GB2482431A

GB2482431A - Transmucosal formulation of compounds providing dihydroartemesinin for use in the treatment of a fluke infestation

Info

Publication number: GB2482431A
Application number: GB1115173.5A
Authority: GB
Inventors: Calvin John Ross
Original assignee: LondonPharma Ltd
Current assignee: LondonPharma Ltd
Priority date: 2009-04-23
Filing date: 2009-04-23
Publication date: 2012-02-01
Anticipated expiration: 2029-04-23
Also published as: GB201115173D0; GB2482431B

Abstract

Pharmaceutical compositions for the treatment of fluke infestations comprising compounds capable of providing dihydroartemesinin and a pharmaceutically acceptable excipient formulated for transmucosal sublingual, buccal or nasal delivery, especially by a spray. The pharmaceutically acceptable excipient is selected from selected from medium/short chain triglycerides, omega-3-marine triglycerides and fish oil, rich in omega-3 acids. The preferred compound capable of providing dihydroartemesinin is artemether. The composition may further comprise an essential oil such as Levomenthol. Also provided are delivery devices containing the compositions.

Description

PHARMACEUIICAL FREPARATWN

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 Arypplicant

Artemesinins, which may be isolated from the plant Arternesia armua 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 adenonia with artemether, Singh and Verma (Archive of Oncology, 10(4): 2002. 279..280) report the treatment of laryngeal squamous cell carcinoma with artesimate.

Singh and Lai (Life Sciences, 70(200 1) 4956) report the selective toxicity of dihydroartemesinin and holotransferrin toward hmnan 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, nonHodgkins Lymphoma, nonsmall cell lung carcinoma, and multiple skin cancers.

Efferth et ci ("Antimalaria drug is also active against cancer, Jut. 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 he effective in the treatment of liver flukes, and in particular schistosomiasis Kciser and Morson (Exp. Parasitot. 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, 11394145) also report that artesunate and arteincther are effective fasciolicides, Utringer eta! (Curr Opin Investig Drugs, 2007 Feb 8(2), 10546) report the use of artemesinins for treatment of individuals infested with Plasmodluin spp. and Schistosoina haematohium 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 Lie disease. Borrelia hurgdoijèri is the predominant cause of Lane disease in the United States, Borrelia a/*elii and Borrelia garinli 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 actone endoperoxide originally isolated from Arternesia annua Woodrow ci ci. Postgrad. MeJJ.

2005; 81:71-78). These compounds include the semi-synthetic derivatives artenimoi, artesunate, artemether and arteether (artemotil). The international Pharmacopoeia (Ph.

mt. World Fieaith 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 fonnulation; and both artenimol and artesunate in the fonn of tablets.

Once taken into the body, the artetnesinins are converted to dihydroaftemesinin and so these active compounds include all those that supply dihydroartemesinin in viva.

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. Furthennore, for long-term cancer treatment, it is particularly preferred that patients are able to either seltadminister 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 dialThoea.

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 pharmaceuticallyacceptable excipient selected the group consisting of: medium chain length triglycerides; short chain triglycerides; oinega4 marine triglycerides; and fish oil, rich in omega3acids, said composition tbrrnulated thr transnmcosal 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 phsrmaceuticallyacceptable excipicnt selected the group consisting of: medium chain length. triglycerides; short chain triglycerides; omcga1marine triglycerides; and fish oil, rich in omega3acids, said composition formulated fhr transmucosal sublingual, is 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 pharniaceuticallyacceptable excipient selected the oup consisting of: medium chain length triglycerides; short chain triglycerides; omega-3 marine triglycerides; and fish oil, rich in omega3acids, said composition formulated for transmucosal stiblingual, buccal or nasal dosage.

