SUBLINGUAL PHARMACEUTICAL COMPOSITION
COMPRISING A NEUTRAL OIL
Field of the Invention
The invention relates to improved methods of delivery for medicaments, and to devices
for drug 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 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 the 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.
It is among the objectives of the present invention to attempt a solution to these problems.
Summary of the Invention
Accordingly, the invention provides a pharmaceutical composition for the sublingual
delivery of a medicament comprising: a neutral oil; and a medicament soluble in said oil;
wherein said medicament is in solution in said oil at a concentration providing a required
dose in a volume of no more than 1ml of composition; providing that said medicament is
not nitroglycerine.
The requirement for a composition for sublingual drug delivery is very different than that
for oral drug delivery. Oral drug delivery requires adsorption of the drug from the
gastrointestinal tract for which the drug is ideally soluble in the aqueous solutions found
there. However, for sublingual drug delivery the product needs to be lipophilic to be
adsorbed from the sublingual region of the body. Thus, formulations having a hydrophilic
nature of this patent would not result in good adsorption. Such formulations are at risk of
being washed down into the gastrointestinal tract without being adsorbed. Many of the
drugs that may be used for sublingual delivery in this way are not absorbed from the
gastrointestinal tract, and might lead to undesirable side-effects.
Particular medicaments envisaged include especially opioids such as fentanyl and
buprenorphine, pharmaceutically acceptable salts thereof, analogues thereof or derivatives

thereof. Other opioids envisaged include: alfentanil, sufentanil, butorphanol, codcine,
hydrocodone, hydromorphone, levorphanol, meperidine, methadone, morphine,
nalbuphine, oxycodone, oxymorphbne, propoxyphene, tramadol, fenpipramide,,
pentazocine, piritramide, tilidine, tramadol, pharmaceutically acceptable salts thereof, or
derivatives thereof, and the like.
Preferably, said medicament is in solution in said oil at a concentration providing a
required dose of medicament in a volume of no more than 500microlitres of composition;
more preferably in a volume of no more than 200microlitres of composition, and most
preferably in a volume of no more than 100microlitres of composition.
The use of such pharmaceutical compositions for delivery of medicaments by the
sublingual route is appropriate, therefore, for those medicaments that have a suitably high
solubility in neutral oils such that a required dose (e.g. an effective dose for a required
pharmaceutical action) may be dissolved in a relatively small volume of composition, as
above. This is particularly important, as the inventors have found that the sublingual
delivery route offers (for many medicaments) substantial and hitherto unappreciated
benefits over other administration routes. It is particularly beneficial over the oral route in
which a medicament is often 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. As a consequence,
unwanted side-effects might be experienced. In order to avoid oral absorption, the
medicament is therefore delivered in a small volume, enough to coat the sublingual
mucosa and to reduce the likelihood that any composition may be swallowed. The skilled
addressee will be readily able to determine whether a chosen medicament has sufficient
solubility, and examples are given below to show how this might be done.
The invention is especially concerned with compositions for the delivery of medicaments
by the sublingual route for systemic treatment of an individual, rather than for
medicaments for use as a topical treatment.

A further preferred feature is that the medicament 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 medicament is stable within the composition, to
pharmaccutically-acccptable limits over a period of at least one month, preferably 6
months and most preferably for a year.
Preferably, said neutral oil comprises a glyceride, and more preferably a triglyceride.
In especially preferred embodiments said triglyceride comprises miglyol, and especially a
miglyol selected from the group comprising: miglyol 810; miglyol 812; miglyol 818;
miglyol 829; and miglyol 840.
Also in especially preferred embodiments said neutral oil comprises an oil selected from
the group comprising: Refined Maize Oil (Ph Eur); Virgin Castor Oil (Ph Eur); Refined
Olive Oil (Ph Eur) and Refined Rapeseed Oil (Ph Eur).
Also in especially preferred embodiments said neutral oil comprises an oil selected from
the group comprising: Glycerol mono-oleates (Ph Eur); Linoleoyl Macrogolglycerides (Ph
Eur); Oleoyl Macrogolglycerides (Ph Eur); Vegetable Fatty Oils (Ph Eur); rich in
triglycerides, Medium Chain Triglycerides (Ph Eur); Coconut Oil (Ph Eur); Fractionated
Palm Kernel Oil (Ph Eur); Hydrogenated Cottonseed Oil (Ph Eur); Omega-3-Marine
Triglycerides (Ph Eur); Fish Oil, Rich in Omega-3-Acids (Ph Eur); Cod Liver Oil (Ph
Eur); Diglycerides; Monoglycerides; and Diglycerol.
Also in especially preferred embodiments said neutral oil comprises derivates or partial
glycerides of an oil selected from the group comprising: Glycerol mono-oleates (Ph Eur);
Linoleoyl Macrogolglycerides (Ph Eur); Oleoyl Macrogolglycerides (Ph Eur); Vegetable
Fatty Oils (Ph Eur); rich in triglycerides, Medium Chain Triglycerides (Ph Eur); Coconut
Oil (Ph Eur); Fractionated Palm Kernel Oil (Ph Eur); Hydrogenated Cottonseed Oil (Ph

