GB2487007A

GB2487007A - Cyclic olefin copolymer containers and delivery devices for the sublingual administration of opioids

Info

Publication number: GB2487007A
Application number: GB1204769.2A
Authority: GB
Inventors: Juliet Victoria High; Martin James Sams; Paul Andrew Jamieson; Calvin John Ross
Original assignee: LondonPharma Ltd
Current assignee: LondonPharma Ltd
Priority date: 2012-03-19
Filing date: 2012-03-19
Publication date: 2012-07-04
Anticipated expiration: 2032-03-19
Also published as: GB201204769D0; GB2487007B

Abstract

A pharmaceutical composition for the sublingual delivery of an opioid comprising an opioid and ethanol, wherein the composition is comprised within a container such that the material of the container that is in contact with the composition is cyclic olefin copolymer (COC). Preferably, the opioid is methadone and is not fentanyl. The composition may further include glycerol. Preferably the container comprises a delivery device to dispense the composition in a single discharge as a spray. The delivery device may further include seals and/or plungers formed from bromobutyl polymer. The composition is preferably for use in the treatment of pain, inducing or maintaining anaesthesia, treating opioid dependence, treating anxiety, treating cough or treating diarrhoea.

Description

COC CONTAINERS AND DELIVERY DEVICES FOR THE SUBLINGUAL

ADMINISTRATION OF OPIOIDS

Field of the Invention

The invention relates to improved methods of delivery of opioids, and to devices for said 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 is prone to loss from the mouth or stomach (e.g. by spitting or vomiting); 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 bite satts and further intestinat 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 fir st pass effect. Furthermore, many bioactive compounds elicit autoinduction of enzymes (e.g. in the hepatic system) that lead to increasing breakdown of 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 orat route of drug administration remains the most common.

The shelf-stability of a medicament is an important consideration in terms of safety, efficacy and cost. Many medicaments (e.g. opioids) are not stable in traditional is delivery devices that are made of e.g. glass or stainless steel (rigid materials required to maintain the shape of the device). Instead, these medicaments are kept in separate, plastic storage containers, with thin, flexible walls making them unsuitable for a delivery device, prior to transfer into a delivery device prior to administration. Such transfer reduces the efficiency of medicament supply: two different containers are required instead of one, and the transfer step introduces the potential for waste and may need to be effected/overseen by a suitable professional (e.g. a pharmacist). The transfer step also introduces the possibility of dispensing error.

Some opioids, such as methadone, are used to treat opioid dependence (as so-called "anti-addictive" drugs). The current methods used to dispense opioids for this purpose are inefficient, particularly for the anti-addictive of choice, methadone.

Methadone is usually made up in a glucose syrup suitable (only) for oral administration and stored in bulk (multiple doses) in a lightweight plastic (e.g. polypropylene) bottle. The administration of single doses to the patient requires professional supervision and skill, and includes the accurate measurement of a dispensed single dose and inspection of the patient after dosing to ensure that they have swallowed the dose (some addicts attempt to spit out the dose to then inject it).

Other disadvantages of using oral methadone for treating opioid dependence include the potential for contamination of the bulk syrup, the relatively high rate of vomiting in patients who are opioid dependent, and the relatively slow (approximately 40 minutes to two hours) and modest euphoric effects experienced by the patient following administration.

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

Summary ofthe Invention

The sublingual delivery route offers (for many medicaments, including opioids) substantial benefits over other administration routes. It is particularly beneficial over the oral route in which a medicament is often lost from the mouth or stomach (e.g. spitting or vomiting), degraded by the various enzymatic and other processes in action in the gut, and leads to absorption by the hepatic route, which can lead to significant is malabsorption as a result of the "first pass effect" in the liver. As a result, orally-dosed medicaments are often given in greater concentration that would be required if they were well-absorbed and could escape the first-pass effect (often giving rise to unwanted side-effects). Sublingual delivery is also beneficial over the injection route because it provides the possibility of administration by non-medically qualified personnel and avoids the risks associated with injecting.

The inventors have surprisingly identified formulation conditions in which pharmaceutical compositions comprising opioids can be prepared for sublingual delivery. Furthermore, the inventors have identified materials that are, surprisingly, suitable for a container for both the storage and delivery of these compositions.

Accordingly, the invention provides a pharmaceutical composition for the sublingual delivery of an opioid, said composition comprising an opioid and ethanol, wherein the composition is comprised within a container and wherein the material of the container that is in contact with the composition is Cyclic Olefin Copolymer (COC). In preferred embodiments said composition additionally comprises glycerol. In particularly preferred embodiments the opioid is not fentanyl. In further preferred embodiments the opioid is methadone.

Preferably the container comprises a delivery device. In any aspect of the invention it is particularly preferred that the delivery device dispenses the composition in a single discharge and/or dispenses the composition as a spray. It is preferred that such a spray comprises liquid droplets having a mean diameter of at least about 10 microns, preferably at least about 20 microns, more preferably between about 20 microns and about 200 microns, and most preferably between about 20 microns and about 100 microns.

