FORMULATIONSAND DELIVERY
Field of the Invention
The invention relates to improved methods of delivery of opioids, and to devices for
said delivery.
Background
The development of drug delivery routes remains an important element in the
progress of the pharmaceutical sciences. Once an active compound has been
identified, the design of delivery mechanisms must overcome challenges of
transporting the medicament to the required site of action in the body whilst
addressing issues including shelf stability, bioavailability, toxicity, and patient
compliance. All of these challenges must be overcome to achieve the desired
therapeutic effect. Amongst the drug delivery options, oral administration is by far
the most common route, with other options including injection, topical, inhalation and
transmucosal administration.
The oral delivery route faces perhaps the most challenging route for a pharmaceutical
to reach the final site of action: the composition is prone to loss from the mouth or
stomach (e.g. by spitting or vomiting); the composition must survive the acidic and
enzymatically-active environment of the stomach; if not absorbed in the stomach, the
medicament must survive the action of bile salts and further intestinal and bacterial
enzymatic action within the intestinal tract, be able to cross from the lumen of the gut
to the intestinal wall for absorption, and then survive the degradation processes of the
liver following transport by the hepatic portal system, often resulting in poor
availability due to the first pass effect. Furthermore, many bioactive compounds elicit
autoinduction of enzymes (e.g. in the hepatic system) that lead to increasing
breakdown of drugs before they reach the systemic circulation, leading to a decrease
of bioavailability of the molecules over time during a medicament administration
regime. Despite these challenges, the oral route of drug administration remains the
most common.
The shelf-stability of a medicament is an important consideration in terms of safety,
efficacy and cost. Some medicaments are not stable in traditional delivery devices
that are made of e.g. glass or stainless steel (rigid materials required to maintain the
shape of the device). Instead, these medicaments are kept in separate, plastic storage
containers, with thin, flexible walls making them unsuitable for a delivery device,
prior to transfer into a delivery device prior to administration. Such transfer reduces
the efficiency of medicament supply: two different containers are required instead of
one, and the transfer step introduces the potential for waste and may need to be
effected/overseen by a suitable professional (e.g. a pharmacist). The transfer step also
introduces the possibility of dispensing error.
Some opioids, such as methadone, are used to treat opioid dependence (as so-called
"anti-addictive" drugs). The current methods used to dispense opioids for this
purpose are inefficient, particularly for the anti-addictive of choice, methadone.
Methadone is usually made up in a glucose syrup suitable (only) for oral
administration and stored in bulk (multiple doses) in a lightweight plastic (e.g.
polypropylene) bottle. The administration of single doses to the patient requires
professional supervision and skill, and includes the accurate measurement of a
dispensed single dose and inspection of the patient after dosing to ensure that they
have swallowed the dose (some addicts attempt to spit out the dose to then inject it).
Other disadvantages of using oral methadone for treating opioid dependence include
the potential for contamination of the bulk syrup and the relatively high rate of
vomiting in patients who are opioid dependent.
It is among the objectives of the present invention to attempt a solution to these
problems.
Summary of the Invention
The sublingual delivery route in principle offers (for many medicaments, including
opioids) substantial benefits over other administration routes. It is particularly
beneficial over the oral route in which a medicament is often lost from the mouth or
stomach (e.g. spitting or vomiting), degraded by the various enzymatic and other
processes in action in the gut, and leads to absorption by the hepatic route, which can
lead to significant malabsorption as a result of the "first pass effect" in the liver. As a
result, orally-dosed medicaments are often given in greater concentration that would
be required if they were well-absorbed and could escape the first-pass effect (often
giving rise to unwanted side-effects). Sublingual delivery is also beneficial over the
injection route because it provides the possibility of administration by non-medically
qualified personnel and avoids the risks associated with injecting.
The inventors have surprisingly identified formulation conditions in which
pharmaceutical compositions comprising opioids can be prepared for sublingual
delivery. Furthermore, the inventors have identified materials that are, surprisingly,
suitable for a container for both the storage and delivery of these compositions.
Accordingly, the invention provides a pharmaceutical composition for the sublingual
delivery of an opioid comprising an opioid and ethanol. In preferred embodiments
said composition additionally comprises glycerol. In particularly preferred
embodiments the opioid is not fentanyl. In further preferred embodiments the opioid
is methadone.
Also provided by the invention is any composition as described above that is
comprised within a container and wherein the material of the container that is in
contact with the composition is Cyclic Olefin Copolymer (COC).
In an alternative embodiment the invention provides a pharmaceutical composition for
the sublingual delivery of an opioid comprising an opioid and a medium chain length
triglyceride wherein the composition is comprised within a container and wherein the
material of the container that is in contact with the composition is polypropylene. In
particularly preferred embodiments the opioid is not methadone. In further preferred
embodiments the opioid is fentanyl.
Furthermore, the inventors provide any composition of the invention within a
container wherein the container comprises a delivery device. In any aspect of the
invention it is particularly preferred that the delivery device dispenses the composition
in a single discharge and/or dispenses the composition as a spray. It is preferred that
such a spray comprises liquid droplets having a mean diameter of at least about 10
microns, preferably at least about 20 microns, more preferably between about 20
microns and about 200 microns, and most preferably between about 20 microns and
about 100 microns.
In any aspect of the invention it is particularly preferred that the delivery device is
non-pressurised and/or comprises seals and/or plungers and wherein the material of
said seals and/or plungers that is in contact with the composition is bromobutyl
polymer.
The inventors also provide a composition of the invention for use in a method of
treatment of the human or animal body by therapy, such as for use in a method of:
(a) reducing pain;
(b) inducing or maintaining anaesthesia;
(c) treating opioid dependence;
(d) treating anxiety;
(d) treating a cough; or
(e) treating diarrhoea.
The inventors also provide a method of treating a human or animal subject in need of
an opioid comprising the administration to said subject of a therapeutically effective
amount of a composition of the invention by the sublingual route, such as wherein
said subject:
(a) is suffering from pain, opioid dependence, anxiety, cough or diarrhoea; or
(b) is in need of anaesthesia.
Detailed Description of the Invention
An opioid is a chemical that binds to opioid receptors. Opioids may be broadly
classed into natural opioids (the "opiates", alkaloids obtained from the opium poppy),
endogenous opioids, semi-synthetic opioids, fully synthetic opioids, and other opioid
receptor agonists. Examples of each class are given below:
Natural opioids - morphine, codeine, thebaine and oripavine.
Endogenous opioids - endorphins, enkephalins, dyno hins and endomorphins.
Semi-synthetic opioids - hydromorphone, hydrocodone, oxycodone, oxymorphone,
desomorphine, diacetylmorphine (heroin), dihydrocodeine, nicomorphine,
dipropanoylmorphine, benzylmorphine, ethylmorphine and buprenorphine.