Eur); Omega-3-Marine Triglycerides (Ph Eur); Fish Oil, Rich in Omega-3-Acids (Ph
Eur); Cod Liver Oil (Ph Eur); Diglycerides; Monoglycerides; and Diglycerol.
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,
C8H16O2) and of capric acid (decanoic acid, C10H20O2). 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 arc 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.
Omega-3-marine triglycerides are defined in the European Pharmacopoeia Monograph
0868 as mixture of mono-, di- and triesters of omega-3 acids with glycerol containing
mainly triesters and obtained either by esterification of concentrated and purified omega-3
acids with glycerol or by transesterification of the omega-3 acid ethyl esters with glycerol.
The origin of the omega-3 acids is the body oil from fatty fish species coming from
families like Engraulidae, Carangidae, Clupeidae, Osmeridae, Salmonidae and
Scombridae. The omega-3 acids are identified as the following acids: alpha-linolenic acid
(C18:3 n-3), moroctic acid (C18:4 n-3), eicosatetraenoic acid (C20.4 n-3), timnodonic
(eicosapentaenoic) acid (C20:5 n-3; EPA), heneicosapentaenoic acid (C21:5 n-3),
clupanodonic acid (C22:5 n-3) and cervonic (docosahexaenoic) acid (C22:6 n-3; DHA).
The sum of the contents of the omega-3 acids EPA and DHA, expressed as triglycerides is
a minimum of 45.0 per cent, and the total omcga-3 acids, expressed as triglycerides is a
minimum of 60.0 per cent. Tocopherol may be added as an antioxidant.
Fish oil, rich in omega-3-acids is also defined in the European Pharmacopeia as purified,
winterised and deodorised fatty oil obtained from fish of the families Engraulidae,

Carangidae, Clupeidae, Osmeridae, Scombridae and Ammodytidae. The omega-3 acids
are defined as the following acids: alpha-linolenic acid (C18:3 n-3), moroctic acid (C18:4
n-3), eicosatetraenoic acid (C20:4 n-3), timnodonic (eicosapentaenoic) acid (C20:5 n-3;
EPA), heneicosapentaenoic acid (C21:5 n-3), clupanodonic acid (C22:5 n-3) and cervonic
(docosahexaenoic) acid (C22:6 n-3; DHA).
The content of the Fish oil, rich in omega-3-acids is as follows:
EPA, expressed as triglycerides: minimum 13.0 per cent,
DHA, expressed as triglycerides: minimum 9.0 per cent,
Total omega-3-acids, expressed as triglycerides: minimum 28.0 per cent.
In preferred embodiments any of said compositions, the compositions consist essentially
of said neutral oil; and a medicament soluble in said oil.
In alternative embodiments of the above compositions, it is preferred that said
composition further comprises a co-solvent selected from the group comprising: ethanol;
isopropanol; propylene glycol; and polyethylene glycol.
In preferred embodiments any of said compositions, the compositions further comprise an
excipient selected from the group comprising: an antioxidant; a preservative; a mucosal
penetration enhancer, and a flavouring. Preferably, said flavouring or mucosal
penetration enhancer comprises 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 oils surprisingly has three benefits: (1) the essential oils act
as penetration enhancers, improving the rate and extent of uptake of such medicaments by
the sublingual mucosa; (2) the essential oils, in many cases, act as co-solvents thereby
increasing the solubility of medicaments; and (3) the essential oils provide a flavour
component, giving organoleptic feedback to a user of the medicament, to confirm that is
has been successfully delivered.