The inventors have found that the tranamucosal sub4ingual, lransmucosal huccal and transmucosal nasal routes for administration of artem ether or arteether are effective for delivery of the pharmaceutical into the systenuc circulation eg. for th.e 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 he administered by noninedically qualified personnel. It has particular advantage, therefore, in treating these conditions. The composition can be delivered eg. 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.

s C8F116O2) and of capric acid (decanoic acid, C10H2002). Medium-chain triglycerides are obtained from the oil extracted from the hard, dried fraction of the endospernr of Cocos nucijèro 1, or from the dried endosperm of Eiaeis guineensis Jacq. When Medium.chain rcriglyceddcs are prepared from the endosperm of Cocos nucjèra 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.

Omega3marine trigiycerides are defined in the European Pharmacopoeia Monograph 0868 as mixture of rnono, di and triesters of omega3 acids with glycerol containing mainly triesters and obtained either by esterifi cation of concentrated and purified omega3 acids with glycerol or by transesterification of the omega3 acid ethyl esters with. glycerol.

The origin of the omega3 acids is the body oil from fatty fish species coming from families like Engraulidae, C'arangidae, Clupeidae, Osnreridae, Sairnonidae and Scorn bridue. The omega3 acids are identified as the following acids: alpha4inolenic acid (C18:3 n3), moroctic acid (C18:4 n3), eicosatetraenoic acid (C20:4 n3), timnodonic (eicosapentaenoic) acid (C20:5 n-3; EPA), heneicosapentaenoic acid (C21:5 m-3), clupanodonic acid (C22:5 n-3) and cervonic (docosahexaenoic) acid (C22:6 n-3; DHA).

The sum of the contents of the omega3 acids EPA and DNA, expressed as triglycerides is a minimum of 45.0 per cent, and the total ornega3 acids, expressed as triglycerides is a minimum of dOA) 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, winteriscd and deodorised fatty oil obtained from fish of the families Engrauiidae, Carczngidae, Ciupeidae, Osmeridac, Scombridac and Ammodytidue. The omega3 acids are defined as the following acids: aipha4inolenic acid (C 18:3 n3), moroctic acid (Ci 8:4 n3), eicosatctraenoic acid (C20:4 n$), timnodonic (eicosapentaenoic) acid (C20:5 n3; EPA), heneicosapentaenoic acid (C21:5 n-3), ciupanodonic acid (C22:5 n3) and cervonic (docosahexaenoic) acid (C22:6 n3; DHA).

The content of the Fish oil, rich in omega3acids is as follows: EPA, expressed as triycerides: minimum 13.0 per cent, DHA, expressed as triglycerides: minimum 90 per cent, Total omega3acids, 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 front these exact compositional limits. Excipients of choice should exhibit analogous chemical properties such as the ability to solubilise artemether or artecther or other compounds providing dihydroartemesinin at the required concentration, not to degrade the pharmaceutically active ingredients, and to be non4oxic.

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 he used in preferred spray formulations described below. The viscosity for these applications should be low enough to be capable of atom.zing, 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 pharmaceuticallyacceptable excipients selected the group consisting of: mediani chain length triglycerides; short chain triglycerides; and omega3 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 t.o transmucosal nasal, buceal, and especially sublingual delivery.

S More preferred compositions comprise: arteniether and a pharmaceutically-acceptable excipient selected the group consisting of: medium chain length triglycerides; short chain triglycerides; and omega3-marine triglycerides, said composition formulated for transmucosal sublingual, huccal or nasal dosage, and especially a composition consisting essentially of: artemether and a pharmaceutically-acceptable excipient selected the group consisting ofi medium chain length triglycerides; short chain triglycerides; and omega-3-marine triglycerides, said composition formulated for transmucosai sublingual, huccal or nasal dosage.

In any of these compositions, it is especially preferred that the composition is 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 I %(w/w) water, and more preferably less than 0.5%(w/w) water, 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 I %(w!w) ethanol, and more preferaHy 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 1.00 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 eg. a suspension. This is particularly important to ensure that delivery of the drug is by the recited transmucosai route. If significant amounts of the active components are not in solution, then there is an hicreased likelihood that some will be swallowed, thereby reducing the beneficial effects of such transmucosal delivery described below.