Fully synthetic opioids - anilidopiperidines (e.g. fentanyl, alphamethylfentanyl,
alfentanil, sufentanil, remifentanil, carfentanyl, ohmefentanyl), phenylpiperidines (e.g
pethidine, ketobemidone, MPPP, allylprodine, prodine, PEPAP),
diphenylpropylamine derivatives (e.g. propoxyphene, dextropropoxyphene,
dextromoramide, bezitramide, piritramide, methadone, dipipanone, Levomethadyl
Acetate [LAAM], difenoxin, diphenoxylate, loperamide), benzomorphan derivatives
(e.g. dezocine, pentazocine, phenazocine), oripavine derivatives (e.g. buprenorphine,
dihydroetorphine, etorphine), and morphinan derivatives (e.g. butorphanol,
nalbuphine, levorphanol, levomethorpfian).
Other opiod receptor agonists - lefetamine, meptazinol, tilidine, tramadol and
tapentadol.
Opioids that are particularly envisaged in the invention include methadone, sufentanil
and fentanyl, and pharmaceutically acceptable salts thereof, analogues thereof or
derivatives thereof. Other opioids envisaged include: alfentanil, buprenorphine,
butorphanol, codeine, hydrocodone, hydromorphone, levorphanol, meperidine,
morphine, nalbuphine, oxycodone, oxymorphbne, propoxyphene, tramadol,
fenpipramide, pentazocine, piritramide, tilidine, tramadol, pharmaceutically
acceptable salts thereof, or derivatives thereof, and the like.
In order to avoid oral absorption, the opioid is delivered in a small volume, large
enough to coat the sublingual mucosa but small enough to reduce the likelihood that
any composition may be swallowed. The skilled addressee will be readily able to
determine whether a chosen opioid has sufficient solubility.
Preferably, the opioid is in solution at a concentration providing a required dose of
medicament in a volume of no more than lOOOmicrolitres of composition, more
preferably in a volume of no more than 5OOmicrolitres, more preferably in a volume
of no more than 400 or 300micro litres of composition, more preferably in a volume of
no more than 200micro litres of composition, and most preferably in a volume of no
more than 1OOmicrolitres of composition.
A further preferred feature is that the opioid is stable in the composition, both with
respect to physicochemical aspects such as remaining in solution and in terms of
chemical (including biochemical) degradation of the medicament over time. It is
particularly preferred, therefore, that the opioid is stable within the composition, to
pharmaceutically-acceptable limits, over a period of at least one month, preferably at
least 2 months, more preferably at least 3 months, more preferably at least 6 months,
more preferably at least 12 months, more preferably at least 18 months, more
preferably at least 2 years, more preferably at least 3 years, more preferably at least 4
years, and most preferably at least 5 years, whilst kept at a temperature(s) between
4°C and 40°C.
It is also preferred that the opioid is stable in the composition (as defined above) when
placed in a container, preferably wherein the container comprises a delivery device,
and it is particularly preferred that the opioid is stable within the composition in said
container, to pharmaceutically-acceptable limits, over a period of at least one month,
preferably at least 2 months, more preferably at least 3 months, more preferably at
least 6 months, more preferably at least 12 months, more preferably at least 18
months, more preferably at least 2 years, more preferably at least 3 years, more
preferably at least 4 years, and most preferably at least 5 years.
Formulations comprising ethanol
In one embodiment the pharmaceutical composition of the invention comprises an
opioid and ethanol. In a particular embodiment the pharmaceutical composition of the
invention consists essentially of an opioid and ethanol. Preferably ethanol is used in
the composition at a concentration of at least 5% (w/w), at least 10% (w/w), at least
15% or at least 18% (w/w) and up to 30% (w/w), up to 40% (w/w) or up to 50%
(w/w). Preferably, ethanol is used at a concentration of between 10%> (w/w) and 30%>
(w/w), more preferably at a concentration of between 15% (w/w) and 25% (w/w),
such as at a concentration of 18% (w/w) to 22% (w/w). As well as acting as a cosolvent,
when ethanol is used at a concentration of more than 18% it also has a
preservative effect. Ethanol is particularly useful for sublingual delivery because it
evaporates after administration, maintaining the medicament in place on the mucosa.
In a further embodiment the pharmaceutical composition of the invention comprising
an opioid and ethanol additionally comprises glycerol. In a particular embodiment the
pharmaceutical composition of the invention consists essentially of an opioid, ethanol
and glycerol. Preferably glycerol is used in the composition at a concentration of at
least 5% (w/w), at least 10% (w/w) or at least 15% (w/w) and up to 35% (w/w), up to
40% (w/w) or up to 50%> (w/w). Preferably, glycerol is used at a concentration of
between 15% (w/w) and 35% (w/w), more preferably at a concentration of between
20% (w/w) and 30% (w/w), such as at a concentration of 24% (w/w) or 25% (w/w).
Glycerol acts as a sweetener and humectant (moisturiser) and, surprisingly, gives
improved opioid solubility and stability (particularly for methadone) in comparison to
other traditional humectants (e.g. propylene glycol).
In a further embodiment the pharmaceutical composition of the invention comprising
an opioid and ethanol additionally comprises water. In a particular embodiment the
pharmaceutical composition of the invention consists essentially of an opioid, ethanol
and water. In a further embodiment the pharmaceutical composition of the invention
comprising an opioid and ethanol additionally comprises glycerol and water. In a
particular embodiment the pharmaceutical composition of the invention consists
essentially of an opioid, ethanol, glycerol and water.
In a preferred embodiment the opioid of the composition comprising ethanol is not
fentanyl. In a further embodiment the opioid of the composition comprising ethanol
is methadone.
If methadone is selected then a total dose is preferably chosen from at least lmg, at
least 5mg, at least 10 mg or at least 15mg and up to 40mg, up to 50mg, up to 60mg, or
up to 120mg, preferably between lOmg and 60mg. Particularly preferred total doses
include lmg, 5mg, lOmg, 20mg, 30mg and 60mg. The concentration of methadone
selected is preferably at least lOmg/ml, at least 15mg/ml, at least 20mg/ml, at least
25mg/ml, at least 50mg/ml or at least 75mg/ml, and up to lOOmg/ml, up to 150mg/ml
or up to 200mg/ml. Preferably the concentration of methadone selected is between
25mg/ml and 150mg/ml, even more preferably between 25mg/ml and lOOmg/ml.
Methadone can be administered from a single dose product (e.g. spray unit)
dispensing e.g. a lmg, lOmg, 20mg, 20mg or 60mg single dose using e.g. a 400m1
pump (especially suitable for treating opioid dependence). Methadone can also be
administered from a multidose product (e.g. spray unit) dispensing e.g. 30 to 50 lots
of e.g. lmg, 5mg or lOmg doses using e.g. a IOOmI pump (especially suitable for
reducing pain).
If methadone is selected it may be present as a racemate (e.g. methadone HC1 or
methadone sulphate) or as the laevorotary or dextrorotary form. L-methadone is
particularly suitable for treating opioid dependence, and D-methadone is particularly
suitable for reducing pain.