In preferred embodiments of any individual such composition, it is preferred that said
medicament is not fentanyl, derivatives thereof such as sufentanil, carfentanil, lofentanil,
alfentanil, or the like, and pharmaceutically acceptable salts thereof.
Also in preferred embodiments of any individual such composition, it is preferred that
said medicament is not an artemesinin (including, without limitation, artemether, arteether
and artesunate).
Also in preferred embodiments of any individual such composition, it is preferred that
said medicament is not dihydropolyprenol (especially dihydroheptaprenol), probucol or
tacrolimus.
Also in preferred embodiments of any individual such composition, it is preferred that
said medicament is not a benzodiazepine.
In some conditions responsive to treatment with compositions or medicaments disclosed
herein, patients may exhibit mucusitis and a dry mouth, especially when taking opioids.
The inventors have found that miglyol may be used as the sole solvent for the active
compounds (with the exception of buprenorphine, which requires the use of ethanol as a
co-colvent); this allows formulations to exclude ethanol and other alcohols as a co-
solvent, which is particularly beneficial, as alcoholic preparations are particularly
irritating to a dry mouth, or to patients having mucusitis and may cause discomfort or pain
to the patient. Accordingly, in preferred embodiments of compositions disclosed herein,
the composition is substantially, or preferably entirely free of ethanol and more preferably
substantially, or preferably entirely free of other alcohols. Formulations such as this have
an additional benefit that they may be used in cultural or religious contexts where alcohol
intake is not permitted.
Additionally, the additional of alcohols to such lipophilic compositions has the effect of
reducing the particle size of droplets (by surface tension and viscosity effects) when the
compositions are delivered in the form of a spray. This can lead to the formation of
droplets less than 20µm, or even less than 10µm, which can allow droplets to reach the

lungs, which is undesirable. Furthermore, alcohols can have the effect of "closing down"
the mucosa, thereby having a deleterious effect on absorption of the medicament.
Also in embodiments of any individual such composition, it is preferred that said
composition has less than 20%(w/w), more preferably less than 10%(w/w); more
preferably still less than 5%(w/w); and most preferably less than l%(w/w) of surfactant.
In especially preferred embodiments, the composition is essentially free of surfactant. A
key feature of the success of sublingual delivery is the provision of an essentially
hydrophobic (lipophilic) composition; this leads to the composition remaining on the
sublingual mucosa for absorption by that route. If surfactants are present within the
composition, there is more likelihood that the composition will be able to mix with the
essentially aqueous saliva in the mouth, leading to increased possibility that the
composition will be moved away from the sublingual mucosa and, in extremis, swallowed
by a user, thereby leading to oral rather than sublingual dosing.
Also included within the scope of the invention is a delivery device adapted to deliver
successive doses of a composition according to any preceding claim, said doses
comprising liquid droplets having a mean diameter of at least about 10 microns.
Preferably the compositions of the present invention are delivered as liquid droplets
having a mean diameter of at least about 20 microns, more preferably a mean diameter of
from about 20 to about 200 microns. Most preferably the formulations are delivered as
liquid droplets have a size distribution of from about 5 microns to about 500 microns,
preferably from about 10 microns to about 200 microns, preferably from about 20 microns
to about 100 microns, more preferably from about 30 microns to about 70 microns.
Choice of these droplet sizes ensures that the spray is prevented from passing into the
lungs.
It is particularly preferred that each individual or successive dose has a volume of less
than 1000 micro litres. 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 or for nasal

delivery) and so in further preferred embodiments, each successive dose has a volume of
less than 600 microlitres; less than 400 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, 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.

Description of Preferred Embodiments
The inventors have found that the use of sublingual delivery of medicaments is more
broadly useful in overcoming the problems of drug delivery described above than has
hitherto been recognised. The sublingual venous bed drains into the systematic
circulation rather than the hepatic circulation, and so the problems of the first pass effect
are removed. Furthermore, the bypassing of the hepatic portal system during drug uptake
prevents the autoinduction that, for many medicaments, leads to reduction of
bioavailability of drugs on successive doses. The use of a sublingual delivery route also
means that medicaments may be delivered, avoiding the oral route, by non-trained
personnel, in contrast to the alternative of intravenous injection that might be used to
avoid the first-pass effect. Additionally, some drugs are not able to be formulated for
intravenous injection. Additional benefits of sublingual delivery are that, by careful
choice of excipients and droplet sizes, accidental delivery of drug by the oral route can be
avoided, thereby preventing the unwanted complications of the oral delivery route.
Whilst some sublingual formulations have been used, these are often formulated using
propellants and irritant excipients such as alcohols. For some patients, e.g. those who
might have sensitive mucosa as a symptom of their condition, these excipients are
unwelcome. In some preferred embodiments, therefore, formulations specifically exclude
propellants and alcoholic excipients.
By way of non-limiting example, the following formulations of oil-soluble medicaments
are proposed:



Additional excipients found by the inventors to be readily soluble in miglyol, and
therefore of us in formulation of the present invention include:
Flavourings: Orange oil; Lemon oil; Aniseed; Peppermint; and Menthol
Preservatives: Propyl parabens and Butyl parabens
Antioxidants: Butylated Hydroxy Toluene; Butylated Hydroxy Anisole and alpha
tocopherol
It has been thought that oil-based excipients can lead to low absorption of medicaments.
International Patent Application WO2007087431 teaches that "... studies also showed that
fentanyl base formulation containing Miglyol had very low permeability ". In contrast to
these findings, the inventors have found that the use of oil-based excipients as recited
herein, for oil-soluble drugs, surprisingly leads to highly efficient uptake of the
medicaments.
As an example, the inventors have carried out confidential trials of sublingual uptake of
the artemesinin arteether, described in co-pending International Patent Application
PCT/GB2008/050999, and reproduced here:

dihydroartemesinin were determined, in order to compare bioavailability by the two
routes.
Figures 1-6 show mean plasma concentration of artemether following two comparison
dose regimes. Figures 7-12 show the corresponding mean plasma concentration of
dihydroartemesinin.
Figures 1 and 7 compare regimes T1 (open squares) and T4 (closed circles): 15mg
artemether via 5 sublingual spray doses vs. 30mg artemether via tablet.
Figures 2 and 8 compare regimes T2 (open squares) and T4 (closed circles): 30mg
artemether via 10 sublingual spray doses vs. 30mg artemether via tablet.
Figures 3 and 9 compare regimes T3 (open squares) and T4 (closed circles): 30mg
artemether via 5 sublingual spray doses vs. 30mg artemether via tablet.
Figures 4 and 10 compare regimes Tl (open squares) and T2 (closed circles): 15mg
artemether via 5 sublingual spray doses vs. 30mg artemether via 10 sublingual spray
doses.
Figures 5 and 11 compare regimes T2 (open squares) and T3 (closed circles): 30mg
artemether via 10 sublingual spray doses vs. 30mg artemether via 5 sublingual spray
doses.
Figures 6 and 12 compare regimes Tl (open squares) and T3 (closed circles): 15mg
artemether via 5 sublingual spray doses vs. 30mg artemether via 5 sublingual spray
doses).
Pharmacokinetic data for each of the four dosage regimes are given in Tables 8-11,
below:

For comparison of bioavailability of artemether via the sublingual spray route described
herein with administration by oral tablets, we have calculated the F-values, commonly
used to compare two dose regimes, generally A and B, for the artemether data, as follows:

This indicates that approximately between 1.7 and 2.2 times more artemether was
absorbed when administered as a sublingual spray as described herein by comparison to
oral administration by tablet, despite the oral dose being twice as large in the first
instance. The indicative bioavailability by the sublingual route is therefore at least twice
that by the oral route for equivalent doses.
Inspection of the data of Tables 8-11, and Figures 1-12 also confirms this general finding
for the primary active metabolite of artemether (dihydroartemesinin).
Avoidance of Autoinduction
It is known that both oral and rectal administration of artemesinins is associated with
autoinduction of the drug metabolism in individuals (see e.g. Ashton M, Hai TN, Sy ND,
Huong DX, Van Huong N, Nieu NT, Cong LD. "Artemisinin pharmacokinetics is time-
dependent during repeated oral administration in healthy male adults.", Drug Metab
Dispos. 1998; 26:25-7, and "Retrospective analysis of artemisinin pharmacokinetics:
application of a semiphysiological autoinduction model", Asimus and Gordi, Br. J Clin
Pharmacol. 2007 June; 63(6): 758-762). As a result, systemically circulating artemesinin

declines with each successive dose, thereby reducing the effectiveness of drug dosage
regimes.
In confidential trials, the inventors have found that administration of artemesinins by the
transmucosal sublingual route avoids such autoinduction, leading to consistent uptake and
accumulating systemic concentration of the active drug metabolite, dihydroartemesinin,
thereby providing significant advantage in administration by the sublingual route. A
similar avoidance of autoinduction is expected with delivery by the transmucosal buccal
or nasal route.
In confidential trials, volunteers followed the following treatment: A single administration
of 30mg artemether sublingual spray 6mg/actuation on days 1 and 5 following an
overnight fast, and twice daily administrations of 30mg artemether sublingual spray
3mg/actuation on days 2, 3,and 4 following a morning or evening meal. Blood samples
were collected for pharmacokinetic analysis at the following time points:
Day 1: Predose, 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 6, 8, and 12 h after dosing.
Days 2, 3, and 4: pre morning dose and 0.5, 1, 2 and 4 h after morning dose and pre
evening dose and 1 hour after evening dose.
Day 5: Predose, 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12 h and 24 h after dosing.
Pharmacokinetic analysis of plasma dihydroartemesinin on days 1 and 5 revealed an
effectively identical response, indicating the lack of autoinduction. Plasma concentration
curves are shown in Figure 14.
Solubility of Medicaments
By way of example, to show how the skilled addressee might determine whether such
compositions are suitable for a given medicament, solubility tests have been carried out
on a number of pharmaceutical actives as detailed below. All drugs were used at their
lowest concentration as used in IV injections, with the exception of Amoxicillin and
Diphenhydramine. Solutions were prepared in Miglyol 810.

Amoxicillin: 4g of Amoxicillin was weighed into a beaker and 50ml of Miglyol was
added. This was then diluted to 100ml with Miglyol. The pale yellow suspension was
magnetically stirred but didn't dissolve. Amoxicillin appears not to be soluble in Miglyol.
However, the Amoxicillin used contained other excipients.
Budesonide: 50mg of Budesonide was weighed into a beaker and 50ml of Miglyol was
added. This was then diluted to 100ml with Miglyol. After extensive magnetic stirring a
suspension was seen that did not dissipate upon further dilution and subsequent stirring.
After the addition of heat and menthol (to separate solutions) the Budesonide was seen to
dissolve. Budesonide appears to be soluble with the addition of heat or menthol.
Diphenhydramine: 2.5g of Diphenhydramine was weighed into a beaker and 50ml of
Miglyol was added. After stirring, a further 150ml of Miglyol was added. A pale white
cloudy suspension was seen that became less cloudy upon magnetic stirring.
Diphenhydramine appears to be sparingly soluble in Miglyol.
Ketoprofen: lg of Ketoprofen was weighed into a beaker and 50ml of Miglyol was added.
A cloudy off-white suspension was seen that did not lighten upon magnetic stirring.
Ketoprofen appears to be insoluble in Miglyol. (See below with respect to solubility
enhancement.)
Ketorolac: 750mg of Ketorolac was weighed into a beaker and 50ml of Miglyol was
added. After stirring, a further 50ml of Miglyol was added. A Pale white, very cloudy
suspension was seen that did not dissipate upon magnetic stirring. Ketorolac appears to
be insoluble in Miglyol.
Lamivudine: 500mg of Lamivudine was weighed into a beaker and 50ml of Miglyol was
added. After extensive magnetic stirring a cloudy white suspension was seen that did not
dissipate. Lamivudine appears to be insoluble in Miglyol.

Lidocaine Base: 1.25g of Lidocaine Base was weighed into a beaker and 50ml of Miglyol
was added. After magnetically stirring for approximately 15 minutes the solution became
slightly less cloudy, and after a further 15 minutes stirring the solution became clear.
Lidocaine Base is readily soluble in Miglyol.
Loratadine: 500mg of Loratadine was weighed into a beaker and 50ml of Miglyol was
added. After magnetically stirring for 15 minutes a clear solution was observed.
Loratadine is readily soluble in Miglyol.
Melatonin: 3.75g of Melatonin was weighed into a beaker and 50ml of Miglyol added.
This was then further diluted to 100ml then 200ml with Miglyol. After magnetic stirring,
a thick pale yellow suspension was seen. After initially diluting to 100ml then to 200ml
the solution did not change. Melatonin appears to be insoluble in Miglyol.
Nalbuphine HCl: 500mg of Nalbuphine HC1 was weighed into a beaker and 50ml of
Miglyol was added. The suspension was magnetically stirred for approximately 40
minutes but no change was seen. Nalbuphine HCl is not soluble in Miglyol.
Naloxone: 100mg of Naloxone was weighed into beaker and 50ml of Miglyol was added.
Upon magnetically stirring a cloudy solution was observed but no particulate matter was
seen on the bottom. Naloxone appears to be sparingly soluble in Miglyol.
Naltrexone Base: lg of Naltrexone Base was weighed into a beaker and 50ml of Miglyol
was added. This was further diluted to 100ml with Miglyol. For the first dilution a cloudy
suspension was seen that did not dissipate. Upon the addition of 50ml of Miglyol and
further stirring the suspension appeared to lighten. Naltrexone Base appears to be
sparingly soluble. It may dissolve completely at a lower concentration. (See below with
respect to solubility enhancement.)
Ondansetron HCl: lg of Ondansetron HCl was weighed into a beaker and 50ml of
Miglyol was added. This was further diluted to 100ml with Miglyol. A cloudy

suspension was seen that did not dissolve upon magnetic stirring or the addition of 50ml
of Miglyol. Ondansetron HC1 appears to be insoluble.
Prilocaine Base: 1.25g of Prilocaine base was weighed into a beaker and 50ml of
Miglyol was added. Upon magnetically stirring for 5 minutes a clear solution was seen
with slight particulate matter resting on the bottom that dissolved after standing.
Prilocaine Base appears to be readily soluble in Miglyol.
Salbutamol Sulphate: 200mg of Salbutamol Sulphate was weighed into a beaker and
50ml of Miglyol was added. After extensive magnetic stirring a cloudy white suspension
was seen. Salbutamol Sulphate appears to be insoluble in Miglyol.
Sildenafil Citrate: lg of Sildenafil Citrate was weighed into a beaker and 10ml of
Miglyol was added. This was further diluted to 50ml with Miglyol. A dense white
suspension was observed that did not dissipate upon magnetic stirring. Sildenafil Citrate
appears to be insoluble in Miglyol.
Sildenafil Base: lg of Sildenafil Base was weighed into a beaker and 10ml of Miglyol
was added. This was further diluted to 50ml with Miglyol. A dense white suspension was
observed that did not dissipate upon magnetic stirring. Sildenafil Base appears to be
insoluble in Miglyol.
Terbutaline Sulphate: 50mg of Terbutalinc Sulphate was weighed into a beaker and 50ml
of Miglyol was added. A fine suspension was seen that did not dissipate upon magnetic
stirring. Terbutaline Sulphate appears to be insoluble in Miglyol.
Tramadol HCl: 2.5g of Tramadol HC1 was weighed into a beaker and 50ml of Miglyol
was added. A cloudy suspension was seen that did not dissipate upon magnetic stirring.
Tramadol HCl appears to be insoluble in Miglyol.

Zidovudine: 500mg of Zidovudine was weighed into a beaker and 50ml of Miglyol was
added. A cloudy white suspension was seen that did not dissipate upon stirring.
Zidovudine appears to be insoluble in Miglyol.
Solubility Enhancement by Essential Oils
Further tests established the solubility enhancement effect of heat and, surprisingly, the
additional of an essential oil; menthol was used in this example.
Ketoprofen: 50mg of Ketoprofen was weighed into a beaker and 50ml of Miglyol was
added. The samples dissolved with heat or menthol, thought much faster with heat.
Ketoprofen is soluble in Miglyol with the addition of heat or menthol.
Naltrexone Base: 100mg of Naltrexone Base was weighed into a beaker and 50ml of
Miglyol was added. The samples dissolved with heat or menthol, thought much faster
with heat. Naltrexone Base appears to be soluble with the addition of heat or menthol.
For the medicaments tested above that showed good solubility in Miglyol (Lidocaine
Base, Prilocaine Base, Loratadine and Budesonide), further studies were carried out to
assess the solubility limits and to provide example formulations to guide the skilled
addressee in applying the invention to formulation for other medicaments:
Lidocaine Base: An approximate solubility limit was found to be approximately
140mg.mr'. Three formulations were made and are shown in Table 10.1.
Prilocaine Base: An approximate solubility limit was found to be approximately
137mg.mr'. Three formulations were made and are shown in Table 10.2.
Loratadine: An approximate solubility limit was found to be approximately 20mg.mr'.
Three formulations were made and are shown in Table 10.3.

Supplementary Figure Captions
Figure 1: Plot of mean plasma Artemether concentration vs time with standard deviation
following a single sublingual administration of 15mg Artemether Sublingual Spray
3mg/actuation (T1) and single oral administration of 30mg Artemether Tablets 10
mg/tablet (T4). Mean + SD (• = reference, T4 , D = test, Tl)
Figure 2: Plot of mean plasma Artemether concentration vs time with standard deviation
following a single sublingual administration of 30mg Artemether Sublingual Spray
3mg/actuation (T2) and single oral administration of 30mg Artemether Tablets 10
mg/tablet (T4). Mean ± SD (• = reference, T4 , □ = test, T2)
Figure 3: Plot of mean plasma Artemether concentration vs time with standard deviation
following a single sublingual administration of 30mg Artemether Sublingual Spray
6mg/actuation (T3) versus single oral administration of 30mg Artemether Tablets 10
mg/tablet (T4). Mean + SD (• = reference, T4 , □ = test, T3)
Figure 4: Plot of mean plasma artemether concentration vs time with standard deviation
following a single sublingual administration of 15mg Artemether Sublingual Spray
3mg/actuation (T1) versus single sublingual administration of 30mg Artemether
Sublingual Spray 3mg/actuation (T2). Mean ± SD (• = reference, T2 , □ = test, T1)
Figure 5: Plot of mean plasma Artemether concentration vs time with standard deviation
following a single sublingual administration of 30mg Artemether Sublingual Spray
3mg/actuation (T2) versus single sublingual administration of 30mg Artemether
Sublingual Spray 6mg/actuation (T3). Mean ± SD (• = reference, T3 , □ = test, T2)
Figure 6: Plot of mean plasma Artemether concentration vs time with standard deviation
following a single sublingual administration of 15mg Artemether Sublingual Spray
3mg/actuation (Tl) versus single sublingual administration of 30mg Artemether
Sublingual Spray 6mg/actuation (T3). Mean + SD (• = reference, T3 , □ = test, T1)

Figure 7: Plot of mean plasma Dihydroartemisinin concentration vs time with standard
deviation following a single sublingual administration of 15mg Artemether Sublingual
Spray 3mg/actuation (T1) and single oral administration of 30mg Artemether Tablets 10
mg/tablet (T4). Mean ± SD (• = reference, T4 , □ = test, Tl)
Figure 8: Plot of mean plasma Dihydroartemisinin concentration vs time with standard
deviation following a single sublingual administration of 30mg Artemether Sublingual
Spray 3mg/actuation (T2) and single oral administration of 30mg Artemether Tablets 10
mg/tablet (T4). Mean ± SD (• = reference, T4 , □ = test, T2)
Figure 9: Plot of mean plasma Dihydroartemisinin concentration vs time with standard
deviation following a single sublingual administration of 30mg Artemether Sublingual
Spray 6mg/actuation (T3) versus single oral administration of 30mg Artemether Tablets
10 mg/tablet (T4). Mean + SD (• = reference, T4 , a = test, T3)
Figure 10: Plot of mean plasma Dihydroartemisinin concentration vs time with standard
deviation following a single sublingual administration of 15mg Artemether Sublingual
Spray 3mg/actuation (Tl) versus single sublingual administration of 30mg Artemether
Sublingual Spray 3mg/actuation (T2). Mean ± SD (• = reference, T2 , □ = test, Tl)
Figure 11: Plot of mean plasma Dihydroartemisinin concentration vs time with standard
deviation following a single sublingual administration of 30mg Artemether Sublingual
Spray 3mg/actuation (T2) versus single sublingual administration of 30mg Artemether
Sublingual Spray 6mg/actuation (T3). Mean ± SD (• = reference, T3 , □ = test, T2)
Figure 12: Plot of mean plasma Dihydroartemisinin concentration vs time with standard
deviation following a single sublingual administration of 15mg Artemether Sublingual
Spray 3mg/actuation (Tl) versus single sublingual administration of 30mg Artemether
Sublingual Spray 6mg/actuation (T3). Mean + SD (• = reference, T3 , a = test, Tl)

CLAIMS
1. A pharmaceutical composition for the sublingual delivery of a medicament
comprising:
a neutral oil; and
a medicament soluble in said oil;
wherein said medicament is in solution in said oil at a concentration providing a
required dose in a volume of no more than 1ml of composition;
providing that said medicament is not nitroglycerine.
2. A composition according to claim 1 wherein said neutral oil comprises a glyceride.
3. A composition according to claim 2 wherein said glyceride comprises a triglyceride.
4. A composition according to claim 3 wherein said triglyceride comprises miglyol.
5. A composition according to claim 4 wherein said miglyol comprises miglyol selected
from the group comprising:
miglyol 810;
miglyol 812;
miglyol 818;
miglyol 829; and
miglyol 840.
6. A composition according to claim 1 wherein said neutral oil comprises an oil selected
from the group comprising:
Refined Maize Oil (Ph Eur);
Virgin Castor Oil (Ph Eur);
Refined Olive Oil (Ph Eur) and
Refined Rapeseed Oil (Ph Eur).