In especially preferred compositions, th.e 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 fiavourings, 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 liquithbased fonnulations which cannot by their nature be encapsulated or "sugarcoated'. The flavours also give a feedback to the user or administrator of the medication that the medication has been successthily 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 inicrolitres, The use of small dose vol ames 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, 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 artem ether or arteether, Such devices are preferably adapted to assist sublingual delivery, especially by nonmedically 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. selitadministration by a patient in a domestic setting, which is likely for long4erm anti cancer therapy) to ensure that over dosing is avoided. Preferably, said device and composition adapted to deliver individual is 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 ao 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 rninimising the likelihood that the medicanient 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 inedicament 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 he attached to e.g. a separate transmucosal buccal, nasal or sublingual delivery device, such as a spray.

En 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 (eg. an artemesinin, and especially artemether or arteether) by the transmucosal sublingual, buccal or nasal routa 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 is 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 infeatation or Lyme disease.

in any of the compositions of the invention it is particularly preferred that the composition also includes a tranaferrin, 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.

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. ii

Disclaimed Embodiments In pref'ened embodiments of the invention, the following nmnbered aspects, disclosed in copending International Patent Application PCT/0B2008/050999 are particularly disclaimed: 1. A pharmaceutical composition comprising: artemether or arteether; and a pharmaccutical1yaccqitable excipicnt selected the group consisting of: To medium chain length triglycerides; short chain triglycerides; oniega-3-marinc triglycerides; and fish oil, rich in omega4acids said composition formulated for transmucosal sublingual, buccal or nasal dosage.

2. A. composition according to aspect I consisting essentially of: artemether or arteether; and one or more pharmaceuticallyacceptable excipients selected the oup consisting of: medium chain length triglycerides; short chain triglycerides; omega-3-marine triglycerides; and fish oil, rich in omega-3acids said composition formulated for transmucosal stiblingual, buccal or nasal dosage.

3. A composition according to aspect I comprising: arteinetiier and a pharmaceutically-acceptable excipient selected the group consisting of: medium chain length triglycerides; short chain triglycerides; omega-3inarine triglycerides; and fish oil, rich in omnega-3-acids said composition fonnulated for transmucosal sublingual, buccal or nasal dosage.

4. A composition according to aspect I consisting essentially of.

artemether and one or more pharniaceuticallyacceptabie excipients selected the group consisting of: medium chain length triglycerides; short chain triglycerides; and omega3marinc triglycerides; and fish oil3 rich, in omega3acids said composition formulated for fransmucosal 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 fonnulated for ftansmucosai sublingual, huccal or nasal dosage.

6. A composition according to any precedin.g 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 fatly acids with between 6 and 12 carbon atoms.

10. A composition according to aspect $ wherein said excipient comprises a medium chain triglycerid; said triglyceride comprising a minimum of 95 per cent of saturated fatty acids with between 8 and 10 carbon atoms.

ii. A composition according to any preceding aspect thrthcr 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 inicrolitres, 15. A medicarnent 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 individenl or successive dose containing no more than 80mg of artemether or arteether.

16. A medicatnent 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 artem ether 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 transmucosai sublingual, huccal 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, buecal 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 transmueosal sublingual, huccai 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 I 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 transmnucosal stiblingual route.

One of the most important aspects of providing a clinically useful treatment for diseases, infections or infestations resnonsive to dihvdroartemesinin (oroduced in vivo fry 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 beliet arteinether is not stable when in contact with water, ethanol, or propellants that might be used for aerosol formulations.

Tables I and 2 show impurities present in Artesnether API, and arteniether in three solvent systems: 20% ethanol 4 80% propellant; 50% ethanol + 50% propellant; 100% ethanol; and a medium chain triglyceride, in this case, the triglyceride sold under the registered trade mark Miglyoi® 810. Miglyol® is a medium chain triglyceride containing saturated CS and ClO fatty acids, typically between 6580% of caprylic acid (C8:0) and 2035% of capric acid (Cl 0:0).

The propellant used in these test was 1,1,1,2 tetrafluoroethane, sold under the registered trade mark Zephex® i 34a, Similar results were obtained for the propellsnts butane, Zephex® 227 (1,1,1,2,3,3,3 heptafl.uoropropane) and for a mixture of butane and propane Table I shows the impurities (as a percentage of the peak area of an FIPLC cbromatow'am of artemetheñ after storage of the compositions at 30T for eight weeks. Table 2 shows the corresponding impurities after storage for eight weeks at 40C.

Table I -Storage at 30°C Relative Retention Time: 0.35 0,68 0.73 0,87 j0.91 1617 % of artemether ArtemetherAPi 0.4 0.1 0.2 20% EtOH 80% propeil ant 1.6 0.3 0.7 0.2 1.3 0.2 50% EtOH 50% propellant 1.0 0.2 0.5 0.2 1. .5 0.2 100% EtOH 0.3 0.2 0.5 0.2 Miglyol 810® [ 0.1 02 Table 2 -Storage at 4012 iiaenuon Time: 0.35 0.68 0.73 iii °/& of arteinether Artetnether API 0,4 0 20% EtOH 80% propellant 4.9 1.9 2.9 0.2 5.3 1.4 50% EtOH 50% propellant 2.2 1.4 2.5 0.2 4.8 1.0 100% EtOH 2.2 0.7 1.6 0,2 1.0 0.7 Miglyol 810® 0.6 0.1 0.2 Representative chromatograrns are shown in Figure 13. it can be seen that the levels of impurities in the Miglyol® 810 formulation are not siificantly higher than those observed in the initial Artemether API. in all other eases, 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 is Miglyol® 810 therefore constitutes a stable formulation for the active ingredient. Being a saturated triglyceride, it is believed that this confers stability to the artem ether. 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 aci&containing inglycerides s When used in a spray delivery system, eg. in a manua1lyactuated 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 tbr the artemnether to be absorbed transmucosaliy. 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 artemethertriglyceride solution is supplemented with menthol, or alternatively with orange oil or vanilla. The inventors have found that this has a number of benefits: (I)lts thnction as a tastemasking 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 mueosa 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 eg. accidentally dispensed directly into the throat, there would be no taste sensation.

(4) A smrising 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 artcrnether added before menthol.

As an example, preferred formulations (for sublingual or buccal paediatric use) are given in Fables 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 are given suitable for use in a spray delivery system. A number of sprays (i.e. individual spray actuations of I OOrnicroiitres) ray be given, dependent on the weight of the child to he treated: Table 3: 3mg Artemether per actuation Raw Material [tern Weight % wiw Artemether 1? 0.090 3.2 Levomenthol Ph. £ir. 0.020 0.7 Miglyol® 810 2.690 96.1 Table 4: 6mg Arteinether per actuation Raw Material Item Weight (g) % w/w ArtemetheriP 0.180 6.4 Levomenthol Ph. Fur. 0.020 0.7 Miglyol® 810 2.600 92.9 Table S outlines an example of a preferred dosage regime for paediatric use. Alternative regimes are envisaged, e.g. dosing at 3mg/kg body weight.

TableS: Paediatric Dosage Regime Weight of Number of Total Number of Total child (kg) doses at 3mg delivered dose doses at 6mg delivered dose Dose per mg/kg Dose per mg/kg spray spray actuation ____________ aetuation ____________ 3 1 1.00 ______ ____________ 4 1 035 _____________ _____________ 2 1.20 ____________ ____________ 6 2 1.00 ____________ ____________ 7 ____ 2 0.86 _________ ____________ 8 3 __ 1,13 ____ 9 3 1.00 _________ _______ 3 0.90 _____ ____________ 11 4 1.09 __________ ___________ 12 --4 1.00 -2 1.00 13 4 0.92 2 0.92 14 5 1.07 2 0.86 5 ____ 1.00 3 ____ 1,20 16 5 0.94 3 1.13 17 ___________ ___________ 3 ____ 1.06 18 ___________ ___________ 3 1.00 19 ____________ ________ 3 0.95 --______ 3 0.90 21 __________ ____________ 3 0.86 22 _____ ___________ 4 1,09 23 _____ ___________ 4 1.04 24 __________ ___________ 4 1.00 --4 0.96 26 ____________ _______ 4 0,92 -.---------_______________ -.+.-- 27 ____________ 4 0.89 28 ___________ 5 L07 29 ______ ________ 5 1,03 5 1.00 Fonnulations for adult use may be prepared at higher concentrations of artemether, such as I 50200 mg/ml. For adult use, individual spray volumes may be larger than the 1 OOmicrolitre example deseribed here for paediatric use.

Bioavailahiiity of Artemether The applicant has carried out confidential trials to asses the uptake of the anentether-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 singledose regimes according to the present invention were studied, and compared to a regime using oraidosed tablets, as follows: fles Spray formulations of artem ether were prepared as detailed above, and administered, on a single occasion to a group of volunteers by the sublingual route. A n umber of successive actuations of the spray were administered as shown in Table 6, below.

Table 6 -Dosage Regime for Single Dose Study Sublingual Spray Formulation Dose per Number of Total Doge Test Formulation Actuation (tug) Actuations (tug) TI AsTablc3 3 5 15

T2 AsTable3 3 10 30

T3 AsTable4 6 5 30

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.

Thhle 7 Dosage Regime for Single Dose Study Oral Tablet Formulation Dose per Tablet Number of Total Doge Test Formulation (nig) Tablets (mg)

T4 Tablet 10 3 30

Following administration of each dosage regime, blood samples were taken from the subjects, and plasma concentrations of artemether and its immediate metabolite dihydroartemesinin were determined, in order to compare bioavailahility by the two routes.

Figures h6 show mean plasma concentration of arteniether following two comparison dose regimes. Figures 7 12 show the coiresponding mean plasma concentration of dihydroartemesinin.

Figures 1 and 7 compare regimes Ti (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 14 (closed circles): 30mg artemether via 5 sublingual spray doses vs. 30mg artemether via tablet.

Figures 4 and 10 compare regimes Ti (open squares) and T2 (closed circles): 15mg artanether via 5 sublingual spray doses vs. 30mg artemether via 10 sublingual spray doses.

Figures 5 and I I compare regimes 12 (open squares) and T3 (closed circles): 30mg artemether via 10 sublingual spray doses vs. 30mg artemether via S sublingual spray doses.

Figures 6 and 12 compare regimes TI (open squares) and T3 (closed circles): 15mg artemether via 5 sublingual spray doses vs. 30mg artemether via 5 subhugual spray doses).

6 Pharniacokinetic data for each of the thur dosage regimes are given in Tables 8 11, below: Table 8: Test Group TI Single sublingual administration of I5mgAneinether sublingual spray: 3mg per actuation Plasma Artemether Plasma Dihydroartemesinin (n=16) (n16) Pharmacokmetic Parameters _____________ (mean ±SD) (mean ±SD AUQ342 (ngdi/mL) 25.85 ± 13.88 29.63 ± 11.58 C(nWinL) 16.11±8,69 18,29±7.52 T (h) _______________ 1.70 ± 0.68 1.83 ± 0.68 t (h) 0.72 ± 0.30 __________________________ _______ _______________ 1.11 ±0.40 ______ CL/Fng/h) 0.74±0.46 0.54±0.15 V/F (L) 0.68 ± 0.33 0.51 ± 0.16 Key: AUC912 (ng.hImL) Area under the concentration curve between 042 h. C (ng/mL) Maximum observed plasma concentration T (h) Time of observed maximum plasma concentration t h) Elimination halfiife A7 (hg) Elimination rate constant CL/F (ng/h) Apparent clearance rate V/F (L) Apparent volume of distribution Table 9: Thst Group 12 Single sublingual administration of3Omg Artemether sublingual spray: 3mg per actuation Plasma Artemether Plasma Dihydroartemesinin (n=16) (n=16) Pharmacokrnetic Parameters ___________ (mean ±SD) (mean ±8Th AUC0.12 ng.h/mL) 76.60 ± 43.12 99.51 ± 50.33 C rng/niL) 32.12 ± 16.39 44.11 ± 28.48 T(h) 133±0.82 2.10±1.17 t)/(h) ____________ 1.39 ±0.49 ____________________ A (11') _____ 0.56 ± 0.20 ______________________ CL/F (rig/h) 0.56±0.37 0,36±0.13 VF (L) 1.00 ± 0.55 0,72 ± 0.36

Key as Table 8

Table 10: Test Group 73 Single sublingual administration of3omg Artemether sublingual spray: 6mg per actuation Plasma Artemether Plasma Dihydroartemesinin (n=i61 (n=16) Phannacokinetic Parameters -.

_________________ (mean ±SD) ______ ___________ AUC012(ng.h/mL) 71.11 ± 41.08 86,19±27.68 C(ng/rnL) 35.24±23.91 _______ 41.14±16.45 ____ T(h) _____ 1.67±0.77 1.88±0.74 t1⁄2(h) _______________ 1.40±0.59 __________ AZ 0.59 ± 0.25 ______________________ CL/F ng/h) _______ 0.63 ± 0.49 0.39 ± 0.15 V/F (L) 1.01 ± 0.49 0.91 ± 0.67

Key as Table 8

io Table 11: Test Group T4 Single oral administration of3omg Artemether Tablets

10mg per Tablet

Plasma Artemether Plasma Dihydroartemesiriin (n=16) (n=16) Pharmacokmetic Parameters _________________ (mean ±8Th (mean ±SD) AUC42�ig.h'mL) 34.59± 21.01 38.49± 12.38 C1 ng/mL) 10.12 ± 7.19 10.99 ± 4.39 _____ _____________ 1.02±0.86 1.39±0.88 tJh) _____________ 3.44±4.26 _______ ________________ 0.31±015 _______________ CL/F(ng/h) __________ 1.11± 1.01 0.76±0.23 VT (L) 3.90±2.90 2.36 ± 1.26

Key as Table 8

From these preliminary results, it can be seen that comparison of the area under the ptasma concentration curve during the 12 hours following the doses (AUC042), a welh 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 hioavailability of artemether via the sublingual spray route described herein with administration by oral tablets we have calculated the Fvalues, commonly used to compare two dose regimes, generally A and B, for the artemether data, as follows: A UCA doseB = AUCB dose4 The results are as follows: FT1T4 = 1.67 * 0,60 (S.D.) = 2.24 ± 0.92 (S.D.) FT..T4 = 2.09 ± 0.69 (S.D.) 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 fbr equivalent doses.

Inspection of the data of Tables 841, and Figures 142 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 phannacokinetics: application oJ'a semiphysiological autoinduction model", Asimus and Gordi. Br, J Clin Pha.nnacol. 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 artentesinins 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 huccal or nasal route.

in confidential trials, volunteers followed the following treatment: A single administration of 30mg arte'mether sublingual spray 6mg/actuation on days I 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 phaimacokinetic 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 l2hafter 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.

DayS: Predose, 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12 hand 24 h after dosing.

Pharmacokinetic analysis of plasma dihydroarteniesinin on days I and 5 revealed an effectively identical response, indicating the lack of autoinduction. Plasma concentration curves are shown in Figure 14.

ireCations 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 (Ti) and single oral administration of 30mg.Artem ether Tablets 10 mg/tablet (T4) Mean ± SD ( reference, T4, o = test, Ti) Figure 2: Plot of mean plasma Artemether concentration vs time with standard deviation following a single sublingual administration of 30ing 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 3: Plot of mean plasma Artemether concentration vs time with standard deviation following a single sublingual administration of 30mg Arteinether Sublingual Spray 6mg/actuation (T3) versus single oral administration of 30mg Artem ether Tablets i 0 mg/tablet (T4). Mean ± SD ( = reference, o = 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 (Ti) versus single sublingual administration of 30mg Artemether Sublingual Spray 3mg/actuation (T2). Mean ± SD (* = reference, T2, o = test. TI) Figure 5: Plot of mean plasma Artemether concentration vs time with standard deviation following a single sublingual administration of 30mg Arteinetber Sublingual Spray 3mg/actuation (T2) versus single sublingual administration of 30mg Artemether Sublingual Spray 6mg/actuation (T3). Mean ± SD ( = reference, T3, o = test, T2) Figure 6: Plot of mean plasma Artemether concentration vs time with standard deviation thilowing a single sublingual administration of 15mg Artemether Sublingual Spray 3mg/actuation (TI) versus single sublingual administration of 30mg Artemether Sublingual Spray 6mg/actuation (T3). Mean ± SD ( = reference, f3, o = teat, Ti) 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 (Ti) and single oral administration of 30mg Artemether Tablets 10 mg/tablet (T4). Mean ± SD ( = reference, T4, o = test, TI) 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 mg/tablet (T4). Mean ± SD ( = reference, T4, D = test, T3) Figure 10: Plot of mean plasma Dihydroartemisinin concentration vs time with standard deviation following a single sublingual administration of 15mg Artem ether Sublingual Spray 3mg/actuation (TI) versus single sublingual administration of 30mg Artemether Sublingual Spray 3mg/actuation (TZ). Mean ± SD (e = reference, T2 * ci = test, TI) 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, o = 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 (Ti) versus single stiblingual administration of 30mg Artemeth.er Stiblingual Spray 6mg/actuation (T3). Mean ± SD ( = reference, T3, o = test, TI)

Claims

CLAIMS1. A pharmaceutical composition for use in the treatment of fluke infestation, said composition comprising: a compound capable of providing dihydroarteminin; and a phannaceuticailyacceptable excipient selected from the group consisting of: medium chain length triglycerides; short chain triglycerides; omega3marine triglycerides; and fish oil, rich in omega3-acids said composition formulated for transmucosal sublingual, huccal or nasal dosage.
2. A composition according to claim I consisting essentially of a compound capable of providing dibydroartemesinin;and a pharmaceuticallyacceptahle excipient selected from the group consisting of: medium chain length trig'ycerides; short chain triglycerides; omega.3marine triglycerides; and fish oil, rich in omega4.acids said composition formulated for transmucosal sublingual, buccal or nasal dosage.
3. A composifion according to claim I or claim 2 consisting essentially of: a compound capable of providing dihydroartemesinin; and a pharmaceutically acceptable excipient consisting essentially of: a triglyceride, liquid at 3T'C; and medium chain length triglycerides; said composition formulated for transmucosai sublingual, bnccai or nasal dosage.
4. A composition according to any one of claims I to 3 where said compound comprises an artemesinin.
5. A compound according to claim 4 wherein said compound comprises artemether or arteether.
6. A composition according to any preceding claim, substantially free of water.
7. A composition according to any preceding claim, substantially free of ethanol.
8. 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.
9. A composition according to any preceding claim fbrmulated for sublingual delivery.
10. A composition according to any preceding claim thrther comprising a transfenin.
11. A composition according to any preceding claim that is contained within a medicament delivery device, 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.
12. A composition according to claim 11 wherein said device comprises a pump spray.
13. A composition according to claim 12 wherein said device is adapted to produce a spray of composition having a mean droplet diameter greater than 20 microns.
14. A composition according to any one of claims I to 10 that is contained within a container comprised within a device for providing pharmaceutical doses with valve means arranged to transfer doses of said pharmaceutical composition to the exterior of the container.
15. A composition according to any one of claims I to 10 that is comprised within a kit that comprises instructions to administer said composition to a patient in need thereof by the transmucosai sublingual, buceal or nasal route.
16. A composition according to any one of claims I to 10 that is comprised within a kit that comprises instructions to administer said composition to a patient in need thereof by the transmucosal sublingual route.