The pharmaceutical composition of the invention comprising an opioid and ethanol is
preferably contained within a container (for storage and/or delivery) wherein the
material of the container that is in contact with the composition is Cyclic Olefin
Copolymer (COC). COC is an amorphous and transparent polymer comprising
copolymers based on cycloolefins and linear olefins. The general formula for COC is
as follows:
The properties of COC may be varied depending on the exact chemical structure of
the copolymer, but typically COC displays low density, high transparency, low
birefringence, very low water absorption, excellent water vapour barrier properties,
heat deflection temperature up to 170°C, and high rigidity/strength/hardness. These
properties make COC a suitable material for medical storage and delivery devices.
One suitable source of COC is from the provider Ticona, who market COC under the
registered trademark "Topas" (Thermoplastic Olefin Polymer of Amorphous Structure
(COC)).
The inventors have surprisingly revealed that some opioid/ethanol compositions (e.g.
comprising methadone HC1) are corrosive within containers consisting of glass or
stainless steel (materials traditionally used for delivery devices). However, the
inventors have identified COC as a suitable material with which opioid/ethanol
compositions are compatible, that is to say that such compositions show high stability
within containers wherein said compositions are in contact with COC.
The provision of a composition for sublingual delivery of an opioid is advantageous
because, in comparison to compositions for oral delivery, it avoids the need for the
administrator to ensure that the composition has been swallowed and avoids the
bioavailability problems associated with oral delivery (e.g. vomiting).
In relation to methadone, the inventors have surprisingly found that sublingual
delivery using a composition of the invention leads to effective uptake without a
substantial initial concentration spike, in contrast to the spikes that have previously
been seen in the art when other opioids have been administered sublingually (e.g.
fentanyl and its derivatives such as sufentanil). The lack of such a methadone
concentration spike ensures that this particular embodiment of the composition of the
invention is suitable e.g. as a medicament for both treating opioid dependence and
reducing pain, because the risk of methadone-induced respiratory depression is
significantly reduced. In addition, the lack of a methadone concentration spike ensures
that said embodiment does not lead to a significant euphoric effect making it
particularly suitable for treating opioid dependence because it is then less likely to be
diverted.
The provision of such a composition in a COC container that is suitable for both the
storage and delivery of the composition is advantageous because it can provide the
administrator with a store of single doses each of which can rapidly be employed to
dispense a single dose to a patient without the need for accurate measurement of a
dispensed single dose. This arrangement also avoids the risk of contamination
associated with bulk (multidose) stores of the opioid and can reduce the potential
waste associated with having separate storage/delivery containers.
Formulations comprising a medium chain length triglyceride
In an alternative embodiment the pharmaceutical composition of the invention
comprises an opioid and a medium chain length triglyceride. In a particular
embodiment the pharmaceutical composition of the invention consists essentially of
an opioid and a medium chain length triglyceride.
Medium chain length triglycerides are defined in the European Pharmacopoeia
Monograph 0868, as:
A mixture of triglycerides of saturated fatty acids, mainly of caprylic acid (octanoic
acid, C H C ) and of capric acid (decanoic acid, C 10H20O2). Medium-chain
triglycerides are obtained from the oil extracted from the hard, dried fraction of the
endosperm of Cocos nucifera L. or from the dried endosperm of Elaeis guineensis
Jacq. When Medium-chain Triglycerides are prepared from the endosperm of Cocos
nucifera L., the title Fractionated Coconut Oil may be used. Medium chain length
triglycerides have a minimum 95.0 per cent of saturated fatty acids with 8 and 10
carbon atoms. Further chemical and physical properties are described in the European
Pharmacopoeia Monograph 0868, and equivalent documents.
In especially preferred compositions, the triglyceride comprises a minimum of 95 per
cent of saturated fatty acids with between 6 and 12 carbon atoms. More preferably,
said triglyceride comprises a minimum of 95 per cent of saturated fatty acids with
between 8 and 10 carbon atoms.
In a preferred embodiment the triglyceride of the composition is a triglyceride sold
under the registered trade mark Miglyol®, and especially a miglyol selected from the
group comprising: miglyol 810; miglyol 812; miglyol 818; miglyol 829; and miglyol
840. Preferably the chosen miglyol is miglyol 810. Miglyol® is a medium chain
triglyceride containing saturated C8 and CIO fatty acids, typically between 65-80% of
caprylic acid (C8:0) and 20-35% of capric acid (C10:0).
Preferably, the triglyceride constitutes at least 90% (w/w) of the pharmaceutical
composition, preferably at least 95% (w/w), more preferably at least 97% (w/w), most
preferably at least 98% (w/w).
In a preferred embodiment the opioid of the composition comprising a medium chain
length triglyceride is not methadone. In a further embodiment the opioid of the
composition comprising a medium chain length triglyceride is fentanyl.
If fentanyl is selected then a total dose is preferably chosen from at least
50micrograms, at least 1OOmicrograms or at least 200micrograms and up to
500micrograms, up to 800 micrograms , up to lmg or up to 5mg. Particularly
preferred total doses include 200 micrograms and 800 micrograms. The concentration
of fentanyl selected is preferably at least 0.01%(w/w), at least 0.05%(w/w) or at least
0.1%(w/w), and up to 0.2%(w/w), up to 0.5%(w/w) or up to 1% (w/w). Preferably the
concentration of fentanyl selected is between 0.05%(w/w) and 0.5%(w/w).
In a further embodiment the opioid of the composition comprising a medium chain
length triglyceride is an analogue of fentanyl, such as alfentanil, sufentanil,
remifentanil, carfentanil and lofentanil.
The pharmaceutical composition of the invention comprising an opioid and a medium
chain length triglyceride is preferably contained within a container (for storage and/or
delivery) wherein the material of the container that is in contact with the composition
is polypropylene (PP). PP is a partially crystalline and transparent polymer. The
general formula for PP is as follows:
The heat and chemical resistance properties of PP and its rigidity make it a suitable
material for medical storage and delivery devices. A suitable source of PP is from the
provider Borealis, who market PP under the registered trademark "Bormed" (e.g.
Bormed HD810MO).
The inventors have surprisingly revealed that some opioid/triglyceride compositions
(e.g. comprising fentanyl and miglyol) are not compatible with COC or indeed with
Zylar ® (Styrene Methyl Methacrylate Acrylic copolymer). However, the inventors
have identified PP as an alternative suitable material with which opioid/ triglyceride
compositions are compatible, that is to say that such compositions show high stability
within containers wherein said compositions are in contact with PP.
Further optional components
In preferred embodiments any of said compositions, the compositions further
comprise a preservative (e.g. propyl or butyl parabens) and or a flavouring (e.g.
blackcurrant flavouring) and/or a sweetener (e.g. sodium saccharin) and/or an
essential oil such as menthol, vanillin or orange oil, lemon oil, clove oil, peppermint
oil, spearmint oil. The inventors have found that the addition of such an essential oil
surprisingly has three benefits: (1) the essential oil acts as a penetration enhancer,
improving the rate and extent of uptake of medicaments by the sublingual mucosa; (2)
the essential oil, in many cases, acts as a co-solvents thereby increasing the solubility
of medicaments; and (3) the essential oil provides a flavour component, giving
organoleptic feedback to a user of the medicament, to confirm that is has been
successfully delivered.