7. A composition according to claim 1 wherein said neutral oil comprises an oil selected
from the group comprising:
Glycerol mono-oleates (Ph Eur);
Linoleoyl Macrogolglycerides (Ph Eur);
Oleoyl Macrogolglycerides (Ph Eur);
Vegetable Fatty Oils (Ph Eur); rich in triglycerides
Medium Chain Triglycerides (Ph Eur);
Coconut Oil (Ph Eur);
Fractionated Palm Kernel Oil (Ph Eur);
Hydrogenated Cottonseed Oil (Ph Eur);
Omega-3-Marine Triglycerides (Ph Eur);
Fish Oil, Rich in Omega-3-Acids (Ph Eur);
Cod Liver Oil (Ph Eur);
Diglycerides;
Monoglycerides;
Diglycerol.
8. A composition according to claim 1 wherein said neutral oil comprises derivates or
partial glycerides of an oil selected from the group comprising:
Glycerol mono-oleates (Ph Eur);
Linoleoyl Macrogolglycerides (Ph Eur);
Oleoyl Macrogolglycerides (Ph Eur);
Vegetable Fatty Oils (Ph Eur); rich in triglycerides
Medium Chain Triglycerides (Ph Eur);
Coconut Oil (Ph Eur);
Fractionated Palm Kernel Oil (Ph Eur);
Hydrogenated Cottonseed Oil (Ph Eur);
Omega-3-Marine Triglycerides (Ph Eur);
Fish Oil, Rich in Omega-3-Acids (Ph Eur);
Cod Liver Oil (Ph Eur);
Diglycerides;
Monoglycerides;

Diglycerol.
9. A composition according to any preceding claim consisting essentially of said neutral
oil; and a medicament soluble in said oil.
10. A composition according to any preceding claim, substantially free of ethanol.
11. A composition according to claim 10, substantially free of alcohols.
12. A composition according to any of claims 1 to 9, further comprising a co-solvent
selected from the group comprising:
ethanol;
isopropanol;
propylene glycol;
polyethylene glycol.
13. A composition according to any preceding claim, further comprising an excipient
selected from the group comprising:
an antioxidant;
a preservative;
a mucosal penetration enhancer;
a flavouring.
14. A composition according to claim 13 wherein said mucosal penetration enhancer
comprises an essential oil.
15. A composition according to claim 13 wherein said flavouring comprises an essential
oil.
16. A pharmaceutical composition according to any preceding claim providing that said
medicament is not fentanyl, derivatives thereof such as sufentanil, carfentanil, lofentanil,
alfentanil, or the like, and pharmaceutically acceptable salts thereof.

17. A pharmaceutical composition according to any preceding claim providing that said
medicament is not an artemesinin (including, without limitation, artemether, arteether and
artesunate).
18. A pharmaceutical composition according to any preceding claim providing that said
medicament is not dihydropolyprenol (especially dihydroheptaprenol), probucol or
tacrolimus.
19. A pharmaceutical composition according to any preceding claim having less than
20% (w/w) of surfactant.
20. A pharmaceutical composition according to claim 19 having less than 10%(w/w) of
surfactant.
21. A pharmaceutical composition according to claim 20 having less than 5%(w/w) of
surfactant.
22. A pharmaceutical composition according to claim 21 having less than l%(w/w) of
surfactant.
23. A pharmaceutical composition according to claim 22 essentially free of surfactant.
24. A delivery device adapted to deliver successive doses of a composition according to
any preceding claim, said doses comprising liquid droplets having a mean diameter of at
least about 10 microns.
25. A delivery device according to claim 24 wherein said droplets have a mean diameter
of at least about 20 microns.
26. A delivery device according to either of claims 24 and 25 wherein said droplets have
a mean diameter of from about 20 to about 200 microns.

27. A delivery device according to any of claims 24 to 26 wherein said doses are
delivered by a pump spray.

The invention provides pharmaceutical compositions for the sublingual delivery of medicaments comprising a neutral
oil and a medicament soluble in said oil, providing that said medicament is not nitroglycerine. The invention also provides delivery
devices adapted for sublingual delivery of such compositions.