In any aspect of the invention it is particularly preferred that the delivery device is non-pressurised and/or comprises seals and/or plungers and wherein the material of said seals and/or plungers that is in contact with the composition is bromobutyl polymer.

The inventors also provide a composition of the invention for use in the treatment of is the human or animal body by therapy, such as for use in: (a) reducing pain; (b) inducing or maintaining anaesthesia; (c) treating opioid dependence; (d) treating anxiety; (d) treating a cough; or (e) treating diarrhoea.

Detailed Description of the Invention

An opioid is a chemical that binds to opioid receptors. Opioids may be broadly classed into natural opioids (the "opiates", alkaloids obtained from the opium poppy), endogenous opioids, semi-synthetic opioids, fully synthetic opioids, and other opioid receptor agonists. Examples of each class are given below: Natural opioids -morphine, codeine, thebaine and oripavine.

Endogenous opioids -endorphins, enkephalins, dynorphins and endomorphins.

Semi-synthetic opioids -hydromorphone, hydrocodone. oxycodone, oxymorphone, desomorphine, diacetylmorphine (heroin), dihydrocodeine, nicomorphine, dipropanoylmorphine, benzylmorphine, ethylmorphine and buprenorphine.

Fully synthetic opioids -anilidopiperidines (e.g. fentanyl, alphamethylfentanyl, alfentanil, sufentanil, remifentanil, earfentanyl, ohmefentanyl), phenylpiperidines (e.g pethidine, ketobemidone, MPPP, allylprodine, prodine, PEPAP), diphenylpropylamine derivatives (e.g. propoxyphene, dextropropoxyphene, dextromoramide, bezitramide, piritramide, methadone, dipipanone, Levomethadyl Acetate [LAAM], difcnoxin, diphenoxylate, loperamidc), benzomorphan derivatives (e.g. dezocine, pentazocine, phenazocine), oripavine derivatives (e.g. buprenorphine, dihydroetorphine, etorphinc), and morphinan derivatives (e.g. butorphanol, nalbuphine, levorphanol, levomethorphan).

Other opiod receptor agonists -lefetamine, meptazinol, tilidine, tramadol and tapentadol.

Opioids that are particularly envisaged in the invention include methadone, sufentanil and fentanyl, and pharmaceutically acceptable salts thereof; analogues thereof or derivatives thereof Other opioids envisaged include: alfentanil, buprcnorphine, butorphanol, codeine, hydrocodone, hydromorphone, levorphanol, mcperidine, morphine, nalbuphine, oxycodone, oxymorphbne, propoxyphene, tramadol, fenpipramide, pentazocine, piritramide, tilidine, tramadol, pharmaceutically acceptable salts thereof, or derivatives thereof, and the like.

In order to avoid oral absorption, the opioid is delivered in a small volume, large enough to coat the sublingual mucosa but small enough to reduce the likelihood that any composition may be swallowed. The skilled addressee will be readily able to determine whether a chosen opioid has sufficient solubility.

Preferably, the opioid is in solution at a concentration providing a required dose of medicament in a volume of no more than 1 000microlitres of composition, more preferably in a volume of no more than SOOmicrolitres, more preferably in a volume of no more than 400 or 300micro litres of composition, more preferably in a volume of no more than 200microlitres of composition, and most preferably in a volume of no more than lOOmicrolitres of composition.

A further preferred feature is that the opioid is stable in the composition, both with respect to physicochemical aspects such as remaining in solution and in terms of chemical (including biochemical) degradation of the medicament over time. It is particularly preferred, therefore, that the opioid is stable within the composition, to pharmaceutically-acceptable limits, over a period of at least one month, preferably at least 2 months, more preferably at least 3 months, more preferably at least 6 months, more preferably at least 12 months, more preferably at least 18 months, more preferably at least 2 years, more preferably at least 3 years, more preferably at least 4 years, and most preferably at least 5 years, whilst kept at a temperature(s) between 4°C and 40°C.

It is also preferred that the opioid is stable in the composition (as defined above) when placed in a container, preferably wherein the container comprises a delivery device, and it is particularly preferred that the opioid is stable within the composition in said container, to pharmaceutically-acceptable limits, over a period of at least one month, preferably at least 2 months, more preferably at least 3 months, more preferably at least 6 months, more preferably at least 12 months, more preferably at least 18 months, more preferably at least 2 years, more preferably at least 3 years, more preferably at least 4 years, and most preferably at least 5 years.

Formulations comprising ethanol The pharmaceutical composition of the invention comprises an opioid and ethanol. In particular embodiments the pharmaceutical composition of the invention consists essentially of an opioid and ethanol. Preferably ethanol is used in the composition at a concentration of at least 5% (w/w), at least 10% (w/w), at least 15% or at least 18% (w/w) and up to 30% (w/w), up to 40% (w/w) or up to 50% (w/w). Preferably, ethanol is used at a concentration of between 10% (w/w) and 30% (w/w), more preferably at a concentration of between 15% (w/w) and 25% (w/w), such as at a concentration of 18% (w/w) to 22% (w/w). As well as acting as a co-solvent, when ethanol is used at a concentration of more than 18% it also has a preservative effect.

Ethanol is particularly useful for sublingual delivery because it evaporates after administration, maintaining the medicament in place on the mucosa.

In preferred embodiments the pharmaceutical composition of the invention comprising an opioid and ethanol additionally comprises glycerol. In a particular embodiment the pharmaceutical composition of the invention consists essentially of an opioid, ethanol and glycerol. Preferably glycerol is used in the composition at a concentration of at least 5% (w/w), at least 10% (w/w) or at least 15% (w/w) and up to 35% (w/w), up to 40% (w/w) or up to 50% (w/w). Preferably, glycerol is used at a concentration of between 15% (w/w) and 35% (w/w), more preferably at a concentration of between 20% (w/w) and 30% (w/w), such as at a concentration of 24% (w/w) or 25% (w/w).

In a preferred embodiment the opioid of the composition comprising ethanol is not is fentanyl. In a further embodiment the opioid of the composition comprising ethanol is methadone.

If the opioid is methadone then a total dose is preferably chosen from at least 5mg, at least 10 mg or at least 15mg and up to 40mg, up to 50mg, up to 60mg, or up to 120mg, preferably between 10mg and 60mg. Particularly preferred total doses include 10mg, 20mg, 30mg and 60mg. The concentration of methadone selected is preferably at least 1 Smg/ml, at least 2Omg/ml, at least 25mg/mi, at least SOmg/ml or at least 7Smg/ml, and up to 1 OOmg/ml, up to 1 SOmg/ml or up to 200mg/ml. Preferably the concentration of methadone selected is between 2Smg/ml and lSOmg/ml, even more preferably between 25mg/ml and 1 OOmg/ml.

The pharmaceutical composition of the invention comprising an opioid and ethanol is contained within a container (for storage and/or delivery) wherein the material of the container that is in contact with the composition is Cyclic Olefin Copolymer (COC).

COC is an amorphous and transparent polymer comprising copolymers based on cycloolefins and linear olefins. The general formula for COC is as follows: CH2 -C?HR CH CH x / The properties of COC may be varied depending on the exact chemical structure of the copolymer, but typically COC displays low density, high transparency, low birefringence, very low water absorption, excellent water vapour barrier properties, heat deflection temperature up to 170°C, and high rigidity/strengthlhardness. These properties make COC a suitable material for medical storage and delivery devices.

One suitable source of COC is from the provider Ticona, who market COC under the registered trademark "Topas" (Thermoplastic Olefin Polymer of Amorphous Structure (COC)).

The inventors have surprisingly revealed that some opioid/ethanol compositions (e.g. comprising methadone HC1) are corrosive within containers consisting of glass or stainless steel (materials traditionally used for delivery devices). However, the inventors have identified COC as a suitable material with which opioid/ethanol compositions are compatible, that is to say that such compositions show high stability within containers wherein said compositions are in contact with COC.

The provision of a composition for sublingual delivery of an opioid (e.g. methadone) is advantageous because, in comparison to compositions for oral delivery, it avoids the need for the administrator to ensure that the composition has been swallowed and avoids the bioavailability problems associated with oral delivery (e.g. vomiting). In relation to treating opioid dependence, sublingual delivery is also likely to provide a quicker and greater euphoric effect in the patient (with onset of approximately 15 minutes in comparison to 40 minutes to two hours for oral delivery), hence increasing compliance.

The provision of such a composition in a COC container that is suitable for both the storage and delivery of the composition is advantageous because it can provide the administrator with a store of single doses each of which can rapidly be employed to dispense a single dose to a patient without the need for accurate measurement of a dispensed single dose. This arrangement also avoids the risk of contamination associated with bulk (multidose) stores of the opioid and can reduce the potential waste associated with having separate storage/delivery containers.

Further optional components In preferred embodiments of any of said compositions, the compositions further comprise a preservative (e.g. propyl or butyl parabens) and/or a flavouring (e.g. blackcurrant flavouring) and/or a sweetener (e.g. sodium saccharin) and/or an essential oil such as menthol, vanillin or orange oil, lemon oil, clove oil, peppermint is oil, spearmint oil. The inventors have found that the addition of such an essential oil surprisingly has three benefits: (1) the essential oil acts as a penetration enhancer, improving the rate and extent of uptake of medicaments by the sublingual mucosa; (2) the essential oil, in many cases, acts as a co-solvents thereby increasing the solubility of medicaments; and (3) the essential oil provides a flavour component, giving organoleptic feedback to a user of the medicament, to confirm that is has been successfully delivered.

Delivery Preferably the compositions of the present invention are comprised within a container that comprises a delivery device, and preferably the device dispenses the composition as a single discharge. Preferably the device is non-pressurised.

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

Larger droplets have larger weight and this is preferable in the invention because a larger weight increases the chances that the droplet, and therefore the opioid, falls rapidly onto the sublingual mucosa thereby reducing the possibility that the droplets become entrained in breath and expelled from the mouth, or taken into the lungs. It is therefore preferred that, for the compositions of the invention that comprise ethanol, the weight of a spray droplet is at least 0.4ng, more preferably at least 3.3ng, more preferably at least 400ng, more preferably at least 3.3 jig, more preferably at least 5 jig.

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 is further by use of smaller volumes (especially in the paediatric context) and so in further preferred embodiments, each dose has a volume of less than 600 micro litres; less than 500 micro litres; less than 400 microlitres; less than 300 micro litres; less than microlitres; or even less than 100 microlitres. Smaller volumes are especially preferred for paediatric use.

Preferably, the delivery devices according to these aspects comprise a spray, preferably a non-pressurised 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.

The material of the container/delivery device that makes contact with a composition ofthe invention should be COC. The container/device may also comprise parts that must be elastomeric, such as seals and/or plungers, and for such parts the inventors have identified bromobutyl polymer, such as bromobutyl rubber (a brominated copolymer of isobutylene and isoprene), as a suitable material that is compatible with any composition of the invention (and particularly as a material suitable for making contact with the a composition of the invention).

A suitable source of bromobutyl polymer is from the provider West Pharmaceutical Services, and in particular West Formulation 4023/50 Gray.

Methods of treatment The inventors describe that a composition of the invention may be used in a method of treatment of the human or animal body by therapy. In particular, said composition could be used in a method whereby the application of an opioid confers medical benefit, including methods of: (a) reducing pain; (b) inducing or maintaining anaesthesia; (c) treating opioid dependence; (d) treating anxiety; (d) treating a cough; or is (e) treating diarrhoea; preferably wherein said composition is administered sublingually in said method.

Furthermore, the inventors describe the use of a composition of the invention in the manufacture of a medicament for reducing pain, inducing or maintaining anaesthesia, or treating opioid dependence, anxiety, cough or diarrhoea.

The inventors also describe a method of treating a human or animal subject in need of an opioid comprising the administration to said subject of a therapeutically effective amount of a composition of the invention, whereby administration is by the sublingual route. In such a method the subject may, for example, be suffering from pain, opioid dependence, anxiety, cough or diarrhoea, or may require anaesthesia.

Examples

Example 1 -methadone formulation Active Pharmaceutical Ingredient The API is supplied by; Macfarlane Smith A Johnson Matthey PLC Business

Wheatfield Road

Edinburgh EH11 2QA Scotland An EDMF is available. Methadone hydrochloride is monographed in the Ph Eur, BP and USP. The Ph Eur/BP monograph is given in Appendix I Its outline properties are; (Ph Eur monograph 0408) H3C CH3

H

4 -& , and enantionier HCI ft / Y Cfh (\*o // / C21H27N0,HCI 345.9 1095-90-5 A white, crystalline powder, soluble in water, freely soluble in alcohol.

Formulation Summary

Note that the use of the term pH herein covers not only aqueous solutions but also ethanolic aqueous, purely ethano lie and other non-aqueous solutions. Thus the term also covers "apparent pH" as defined in the USP ie the apparent pH reading from formulations not wholly aqueous.

Initial formulation work considered the solubility of methadone hydrochloride at a concentration of 100 mg/ml in aqueous solutions with ethanol and propylene glycol as co-solvents. Dissolution was noticeably faster in solutions containing ethanol as a co-solvent. It was also observed that after storage for approximately 1 month at 4°C and 40°C a fine particulate precipitate was formed in a purely aqueous solution compared with an aqueous ethanolic solution. It was proposed that to aid sublingual absorption of basic drugs such as methadone the pH should be buffered to approach the pKa of the drug, 8.2 for methadone. Therefore various buffer systems were employed to adjust the pH of the formulation. It was generally observed that when attempts were made to adjust the pH above 7.0 precipitation occurred on mixing or on storage. The precipitate is thought to be methadone base. Therefore it appeared that the use of buffering agent with methadone at pHs over 7 was not possible.

It was decided to concentrate on aqueous formulations containing ethanol (to aid solubility and act as a preservative), propylene glycol or glycerol (moisturiser), sodium saccharin (sweetener) and blackcurrant (flavour). Several different strengths may be required for the eventual product formulations, therefore to bracket the possible doses required, strengths of 10 mg per 400pJ dose (25 mg/ml) and 60 mg per 400tl dose (150 mg/ml) were chosen.

These formulations all proved to be stable over the six month study with no evidence of degradation. However a number of units were observed to have leaked, particularly those at the higher strength. Additionally the contents of a small number of units were observed to have changed colour to orange brown. These were observed at all temperatures and across the formulations and also in placebo units that had been prepared. A new ultrasonic welder was found to give a much improved and consistent seal.

It was therefore decided to repeat the formulations containing glycerol but omitting the blackcurrant flavour. These formulations proved to be stable after 6 months storage and were chosen for progression to a Phase I study as 10, 20 & 30 mg formulations. These lots were prepared to GMP, placed on stability and one and three month data was satisfactory.

Formulation Following initial preformulation work the following formulations were prepared at 100mg mY' (SOml); _______________ PDO1/07 PDO1/OSa PDO1/08b __________ g %w/w g %w/w g %w/w Methadone HC1 5.00 9.03 5.00 9.47 5.00 8.95 Sodium 0.40 0.72 0.40 0.76 0.40 0.72 Saccharin _________ _________ _________ _________ _________ _________ mus ______ ______ 9.88 18.71 Propykne 12.95 23.19 Purified Water 50.0 90.25 37.50 71.06 37.50 67.14 _______________ 55.40 100.00 52.78 100.00 55.85 100.00 1. 50mg methadone hydrochloride was weighed into a SOml volumetric flask.

2. Approximately 35m1s of solvent was added and the flask shaken until the methadone dissolved.

3. Sodium saccharin was added to the flask and shaken until fully dissolved.

4. The flask was made up to volume with solvent and shaken until homogeneous.

5. The pH was adjusted to 8.2 with 0. 1M NaOH.

PDO1/07 required ultrasonication to dissolve the methadone HCL. Na saccharin dissolved readily. Initial pH 4.7. Much 0. 1M NaOH was added with precipitation at each addition which re-dissolved. Final pH 7.0.

PDO1/08a dissolved the API on shaking as well as the Na saccharin. Initial pH 4.9, adjustment as the previous formulation.

PDO1!08b required ultrasonication to dissolve the methadone HCL. Na saccharin dissolved readily. Initial pH 4.9, adjustment as the previous formulations.

None of these initial formulations could be raised to a higher pH than 7.0 due to precipitation. Each formulation was transferred into serum bottles and placed on storage at 4, 25 and 40°C.

After storage for 1 week all samples remained clear, colourless solutions except for PDO1/08b at 4°C which had significant precipitation. The solutions were allowed to equilibrate to room temperature and examined after six months storage; is PDO 1/07; all solutions were clear and colourless with fine white crystals at 4°C and needle-like white crystals at 25°C. No particulates at 40°C. The samples were not re-examined.

PDO1/08a; all solutions were clear and colourless with no particulates. The pH of the solutions was; 4°C 7.2.

25°C 71 40°C 7.1 After 14 months storage the 25 and 40°C solutions were unchanged, the 4°C sample was as the other temperatures but with a number of crystals present.

PDO1!08b; all solutions were clear and colourless with small white crystals adhering to the glass at 4°C and two large white crystals at 25°C. No particulates at 40°C. The samples were not re-examined.

The above emphasises that ethanolic aqueous formulations are more suitable for methadone formulation.

The level of ethanol in the formulations was explored using the following formulations (SOml); _______________ PDO1/tla PDO1/llb PDO1/llc __________ g %w/w g %w/w g %w/w Methadone HC1 5.00 9.2 5.00 9.3 5.00 9.4 Sodium 0.40 0.7 0.40 0.7 0.40 0.7 Saccharin _________ _________ _________ _________ _________ _________ Ethanol, 3.16 5.8 5.53 10.3 7.90 14.8 anhydrous _________ _________ _________ ________ ________ _________ Purified Water 46.00 84.3 43.00 79.7 40.00 75.1 ______________ 54.56 100.00 53.93 100.00 53. 30 100.00 1. The methadone hydrochloride was weighed into a SOml volumetric flask.

2. The ethanol was added followed by water to approximately 3Oml.

3. The flask was shaken to dissolve the methadone.

4. The sodium saccharin was added and dissolved by shaking.

5. The volume was made up with water.

The dissolving of methadone was notably slower in PDOI/1 la than with the other formulations with higher levels of ethanol. The sodium saccharin dissolved readily in all formulations. The pH of all formulations was 5.0. Each formulation was transferred into serum bottles and placed on storage at 4, 25 and 40°C. After four months storage the solutions were allowed to equilibrate to room temperature and examined; PDO1/1 la; 4°C contained a large quantity of white crystalline material, 25 & 40 °C were clear colourless solutions. PDO1/1 ib; As PDO1/1 la but not so much material at 4°C. PDO1/llc; all solutions were clear and colourless, pH; 4°C 5.1 25°C 5.3 40°C 5.3 After 13 months storage PDO1/1 ic 25 and 40°C samples were unchanged, 4°C sample was as the other temperatures with the addition of fine white needle crystals.

The previous formulation work has shown that attempts to raise the pH of the formulations has resulted in the formation of a precipitate which can be redissolved in ethanol, anhydrous. Therefore if a higher pH is required the formulation will need the presence of ethanol to keep the methadone base in solution. The following formulation was prepared using pH 8.5 phosphate buffer; ___________________ ___________ PDO1/17 __________________ g % w/w Batch Methadone HC1 6.000 10.96 Maefarlan Smith 06-00988 Ethanol, anhydrous 5.530 10.10 Hayman 07/10 1 A2 Propylene Glyeol 5.698 10.41 Merk K37090378 718 Phosphate Buffer 37.500 68.52 ________________________ ___________________ 54.728 99.99 ___________________________ 8.5 Buffer ____________ ____________ _____________________________ NaDihydrogen 0.6 BDHA69182 Phosphate ___________ __________________________ Na Hydroxide ___________ VWR Prolabs J005 Purified Water ___________ To 100 __________________________ 1. The methadone was weighed into a 50m1 flask and the ethanol added.

2. The flask was stirred to dissolve the methadone.

3. Stage 2 did not result in a solution so the propylene glycol was added and stirred again without producing a solution.

4. The phosphate buffer was added to within 5 ml of the total volume and mixed.

5. The pH was adjusted to 8.5 and the solution made up to volume.

As the phosphate buffer was gradually added with mixing the methadone dissolved.

As more was added a precipitate formed from pH 7.2. The formulation was transferred to a 1 OOml flask and ethanol added in lOml portions. After the addition of SOmls of ethanol the precipitate dissolved to give a clear, colourless solution pH 7.2.

From the above it appears that the ethanolie aqueous type formulation is incapable of formulation at pH higher than approximately 7.0. The solution was checked after three months storage and found to be clear and colourless with white crystals and so was discarded.

The effect of raising the ethanol level was investigated in the following formulation; ____________________ ____________ PDO1I2O __________________ ___________ % w/w Batch Methadone HC1 6.00 11.8 Macfarlan Smith 06-00988 Ethanol,anhydrous 19.75 38.9 Hayman07/101A2 Phosphate Buffer 25.90 49.3 ________________________ __________________ 51.65 ___________ __________________________ The method of preparation was as above (50m1). The methadone failed to dissolve in the ethanol but initially dissolved on addition of the buffer. As approximately 2Oml buffer was added transient precipitation occurred but rapidly cleared with stirring. The final pH was 7.3. The solution was filled into serum bottles and stored at 4°C. After three months storage the solution was found to remain clear, colourless and particle free, pH 7.2. After one year's storage very fine white crystals were observed.

Following from the above formulations were prepared using water and citrate buffer; _________________ PDO1/22a PDO1/22b Batch __________ g %w/w g %wlw __________ Methadone HC1 6.000 10.96 6.000 10.96 Macfarlan Smith ___________________ __________ __________ __________ __________ 06-00988 Ethanol,anhydrous 5.530 10.10 5.530 10.10 Hayman07/101A2 Propylene Glycol 5.698 10.41 5.698 10.41 MerkK37090378 _________________ _________ _________ _________ _________ 718 Purified Water 37.500 68.52 _______________ CitrateBuffer 37.500 68.52 _______________ __________________ 54.728 99.99 54.728 99.99 __________________ Citrate Buffer __________ __________ __________ __________ ____________________ CitricAcid 2.4 _________ ________ ________ FisherOS87l2l Sodium Hydroxide 1.4 _________ _________ _________ VWR Prolabo J005 Purified Water To 250ml _________ _________ _________ _________________ pHformulation 4.8 ________ 6.7 ________ _______________ The buffer was adjusted to pH 7.0 with 1M sodium hydroxide.

For both formulations the methadone hydrochloride dissolved within five minutes in the water/buffer and ethanol mix. The propylene glycol mixed into the solution easily leaving a clear, colourless solution. The solutions were placed at 4°C storage. After storage for up to one month the solutions were examined physically and found not to have changed pH. After 21⁄2 months storage no change was observed and the pHs were 5.2 and 6.9 respectively. After 11 months storage no change was noted.

A formulation review was conducted at this stage in the study. Tt was decided to concentrate on aqueous formulations containing ethanol (to aid solubility and act as a preservative), propylene glycol or glycerol (moisturiser), sodium saccharin (sweetener) and blackcurrant (flavour). Several different strengths may be required for the eventual product formulations, therefore to bracket the possible doses required, strengths of 10 mg per 400 p1 dose (25 mg/mI) and 60 mg per 400R1 dose (150 mg/ml) were chosen and lOOml volumes of each of the following formulations were prepared; __________ PDO1/36a PDO1/36b PDO1/36c PDO1/36d mgunit' %w/w mg %wlw mg %wlw mg %wlw _______________ _________ ________ unit' _______ unit' _______ unit' _______ Methadone HC1 60.0 13.53 60.0 12.99 10.0 2.53 10.0 2.42 Blackeurrant 2.2 0.50 2.2 0.48 2.0 0.51 2.0 0.48 flavour _________ ________ _______ _______ ______ _______ ______ _______ NaSaccharin 1.1 0.25 _-_---1.0 0.25 Ethanol, 90.0 20.29 90.0 19.48 80.0 20.22 80.0 19.40 anhydrous _________ _______ _______ _______ ______ _______ ______ _______ Propylene glycol 110.0 24.80 -100.0 25.28 _-______ Glycerol -115.0 24.89 _____ -105.0 25.46 Water 180.3 40.64 194.8 42.16 202.6 51.21 215.4 52.23 _______________ 443.6 100.01 462.0 100.00 395.6 100.00 412.4 99.99 Mean ifil weight 392.8 414.5 390.8 406.4 RSD% 1.3 1.6 1.0 _-1.0 _- _______________________ Suppler Batch Methadone HC1 Macfarlan Smith 06-00988 Blackeurrant flavour Firmenich 17577392 Na Saccharin Merck S37153 328 Ethanol, anhydrous Hayman 07/10 1 A2 Propylene glycol Merck K37090378 718 Glycerol VWR 07D120030 The formulations were prepared in 1 OOml volumetric flasks with shaking, all were clear and colourless. Placebo formulations were also prepared for each of the above (lots a & b; mean fill weights 388.5 & 406.2mg, RSD 0.5 & 0.6% respectively). The formulations were filled into 70 spray units (400p1) and the remainder into serum bottles. The samples were stored under TCH conditions at 5, 25/60, 30/65 & 40/75 °C/RH. The spray units were weighed before being placed on storage -see stability sections below for results.

These formulations all proved to be stable over the six month study with no evidence of degradation (see stability sections below for results). However a number of units were observed to have leaked particularly those at the higher strength. The percentage of units that had leaked is shown below. Additionally the contents of a small number of units were observed to have changed colour to orange brown. These were observed at all temperatures and across the formulations and also in placebo units that had been prepared.

PDO1/036a PDO1/036b PDO1/036c PDO1/036dj 20% 16% 4% 6% It was therefore decided to repeat the formulations containing glycerol (as PDO1/036b and PDO1/036d) but omitting the blackcurrant flavour. lOOml volumes of the following formulations were therefore prepared in lOOml volumetric flasks with shaking.

___________________ PDO1/049 PDO1/O51 _______________ g %w/w g %w/w Methadone IIC1 15.01 14.0 2.54 2.5 Ethanol, anhydrous 20.08 18.8 20.21 19.7 Glycerol 25.00 23.4 25.08 24.4 Purified water 46.96 43.9 54.98 53.5 TOTAL 107.05 100.1 102.81 100.1 Materials _______________________ Supplier Batch Methadone hydrochloride Macfarlan Smith 06-00988 Ethanol, anhydrous Hayman 07/875 Al Glycerol VWR 07D 120030 Water Lab supply _______________________ For each formulation 100 spray unitdevices were filled with 400 p1 and placed on stability at ICH 5°C, 25°C/60%RH, 40°C/75%RH for a six month period, results are shown in the stability sections below. At two weeks storage the samples were checked for discolouration and weight loss. No discoloration was observed in any sample and the weight loss was satisfactory except for 5 units found to have high weight loss. At the one month timepoint 6/180 units had weight loss> 5% over all storage conditions. No discolouration was observed. At 2 months 10/144 units had weight loss> 5%. No discolouration was observed. At 3 months 8/108 units had weight loss> 5%. No discolouration was observed. At 6months 4/72 had weight loss >5%. No discolouration was observed.

PDO1/049 PDO1/051 Mean fill weight 418.6 410.5 (mg) RSD(%) 2.6 1.9 These formulations proved to be stable and were chosen for progression to a Phase I study as 10, 20 & 30 mg formulations.

In preparation for this, laboratory batches were prepared to check that the formulations deliver the correct dose. As some of the product is retained by the device and based on experience with earlier lots an 8% overage was used. The formulations (10 & 20mg were prepared in lOOml volumetric flasks; 30mg was a 11 scale-up batch) were; _________________ PD01I59a PD01/59b PD01I59c PDO1/60 Batch ________________ 10mg 20mg 30mg 30mg ___________ Methadone HCI 2.7g 5.4g 8.2g 81.Og 06-00988 Ethanol, 20.Sg 20.5g 20.Sg 205.Og 07/875 Al anhydrous __________ __________ __________ __________ ___________ Glycerol 25.Og 25.Og 25.lg 250.Og 07Dl20030 Water to l0Oml to lOOm! to lOOml 489.Og __________ ________________ __________ __________ __________ 1025g ___________ The batches were assayed; PD01/59a PDO1/59b PDO1/59c PDO1/60 Methadone 27.6 56.4 83.9 83.3 HC1 mg/mi For the clinical trial supplies lots were prepared to GMP in a licensed facility using the ultrasonic welder and placed on stability test. The batches manufactured were; 08-212 10mg 08-213 20mg 08-214 30mg 08-212 08-213 08-214 Batch

