also they employ
halogenated
propellants 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.
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4
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
W002/094234 (Rabinowitz), WO 03/080022 (Birch) and WO 2004/071491 (Blondino).
W002/094234 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.
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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
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6
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
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7
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
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-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.
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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;
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-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.
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11
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.
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12
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
Valois
Spray Buttons Nasal Actuators Throat Actuators Dental Actuators
155 GPC CB 18 NAC 132 C GP 251 EB 406
155 GPCS CB 18 NAL 132 L GP 251 EB 407
165 GPC CB 18 NEC 139 foldable
165 GPCS CB 18 W NAC 137 C
852 CB 19 137 L
A3 147 NE 251 EB 408
Calmar
Spray Buttons Nasal Actuators Throat Actuators Dental Actuators
Standard Head 2-piece Nasal Short Throat Capillary Tube
3-piece Nasal Medium Throat
Long Throat
Articulated Throat
Rexam
Spray Buttons Nasal Actuators Throat Actuators Dental Actuators
9590 4345 9180 9410
AA5733 4234 5200
AB3960 AA9994
5561 5860
4095 585
AA8238 4325
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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, W003097141 and
W00232487.
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.
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Examples
Examples 1-4
Compositions were prepared as follows:
Ex 1 Ex 2 Ex 3 Ex 4
Buprenorphine base (% w/v 0.2 0.1 0.1 0.1
Levomenthol (% w/w) 0.2 0.2 - -
Peppermint oil (% w/w) - - - 0.5
Sodium saccharin (% w/w) 0.45 - 0.45 -
Ethanol anhydrous (%) to 100 to 100 to 100 to 100
Measured pH 8.38 9.08 8.36 8.43
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:
Ex 5 Ex 6 Ex 7 Ex 8
Buprenorphine base (% w/v 0.2 0.2 0.2 0.1
Levomenthol (% w/w) - 0.2 - -
Peppermint oil (% w/w) - - 0.5 0.5
Saccharin (% w/w) 0.05 0.05 0.05 0.40
Ethanol anhydrous (%) to 100 to 100 to 100 to 100
Measured pH 4.92 4.93 4.97 2.94
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:
Ex 9 Ex 10 Ex 11 Ex 12
Buprenorphine base (% w/v 0.1 0.1 0.2 0.1
Levomenthol (% w/w) 0.2 - - -
Peppermint oil (% w/w) - 0.5 0.5 -
Sodium saccharin (% w/w) 0.45 0.45 0.45 -
Ethanol anhydrous (%) to 100 to 100 to 100 to 100
Measured pH 8.36 7.98 8.08 9.04
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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:
Ex 13 Ex 14 Ex 15 Ex 16
Buprenorphine base (% w/v 4 4 4 4
Levomenthol (% w/w) 0.2 - - 0.2
Peppermint oil (% w/w) - 0.5 - -
Sodium saccharin (% w/w)
- - - -
Saccharin (% w/w)
- - - -
Ethanol anhydrous (%) to 100 to 100 to 100 to 100
Measured pH 8.63 8.35 8.67 NM
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 very
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:
Ex 17 Ex 18 Ex 19 Ex 20
Buprenorphine base (% w/v) 4 4 4 4
Levomenthol (% w/w) - 0.2 - 0.2
Peppermint oil (% w/w) - - 0.5 -
Sodium saccharin (% w/w) - - - 0.45
Saccharin (% w/w) 0.40 0.40 0.40
Ethanol anhydrous (%) to 100 to 100 to 100 to 100
Measured pH 5.89 5.85 5.87 8.77
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.
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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 400C 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:
Ex 21 Ex 22 Ex 23 Ex 24
Buprenorphine base (% w/v) 8 8 8 4
Levomenthol (% w/w) - - - -
Peppermint oil (% w/w) - - - -
Sodium saccharin (% w/w) - - - -
Saccharin (% w/w) - - - -
Citric acid % w/w 4.13 8.22 4.11 2.05
Water/ethanol 1:1 w/w (% to 100 to 100
w/w)
Ethanol anhydrous % w/w to 100 to 100 - -
Measured pH 4.83 4.20 4.55 4.64
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 profiles
at markedly lower pH was obtained from the 3 compositions containing (i)
saccharin; (ii)
saccharin with peppermint oil; and (iii) saccharin with L-menthol.
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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:
