WO2010122276A1

WO2010122276A1 - Drug delivery

Info

Publication number: WO2010122276A1
Application number: PCT/GB2009/050416
Authority: WO
Inventors: Clive Booles
Original assignee: LondonPharma Ltd
Current assignee: LondonPharma Ltd
Priority date: 2009-04-23
Filing date: 2009-04-23
Publication date: 2010-10-28
Anticipated expiration: 2011-10-23

Abstract

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

Description

DRUG DELIVERY

Field of the Invention

The invention relates to improved methods of delivery for medicaments, and to devices for drug delivery.

Background

The development of drug delivery routes remains an important element in the progress of the pharmaceutical sciences. Once an active compound has been identified, the design of delivery mechanisms must overcome challenges of transporting the medicament to the required site of action in the body whilst addressing issues including shelf stability, bioavailability, toxicity, and patient compliance. All of these challenges must be overcome to achieve the desired therapeutic effect. Amongst the drug delivery options, oral administration is by far the most common route, with other options including injection, topical, inhalation and transmucosal administration.

The oral delivery route faces perhaps the most challenging route for a pharmaceutical to reach the final site of action: The composition must survive the acidic and enzymatically- active environment of the stomach; if not absorbed in the stomach, the medicament must survive the action of bile salts and further intestinal and bacterial enzymatic action within the intestinal tract, be able to cross from the lumen of the gut to the intestinal wall for absorption, and then survive the degradation processes of the liver following transport by the hepatic portal system, often resulting in poor availability due to the first pass effect. Furthermore, many bioactive compounds elicit autoinduction of enzymes (e.g. in the hepatic system) that lead to increasing breakdown the drugs before they reach the systemic circulation, leading to a decrease of bioavailability of the molecules over time during a medicament administration regime. Despite these challenges, the oral route of drug administration remains the most common.

It is among the objectives of the present invention to attempt a solution to these problems.

Summary of the Invention

Accordingly, the invention provides a pharmaceutical composition for the sublingual delivery of a medicament comprising: a neutral oil; and a medicament soluble in said oil; providing that said medicament is not nitroglycerine.

Particular medicaments envisaged include especially opioids such as fentanyl and buprenorphine, pharmaceutically acceptable salts thereof, analogues thereof or derivatives thereof. Other opioids envisaged include: alfentanil, sufentanil, butorphanol, codeine, hydrocodone, hydromorphone, levorphanol, meperidine, methadone, morphine, nalbuphine, oxycodone, oxymorphbne, propoxyphene, tramadol, fenpipramide, , pentazocine, piritramide, tilidine, tramadol, pharmaceutically acceptable salts thereof, or derivatives thereof, and the like.

Preferably, said neutral oil comprises a glyceride, and more preferably a triglyceride.

In especially preferred embodiments said triglyceride comprises miglyol, and especially a miglyol selected from the group comprising: miglyol 810; miglyol 812; miglyol 818; miglyol 829; and miglyol 840. Also in especially preferred embodiments said neutral oil comprises an oil selected from the group comprising: Refined Maize Oil (Ph Eur); Virgin Castor Oil (Ph Eur); Refined Olive Oil (Ph Eur) and Refined Rapeseed Oil (Ph Eur).

Also in especially preferred embodiments said neutral oil comprises an oil selected from the group comprising: Glycerol mono-oleates (Ph Eur); Linoleoyl Macrogolglycerides (Ph Eur); Oleoyl Macrogolglycerides (Ph Eur); Vegetable Fatty Oils (Ph Eur); rich in triglycerides, Medium Chain Triglycerides (Ph Eur); Coconut Oil (Ph Eur); Fractionated Palm Kernel Oil (Ph Eur); Hydrogenated Cottonseed Oil (Ph Eur); Omega-3 -Marine Triglycerides (Ph Eur); Fish Oil, Rich in Omega-3-Acids (Ph Eur); Cod Liver Oil (Ph Eur); Diglycerides; Monoglycerides; and Diglycerol.

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

Medium chain length triglycerides are defined in the European Pharmacopoeia Monograph 0868, as:

A mixture of triglycerides of saturated fatty acids, mainly of caprylic acid (octanoic acid, C8H16O2) and of capric acid (decanoic acid, C10H20O2). Medium-chain triglycerides are obtained from the oil extracted from the hard, dried fraction of the endosperm of Cocos nucifera L. or from the dried endosperm oϊElaeis guineensis Jacq. When Medium-chain Triglycerides are prepared from the endosperm of Cocos nucifera L., the title Fractionated Coconut Oil may be used. Medium chain length triglycerides have a minimum 95.0 per cent of saturated fatty acids with 8 and 10 carbon atoms. Further chemical and physical properties are described in the European Pharmacopoeia Monograph 0868, and equivalent documents. Omega-3 -marine triglycerides are defined in the European Pharmacopoeia Monograph 0868 as mixture of mono-, di- and triesters of omega-3 acids with glycerol containing mainly triesters and obtained either by esterification of concentrated and purified omega-3 acids with glycerol or by transesterification of the omega-3 acid ethyl esters with glycerol. The origin of the omega-3 acids is the body oil from fatty fish species coming from families like Engraulidae, Carangidae, Clupeidae, Osmeridae, Salmonidae and Scombridae. The omega-3 acids are identified as the following acids: alpha- lino lenic acid (C18:3 n-3), moroctic acid (C18:4 n-3), eicosatetraenoic acid (C20:4 n-3), timnodonic (eicosapentaenoic) acid (C20:5 n-3; EPA), heneicosapentaenoic acid (C21 :5 n-3), clupanodonic acid (C22:5 n-3) and cervonic (docosahexaenoic) acid (C22:6 n-3; DHA). The sum of the contents of the omega-3 acids EPA and DHA, expressed as triglycerides is a minimum of 45.0 per cent, and the total omega-3 acids, expressed as triglycerides is a minimum of 60.0 per cent. Tocopherol may be added as an antioxidant.

Fish oil, rich in omega-3-acids is also defined in the European Pharmacopeia as purified, winterised and deodorised fatty oil obtained from fish of the families Engraulidae, Carangidae, Clupeidae, Osmeridae, Scombridae and Ammodytidae. The omega-3 acids are defined as the following acids: alpha-lino lenic acid (C 18:3 n-3), moroctic acid (C 18:4 n-3), eicosatetraenoic acid (C20:4 n-3), timnodonic (eicosapentaenoic) acid (C20:5 n-3; EPA), heneicosapentaenoic acid (C21 :5 n-3), clupanodonic acid (C22:5 n-3) and cervonic (docosahexaenoic) acid (C22:6 n-3; DHA).

The content of the Fish oil, rich in omega-3-acids is as follows: EPA, expressed as triglycerides: minimum 13.0 per cent, DHA, expressed as triglycerides: minimum 9.0 per cent,

Total omega-3-acids, expressed as triglycerides: minimum 28.0 per cent.

In preferred embodiments any of said compositions, the compositions consist essentially of said neutral oil; and a medicament soluble in said oil. In alternative embodiments of the above compositions, it is preferred that said composition further comprises a co-solvent selected from the group comprising: ethanol; isopropanol; propylene glycol; and polyethylene glycol.

In preferred embodiments any of said compositions, the compositions further comprise an excipient selected from the group comprising: an antioxidant; a preservative; and a flavouring. Preferably, said flavouring comprises an essential oil such as menthol, vanillin or orange oil, lemon oil, clove oil, peppermint oil, spearmint oil.

In preferred embodiments of any individual such composition, it is preferred that said medicament is not fentanyl, derivatives thereof such as sufentanil, carfentanil, lofentanil, alfentanil, or the like, and pharmaceutically acceptable salts thereof.

Also in preferred embodiments of any individual such composition, it is preferred that said medicament is not an artemesinin (including, without limitation, artemether, arteether and artesunate).

Also in preferred embodiments of any individual such composition, it is preferred that said medicament is not a benzodiazepine.

In some conditions responsive to treatment with compositions or medicaments disclosed herein, patients may exhibit mucusitis and a dry mouth, especially when taking opioids. The inventors have found that miglyol may be used as the sole solvent for the active compounds (with the exception of buprenorphine, which requires the use of ethanol as a co-colvent); this allows formulations to exclude ethanol and other alcohols as a co- solvent, which is particularly beneficial, as alcoholic preparations are particularly irritating to a dry mouth, or to patients having mucusitis and may cause discomfort or pain to the patient. Accordingly, in preferred embodiments of compositions disclosed herein, the composition is substantially, or preferably entirely free of ethanol and more preferably substantially, or preferably entirely free of other alcohols. Formulations such as this have an additional benefit that they may be used in cultural or religious contexts where alcohol intake is not permitted. Also included within the scope of the invention is a delivery device adapted to deliver successive doses of a composition according to any preceding claim, said doses comprising liquid droplets having a mean diameter of at least about 10 microns.

Preferably the compositions of the present invention are delivered as liquid droplets having a mean diameter of at least about 20 microns, more preferably a mean diameter of from about 20 to about 200 microns. Most preferably the formulations are delivered as liquid droplets have a size distribution of from about 5 microns to about 500 microns, preferably from about 10 microns to about 200 microns, preferably from about 20 microns to about 100 microns, more preferably from about 30 microns to about 70 microns. Choice of these droplet sizes ensures that the spray is prevented from passing into the lungs.

It is particularly preferred that each individual or successive dose has a volume of less than 1000 micro litres. The use of small dose volumes reduces the likelihood that the composition will be swallowed, or spat out, by the patient. The likelihood is reduced further by use of smaller volumes (especially in the paediatric context or for nasal delivery) and so in further preferred embodiments, each successive dose has a volume of less than 600 micro litres; less than 400 micro litres; less than 200 micro litres; or even less than 100 micro litres. Smaller volumes are especially preferred for paediatric use.

Preferably, the delivery devices according to these aspects comprise a spray, and especially a pump spray. The use of a pump spray increases the area of mucosa to which the composition is applied, thereby increasing absorption and minimising the likelihood that the medicament is swallowed. Description of Preferred Embodiments

The inventors have found that the use of sublingual delivery of medicaments is more broadly useful in overcoming the problems of drug delivery described above than has hitherto been recognised. The sublingual venous bed drains into the systematic circulation rather than the hepatic circulation, and so the problems of the first pass effect are removed. Furthermore, the bypassing of the hepatic portal system during drug uptake prevents the autoinduction that, for many medicaments, leads to reduction of bioavailability of drugs on successive doses. The use of a sublingual delivery route also means that medicaments may be delivered, avoiding the oral route, by non-trained personnel, in contrast to the alternative of intravenous injection that might be used to avoid the first-pass effect. Additionally, some drugs are not able to be formulated for intravenous injection. Additional benefits of sublingual delivery are that, by careful choice of excipients and droplet sizes, accidental delivery of drug by the oral route can be avoided, thereby preventing the unwanted complications of the oral delivery route.

Whilst some sublingual formulations have been used, these are often formulated using propellants and irritant excipients such as alcohols. For some patients, e.g. those who might have sensitive mucosa as a symptom of their condition, these excipients are unwelcome. In some preferred embodiments, therefore, formulations specifically exclude propellants and alcoholic excipients.

By way of non- limiting example, the following formulations of oil-soluble medicaments are proposed:

Example A: Nicotine

Butylated hydroxy toluene Example B: Buprenorphine

Example C: Fentanyl

Additional excipients found by the inventors to be readily soluble in miglyol, and therefore of us in formulation of the present invention include:

Flavourings: Orange oil; Lemon oil; Aniseed; Peppermint; and Menthol

Preservatives: Propyl parabens and Butyl parabens

Antioxidants: Butylated Hydroxy Toluene; Butylated Hydroxy Anisole and alpha tocopherol

It has been thought that oil-based excipients can lead to low absorption of medicaments. International Patent Application WO2007087431 teaches that "... studies also showed that fentanyl base formulation containing Miglyol had very low permeability" . In contrast to these findings, the inventors have found that the use of oil-based excipients as recited herein, for oil-soluble drugs, surprisingly leads to highly efficient uptake of the medicaments.

As an example, the inventors have carried out confidential trials of sublingual uptake of the artemesinin arteether, described in co-pending International Patent Application PCT/GB2008/050999, and reproduced here: Trials were carried out on healthy male adult human volunteers (16 subjects per cohort), and subject to normal ethical approval. Three single-dose regimes according to the present invention were studied, and compared to a regime using oral-dosed tablets, as follows:

Sub-Lingual Spray Regimes

Spray formulations of artemether were prepared as detailed above, and administered, on a single occasion, to a group of volunteers by the sublingual route. A number of successive actuations of the spray were administered, as shown in Table 6, below.

Table 6 - Dosage Regime for Single Dose Study Sublingual Spray Formulation

Dose per Number of Total Doge

Test Formulation Actuation (mg) Actuations (^mg)

Tl As Table 3 3 5 15

T2 As Table 3 3 10 30

T3 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 for Single Dose Study Oral Tablet Formulation

Dose per Tablet Number of Total Doge

Test Formulation (^mg) Tablets (^mg)

^~Υ4 Tablet ΪO 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 bioavailability by the two routes.

Figures 1-6 show mean plasma concentration of artemether following two comparison dose regimes. Figures 7-12 show the corresponding mean plasma concentration of dihydroartemesinin.

Figures 1 and 7 compare regimes Tl (open squares) and T4 (closed circles): 15mg artemether via 5 sublingual spray doses vs. 30mg artemether via tablet.

Figures 2 and 8 compare regimes T2 (open squares) and T4 (closed circles): 30mg artemether via 10 sublingual spray doses vs. 30mg artemether via tablet.

Figures 3 and 9 compare regimes T3 (open squares) and T4 (closed circles): 30mg artemether via 5 sublingual spray doses vs. 30mg artemether via tablet. Figures 4 and 10 compare regimes Tl (open squares) and T2 (closed circles): 15mg artemether via 5 sublingual spray doses vs. 30mg artemether via 10 sublingual spray doses.

Figures 5 and 11 compare regimes T2 (open squares) and T3 (closed circles): 30mg artemether via 10 sublingual spray doses vs. 30mg artemether via 5 sublingual spray doses.

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

Pharmacokinetic data for each of the four dosage regimes are given in Tables 8-11, below:

Table 8: Test Group Tl

Single sublingual administration of 15mg Artemether sublingual spray:

3mgper actuation

^*Key:

AUCo-12 (ng.h/mL) Area under the concentration curve between 0-12 h. C_ma_x (ng/mL) Maximum observed plasma concentration T_max (h) Time of observed maximum plasma concentration ta (h) Elimination half- life

Mh^"1) Elimination rate constant

CL/F (ng/h) Apparent clearance rate V/F (L) Apparent volume of distribution Table 9: Test Group T2

Single sublingual administration of30mg Artemether sublingual spray:

3mgper actuation

Key as Table 8

Table 10: Test Group T3

Single sublingual administration ofSOmg Artemether sublingual spray: όmgper actuation

Key as Table 8

Table 11: Test Group T4

Single oral administration of 30mg Artemether Tablets lOmgper Tablet

Key as Table 8

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

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

AUC _Λ dose_E r A ,_-Bτ, —

AUC „ dose .

The results are as follows:

Fτi-τ4 = 1.67 ± 0.60 (S.D.) Fτ2-τ4 = 2.24 ± 0.92 (S.D.) Fτ3-τ4 = 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 for equivalent doses.

Inspection of the data of Tables 8-11, and Figures 1-12 also confirms this general finding for the primary active metabolite of artemether (dihydroartemesinin). Avoidance of Autoinduction

It is known that both oral and rectal administration of artemesinins is associated with autoinduction of the drug metabolism in individuals (see e.g. Ashton M, Hai TN, Sy ND, Huong DX, Van Huong N, Nieu NT, Cong LD. "Artemisinin pharmacokinetics is time- dependent during repeated oral administration in healthy male adults. ", Drug Metab Dispos. 1998; 26:25-7, and "Retrospective analysis of artemisinin pharmacokinetics: application of a semiphysiological autoinduction model", Asimus and Gordi, Br. J Clin Pharmacol. 2007 June; 63(6): 758-762). As a result, systemically circulating artemesinin declines with each successive dose, thereby reducing the effectiveness of drug dosage regimes.

In confidential trials, the inventors have found that administration of artemesinins by the transmucosal sublingual route avoids such autoinduction, leading to consistent uptake and accumulating systemic concentration of the active drug metabolite, dihydroartemesinin, thereby providing significant advantage in administration by the sublingual route. A similar avoidance of autoinduction is expected with delivery by the transmucosal buccal or nasal route.

In confidential trials, volunteers followed the following treatment: A single administration of 30mg artemether sublingual spray 6mg/actuation on days 1 and 5 following an overnight fast, and twice daily administrations of 30mg artemether sublingual spray 3mg/actuation on days 2, 3, and 4 following a morning or evening meal. Blood samples were collected for pharmacokinetic analysis at the following time points:

Day 1 : Predose, 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 6, 8, and 12 h after dosing. Days 2, 3, and 4: pre morning dose and 0.5, 1, 2 and 4 h after morning dose and pre evening dose and 1 hour after evening dose.

Day 5: Predose, 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12 h and 24 h after dosing. Pharmacokinetic analysis of plasma dihydroartemesinin on days 1 and 5 revealed an effectively identical response, indicating the lack of autoinduction. Plasma concentration curves are shown in Figure 14.

Figure Captions

Figure 1 : Plot of mean plasma Artemether concentration vs time with standard deviation following a single sublingual administration of 15mg Artemether Sublingual Spray 3mg/actuation (Tl) and single oral administration of 30mg Artemether Tablets 10 mg/tablet (T4). Mean ± SD (• = reference, T4 , D = test, Tl)

Figure 2: Plot of mean plasma Artemether concentration vs time with standard deviation following a single sublingual administration of 30mg Artemether Sublingual Spray 3mg/actuation (T2) and single oral administration of 30mg Artemether Tablets 10 mg/tablet (T4). Mean ± SD (• = reference, T4 , D = test, TZ)

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 15mg Artemether Sublingual Spray 3mg/actuation (Tl) versus single sublingual administration of 30mg Artemether Sublingual Spray 3mg/actuation (T2). Mean ± SD (• = reference, T2 , D = test, Tl)

Figure 5 : Plot of mean plasma Artemether concentration vs time with standard deviation following a single sublingual administration of 30mg Artemether Sublingual Spray 3mg/actuation (T2) versus single sublingual administration of 30mg Artemether Sublingual Spray 6mg/actuation (T3). Mean ± SD (• = reference, T3 , D = test, T2) Figure 6: Plot of mean plasma Artemether concentration vs time with standard deviation following a single sublingual administration of 15mg Artemether Sublingual Spray 3mg/actuation (Tl) versus single sublingual administration of 30mg Artemether Sublingual Spray 6mg/actuation (T3). Mean ± SD (• = reference, T3 , D = test, Tl)

Figure 7: Plot of mean plasma Dihydroartemisinin concentration vs time with standard deviation following a single sublingual administration of 15mg Artemether Sublingual Spray 3mg/actuation (Tl) and single oral administration of 30mg Artemether Tablets 10 mg/tablet (T4). Mean ± SD (• = reference, T4 , D = test, Tl)

Figure 8: Plot of mean plasma Dihydroartemisinin concentration vs time with standard deviation following a single sublingual administration of 30mg Artemether Sublingual Spray 3mg/actuation (T2) and single oral administration of 30mg Artemether Tablets 10 mg/tablet (T4). Mean ± SD (• = reference, T4 , D = test, TZ)

Figure 9: Plot of mean plasma Dihydroartemisinin concentration vs time with standard deviation following a single" sublingual administration of 30mg Artemether Sublingual Spray 6mg/actuation (T3) versus single oral administration of 30mg Artemether Tablets 10 mg/tablet (T4). Mean ± SD (• = reference, T4 , D = test, T3)

Figure 10: Plot of mean plasma Dihydroartemisinin concentration vs time with standard deviation following a single sublingual administration of 15mg Artemether Sublingual Spray 3mg/actuation (Tl) versus single sublingual administration of 30mg Artemether Sublingual Spray 3mg/actuation (T2). Mean ± SD (• = reference, T2 , D = test, Tl)

Figure 11 : Plot of mean plasma Dihydroartemisinin concentration vs time with standard deviation following a single sublingual administration of 30mg Artemether Sublingual Spray 3mg/actuation (T2) versus single sublingual administration of 30mg Artemether Sublingual Spray 6mg/actuation (T3). Mean ± SD (• = reference, T3 , D = test, T2)

Figure 12: Plot of mean plasma Dihydroartemisinin concentration vs time with standard deviation following a single sublingual administration of 15mg Artemether Sublingual Spray 3mg/actuation (Tl) versus single sublingual administration of 30mg Artemether Sublingual Spray 6mg/actuation (T3). Mean ± SD (• = reference, T3 , D = test, Tl)

Claims

1. A pharmaceutical composition for the sublingual delivery of a medicament comprising: a neutral oil; and a medicament soluble in said oil; providing that said medicament is not nitroglycerine.

2. A composition according to claim 1 wherein said neutral oil comprises a glyceride.

3. A composition according to claim 2 wherein said glyceride comprises a triglyceride.

4. A composition according to claim 3 wherein said triglyceride comprises miglyol.

5. A composition according to claim 4 wherein said miglyol comprises miglyol selected from the group comprising: miglyol 810; miglyol 812; miglyol 818; miglyol 829; and miglyol 840.

6. A composition according to claim 1 wherein said neutral oil comprises an oil selected from the group comprising: Refined Maize Oil (Ph Eur);

Virgin Castor Oil (Ph Eur);

Refined Olive Oil (Ph Eur) and

Refined Rapeseed Oil (Ph Eur).

7. A composition according to claim 1 wherein said neutral oil comprises an oil selected from the group comprising:

Glycerol mono-oleates (Ph Eur); Linoleoyl Macrogolglycerides (Ph Eur); Oleoyl Macrogolglycerides (Ph Eur); Vegetable Fatty Oils (Ph Eur); rich in triglycerides Medium Chain Triglycerides (Ph Eur); Coconut Oil (Ph Eur);

Fractionated Palm Kernel Oil (Ph Eur); Hydrogenated Cottonseed Oil (Ph Eur); Omega-3 -Marine Triglycerides (Ph Eur); Fish Oil, Rich in Omega-3-Acids (Ph Eur); Cod Liver Oil (Ph Eur);

Diglycerides; Monoglycerides; Diglycerol.

8. A composition according to claim 1 wherein said neutral oil comprises derivates or partial glycerides of an oil selected from the group comprising:

Glycerol mono-oleates (Ph Eur);

Linoleoyl Macrogolglycerides (Ph Eur);

Oleoyl Macrogolglycerides (Ph Eur); Vegetable Fatty Oils (Ph Eur); rich in triglycerides

Medium Chain Triglycerides (Ph Eur);

Coconut Oil (Ph Eur);

Fractionated Palm Kernel Oil (Ph Eur);

Hydrogenated Cottonseed Oil (Ph Eur); Omega-3 -Marine Triglycerides (Ph Eur);

Fish Oil, Rich in Omega-3-Acids (Ph Eur);

Cod Liver Oil (Ph Eur);

Diglycerides;

Monoglycerides; Diglycerol.

9. A composition according to any preceding claim consisting essentially of said neutral oil; and a medicament soluble in said oil.

10. A composition according to any preceding claim, substantially free of ethanol.

11. A composition according to claim 10, substantially free of alcohols.

12. A composition according to any of claims 1 to 9, further comprising a co-solvent selected from the group comprising: ethanol; isopropanol; propylene glycol; polyethylene glycol.

13. A composition according to any preceding claim, further comprising an excipient selected from the group comprising: an antioxidant; a preservative; a flavouring.

14. A composition according to claim 13 wherein said flavouring comprises an essential oil.

15. A pharmaceutical composition according to any preceding claim providing that said medicament is not fentanyl, derivatives thereof such as sufentanil, carfentanil, lofentanil, alfentanil, or the like, and pharmaceutically acceptable salts thereof.

16. A pharmaceutical composition according to any preceding claim providing that said medicament is not an artemesinin (including, without limitation, artemether, arteether and artesunate).

17. A delivery device adapted to deliver successive doses of a composition according to any preceding claim, said doses comprising liquid droplets having a mean diameter of at least about 10 microns.

18. A delivery device according to claim 17 wherein said droplets have a mean diameter of at least about 20 microns.

19. A delivery device according to either of claims 17 and 18 wherein said droplets have a mean diameter of from about 20 to about 200 microns.