GB2482615A

GB2482615A - Transmucosal formulation of compounds providing dihydroartemesinin for use in the treatment of Lyme disease

Info

Publication number: GB2482615A
Application number: GB1115179.2A
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: 2012-02-08
Anticipated expiration: 2029-04-23
Also published as: GB201115179D0; GB2482615B

Abstract

Pharmaceutical compositions for the treatment of Lyme disease (Borreliosis) 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

NIARMACEUT1CAL PREPARATION

Field of the Invention

The invention relates to pharmaceutical compositions, delivery methods, delivery devices and methods for the treatment of cancer. The invention abo relates to pharmaceutica' compositions, delivery methods, delivery devices and methods for the treatment of fluke infestations and Lyme disease (Borreliosis).

Background and Prior Art Knogpliennt

Artemesinins, which may be isolated from the plant Arte.anesia annua are known for the treatment of malaria, and have also been shown to he 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 (Jnkgrative Cancer Therapie 5(4): 2006, 391-394) report the treatment of pituitary adenoma with artemether.

Singh and Verma (Archive of Oncology, 10(4): 2002, 279280) report the treatment of laryngeal squamous cell carcinoma with artesunate.

Singh and Lai (Life Sciences, 70(200 1) 4956) 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 th.e use of artemisinins for the treatment of various cancers, including breast cancer, nonHodgkin's Lyrnphoma, nonsmall cell lung carcinoma, and multiple skin cancers.

Efferth et a! (Anti.malaria drug is also active against cancer21, mt. 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 schistosomniasi& Keiser and Morson (Exp. Parasitat, 11 8(2), 2008: 228 37) report the activity of artesunate and artemether against the liver fluke Fasciola hepatica.

Keiser et a! J Antimicrobial Chemotherapy, 2006, 7, 11391 145) also report that artesunate and artemether are effective fasciolicides, Utzinger et a! (Curr Opin Investig Drugs, 2007 Feb 8(2), 1 05-1 6) report the use of artemesinins for treatment of individuals infested with Plasmodiurn spp. and Schistosomna 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 hurgdo;jèri is the predominant cause of Lymne disease in the Uhited States, Borrelia qftelii and Borrelia garinil 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 Arteinesia ammo (Woodrow et al. Postgrad. Med.J.

2005; 81:71-78). These compounds include the semi-synthetic derivatives artenimol, artesurtate, artemether and arteether (artemotifl. The International Pharmacopoeia (Ph.

Jut, World Health Organi sation) 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 tbrni of capsules or tablets; arteether in an injectable formulation; and both artcnimol and artesunate in the form of tablets, to 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 hioavailahility and the presence of a first pass effect when taken by the oral route, as will be discussed below. Furthermore, for ong-teriu 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 Lynre disease; injectable treatn.ients 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 ia therefore amongst the objects of the present invention to address $0 these and other issues.

$oftie Invention Accordingly, in a first aspect, the invention provides a pharmaceutical composition for the treatment of neoplasnis comprising: a compound capable of providing S dihydroartemesinin; and a phannaceutieaUyacceptahle excipient selected the group consisting of: medium chain length triglycerides; short chain triglycerides; omega3 marine triglycerides; and fish oil, rich in omega3acids, said composition formulated for transmucosal sublingual, buccal or nasal dosage.

In a second aspect, the invention provides a pharmaceutical composition for the treaftnent of fluke infestation comprising: a compound capable of providing dihydroartemesinin; and a pharmaceuticallyacceptahle excipient selected the group consisting of: medium chain length triglycerides; short chain triglycerides; omega4marine triglycerides; and fish oil, rich in omega-I-acids, said composition fonnulated for transmucosal sublingual, buccal or nasal dosage.

In a third aspect, the invention provides a pharmaceutical composition for the treatment of Lyme disease (boneliosis) comprising: a compound capable of providing ihydroarteniesinin; 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-I-acids, said composition formulated for transmucosal sublingual, buccal or nasal dosage.

The inventors have found that the transmucosal sublingual, transmucosal buccal and transmucosal nasal routes for administration of artemether or arteether are effective for delivery of the pharmaceutical into the systemic circulation eg. 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 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, a Cfll 1602) and of capric acid (decanoic acid, C10H2002). Mediumchain triglycerides are obtained from the oil extracted. from the hard, dried fraction of the endosperm of Cocos nuctfèra L. or from the dried endospenn of Eloels guineensis Jacq. When Mediumchain Triglycerides are prepared from the endosperna of Cocos nuc?fera L, the title Fractionated Coconut Oil may be used. Medium chain length triglycerides have a minimum 95O 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.

0mega-3marine triglycerides are defined in the European Phannacopoeia Monograph 0868 as mixture of mono, di and triesters of omega3 acids with glycerol containing mainly triesters and obtained either by esterification of concentrated and purified omega3 acids with glycerol or by transesterification of the omega3 acid ethyl esters with glycerol.

The orin of the omega3 acids is the body oil from fatty fish species coming from families like Engraulidae, C'arangidae, Ciupeidae, Osineridae, Salmonidae and Scombridae. 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 (020:5 n3; EPA), heneicosapentaenoic acid (C21:5 n3), ciupanodonic acid (C22:5 n3) and cervonic (docosahexaenoic) acid (022:6 n3; DHA).

The sum of the contents of the omega3 acids EPA and.DHA, expressed as trigycerides is a minimum, of 45,0 per cent, and the total oniega3 acids, expressed as thglycerides is a minimum of 600 per cent, Tocopherol may he added as an antioxidant.

Fish oil, rich in omega3acids is also defined in the European Pharmacopeia as purified, winterised and deodorised fatty oil obtained from fish of the families Eng.rauiidae, (arangidae. C'lupeidae, Osrneridae, Sco,nbridae and Aminodytidae. The omega3 acids o are defined as the following acids: a/pha4inolenic acid (Ci8:3 n3\ moroctic acid (C18:4 n3). eicosatetraenoic acid (C20:4 n-I), timnodonic (eicosapentaenoic) acid (C20:5 n-3; EPA), heneicosapentaenoic acid (C21:5 n3). clupanodonic acid (C22:5 n-I) and cervonic (docosahexaenoic) acid (C22:6 ml; DHA).

The content of the Fish oil, rich in omega3acids is as follows: EPA, expressed as triglycerides: minimum 110 per cent, DHA, expressed as triglycerides: minimum 90 per cent, Total omcga3-acids, cxpresscd as triglycerides: minimum 2&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 th.e recited excipicnts, 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 he non-1oxic, 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 sp ray formulations described below. The viscosity for these applications should be low enough to be capable of atontizing, 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 37t, and medium chain triglycerides (as defined herein).

Particularly preferred compositions of the invention consist essentially of: artemether or arteether; and one or more phannaceuticallyacceptahle excipients selected the group consisting of: mediuni 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 (eg. higher molecular weight lipids) renders a composition that is ideally suited to transmueosal nasal, huccal. and especially sublingual delivery.

More preferred compositions comprise: artemether and a pharmaceuticaliyacceptahle exeipient selected the group consisting oft medium chain length triglycerides; short chain triglycerides; and omega3-marine triglycerides, said composition formulated for transmucosal sublingual, buccal or nasal dosage, and especially a composition consisting essentially of: artemether and a phannaceuticallyacccptable excipient selected the group consisting of: medium chain length triglycerides; short chain triglycerides; and omega-3 marine triglycerides, said composition formulated for transmucosal sublingual, buceal 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 shelf4ife of the compositions, especially when stored at ambient temperatures. Preferred compositions would have less than 1. %(w!w) water, and more preferably less than ftS%(w/w) water, and most preferably less than 0i%(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 1 %(wlw) ethanol, and more preferably less than 05%(w/w) ethanol and most preferably less than 0.1 %(/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 transnmeosal 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 paediatrie use, and are also more likely to ensure that the pharmaceutically active components remain in solution over a wide temperature range, rather than having son.e portion as eg. a suspension. This is particularly important to ensure that delivery of the drug is by the recited transmucosal route. if significant amounts of the active components are not in solution, then there is an increased likelihood that some will be swallowed, therdby reducing the beneficial effects of such transmucosal deliveiy 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 soluhilising 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 liquidbased fbnuuiations which cannot by their nature be encapsulated or Rsugarcoated. 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 thrtherm.ore 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 microlitres. The use of small dose volumes reduces the likelihood that the composition will be swallowed, or spat out, by the patient The likelihood is reduced further by use of smaller volumes (especially in the paediatric context 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 vol tunes 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 dihydroarternesinin, such as arteniether or arteether. Such devices arc preferably adapted to assist sublingual delivery, especially by non-medically trained personnel. Limiting the amount of active pharmaceutical delivered with each dose is especially important in the context of treatment by less skilled personnel (eg. self-administration by a patient in a domestic setting, which is likely for long-tenn 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 minimnising 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, inadverten.t delivery of the medicanient to the lungs is avoided, or reduced.

In a fourth aspect, the invention also provides a device tbr 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 attadhed to e.g. a separate transmueosal 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 transm.ucosal sublingual, buccal or nasal route. Preferably, said kit has instructions to administer said composition to a patient in need thereof by the stiblingual 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 (cOg. an artemesinin, and especially artemether or arteether) by the transmucosai 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 phannaceutical composition according to any of the aspects) or preferred aspects) described above for the treatment of neoplastic diseases, fluke infestation or Lymc disease.

Preferably, any of the pharmaceutical compositions or devices provided by the present invention are for the treatment of neopiasms, 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 holotransfcrrin, as this enhances the action of dihydroartemesinin.

In any methods of treatment of the invention it is also particularly preferred to co-administer a transfenin, such as holotransfenmn, as this enhances the action of dihydroartemesinin.

Also included within the scope of the invention are phannaceutical compositions, mcdicament delivery devices, kits and methods substantially as described herein, with reference to, and as illustrated by any appropriate combination of the accompanying drawings.

Disdained Embodiments In prefen'ed embodiments of the invention, the fbulowing numbered aspects, disclosed in co-pending International Patent Application PCT/0B2008/050999 are particularly S disclaimed: 1. A phannaceutical composition comprising: artemether or arteether; and a pharmaceuticallyacceptable excipient selected the group consisting of; medium chain length triglycerides; short chain triglycerides; omega3marine triglycerides; and fish oil, rich in omega4acids said composition formulated for transmucosal sublingual, huccal or nasal dosage 2. A composition according to aspect 1 consisting essentially of artemether or arteether; and one or more pharniaceuticallyacceptahie excipients selected the group consisting of: medium dhain length triglycerides; short chain triglycerides; omega3marine triglycerides; and fish oil, rich in omega3 acids said composition formulated for fransinucosal sublingual, buccal or nasal dosage.

3. A composition according to aspect I comprising: artemether and a phannaceuticallyacceptable excipient selected the group consisting of medium chain length triglycerides; short chain triglycerides; omega3marine triglycerides; and fish oil, rich in omega4-acids said composition formulated for transmucosai sublingual, buccal or nasal dosage.

4, A composition according to aspect I consisting essentially of: astern ether and one or more phannaceutica1lyacceptab1 e excipients selected the group consisting of: medium chain length triglycerides; short chain triglycerides; and omega3marine triglycerides; and fish oil, rich in omega3acids said composition formulated for transmucosal sublingual, buccal or nasal dosage.

5. A composition according to aspect I consisting essentially of: artemether or arteether; and a pharmaceutically acceptable excipient consisting essentially oF a triglyceride, liquid at 37°C; and mcdi urn chain length triglycerides; said composition formulated for franamucosal 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 artcmcther 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.

ii. A composition according to any preceding aspect further comprising an essential oil such as menthol, vanillin or orange oil, lemon oil, clove oil, peppennint 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 microlitres, 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 arternether or arteether.

16. 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 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.

ao 19. .A device fur providing phannaceutical doses comprising a container containing a phannaceutical composition according to any of aspects I to 13, and valve means arranged to transfer doses of said pharmaceutical composition to the exterior of the container.

20. A kit fin the treatment or prophylaxis of malaria comprising a composition according to any of aspects 1 to 1$ and instructions to administer said composition to a patient in need thereof by the transmueosal sublingual, buccal or nasal route.

21. A kit for the treatment or prophylaxis 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 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 transmucosai sublingual, buecal or nasal route.

23. A method of treating a disease responsive to artemether comprising the administration to a patient in nced thereof of a therapeutically effective amount of artemether by the fransmucosal sublingual, huccal 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 fransmucosal sublingual, buccal or nasal route.

27. 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 transmucosai sublingual route.

çñtiondPrefthed Embodiments of the lnventjQfl One of the most important aspects of providing a clinically useful treatment for diseases, infections or infestations resnonsive to dihydroartemesinin (produced in vivo by 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 surprising'y increased bioavailability of the dmg when administered by sublingual spray in comparison to oral administration by tabkt, The inventors have also found that, contrary to accepted beliet artemether 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 Artemether API, and artemether 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 Miglyol® 810. Miglyol® is a medium chain triglyceride containing saturated C8 and ClO fatty acids, t3pically between 6540% of capryhc acid (C8:0) and 2045% of capric acid (Ci 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 propeilants butane, Zephex® 227 (1,1,1,2,3,3,3 heptatluoropropane) and for a mixture of butane and propane.

Table I shows the impurities (as a percentage of the peak area of an HPLC chromatograni 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 40C.

Thhie I -Storage at 30°C R&attve Reteuthm Time: 035 f 0.68 [0.73 0.87 0,91 1.17 % of artemether Artemether API 0.4 0.1 (12 20% EtOH 80% propellant 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% EtOHI (13 0.2 0.5 0.2 Miglyol8lO® 0.4 0.1 0.2 Table 2 Storage at 40°C Relative Retentioii TUne: 0,35 0.68 0.73 0.87 0.91 1.17 %ofartemether Artemether API 0,4 0.1 -0.2 20% EtOB 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 i00%EtOH 2.2 0,7 1.6 0.2 1.0 0.7 Miglyol 810® 0.6 0.1 0.2 Representative chromatograins 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 iv observed in the initial Artemether API. In all other cases, the impurities are at levels that exceed those pennitted under the 1CM 1-larmonised 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 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 acid-containing triglycerides.

When used in a spray delivery system, eg. 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 fonnulation, The use of such medium chain triglycerides also produces a formulation of appropriate viscosity and surface tension für 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 he absorbed transmucosaily. The hydrophobic nature of the composition resists being washed out of the mouth by the action of saliva, which would 16 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 f his has a number of benefits; (1) Its fur ction 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 cheek 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 surprising feature is that the essential oil (especially Ievomenthol) also assists with the solubilisation of the artemether. In a solubility trial, dissolution of artemether in rniglyol occurred after 4 minutes 30 seconds when menthol added before artemether compared to 5 minutes 55 seconds *hen artemcther added before menthol.

As an example, preferred fonnulations (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 are given suitable for use in a spray delivery system. A number of sprays (i.e. individual spray actuations of I OOmicrolitres) may be given, dendent on the weight of the child to he treated: Table 3: 3mg Artemether per actuation Raw Material lien Weight (g) % w/w Artemether IF 0.090 32 Levomenthol Ph, Fur. 0.020 0.7 Miglyol® 810 2.690 96.1 is Table 4: 6mg Artemether per actuation Raw Material Item Weight (g) % wfw Artemether lP 0.180 6.4 Levomenthol Ph. Eur. 0.020 [ 0.7 Miglyol® 810 2.600 92.9 Table 5 outlines an example of a preferred dosage regime for paediatric use. Alternative regimes are envisaged, e.g. dosing at 3mg/kg body weight.

Table 5: Paediatric Dosage Regime Weight of Number of Total Number of Total child ikg) doses at 3mg delivered dose doses at 6mg delivered dose Dose per: mg/kg Dose per mg/kg spray spray _____________ actuation ______ actuation ______________ 3 1 1.00 _________ __________ 4 1 035 _________ __________ 2 1.20 ________ 6 2 iMO _______ 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 L06 18 3 tOO 19 3 0.95 -20 ___ _________ 3 0.90 21 3 0.86 22 --4 1.09 23 ______ ______ 4 1.04 24 ___________ _______ 4 tOO 4 0.96 26 ______ 4 0.92 27 _____________ 4 0.89 28 ____________ ____________ 5[ 1.07 - 9___ _______ _______I__.03 0 _______ ______ I Formulations fOr adult use may he prepared at higher concentrations of artemether, such as 150-200 mg/mi. For adult use, individual spray volumes may he larger than the 1 OOmicrolitre example described here for paediatric use.

Bioavailability of Artemether The applicant has carried out confidential trials to asses the uptake of the arteinether 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 orahdosed tablets, as follows: inalSraRe'mes U) 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.

Table 6 Dosage Regime/or Single Dose Study Sublingtiai Spray Formulation Dose per Number of Total Doge Test Fonnulation Actuation (nig) Actuations (rng)

Ti AsTable3 3 5 15

T2 As Table 3 3 10 30

13 As Table 4 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.

Table 7 Dosage Regime fbr Single Dose Study Oral Tablet Formulation Dose per Tablet Number of Total Doge Test Formulation (mg) Tablets (mg)

T4 Tablet 10 3 30

Following administration, of eadh dosage regime, blood samples were taken from the S subjects, and plasma concentrations of' artem ether and its immediate metabolite dihydroartemesinin were determined, in order to compare bioavailability by the two routea Figures 1-6 show mean plasma concentration of artemether foil owing two comparison dose regimes Figures 7-12 show th.e corresponding 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 T4 (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): 1 Sing artemether via 5 sublingual spray doses vs. 30mg artemether via 10 sublingual spray doses.

Figures 5 and 11 compare regimes T2 (open squares) and 13 (dosed circles): 30mg artemether via 10 sublingual spray doses vs. 30mg artemether via 5 sublingual spray doses.

Figures 6 and 12 compare regimes Ti (open squares) and 13 (closed circles): I 5mg artemether via 5 sublingual spray doses vs. 30mg artemether via 5 sublingual spray doses) Phannacokinetic data for each of the four dosage regimes are given in Tables 8-41, below: Table 8: Thrt Group TI Single sublingual administration of 15mg Artemether sublingual spray: is 3mg per actuation Plasma Artemether Plasma Dihydroattemesinin (n=16) (n=16) Phannacokinetic Parameters _____ _____________ (mean ±SD) (mean ±SD) ______ AUC.12 (ng±JmL) 25.85 ± 13.88 29.63 ± 1138 C (ng/mL) ______ 16,11 ± 8.69 18.29 ± 7.52 T(h) 1.70±0.68 1.83±0.68 __________________ ______ 0.72 ±_0.30 _______________ ________ AJh1) 1.11±0.40 ______________________ CLtP (ng/h) _____ 034 ± 0,46 0.54 ± 0.15 WF (L) 0.68 ± 0,33 0,51 ± 0.16 tKey: AUC012 (ng.hImL) Area under the concentration curve between 042 h. C (nglmL) Maximum observed plasma concentration T (h) Time of observed maximum plasma concentration t1⁄4 h) Elimination half4ife 2 (If') Elimination rate constant CliP (ng/h) Apparent clearance rate V/F (L) Apparent volume of distribution Table 9: Test Group T2 Single sublingual administration of30mg Artemether sublingual spray: 3mg per actuation Plasma Arternether Plasma Dihydroartemesinin (n=16) (n=16) Pharmacokinetie Parameters -, ___________ _______ (mean ±SD) (mean ±SD) AUC12 (ng.h/mL) 76.60± 4112 99.51 ±. 50.33 Crnax(ng/mL) 32.12±16.39 44.11±28.48 Lax (Ii) _________ 1.73 ± 0.82 2.10 ± 1,17 t1⁄2th) 1.39±0.49 _____ ___________ ), (h") 036 ± 0.20 _________________________ CL/F (ng/h) 0.56±0.37 _____ 0.36±0.13 V/F (L) 1.00 ± 0.55 0,72 ± 0.36

Key as Table 8

Table 10: Test Group T3 Single sublingual administration of'3Omg Artemether sublingual spray: 6mg per actuation Plasma Arternether Plasma Dihydroartemesinin (n=16) (n=16 Pharmacokmetie Parameters ______ (mean ±SD (mean ±SD) AIJC0.12 (ng.himL) 71.1!±41.08 86.19 ± 27.68 C(nWmL) 35.24±23.91 -41.14±16.45 T(h) 1.67±037 1,88±0.74 -- ________________ ____ 1,40±0,59 ______________________ ? (li'1) _________ 0.59 ± 0.25 _________________________ CL/F (ngfh) ____ 0.63±0.49 0.39 ± 0.15 V/F (L) 1.01 ± 0.49 0.91 ± 0,67

Key as Table 8

Table 11: Test Group T4 Single oral administration of3omg Arte?nether Tablets

10mg per Tablet

Plasma Artemether Plasma Dihydroartemesinin (n=16) (n=i6) Pharmacokmetic Parameters _____________ (mean ±SD) (mean ±SD) AUC0,2 ng.hImL) 34.59 ± 21,01 _____ 38.49 ± 12.38 Caxng/niL) --10.12±7.19 10.99±4.39 1.02±0.86 ______ 1.39±0.88 t h) ______________ 3.44 ± 4.26 ________________________ Lth) 0.31±0.15 ____________________ CL/F ng/h) ____ 1.11± 1.01 0.76±0.23 V1P(L) 3.90±2.90 2,36±1.26

Key as Table 8

From these preliminary results, it can he seen that comparison of the area under the plasma concentration curve during the 12 hours following the doses (AUC012), a welh accepted measure of absorption, shows significant and surprisingly higher absorption of artemeth.er 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 Fvaiues, commonly used to compare two dose regimes, generally A and 13, lix the artemether data, as follows: AUCA doses = AUCB dase4 The results are as follows: Fr;r4 = I 67 ± 0.60 (S.D) FT2.T4 = 224 ± Q92 (SD) FT = 2.09 ± 69 (SD) This indicates that approximately between I 3 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 stiblingual route is therefore at least twice that by the oral route for equivalent doses.

Inspection of the data of Tables 841, and Figures 142 also confirms this general finding for the prinwy active metabolite of artemether (dihydroartemesinin) Avoidance of Autoinduction so It is known that both oral and rectal administration of artemesinins is associated with autoinduction of the drug metabolism in individuals (see eg. Ashton M, Hai TN, Sy ND, Huong DX, Van throng N, Nieu NT, Cong LD. "Artemisininpharmaco/dnetics is tirne dependent during repeated oral administration in healthy male adults. , Drug Metab Dispos. 1998; 26:25-7. and Retrospective analysis of artemisinin pharmacokinetics: application of a seniphysiological autoinduction model'', Asimus and Gordi, Br. J Cia 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, dihydroartmnesinin, thereby providing significant advantage in administration by the sublingual route. A similar avoidance of autoinduction is expected with delivery by the tansmucosal huccal or nasal route.

In confidential trials, volunteers followed the following treatment: A single administration of 30mg artemether sublingual spray 6mg/actuation on days I and 5 tbllowing an overnight fast, and twice daily administrations of 30mg artemether sublingual spray 3mg/actuation on days 2, 3,and 4 following a morning or evening meal. Blood samples were collected for pharmacokinetic analysis at the following time points: Day 1: Predose, 0.25, 0.5, 0.75,1, 1.5,2, 23.3,4,6,8, and 12 h after dosing.

Days 2, 3, and 4: pre morning dose and 03, 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, 23, 3, 4, 6, 8, 12 h and 24 h after dosing.

Phannacoldnetic analysis of plasma dihydroartemesinin on days I and 5 revealed an effectively identical response, indicating the lack of autoinduction. Plasma concentration curves are 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 o 3mg/actuation (TI) and single oral administration of 30mg Artemether Tablets 10 mg/tablet (T4). Mean ± SD ( = reference, T4, o = 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, o = 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, D = test, T3) Figure 4: Plot of mean plasma artemether concentration vs time with standard deviation following a single sublingual administration of! 5mg Artenietber 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 Artemether Sublingual Spray 3mg/actuation (T2) versus single sublingual administration of 30mg Artemether Sublingual Spray 6mg/actuation (T3). Mean ± SD ( = reference, 11, D = test, l'2) Figure 6: Plot of mean plasma Artemether concentration vs time with standard deviation following a single sublingual administration of I Sing Artemether Sublingual Spray 3mg/actuation (Ti) versus single sublingual administration of 30mg Artemether Sublingual Spray ómg1actuation (T3) Mean ± SD ( = reference, T3, o = test, TI) Figure 7: Plot of mean plasma Dihydroartemisinin concentration vs time with standard deviation following a singk sublingual administration of 15mg Artemether Sublingual Spray 3mglactuation (Ti) and single oral administration of 30mg Artemether Tablets 10 mg/tablet (14). Mean ± SD = reference, 14, 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 (12) and single oral administration of 30mg Artemether Tahkts 10 mg/tablet (14). Mean ± SD (* = reference, N, D = test, 12) Figure 9: Plot of mean plasma Dihydroartemisinin concentration vs time with standard deviation following a singi& sublingual administration of 30mg Artemether Sublingual Spray ómg'actuation (13) versus single oral administration of 30mg Artemether Tablets mg/tablet (14). Mean ± SD ( = reference, 14, o = test, 13) Figure 10: Plot of mean plasma Dihydroaem isinin 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 (12). Mean ± SD (s = reference, T2 * o = 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 (12) versus single sublingual administration of 30mg.Artem ether Sublingual Spray 6mg/actuation (13). Mean ± SD ( = reference. 13, o = test, 12) 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 Artemnether Sublingual Spray 6mg/actuation (T3). Mean, ± S.D (* = referenc; 13,o = test. 11)

Claims

CLAIMS1. A pharmaceutical composition for use in the treatment of Lyme disease (l3orrebosis), said composition comprising: a compound capable of providing dihydroartemesinin; and a phannaceuticallyacceptable excipient selected from the oup consisting of: medium chain length triglycerides; short chain triglycerides; omega3marine triglycerides; and fish oil, rich in omega3acids said composition formulated for transmucosal sublinia1, huccal or nasal dosage.
2. A composition according to claim I consisting essentially of: Is a compound capable of providing dihydroartemesinin;and a phannaceuticaiiyacctable excipient selected from the woup consisting oti medium chain length triglycerides; short chain triglycerides; omega-3marine triglycerides; and fish oil, rich in omega3 acids said composition lbrm ulated for transmucosal stiblingual, buccal or nasal dosageS
3. A composition 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 37°C; and medium chain length triglycerides; said composition t'brrnuated i.or transmucosal sublingual. buccal or nasal dosage.
4. A composition according to any one of claims I to 3 *here said compound comprises an artemesinin.
5. A compotind according to claim 4 wherein said compotmd comprises artemetber 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 thrther comprising an essential oil such as menthol, vanillin or orange oil, lemon oil, clove oil, peppermint oil, speannint oil.9. A composition according to any preceding claim thnnulated for sublingual delivery.10. A composition according to any preceding claim further comprising a transferrin.is il. 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 1 to 10 that is contained within a container comprised within a device fbr providing phannaceutical doses with valve means arranged to transfer doses of said pharmaceutical composition to the exterior of the container.iS. 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, buccal or nasal route.I 6. 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 stiHingual route.