SUBLINGUAL SPRAY FORMULATION COMPRISING
DIHYDROARTEMESININ
Field of the Invention
The invention relates to pharmaceutical compositions, delivery methods, delivery devices
and methods for the treatment of cancer. The invention also relates to pharmaceutical
compositions, delivery methods, delivery devices and methods for the treatment of fluke
infestations and Lyme disease (Borreliosis).
Background and Prior Art Known to the Applicant
Artemesinins, which may be isolated from the plant Artemesia annua are known for the
treatment of malaria, and have also been shown to be effective for the treatment of a wide
range of cancers, i.e. neoplasms, and especially malignant neoplasms. Amongst reported
successes are the following:
Sing and Panwar {Integrative Cancer Therapies, 5(4): 2006, 391-394) report the treatment
of pituitary adenoma with artemether.
Singh and Verma (Archive of Oncology, 10(4): 2002, 279-280) report the treatment of
laryngeal squamous cell carcinoma with artesunate.

Singh and Lai {Life Sciences, 70(2001) 49-56) report the selective toxicity of
dihydroartemesinin and holotransferrin toward human breast cancer cells.
Rowen (Townsend Letter for Doctors and Patients, December 2002) provides a summary
of the use of artemisinins for the treatment of various cancers, including breast cancer,
non-Hodgkin's Lymphoma, non-small cell lung carcinoma, and multiple skin cancers.
Efferth et al ("Anti-malaria drug is also active against cancer", Int. J. Oncology, 18; 767-
773, 2001) report activity of artemesinins against 55 cancer lines.
It is believed that the artemesinins have this broad effect on a large range of cancer cells
because of their ability to react with ferrous iron to form free radicals: and most cancer
cells have high rates of iron intake.
In addition, artemesinins have been shown to be effective in the treatment of liver flukes,
and in particular schistosomiasis. Keiser and Morson {Exp. Parasitol., 118(2), 2008: 228-
37) report the activity of artesunate and artemether against the liver fluke Fasciola
hepatica.
Keiser et al {J. Antimicrobial Chemotherapy, 2006, 57, 1139-1145) also report that
artesunate and artemether are effective fasciolicides.
Utzinger et al {Curr Opin Investig Drugs, 2007 Feb 8(2), 105-16) report the use of
artemesinins for treatment of individuals infested with Plasmodium spp. and Schistosoma
haematobium with promising activity or artemesinins against intestinal and liver flukes,
as well as against cancer cells.
Recent observations have also found that artemesinins are active against bacteria of the
genus Borrelia, the causative agent of Lyme disease. Borrelia burgdorferi is the
predominant cause of Lyme disease in the United States, Borrelia afzelii and Borrelia
garinii being more common agents in most European cases.

Accordingly, amongst the active pharmaceuticals of use in the treatment of these
conditions are a number of compounds derived from artemesenin, a sesquiterpene lactone
endoperoxide originally isolated from Artemesia annua (Woodrow etal. Postgrad. Med. J.
2005; 81:71-78). These compounds include the semi-synthetic derivatives artenimol,
artesunate, artemether and arteether (artemotil). The International Pharmacopoeia {Ph.
Int., World Health Organisation) lists a number of these for the treatment of malaria
(against which they are also active), viz: Artemether in the form of capsules, tablets or an
injectable formulation; Artemesenin in the form of capsules or tablets; arteether in an
injectable formulation; and both artenimol and artesunate in the form of tablets.
Once taken into the body, the artemesinins are converted to dihydroartemesinin and so
these active compounds include all those that supply dihydroartemesinin in vivo.
One particular problem with the administration of artemesinins is their low bioavailability
and the presence of a first pass effect when taken by the oral route, as will be discussed
below. Furthermore, for long-term cancer treatment, it is particularly preferred that
patients are able to either self-administer medication, or that medication can be
administered by a non-qualified helper, and particularly in the home environment. This
allows patients to remain at home, and reduces pressure on the healthcare system.
Furthermore, cancer patients are often immune-compromised, and it is therefore
particularly beneficial to keep them out of e.g. a hospital environment where the chances
of contracting infections are higher. For these reasons at least, oral doses of artemesinins
are not effective, especially for long-term treatment as might be required for cancer
therapy, for treatment of fluke infestations or treatment of Lyme disease; injectable
treatments are prone to risk of infection, need medically-qualified personnel and are not
stable during storage; suppository administration is also not acceptable in many cultures,
and might not be repeatably absorbed where patients are experiencing diarrhoea.
It can be seen that all of these formulations face the difficulties of administration
described above. It is therefore amongst the objects of the present invention to address
these and other issues.