Delivery
Preferably the compositions of the present invention are comprised within a container
that comprises a delivery device, and preferably the device dispenses the composition
as a single discharge. Preferably the device is non-pressurised.
The compositions of the present invention can be delivered as a liquid bolus or,
preferably, as a spray comprising liquid droplets having a mean diameter of at least
about 10 microns, preferably at least 20 microns, more preferably from about 20 to
about 200 microns, most preferably from about 20 to about 100 microns. Preferably
the compositions are delivered as liquid droplets that have a size distribution of from
about 5 microns to about 500 microns, preferably from about 10 microns to about 200
microns, more preferably from about 20 microns to about 100 microns. Choice of
these droplet sizes ensures that the spray is prevented from passing into the lungs.
Larger droplets have larger weight and this is preferable in the invention because a
larger weight increases the chances that the droplet, and therefore the opioid, falls
rapidly onto the sublingual mucosa thereby reducing the possibility that the droplets
become entrained in breath and expelled from the mouth, or taken into the lungs. It is
therefore preferred that, for compositions of the invention comprising ethanol, the
weight of a spray droplet is at least 0.4ng, more preferably at least 3.3ng, more
preferably at least 400ng, more preferably at least 3.3mg, more preferably at least 5 g.
For compositions of the invention comprising miglyol it is preferred that the weight of
a spray droplet is at least 0.52ng, more preferably at least 4.2ng, more preferably at
least 520ng, more preferably at least 4^g, more preferably at least 5mg.
It is particularly preferred that each individual or successive dose has a volume of less
than 1000 microlitres. The use of small dose volumes reduces the likelihood that the
composition will be swallowed, or spat out, by the patient. The likelihood is reduced
further by use of smaller volumes (especially in the paediatric context) and so in
further preferred embodiments, each dose has a volume of less than 600 microlitres;
less than 500 microlitres; less than 400 microlitres; less than 300 microlitres; less than
200 microlitres; or even less than 100 microlitres. Smaller volumes are especially
preferred for paediatric use.
Preferably, the delivery devices according to these aspects comprise a spray,
preferably a non-pressurised spray, and especially a pump spray. The use of a pump
spray increases the area of mucosa to which the composition is applied, thereby
increasing absorption and minimising the likelihood that the medicament is
swallowed.
The material of the container/delivery device that makes contact with a composition
of the invention should be COC (for compositions comprising ethanol) or PP (for
compositions comprising a medium chain length triglyceride). The container/device
may also comprise parts that must be elastomeric, such as seals and/or plungers, and
for such parts the inventors have identified bromobutyl polymer, such as bromobutyl
rubber (a brominated copolymer of isobutylene and isoprene), as a suitable material
that is compatible with any composition of the invention (and particularly as a
material suitable for making contact with the a composition of the invention).
A suitable source of bromobutyl polymer is from the provider West Pharmaceutical
Services, and in particular West Formulation 4023/50 Gray.
Methods of treatment
A composition of the invention may be used in a method of treatment of the human or
animal body by therapy. In particular, a composition of the invention may be used in
a method whereby the application of an opioid confers medical benefit, including
methods of:
(a) reducing pain;
(b) inducing or maintaining anaesthesia;
(c) treating opioid dependence;
(d) treating anxiety;
(d) treating a cough; or
(e) treating diarrhoea;
preferably wherein said composition is administered sublingually in said method.
Furthermore, the inventors provide the use of a composition of the invention in the
manufacture of a medicament for reducing pain, inducing or maintaining anaesthesia,
or treating opioid dependence, anxiety, cough or diarrhoea.
The inventors also provide a method of treating a human or animal subject in need of
an opioid comprising the administration to said subject of a therapeutically effective
amount of a composition of the invention, whereby administration is by the sublingual
route. In such a method the subject may, for example, be suffering from pain, opioid
dependence, anxiety, cough or diarrhoea, or may require anaesthesia.
Examples
Example 1 - methadone formulation
Active Pharmaceutical Ingredient
The API is supplied by;
Macfarlane Smith
A Johnson Matthey PLC Business
Wheatfield Road
Edinburgh
EH11 2QA
Scotland
An EDMF is available. Methadone hydrochloride is monographed in the Ph Eur, BP
and USP. The Ph Eur/BP monograph is given in Appendix I
Its outline properties are;
(Ph Eur monograph 0408)
C2i 27NO,HCI 345.9 1095-90-5
A white, crystalline powder, soluble in water, freely soluble in alcohol.
Formulation Summary
Note that the use of the term pH herein covers not only aqueous solutions but also
ethanolic aqueous, purely ethanolic and other non-aqueous solutions. Thus the term
also covers "apparent pH" as defined in the USP ie the apparent pH reading from
formulations not wholly aqueous.
Initial formulation work considered the solubility of methadone hydrochloride at a
concentration of 100 mg/ml in aqueous solutions with ethanol and propylene glycol as
co-solvents. Dissolution was noticeably faster in solutions containing ethanol as a cosolvent.
It was also observed that after storage for approximately 1 month at 4°C and
40°C a fine particulate precipitate was formed in a purely aqueous solution compared
with an aqueous ethanolic solution. In addition, methadone dropped out of the
propylene glycol based solution after 1 week at 5°C and after 19 weeks at all tested
temperatures (in contrast to glycerol based compositions where methadone remained
in solution under the same conditions).
It was proposed that to aid sublingual absorption of basic drugs such as methadone the
pH should be buffered to approach the pKa of the drug, 8.2 for methadone. Therefore
various buffer systems were employed to adjust the pH of the formulation. It was
generally observed that when attempts were made to adjust the pH above 7.0
precipitation occurred on mixing or on storage. The precipitate is thought to be
methadone base. Therefore it appeared that the use of buffering agent with methadone
at pHs over 7 was not possible.
It was decided to concentrate on aqueous formulations containing ethanol (to aid
solubility and act as a preservative), propylene glycol or glycerol (moisturiser),
sodium saccharin (sweetener) and blackcurrant (flavour). Several different strengths
may be required for the eventual product formulations, therefore to bracket the
possible doses required, strengths of 10 mg per 400m1dose (25 mg/ml) and 60 mg per
400m1dose (150 mg/ml) were chosen.
These formulations all proved to be stable over the six month study with no evidence
of degradation. However a number of units were observed to have leaked, particularly
those at the higher strength. Additionally the contents of a small number of units were
observed to have changed colour to orange brown. These were observed at all
temperatures and across the formulations and also in placebo units that had been
prepared. A new ultrasonic welder was found to give a much improved and consistent
seal.
It was therefore decided to repeat the formulations containing glycerol (instead of
propylene glycol) but omitting the blackcurrant flavour. These formulations proved to
be stable after 6 months storage and were chosen for progression to a Phase I study as
10, 20 & 30 mg formulations. These lots were prepared to GMP, placed on stability
and one and three month data was satisfactory.
Formulation
Following initial preformulation work the following formulations were prepared at
lOOmg ml 1 (50ml);
1. 50mg methadone hydrochloride was weighed into a 50ml volumetric flask.
2 . Approximately 35mls of solvent was added and the flask shaken until the
methadone dissolved.
3 . Sodium saccharin was added to the flask and shaken until fully dissolved.
4 . The flask was made up to volume with solvent and shaken until homogeneous.
5 . The pH was adjusted to 8.2 with 0.1M NaOH.
PD01/07 required ultrasonication to dissolve the methadone HCL. Na saccharin
dissolved readily. Initial pH 4.7. Much 0.1M NaOH was added with precipitation at
each addition which re-dissolved. Final pH 7.0.
PD01/08a dissolved the API on shaking as well as the Na saccharin. Initial pH 4.9,
adjustment as the previous formulation.
PD01/08b required ultrasonication to dissolve the methadone HCL. Na saccharin
dissolved readily. Initial pH 4.9, adjustment as the previous formulations.
None of these initial formulations could be raised to a higher pH than 7.0 due to
precipitation. Each formulation was transferred into serum bottles and placed on
storage at 4, 25 and 40°C.
After storage for 1 week all samples remained clear, colourless solutions except for
PD01/08b (comprising propylene glycol) at 4°C which had significant precipitation.
The solutions were allowed to equilibrate to room temperature and examined after six
months storage;
PD01/07; all solutions were clear and colourless with fine white crystals at 4°C and
needle-like white crystals at 25°C. No particulates at 40°C. The samples were not r e
examined.
PD01/08a; all solutions were clear and colourless with no particulates. The pH of the
solutions was; 4°C 7.2.
25°C 7.1
40°C 7.1
After 14 months storage the 25 and 40°C solutions were unchanged, the 4°C sample
was as the other temperatures but with a number of crystals present.
PD01/08b; all solutions were clear and colourless with small white crystals adhering
to the glass at 4°C and two large white crystals at 25°C. No particulates at 40°C. The
samples were not re-examined.
The above emphasises that ethanolic aqueous formulations are more suitable for
methadone formulation.
The level of ethanol in the formulations was explored using the following
formulations (50ml);
1. The methadone hydrochloride was weighed into a 50ml volumetric flask.
2 . The ethanol was added followed by water to approximately 30ml.
3 . The flask was shaken to dissolve the methadone.
4 . The sodium saccharin was added and dissolved by shaking.
5. The volume was made up with water.
The dissolving of methadone was notably slower in PDO 1/1 l a than with the other
formulations with higher levels of ethanol. The sodium saccharin dissolved readily in
all formulations. The pH of all formulations was 5.0. Each formulation was
transferred into serum bottles and placed on storage at 4, 25 and 40°C. After four
months storage the solutions were allowed to equilibrate to room temperature and
examined;
PDOl/l la; 4°C contained a large quantity of white crystalline material, 25 & 40 °C
were clear colourless solutions. PDOl/l lb; As PDOl/lla but not so much material at
4°C. PDOl/l lc; all solutions were clear and colourless, pH; 4°C 5.1
25°C 5.3
40°C 5.3
After 13 months storage PDOl/1 l c 25 and 40°C samples were unchanged, 4°C sample
was as the other temperatures with the addition of fine white needle crystals.
The previous formulation work has shown that attempts to raise the pH of the
formulations has resulted in the formation of a precipitate which can be redissolved in
ethanol, anhydrous. Therefore if a higher pH is required the formulation will need the
presence of ethanol to keep the methadone base in solution. The following
formulation was prepared using pH 8.5 phosphate buffer;
1. The methadone was weighed into a 50ml flask and the ethanol added.
2 . The flask was stirred to dissolve the methadone.
3 . Stage 2 did not result in a solution so the propylene glycol was added and
stirred again without producing a solution.
4 . The phosphate buffer was added to within 5 ml of the total volume and mixed.
5 . The pH was adjusted to 8.5 and the solution made up to volume.
As the phosphate buffer was gradually added with mixing the methadone dissolved.
As more was added a precipitate formed from pH 7.2. The formulation was
transferred to a 100ml flask and ethanol added in 10ml portions. After the addition of
50mls of ethanol the precipitate dissolved to give a clear, colourless solution pH 7.2.
From the above it appears that the ethanolic aqueous type formulation is incapable of
formulation at pH higher than approximately 7.0. The solution was checked after
three months storage and found to be clear and colourless with white crystals and so
was discarded.
The effect of raising the ethanol level was investigated in the following formulation;
The method of preparation was as above (50ml). The methadone failed to dissolve
the ethanol but initially dissolved on addition of the buffer. As approximately 20ml
buffer was added transient precipitation occurred but rapidly cleared with stirring. The
final pH was 7.3. The solution was filled into serum bottles and stored at 4°C. After
three months storage the solution was found to remain clear, colourless and particle
free, pH 7.2. After one year's storage very fine white crystals were observed.
Following from the above formulations were prepared using water and citrate buffer;
The buffer was adjusted to pH 7.0 with 1M sodium hydroxide.
For both formulations the methadone hydrochloride dissolved within five minutes in
the water/buffer and ethanol mix. The propylene glycol mixed into the solution easily
leaving a clear, colourless solution. The solutions were placed at 4°C storage. After
storage for up to one month the solutions were examined physically and found not to
have changed pH. After 2½ months storage no change was observed and the pHs were
5.2 and 6.9 respectively. After 11 months storage no change was noted.
A formulation review was conducted at this stage in the study. It was decided to
concentrate on aqueous formulations containing ethanol (to aid solubility and act as a
preservative), propylene glycol or glycerol (moisturiser), sodium saccharin
(sweetener) and blackcurrant (flavour). Several different strengths may be required for
the eventual product formulations, therefore to bracket the possible doses required,
strengths of 10 mg per 400m1dose (25 mg/ml) and 60 mg per 400m1dose (150 mg/ml)
were chosen and 100ml volumes of each of the following formulations were prepared;
The formulations were prepared in 100ml volumetric flasks with shaking, all were
clear and colourless. Placebo formulations were also prepared for each of the above
(lots a & b; mean fill weights 388.5 & 406.2mg, RSD 0.5 & 0.6% respectively). The
formulations were filled into 70 spray units (400m1) and the remainder into serum
bottles. The samples were stored under ICH conditions at 5, 25/60, 30/65 &
40/75 °C/RH. The spray units were weighed before being placed on storage - see
stability sections below for results.
These formulations all proved to be stable over the six month study with no evidence
of degradation (see stability sections below for results). However a number of units
were observed to have leaked particularly those at the higher strength. The percentage
of units that had leaked is shown below. Additionally the contents of a small number
of units were observed to have changed colour to orange brown. These were observed
at all temperatures and across the formulations and also in placebo units that had been
prepared.
It was therefore decided to repeat the formulations containing glycerol (as PD01/036b
and PD01/036d) but omitting the blackcurrant flavour. 100ml volumes of the
following formulations were therefore prepared in 100ml volumetric flasks with
shaking.