Summary of the Invention
Accordingly, in a first aspect, the invention provides a pharmaceutical composition for the
treatment of neoplasms comprising: a compound capable of providing
dihydroartemesinin; and a pharmaceutically-acceptable excipient selected the group
consisting of: medium chain length triglycerides; short chain triglycerides; omega-3-
marine triglycerides; and fish oil, rich in omega-3-acids, said composition formulated for
transmucosal sublingual, buccal or nasal dosage.
In a second aspect, the invention provides a pharmaceutical composition for the treatment
of fluke infestation comprising: a compound capable of providing dihydroartemesinin;
and a pharmaceutically-acceptable excipient selected the group consisting of: medium
chain length triglycerides; short chain triglycerides; omega-3-marine triglycerides; and
fish oil, rich in omega-3-acids, said composition formulated for transmucosal sublingual,
buccal or nasal dosage.
In a third aspect, the invention provides a pharmaceutical composition for the treatment of
Lyme disease (borreliosis) comprising: a compound capable of providing
ihydroartemesinin; and a pharmaceutically-acceptable excipient selected the group
consisting of: medium chain length triglycerides; short chain triglycerides; omega-3-
marine triglycerides; and fish oil, rich in omega-3-acids, said composition formulated for
transmucosal sublingual, buccal or nasal dosage.
The inventors have found that the transmucosal sub-lingual, transmucosal buccal and
transmucosal nasal routes for administration of artemether or arteether are effective for
delivery of the pharmaceutical into the systemic circulation e.g. for the treatment of
cancer and fluke infestation. Furthermore, for the first time, it provides an administration
route that is acceptable to patients requiring treatment, and that may be administered by
non-medically qualified personnel. It has particular advantage, therefore, in treating these
conditions. The composition can be delivered e.g. sublingually as a liquid bolus, or, more
preferably, as a spray.

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 ofElaeis 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.
Short chain triglycerides are triglycerides having chain lengths of less than 6 carbon
atoms.
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-linolcnic 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 omega-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.
Authorized antioxidants in concentrations not exceeding the levels specified by the
competent authorities may be added.
Whilst these definitions serve to define particularly preferred compositions of the recited
excipients, the skilled addressee will appreciate that the composition of appropriate
alternative excipients may also deviate from these exact compositional limits. Excipients
of choice should exhibit analogous chemical properties such as the ability to solubilise
artemether or arteether or other compounds providing dihydroartemesinin at the required
concentration, not to degrade the pharmaceutically active ingredients, and to be non-toxic.
The excipients should also have analogous physical properties such as at least being liquid
at body temperature, and preferably having a suitable viscosity to allow the excipient to
be used in preferred spray formulations described below. The viscosity for these
applications should be low enough to be capable of atomizing, as described below, when
used in a pump spray.
As an example, compositions might consist essentially of artemether or arteether and a
pharmaceutically acceptable excipient consisting essentially of a triglyceride, liquid at
37°C, and medium chain triglycerides (as defined herein).
Particularly preferred compositions of the invention consist essentially of: artemether or
arteether; and one or more pharmaceutically-acceptable excipients selected the group
consisting of: medium chain length triglycerides; short chain triglycerides; and omega-3-
marine triglycerides, said composition formulated for transmucosal sublingual, buccal or

nasal dosage. The exclusion of significant amounts of other materials (e.g. higher
molecular weight lipids) renders a composition that is ideally suited to transmucosal
nasal, buccal, and especially sublingual delivery.
More preferred compositions comprise: artemether and a pharmaceutically-acceptable
excipient selected the group consisting of: medium chain length triglycerides; short chain
triglycerides; and omega-3-marine triglycerides, said composition formulated for
transmucosal sublingual, buccal or nasal dosage, and especially a composition consisting
essentially of: artemether and a pharmaceutically-acceptable excipient selected the group
consisting of: medium chain length triglycerides; short chain triglycerides; and omega-3-
marine triglycerides, said composition formulated for transmucosal sublingual, buccal or
nasal dosage.
In any of these compositions, it is especially preferred that the composition is
substantially free of water, as the inventors have found, contrary to accepted belief, that
water can significantly reduce the shelf-life of the compositions, especially when stored at
ambient temperatures. Preferred compositions would have less than l%(w/w) water, and
more preferably less than 0.5%(w/w) wateT, and most preferably less than 0.1%(w/w)
water.
Also in any of these compositions, it is especially preferred that the composition is
substantially free of ethanol. Again, the inventors have found that ethanol leads to
degradation of the pharmaceutically active components. Preferred compositions in
particular have less than l%(w/w) ethanol, and more preferably less than 0.5%(w/w)
ethanol and most preferably less than 0.1%(w/w) ethanol.
Also in any of these compositions, it is preferred that artemether or arteether is present at
a concentration of between 2 and 250 milligrams per gram of excipient. This
concentration provides an appropriate level for the expected volumes used for the
described transmucosal delivery. More preferably, the composition comprises: artemether
or arteether, dissolved in the excipient at a concentration of between 2 and 200 milligrams
per gram of excipient. Other preferred concentrations are between 2 and 100 milligrams
per gram; between 2 and 50 milligrams per gram. The lower concentrations provide

compositions particularly suitable for paediatric use, and are also more likely to ensure
that the pharmaceutically active components remain in solution over a wide temperature
range, rather than having some portion as e.g. a suspension. This is particularly important
to ensure that delivery of the drug is by the recited transmucosal route. Tf significant
amounts of the active components are not in solution, then there is an increased likelihood
that some will be swallowed, thereby reducing the beneficial effects of such transmucosal
delivery described below.
In especially preferred compositions, the said excipient comprises a medium chain
triglyceride, said triglyceride comprising a minimum of 95 per cent of saturated fatty
acids with between 6 and 12 carbon atoms. More preferably, said excipient comprises a
medium chain triglyceride, said triglyceride comprising a minimum of 95 per cent of
saturated fatty acids with between 8 and 10 carbon atoms.
Also in any such composition, it is also particularly preferred that the composition further
comprises an essential oil such as menthol, vanillin or orange oil, lemon oil, clove oil,
peppermint oil, spearmint oil. Particular technical advantages of such an essential oil,
especially menthol, which acts as a solubilising agent, are described further below. In
addition to any solubilising effect such essential oils also act as flavourings, having a
number of benefits: the flavours mask unpleasant tastes of the medicament thereby
leading to increased patient compliance. This is particularly important for such
essentially liquid-based formulations which cannot by their nature be encapsulated or
"sugar-coated". The flavours also give a feedback to the user or administrator of the
medication that the medication has been successfully delivered (the patient can taste it),
and furthermore that it has been delivered to the correct place.
In a second aspect, the invention provides a medicament delivery device containing a
composition described herein, said device adapted to deliver individual or successive
doses of said composition, each individual or successive dose having 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 micro litres; less than 400 micro litres; less than 200 micro litres; or even less
than 100 micro litres. Smaller volumes are especially preferred for paediatric use, or nasal
delivery.
In a third aspect, the invention provides a medicament delivery device containing a
composition described herein, said device and composition adapted to deliver individual
or successive doses of said composition, each individual or successive dose containing no
more than 100mg, and preferably no more than 80mg of a compound capable of providing
dihydroartemesinin, such as artemether or arteether. Such devices are preferably adapted
to assist sublingual delivery, especially by non-mcdically trained personnel. Limiting the
amount of active pharmaceutical delivered with each dose is especially important in the
context of treatment by less skilled personnel (e.g. self-administration by a patient in a
domestic setting, which is likely for long-term anti cancer therapy) to ensure that over-
dosing is avoided. Preferably, said device and composition adapted to deliver individual
or successive doses of said composition, each individual or successive dose containing no
more than 10mg of a compound capable of providing dihydroartemesinin, such as
artemether or arteether. This provides an appropriate device 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. More preferably, said device is adapted to produce a
spray of composition having a mean droplet diameter greater than 20 microns, or even
greater than 50 microns, or preferably greater than 75 microns. In this way, inadvertent
delivery of the medicament to the lungs is avoided, or reduced.
In a fourth aspect, the invention also provides a device for providing pharmaceutical doses
comprising a container containing a pharmaceutical composition described herein, and
valve means arranged to transfer doses of said pharmaceutical composition to the exterior
of the container. Such a device may be attached to e.g. a separate transmucosal buccal,
nasal or sublingual delivery device, such as a spray.

In a fifth aspect, the invention provides a kit for the treatment of neoplasms, fluke
infestation or Lyme disease comprising a composition described herein and instructions to
administer said composition to a patient in need thereof by the transmucosal sublingual,
buccal or nasal route. Preferably, said kit has instructions to administer said composition
to a patient in need thereof by the sublingual route.
In a sixth aspect, the invention provides a method of treating neoplastic diseases, fluke
infestation or Lyme disease comprising the administration to a patient in need thereof of a
therapeutically effective amount of a compound providing dihydroartesinin (e.g. an
artemesinin, and especially artemether or arteether) by the transmucosal sublingual,
buccal or nasal route. More preferably, said administration is by the sublingual route.
Also included in the scope of the invention is the use of a compound providing
dihydrartemesinin in the preparation of a pharmaceutical composition according to any of
the aspects, or preferred aspects, described above for the treatment of neoplastic diseases,
fluke infestation or Lyme disease.
Preferably, any of the pharmaceutical compositions or devices provided by the present
invention are for the treatment of neoplasms, fluke infestation or Lyme disease.
In any of the compositions of the invention it is particularly preferred that the composition
also includes a transferrin, such as holotransferrin, as this enhances the action of
dihydroartemesinin.
In any methods of treatment of the invention it is also particularly preferred to co-
administer a transferrin, such as holotransferrin, as this enhances the action of
dihydroartemesinin.
In any methods of treatment of the invention it is also particularly preferred that said
compound providing dihydroartemesinin is formulated in a composition described above.
Also included within the scope of the invention are pharmaceutical compositions,
medicament delivery devices, kits and methods substantially as described herein, with

reference to, and as illustrated by any appropriate combination of the accompanying
drawings.
Disclaimed Embodiments
In preferred embodiments of the invention, the following numbered aspects, disclosed in
co-pending International Patent Application PCT/GB2008/050999 are particularly
disclaimed:
1. A pharmaceutical composition comprising:
artemether or arteether; and
a pharmaceutically-acceptable excipient selected the group consisting of:
medium chain length triglycerides;
short chain triglycerides;
omega-3-marine triglycerides; and
fish oil, rich in omega-3-acids
said composition formulated for transmucosal sublingual, buccal or nasal dosage.
2. A composition according to aspect 1 consisting essentially of:
artemether or arteether; and
one or more pharmaceutically-acceptable excipients selected the group consisting
of:
medium chain length triglycerides;
short chain triglycerides;
omega-3-marine triglycerides; and
fish oil, rich in omega-3-acids
said composition formulated for transmucosal sublingual, buccal or nasal dosage.
3. A composition according to aspect 1 comprising:
artemether and
a pharmaceutically-acceptable excipient selected the group consisting of:
medium chain length triglycerides;
short chain triglycerides;

omega-3-marine triglycerides; and
fish oil, rich in omega-3-acids
said composition formulated for transmucosal sublingual, buccal or nasal dosage.
4. A composition according to aspect 1 consisting essentially of:
artemether and
one or more pharmaceutically-acceptable excipients selected the group consisting
of:
medium chain length triglycerides;
short chain triglycerides; and
omega-3-marine triglycerides; and
fish oil, rich in omega-3-acids
said composition formulated for transmucosal sublingual, buccal or nasal dosage.
5. A composition according to aspect 1 consisting essentially of:
artemether or arteether, and
a pharmaceutically acceptable excipient consisting essentially of:
a triglyceride, liquid at 37°C; and
medium chain length triglycerides;
said composition formulated for transmucosal sublingual, buccal or nasal dosage.
6. A composition according to any preceding aspect, substantially free of water.
7. A composition according to any preceding aspect, substantially free of ethanol.
8. A pharmaceutical composition according to any preceding aspect wherein artemether
or arteether is present at a concentration of between 2 and 250 milligrams per gram of
excipient.
9. A composition according to any preceding aspect wherein said excipient comprises a
medium chain triglyceride, said triglyceride comprising a minimum of 95 per cent of
saturated fatty acids with between 6 and 12 carbon atoms.

10. A composition according to aspect 8 wherein said excipient comprises a medium
chain triglyceride, said triglyceride comprising a minimum of 95 per cent of saturated
fatty acids with between 8 and 10 carbon atoms.
11. A composition according to any preceding aspect further comprising an essential oil
such as menthol, vanillin or orange oil, lemon oil, clove oil, peppermint oil, spearmint oil.
12. A composition according to any preceding aspect for the treatment or prophylaxis of
malaria.
13. A composition according to any preceding aspect formulated for sublingual delivery.
14. A medicament delivery device containing a composition according to any preceding
aspect, said device adapted to deliver individual or successive doses of said composition,
each individual or successive dose having a volume of less than 1000 micro litres.
15. A medicament delivery device containing a composition according to any preceding
aspect, said device and composition adapted to deliver individual or successive doses of
said composition, each individual or successive dose containing no more than 80mg of
artemether or arteether.
16. A medicament delivery device containing a composition according to any preceding
aspect, said device and composition adapted to deliver individual or successive doses of
said composition, each individual or successive dose containing no more than 10mg of
artemether or arteether.

17. A delivery device according to any of aspects 14 to 16 wherein said device comprises
a pump spray.
18. A delivery device according to aspect 17 wherein said device is adapted to produce a
spray of composition having a mean droplet diameter greater than 20 microns.

19. A device for providing pharmaceutical doses comprising a container containing a
pharmaceutical composition according to any of aspects 1 to 13, and valve means
arranged to transfer doses of said pharmaceutical composition to the exterior of the
container.
20. A kit for the treatment or prophylaxis of malaria comprising a composition according
to any of aspects 1 to 13 and instructions to administer said composition to a patient in
need thereof by the transmucosal sublingual, buccal or nasal route.
21. A kit for the treatment or prophylaxis of malaria comprising a composition according
to any of aspects 1 to 13 and instructions to administer said composition to a patient in
need thereof by the sublingual route.
22. A method of treating a disease responsive to artemether or arteether comprising the
administration to a patient in need thereof of a therapeutically effective amount of
artemether or arteether by the transmucosal sublingual, buccal or nasal route.
23. A method of treating a disease responsive to artemether comprising the
administration to a patient in need thereof of a therapeutically effective amount of
artemether by the transmucosal sublingual, buccal or nasal route.
24. A method according to either aspect 22 or 23 wherein said administration is by the
sublingual route.

25. A method according to any of aspects 22 to 24 wherein said disease is malaria.
26. A kit for the treatment of malaria comprising a composition according to any of
aspects 1 to 13 and instructions to administer said composition to a patient in need thereof
by the transmucosal sublingual, buccal or nasal route.
27. A kit for the treatment of malaria comprising a composition according to any of
aspects 1 to 13 and instructions to administer said composition to a patient in need thereof
by the transmucosal sublingual route.

Description and Preferred Embodiments of the Invention
One of the most important aspects of providing a clinically useful treatment for diseases,
infections or infestations responsive to dihydroartemesinin (produced in vivo by
metabolisms of an artemesinin such as artemether, arteether and artesunate) is to provide a
formulation and an administration route for the active ingredient that can withstand the
challenges of those communities where the disease is an especially acute problem. For
example, any formulation needs to be stable for long periods of time, and at the relatively
high temperatures encountered in countries where e.g. schistosomiasis is endemic. The
medicament will often need to be administered (without delay) to individuals who are
weak, perhaps malnourished, and possibly suffering from vomiting and diarrhoea. In
many cases, the medicament may also need to be administered by non-medically-trained
personnel. It is also important for any active ingredient to have good (and consistent)
bioavailability, to ensure that the drug reaches the site of action without adverse side
effects.
In order to address these problems, the inventors have found that the transmucosal
sublingual, buccal or nasal route of administration of artemether provides a greater
likelihood of higher and more reproducible levels of bioavailability than that
demonstrated by the oral (i.e. swallowed) or intramuscular route. Navaratnam et al (Clin
Pharmacokinct, 2000, Oct; 39(4): 255-270) report the bioavailability of artemether in
animals by oral administration to be as low as 19-35%, and only 54% when administered
by intramuscular injection. In humans, the bioavailability of artemether was low in both
the intramuscular (25%) and intrarectal (35%) route, with considerable variability in
absorption. The authors report that "Preliminary studies in children with cerebral
malaria indicated that the bioavailability of intramuscular artemether is highly variable
and could potentially affect treatment outcome in the most severely ill patients".
The use of the transmucosal sublingual, buccal or nasal route of administration avoids the
first-pass effect that occurs with oral and rectal administration. Whilst adults might be
able to tolerate the large oral doses of artemether required to overcome the low

bioavailability of the drug for short periods of time, this is not the case in children, and so
the compositions disclosed herein are particularly suitable for the treatment of diseases
such as cancer that might require protracted periods of medication, or that might be for
paediatric use.
Preliminary results of initial, confidential, dose ranging studies are presented below,
indicating surprisingly increased bioavailability of the drug when administered by
sublingual spray in comparison to oral administration by tablet.
The inventors have also found that, contrary to accepted belief, artemether is not stable
when in contact with water, ethanol, or propellants that might be used for aerosol
formulations.
Tables 1 and 2 show impurities present in Artemether API, and artemether in three
solvent systems: 20% ethanol + 80% propellant; 50% ethanol + 50% propellant; 100%
ethanol; and a medium chain triglyceride, in this case, the triglyceride sold under the
registered trade mark Miglyol® 810. Miglyol® is a medium chain triglyceride containing
saturated C8 and C10 fatty acids, typically between 65-80% of caprylic acid (C8:0) and
20-35% of capric acid (C10:0).
The propellant used in these test was 1,1,1,2 tetrafluoroethane, sold under the registered
trade mark Zephex® 134a. Similar results were obtained for the propellants butane,
Zephex® 227 (1,1,1,2,3,3,3 heptafluoropropane) and for a mixture of butane and
propane.
Table 1 shows the impurities (as a percentage of the peak area of an HPLC chromatogram
of artemether) after storage of the compositions at 30°C for eight weeks. Table 2 shows
the corresponding impurities after storage for eight weeks at 40°C.


Representative chromatograms are shown in Figure 13. It can be seen that the levels of
impurities in the Miglyol® 810 formulation are not significantly higher than those
observed in the initial Artemether API. In all other cases, the impurities are at levels that
exceed those permitted under the ICH Harmonised Tripartite Guidelines for Impurities in
New Drug Products without specific identification or further toxicological examination.
A solution in a medium chain triglyceride, especially a saturated triglyceride such as
Miglyol® 810 therefore constitutes a stable formulation for the active ingredient. Being a
saturated triglyceride, it is believed that this confers stability to the artemether. Given its

chemical structure, it is likely that the main route of degradation of artemether is via
reduction mechanisms, which might explain the protection afforded by such saturated
fatty acid-containing triglycerides.
When used in a spray delivery system, e.g. in a manually-actuated pump spray, the
triglyceride also acts as a pump and valve lubricant, thereby removing the need to add
additional lubricants to the formulation. The use of such medium chain triglycerides also
produces a formulation of appropriate viscosity and surface tension for use in a pump
spray delivery system.
Further advantages also flow from the use of medium chain triglyceride: being
hydrophobic, the triglyceride adheres to the mucosa of the mouth, and so allows time for
the artemether to be absorbed transmucosally. The hydrophobic nature of the
composition resists being washed out of the mouth by the action of saliva, which would
otherwise cause the active ingredient to be swallowed.
In especially preferred embodiments of the invention, the artemether-triglyceride solution
is supplemented with menthol, or alternatively with orange oil or vanilla. The inventors
have found that this has a number of benefits:
(1) Its function as a taste-masking agent is particularly important in the context of
administration of drugs to children or to patients who need to take the medication over
prolonged periods of time; any bad taste of the drug experienced by the patient makes
patient compliance less likely.
(2) The essential oil also acts as a penetration enhancer to improve the uptake of the
pharmaceutical ingredient through the mucosa of the mouth.
(3) The addition of a flavour also allows the person administering the drug to check firstly
that the drug has been dispensed (the patient can taste or smell it) and secondly that it has
been dispensed into the right place - if the drug were e.g. accidentally dispensed directly
into the throat, there would be no taste sensation.

(4) A surprising feature is that the essential oil (especially levomenthol) also assists with
the solubilisation of the artemether. In a solubility trial, dissolution of artemether in
miglyol occurred after 4 minutes 30 seconds when menthol added before artemether
compared to 5 minutes 55 seconds when artemether added before menthol.
As an example, preferred formulations (for sublingual or buccal paediatric use) are given
in Tables 3 and 4. For adult use, or for the treatment of some indications, concentrations
higher or lower than those exemplified are envisaged. Two different dose concentrations
arc given suitable for use in a spray delivery system. A number of sprays (i.e. individual
spray actuations of 100micro litres) may be given, dependent on the weight of the child to
be treated:

Bioavailability of Artemcther
The applicant has carried out confidential trials to asses the uptake of the artemether-
containing compositions of the present invention when delivered by the sublingual route,
by comparison to oral administration by tablet.
Trials were carried out on healthy male adult human volunteers (16 subjects per cohort),
and subject to normal ethical approval. Three single-dose regimes according to the
present invention were studied, and compared to a regime using oral-dosed tablets, as
follows:
Sub-Lingual Spray Regimes
Spray formulations of artemether were prepared as detailed above, and administered, on a
single occasion, to a group of volunteers by the sublingual route. A number of successive
actuations of the spray were administered, as shown in Table 6, below.

Reference Oral Dose
As a reference, a fourth group of volunteers were administered tablets containing
artemether, on a single occasion, as shown in Table 7, below.


Following administration of each dosage regime, blood samples were taken from the
subjects, and plasma concentrations of artemcthcr and its immediate metabolite
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.

From these preliminary results, it can be seen that comparison of the area under the
plasma concentration curve during the 12 hours following the doses (AUC0-12), a well-
accepted measure of absorption, shows significant and surprisingly higher absorption of
artemether when administered sublingually as a spray formulation as disclosed herein by
comparison to oral tablet dosing.
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 Mctab
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: Prcdose, 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 arc shown in Figure 14.

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 , □ = 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 (Tl) versus single sublingual administration of 30mg Artemether
Sublingual Spray 3mg/actuation (T2). Mean + SD (• = reference, T2 , □ = test, Tl)
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 , D = 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, Tl)

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 (Tl) and single oral administration of 30mg Artemether Tablets 10
mg/tablet (T4). Mean± SD (• = reference, T4 , n = 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 , o = 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 , □ = 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 , □ = test, Tl)

CLAIMS
1. A pharmaceutical composition for the treatment of neoplasms comprising:
a compound capable of providing dihydroartemesinin;
and
a pharmaceutically-acceptable excipient selected the group consisting of:
medium chain length triglycerides;
short chain triglycerides;
omega-3-marine triglycerides; and
fish oil, rich in omega-3-acids
said composition formulated for transmucosal sublingual, buccal or nasal dosage.
2. A pharmaceutical composition for the treatment of fluke infestation comprising:
a compound capable of providing dihydroartemesinin;
and
a pharmaceutically-acceptable excipient selected the group consisting of:
medium chain length triglycerides;
short chain triglycerides;
omega-3-marine triglycerides; and
fish oil, rich in omega-3-acids
said composition formulated for transmucosal sublingual, buccal or nasal dosage.
3. A pharmaceutical composition for the treatment of Lyme disease (Borreliosis)
comprising:
a compound capable of providing dihydroartemesinin;
and
a pharmaceutically-acceptable excipient selected the group consisting of:
medium chain length triglycerides;
short chain triglycerides;
omega-3-marine triglycerides; and
fish oil, rich in omega-3-acids
said composition formulated for transmucosal sublingual, buccal or nasal dosage.

4. A composition according to any of claims 1 to 3 consisting essentially of:
a compound capable of providing dihydroartemesinin;and
a pharmaceutically-acceptable excipient selected the group consisting of:
medium chain length triglycerides;
short chain triglycerides;
omega-3-marine triglycerides; and
fish oil, rich in omcga-3-acids
said composition formulated for transmucosal sublingual, buccal or nasal dosage.
5. A composition according to any of claims 1 to 3 consisting essentially of:
a compound capable of providing dihydroartemesinin; and
a pharmaceutically acceptable excipient consisting essentially of:
a triglyceride, liquid at 37°C; and
medium chain length triglycerides;
said composition formulated for transmucosal sublingual, buccal or nasal dosage.
6. A composition according to any of claims 1 to 5 where said compound comprises an
artemesinin.
7. A compound according to claim 6 wherein said compound comprises artemether or
arteether.
8. A composition according to any preceding claim, substantially free of water.
9. A composition according to any preceding claim, substantially free of ethanol.

10. A composition according to any preceding claim further comprising an essential oil
such as menthol, vanillin or orange oil, lemon oil, clove oil, peppermint oil, spearmint oil.
11. A composition according to any preceding claim formulated for sublingual delivery.

12. A medicament delivery device containing a composition according to any preceding
claim, said device adapted to deliver individual or successive doses of said composition,
each individual or successive dose having a volume of less than 1000 microlitres.
13. A delivery device according to claim 12 wherein said device comprises a pump spray.
14. A delivery device according to claim 13 wherein said device is adapted to produce a
spray of composition having a mean droplet diameter greater than 20 microns.
15. A device for providing pharmaceutical doses comprising a container containing a
pharmaceutical composition according to any of claims 1 to 11, and valve means arranged
to transfer doses of said pharmaceutical composition to the exterior of the container.
16. A method of treating a neoplastic disease comprising the administration to a patient
in need thereof of a therapeutically effective amount of a compound providing
dihydroartemesinin by the transmucosal sublingual, buccal or nasal route,
17. A method according to claim 16 wherein said disease comprises a malignant
neoplasm.
18. A method according to claim 17 wherein said disease is selected from the group
comprising:
pituitary adenoma;
squamous cell carcionoma;
breast cancer;
non-Hodgkin's Lymphoma;
skin cancer;
lung cancer; and
non-small cell lung carcinoma.
19. A method of treating a fluke infestation comprising the administration to a patient in
need thereof of a therapeutically effective amount of a compound providing
dihydroartemesinin by the transmucosal sublingual, buccal or nasal route.

20. A method of treating Lyme disease (borreliosis) comprising the administration to a
patient in need thereof of a therapeutically effective amount of a compound providing
dihydroartemesinin by the transmucosal sublingual, buccal or nasal route.
21. A method according to any of claims 16 to 20 wherein said compound comprises an
artemesinin.
22. A method according to claim 21 wherein said compound comprises artemether or
arteether.
23. A method according to any of claims 16 to 22 wherein said administration is by the
sublingual route.
24. A method according to any of claims 16 to 22 wherein said compound providing
dihydroartemesinin is formulated in a composition according to any of claims 1 to 13.
25. A kit for the treatment of a neoplasm comprising a composition according to any of
claims 1 to 13 and instructions to administer said composition to a patient in need thereof
by the transmucosal sublingual, buccal or nasal route.
26. A kit for the treatment of a neoplasm comprising a composition according to any of
claims 1 to 11 and instructions to administer said composition to a patient in need thereof
by the transmucosal sublingual route.
27. A kit for the treatment of a fluke infestation comprising a composition according to
any of claims 1 to 11 and instructions to administer said composition to a patient in need
thereof by the transmucosal sublingual, buccal or nasal route.
28. A kit for the treatment of a fluke infestation comprising a composition according to
any of claims 1 to 11 and instructions to administer said composition to a patient in need
thereof by the transmucosal sublingual route.

29. A kit for the treatment of Lyme disease (borreliosis) comprising a composition
according to any of claims 1 to 11 and instructions to administer said composition to a
patient in need thereof by the transmucosal sublingual, buccal or nasal route.
30. A kit for the treatment of Lyme disease (borreliosis) comprising a composition
according to any of claims 1 to 11 and instructions to administer said composition to a
patient in need thereof by the transmucosal sublingual route.

The invention provides pharmaceutical compositions for the treatment of neoplastic diseases, fluke infestations and
Lyme disease, comprising compounds capable of providing dihydroartemesinin and a medium chain triglyceride formulated for
transmucosal sublingual, buccal or nasal delivery, especially by a spray. Also provided are delivery devices containing the compositions.