Materials
For each formulation 100 spray unitdevices were filled with 400m1 and placed on
stability at ICH 5°C, 25°C/60%RH, 40°C/75%RH for a six month period, results are
shown in the stability sections below. At two weeks storage the samples were
checked for discolouration and weight loss. No discoloration was observed in any
sample and the weight loss was satisfactory except for 5 units found to have high
weight loss. At the one month timepoint 6/180 units had weight loss > 5% over all
storage conditions. No discolouration was observed. At 2 months 10/144 units had
weight loss > 5%. No discolouration was observed. At 3 months 8/108 units had
weight loss > 5%. No discolouration was observed. At 6months 4/72 had weight loss
>5%. No discolouration was observed.
These formulations proved to be stable and were chosen for progression to a Phase I
study as 10, 20 & 30 mg formulations.
In preparation for this, laboratory batches were prepared to check that the
formulations deliver the correct dose. As some of the product is retained by the device
and based on experience with earlier lots an 8% overage was used. The formulations
(10 & 20mg were prepared in 100ml volumetric flasks; 30mg was a 1 1 scale-up batch)
were;
The batches were assayed;
For the clinical trial supplies lots were prepared to GMP in a licensed facility using
the ultrasonic welder and placed on stability test. The batches manufactured were;
08-212 lOmg
08-213 20mg
08-214 30mg
The batches were prepared as 1L lots filled at 400m1. 615 units (approximately) were
prepared from each lot. No issues were encountered during manufacture. Half the
stability samples were packed in heat sealed aluminium pouches. See the stability
sections below for the stability results.
Device Design & Manufacture
The main body of the device was composed of Topas® COC. A bromobutyl polymer
was used for the drug chamber stopper and screw cap stopper (West Pharmaceutical
Services, West Formulation 4023/50 Gray).
Analytical Method Development and Validation - HPLC
The Ph Eur monograph for methadone hydrochloride does not have a HPLC method.
A method was used on the HP1050 system using the following;
Column Phenominex Gemini C18 150 x 4.6mm (HC-COL-001)
Flow 1.0 ml min
Detector uv @ 2 1Onm
Column Temperature 30°C
Injection Volume 2m1
Mobile Phase 1:1 v/v acetonitrile:water 0.1% trifluoroacetic acid
The run time for methadone hydrochloride was found to be 5.1 minutes with one other
peak (0.19%) at 2.6 minutes.
It was felt that the use of a milder buffer agent would be preferable so a pH 3.0
phosphate buffer would be evaluated keeping the remaining method details the same
but running on the Agilent 1100 system. Initially the methadone hydrochloride peak
was at 2.65 minutes but reducing the acetonitrile content to 40% gave 4.85 minutes
and to 35% gave 8.5 minutes.
In order to show that degradation of methadone is detected and quantified by the
HPLC method the solutions prepared as PDOl/01 were taken after 2½ months storage
and had reagents added to force degradation. Details of PDOl/01 are;
A 100mg/ml methadone hydrochloride in water stored at 4°C
B 100mg/ml methadone hydrochloride in water stored at 40°C
C 100mg ml methadone hydrochloride in water/ethanol, 50:50, stored at 4°C
D 100mg/ml methadone hydrochloride in water/ethanol, 50:50, stored at 40°C
The solutions were filtered and 4 x 750m1aliquots of each solution were added to 4
separate 1.5ml amber HPLC vials. 750m1of the appropriate reagent was then added as
listed below;
1M Hydrochloric Acid - Vial 1
0.1M Sodium Hydroxide - Vial 2
6% v/v Hydrogen Peroxide - Vial 3
Purified Water - Vial 4
A cap was crimped onto the vials and placed at 25°C for a week. The vials to which
the sodium hydroxide solution was added turned a milky white. After a week's
storage vials from lot A were diluted to 10ml with mobile phase and run on the
HP1050 using the above method. Some degradation was noted for the hydrogen
peroxide samples; in particular the following peaks; 2.45 mins 0.4%
2.60 mins 1.78% (two peaks)
2.97 mins 0.3%
The solution with sodium hydroxide added gave low methadone assays probably due
to insoluble methadone base. The results show methadone to be stable (no detected
degradation) with acids and bases. However the degradation found with the addition
of hydrogen peroxide shows methadone may be susceptible to oxidation.
Stability Summary
PD01/07 (aqueous) and PD01/08b (aqueous/propylene glycol) both with sodium
saccharin were examined after 14 weeks storage at 4, 25 & 40°C and found not to
have degraded. However after six months storage PD01/07 had white crystals at 4°C
and 25°C. PD01/08b had white crystals at 4°C from 1 week onwards and at 25°C at 6
months. PD01/08a (aqueous ethanolic) had clear colourless solutions at 4, 25 and
40°C at 14 months. From this it appears that he best formulation type for the product
should be based on aqueous ethanolic solutions (omitting propylene glycol).
PDOl/1 la, b & c which were aqueous formulations with escalating levels of ethanol
were examined after 6 and 13 weeks at 4, 25 & 40°C and found not to have degraded.
Physically all formulations gave clear colourless solutions at 4, 25 and 40°C at 13
weeks. After 4 months storage PDOl/1 l a had white crystals at 4°C as did PDOl/1 lb.
PDOl/1 l c had no crystal at any temperature. However at 13months PDOl/1 l c had
white crystals at 4°C. From this it appears that at least 15% ethanol in an aqueous
solution is required to maintain methadone solubility.
PD01/20 was prepared which has a higher (38.9%) level of ethanol and used a
phosphate buffer. It was stored at 4°C and was a clear colourless solution at 3 months
but had white crystals at 1 year.
PD01/22 a & b, ethanol/water and ethanol/aqueous citrate buffer respectively
formulations with propylene glycol were examined after 4 weeks storage at 4°C and
found not to have degraded. Methadone was 11%. Physically the solutions when
stored at 4°C were clear and colourless at 2 weeks, 10 weeks and 11 months.
PD01/36a - d were 60 and lOmg formulations based on aqueous/ethanolic solvent
containing blackcurrant flavour with either sodium saccharin or glycerol. The sodium
saccharin formulations also contained propylene glycol. The formulations were filled
into spray devices as described above. The devices stored at 5, 25, 30 and 40°C ICH
conditions were examined after 1, 2 and 6 months and were found not to have
degraded. Assay, delivered dose and ethanol content results were all satisfactory.
After three months storage some units at 5°C across all formulations and placebos
were discoloured pale orange/brown. The stored solutions were clear and colourless.
At six months the discolouration was noted again. The discoloration was attributed to
the blackcurrant flavour.
The glycerol formulations outlined in the previous paragraph were repeated with the
blackcurrant flavour omitted; PDO1/049 & 5 1 (60 and lOmg) and filled into the spray
devices. The devices stored at 5, 25, and 40°C ICH conditions were examined after 1,
2 and 6 months and were found not to have degraded. All solutions were clear and
colourless. Assay, delivered dose and ethanol content results were all satisfactory.
It was concluded that the discolouration issue had been resolved and that these
formulations formed the basis for formulations suitable to be taken into a Phase I
study. The study would, for safety reasons, have an escalating dose of 10, 20 and 30
mg only. It was decided that an 8% overage would be applied to the methadone HC1
concentration to allow for material left in the device ie the devices would deliver 10,
20 & 30 mg methadone HC1.
The clinical trial batches were prepared in a GMP facility as; 08-212, 08-213 & 08-
214 for the 10, 20 & 30mg batches respectively. Samples were placed on stability
storage at 5, 25, 30 and 40°C ICH conditions, half the samples were packed in heat
sealed aluminium pouches. Units have been examined at 1, 3 and 6 months. No
changes in physical appearance have been found at any temperature. Assay, delivered
dose, methadone HC1 concentration and ethanol content results were all satisfactory.
No significant degradation has been observed at any temperature.
Stability at 9months was completed for units from 5, 25 and 30°C ICH conditions and
all results for content by HPLC and ethanol content by GC were in limits and no
colour change or solubility issues were seen at this time point. Due to contractual
problems stability at 12 months was not possible therefore stability at 16 months was
completed. The units were tested at 5, 25 and 30°C; all HPLC results were within
limits and GC results (with the exception of one sample) were within limits. No
colour change or solubility issues were seen at this time point. No degradation was
observed and this product has a shelf life of 2 years.
Stability Results
Definitions:
Description - conforms if clear, colourless solution
Degradation -
As ICH guidelines;
Reporting threshold 0.1%
Identification threshold 0.2%
Qualification threshold 0.5%
Uniformity of content -
The preparation complies with the test if not more than one individual content is
outside the limits of 85 per cent to 115 per cent of the average content and none is
outside the limits of 75 per cent to 125 per cent of the average content. The
preparation fails to comply with the test if more than three individual contents are
outside the limits of 85 per cent to 115 per cent of the average content or if one or
more individual contents are outside the limits of 75 per cent to 125 per cent of the
average content. If 2 or 3 individual contents are outside the limits of 85 per cent to
115 per cent but within the limits of 75 per cent to 125 per cent, determine the
individual contents of another 20 dosage units taken at random. The preparation
complies with the test if not more than three of the individual contents of the 30 units
are outside the limits of 85 per cent to 115 per cent of the average content and none is
outside the limits of 75 per cent to 125 per cent of the average content.
Uniformity of mass -
Determine the individual masses of 10 containers emptied as completely as possible,
and calculate the average mass. Not more than 2 of the individual masses deviate by
more than 10 per cent from the average mass and none deviates by more than 20 per
cent.
PD01/07 & 08a
PD01/07
PD01/08a
PD01/08b
PDOl/lla, b&c
PDOl/lla
PDOl/llb
PD01/22a&b
PD01/22a
PD01/22b
PD01/36
After standing at room temperature for 8 days prior to testing all the propylene glycol
formulations had gained weight. Additional peaks were found in the chromatograms which
were also observed identically in the placebos. These were therefore concluded to be from the
excipients and are not degradents and thus were not reported.
PD01/36a
PD01/36D
PD01/36C
PD01/36d
After three months storage it was observed that some of the 60mg units had leaked and had a
white crystalline deposit around the base of the units and plugs. This occurred at all
temperatures.
It was also noted that some units stored at 5°C across all formulations and placebos were
discoloured pale orange/brown. The stored bulk solutions were still clear and colourless.
At six months pale orange/brown discolouration was noted in a few (2 @ 40°C, 2@30°C &
1@5°C) out of 79 units assayed. Some continuing evidence of poor sealing is shown by high
weight loss displayed by some units.
PD01/049 & 51
Delivered Ethanol
Methadone Delivered dose as Content
PD01/051 (mg/dose) dose (nig) %of fill Degradation %w/w
No significant
Initial n=5 9.6 386.3 95.7 degradation 19.3
5°C
No significant
1 month n=3 9.8 390.0 94.5 degradation 17.5
No significant
2 month n=4 9.6 391.5 95.9 degradation 18.7
No significant
3 month n=4 10.0 400.2 96.9 degradation
No significant
6 month n=4 9.1 397.9 97.1 degradation 16.8
25°C/60%RH
No significant
1 month n=3 9.3 393.7 93.3 degradation 18.6
n=4 No significant
2 month 9.7 388.1 94.9 degradation 19.2
n=4 No significant
3 month 9.8 384.6 93.7 degradation
n=4 No significant
6 month 9.1 392.7 93.5 degradation 18.9
40°C/75%RH
No significant
1 month n=3 9.7 387.0 95.1 degradation 18.5
No significant
2 month n=4 9.7 393.0 95.2 degradation 18.3
No significant
3 month n=2 9.9 386.5 94.1 degradation
6 month n=4 398.1 97.7 18.6
All solutions were clear and colourless
Phase I Clinical trial Supplies 08-212, 08-213 & 08-214;
P = Pouched, U = Unpouched.
08-212, l O g
08-212, lOmg
All solutions were clear and colourless.
08-213, 20 g
08-213, 20mg
All solutions were clear and colourless.
08-214, 30mg
08-214, 30mg
All solutions were clear and colourless.
Pharmacokinetic studies
A confidential phase 1, single centre, open label, semi randomized three way crossover
trial was carried out to determine the pharmacokinetics of single doses of methadone
sublingual spray, and to establish the relative bioavailability with methadone syrup in
healthy male subjects.
Objectives:
The primary objectives of this study were to:
· assess the single dose pharmacokinetics of methadone sublingual spray in healthy
male subjects;
• determine the bioavailability of methadone sublingual spray relative to methadone
syrup in healthy male subjects; and
determine the dose proportionality between two different doses of methadone
sublingual spray
The secondary objectives of this study were to:
establish the safety, tolerability and taste acceptance of methadone sublingual
spray in healthy subjects
Methodology/study design:
Subjects were required to provide their written informed consent prior to any study related
procedures being conducted. Subjects were screened for eligibility within 28 days of first
study admission on Day - 1. Eligible subjects were required to participate in three study
periods, with a washout interval of at least one week between the study periods. For each
treatment period, subjects were admitted to the clinical unit the evening prior to dosing.
Naltrexone block was administered to subjects at the investigators discretion. Subjects
received their three treatments in a semi-randomised way such that the highest dose
sublingual spray was only given after each individual subject had first received the lower
dose sublingual spray. Subjects were closely monitored in the clinic for at least 24 hours
after dosing and returned for 2 outpatient visits for blood sampling. After the last
treatment period, subjects returned for a post study follow up visit.
Number of subjects (analysed):
A total of 7 healthy male subjects were enrolled in the study. One subject was withdrawn
following the first treatment period (methadone syrup). The replacement subject
completed the remaining two treatment periods. Five subjects completed all three
treatment periods. Seven (7) subjects entered the study and were included in the safety
and pharmacokinetic populations.
Diagnosis and Main Criteria for Inclusion:
Healthy male subjects aged 18-45 and with a BMI within the range 18-29 were eligible
for the trial.
Test Product, Dose and Mode of Administration Batch Number(s):
Methadone sublingual spay lOmg/actuation, batch number 08-212 (Treatment A)
Methadone sublingual spay 20mg/actuation, batch number 08-213 (Treatment B)
Reference Product, Dose and Mode of Administration, Batch Number(s):
Biophine syrup (5mg methadone HCl/mL), batch number 100492 (Treatment C)
Duration of Treatment:
The planned study duration was approximately 8 weeks, while the duration of treatment
was approximately 3 weeks.
Criteria for Evaluation:
Pharmacokinetic variables -
Blood samples were collected for pharmacokinetic analysis at the following timepoints:
Predose and 2, 5, 10, 15, 30, 45, 60 minutes and 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 48 and 72
hours after dosing .The following pharmacokinetic parameters for methadone were
calculated by standard non-compartmental methods using WinNonlin Ver 5.0.1: AUC o-t,
AUC Cmax, Tmax, , 1 /2, CL F, V/F and F. SPSS Ver 17.0 was used for the statistical
analysis.
Statistical Methods:
All statistical analyses were appropriate to the nature and distribution of the data
collected. These are detailed in the pharmacokinetic analysis plan.
Pharmacokinetics -
Pharmacokinetic samples from all treatment periods were analysed for methadone
concentrations. Statistical analysis was based on data from all treatment periods for all
subjects studied. Individual subject profiles and mean profiles of the plasma concentration
for methadone by treatment were produced.
The pharmacokinetic parameters AUC o t , AUC o ¥, Cmax, Tmax, ¾ 1 1/2 , CL/F, V/F and F
were listed by treatment, and where appropriate suitable statistical comparisons were
made.
Summary of Pharmacokinetic Results and Conclusions:
Summary PK Parameters for methadone by treatment -
Pharmacokinetic Summary
Treatment A Treatment B Treatment C
Parameter Statistic
Mean 1067.49 2147.34 1287.72
AUC 0-72 (ng.h/mL)
CV 8.34 8.38 17.61
1319.17 2752.84 1777.47
AUC (ng.h/mL) Mean
CV 7.87 12.95 22.60
35.9 73.4 44.4
m (ng/mL) Mean
CV% 15.95 13.20 19.99
29.65 31.51 37.73
t (hours) Mean
CV 9.80 13.34 19.83
tm (hours) 3.0 4.0 2.0
Median
Range 1.5 - 6.0 0.8 - 4.0 1.5 - 8.0
326101 331044 312280
V/F (mL) Mean
CV 13.18 8.18 18.24
Mean 7617.50 7364.60 5841.57
CL/F (mL/hour)
CV 8.07 12.58 19.89
Summary of statistical analysis of bioavailability and dose proportionality -
Pharmacokinetic Summary Treatment A/ Treatment Treatment
Parameter Statistic Treatment C B/Treatment C B/Treatment A
Ratio of
0.845 1.747 2.011
LOg 10 AUC means
0.733 - 0.973 1.483 - 2.058 1.841 - 2.197
90% CI
Ratio of
0.825 1.689 2.050
Log 1 Cm
means
0.650 - 1.048 1.392- 2.050 1.757 - 2.392
90% CI
T 0.37 0 0.42
Z
Pvalue 0.72 1.00 0.67
2.47 1.78 -0.89
t t 1
Pvalue 0.03 0.11 0.39
Following sublingual administration of methadone, the rate of absorption as indicated by
t m was slower than that for the oral comparator dosage form. Additionally, the tmax was
longer (4.Oh vs 3 .Oh) for treatment B (20mg methadone sublingual spray) than for
treatment A (lOmg methadone sublingual spray). The relative bioavailability of treatment
A compared to treatment C was 84.5% based on AUC and 82.5% based on Cmax: this
increases to about 88% if comparisons are made on paired observations only. The /2 for
the oral formulation was about 20% longer than for treatment A, the sublingual
formulation, a difference that was statistically significant. Treatments A and B were
shown to be dose proportional.
A comparison of plasma methadone concentration profiles for sublingual and syrup
administration of a 1Omg dose is shown in Figure 1. Surprisingly, sublingual
administration does not lead to an initial spike in blood methadone concentration, in
comparison to what has been previously observed with other opioids delivered
sublingually (and to some extent in comparison to the oral route as demonstrated by the
syrup data).
For most of the PK parameters, the variability as evidenced by CV% was lower following
the sublingual route of administration than for that following the oral route of
administration, making the sublingual composition of the invention a safer methadone
product.
Example 2 - fentanyl formulation
Stability for Fentanyl in miglyol: 200ug/dose
Stability for Fentanyl in miglyol: 800ug/dose
Miglyol is not compatible with Topas, therefore this formulation had to be used in
polypropylene. No degradation of fentanyl was observed at any timepoint or temperature
but there was some indication of degradation of the orange flavour.
CLAIMS
1. A pharmaceutical composition for the sublingual delivery of an opioid comprising an
opioid and ethanol.
2. A composition according to claim 1 that additionally comprises glycerol.
3. A composition according to claim 1 or claim 2 wherein the opioid is not fentanyl.
4. A composition according to any one of claims 1to 3 wherein said opioid is methadone.
5. A composition according to any one of claims 1 to 4 that is comprised within a
container and wherein the material of the container that is in contact with the composition
is Cyclic Olefin Copolymer (COC).
6. A pharmaceutical composition for the sublingual delivery of an opioid comprising an
opioid and a medium chain length triglyceride wherein the composition is comprised
within a container and wherein the material of the container that is in contact with the
composition is polypropylene.
7. A composition according to claim 6 wherein the opioid is not methadone.
8. A composition according to claim 6 wherein said opioid is fentanyl.
9. A composition according to any one of claims 5 to 8 wherein the container comprises a
delivery device.
10. A composition according to claim 9 wherein the delivery device dispenses the
composition in a single discharge.
11. A composition according to claim 9 or claim 10 wherein the delivery device
dispenses the composition as a spray.
12. Acomposition according to claim 11wherein said spray comprises liquid droplets
having a mean diameter of at least about 10 microns, preferably at least about 20 microns,
more preferably between about 20 microns and about 200 microns, and most preferably
between about 20 microns and about 100 microns.
13. Acomposition according to any one of claims 9to 12 wherein the delivery device is
non-pressurised.
14. Acomposition according to any one of claims 9to 13 wherein the delivery device
comprises seals and/or plungers and wherein the material of said seals and/or plungers
that is in contact with the composition is bromobutyl polymer.
15. Acomposition according to any one of the preceding claims for use in a method of
treatment of the human or animal body by therapy.
16. Acomposition according to any one of the preceding claims for use in a method of:
(a) reducing pain;
(b) inducing or maintaining anaesthesia;
(c) treating opioid dependence;
(d) treating anxiety;
(d) treating a cough; or
(e) treating diarrhoea.
17. Amethod of treating a human or animal subject in need of an opioid comprising the
administration to said subject of a therapeutically effective amount of a composition
according to any one of claims 1to 14 by the sublingual route.
18. Amethod according to claim 17 wherein said subject:
(a) is suffering from pain, opioid dependence, anxiety, cough or diarrhoea; or
(b) is in need of anaesthesia.