___________ _______ _______ _______ ESN

________________ 10mg 20mg 30mg ___________ Methadone HC1 27.Og 54.Og 81.Og 4175 Ethanol, 205.Og 205.Og 205.Og 4163 (plus anhydrous 35.5g 4180 ________________ __________ __________ __________ in 08-2 14) Glycerol 250.Og 250.Og 250.Og 4162 Water 538.Og 516.Og 486.Og 4157 ________________ 1020g 1025g 1022g __________ The batches were prepared as 1L lots filled at 400 jil. 615 units (approximately) were is prepared from each lot. No issues were encountered during manufacture. Half the stability samples were packed in heat sealed aluminium pouches. See the stability sections below for the stability results.

Device Design & Manufacture The main body of the device was composed of Topas® COC. A bromobutyl polymer was used for the drug chamber stopper and screw cap stopper (West Pharmaceutical Services, West Formulation 4023/50 Gray).

Analytical Method Development and Validation -HPLC The Ph Eur monograph for methadone hydrochloride does not have a HPLC method.

A method was used on the HP 1050 system using the following; Column Phenominex Gemini Cl8 150 x 4.6mm (HC-COL-001) Flow 1.0 ml min' Detector uv at 2lOnm Column Temperature 30°C Injection Volume 2p1 Mobile Phase 1:1 v/v acetonitrile:water 0.1% trifluoroacetic acid The run time for methadone hydrochloride was found to be 5.1 minutes with one other peak (0.19%) at 2.6 minutes.

It was felt that the use of a milder buffer agent would be preferable so a pH 3.0 phosphate buffer would be evaluated keeping the remaining method details the same but running on the Agilent 1100 system. Initially the methadone hydrochloride peak was at 2.65 minutes but reducing the acetonitrile content to 40% gave 4.85 minutes and to 35% gave 8.5 minutes.

In order to show that degradation of methadone is detected and quantified by the HPLC method the solutions prepared as PDO1/01 were taken after 2'/2 months storage and had reagents added to force degradation. Details ofPDOl/01 are; A l00g/ml methadone hydrochloride in water stored at 4°C B 100 pg/ml methadone hydrochloride in water stored at 40°C C 100g/ml methadone hydrochloride in water/ethanol, 50:5 0, stored at 4°C D l00g/ml methadone hydrochloride in water/ethanol, 50:5 0, stored at 40°C The solutions were filtered and 4 x 750R1 aliquots of each solution were added to 4 separate 1.Sml amber HPLC vials. 750R1 of the appropriate reagent was then added as listed below; 1M Hydrochloric Acid -Vial 1 0.1M Sodium Hydroxide -Vial 2 6% v/v Hydrogen Peroxide -Vial 3 Purified Water -Vial 4 A cap was crimped onto the vials and placed at 25°C for a week. The vials to which the sodium hydroxide solution was added turned a milky white. After a week's storage vials from lot A were diluted to 1 Oml with mobile phase and run on the is HP 1050 using the above method. Some degradation was noted for the hydrogen peroxide samples; in particular the following peaks; 2.45 mins 0.4% 2.60 mins 1.78% (two peaks) 2.97 mins 0.3% The solution with sodium hydroxide added gave low methadone assays probably due to insoluble methadone base. The results show methadone to be stable (no detected degradation) with acids and bases. However the degradation found with the addition of hydrogen peroxide shows methadone may be susceptible to oxidation.

Stability Summary

PDO1!07 (aqueous) and PDO1/08b (aqueous/propylene glycol) both with sodium saccharin were examined after 14 weeks storage at 4, 25 & 40°C and found not to have degraded. However after six months storage PDO1/07 had white crystals at 4°C and 25°C. PDO1/08b had white crystals at 4°C from 1 week onwards and at 25°C at 6 months. PDO1/08a (aqueous ethanolic) had clear colourless solutions at 4, 25 and 40°C at 14 months. From this it appears that he best formulation type for the product should be based on aqueous ethanolic solutions.

PDO1/l la, b & e which were aqueous formulations with escalating levels of ethanol were examined after 6 and 13 weeks at 4, 25 & 40°C and found not to have degraded.

Physically all formulations gave clear colourless solutions at 4, 25 and 40°C at 13 weeks. After 4 months storage PDO1/lla had white crystals at 4°C as did PDO1/1 lb. PDO1/l le had no crystal at any temperature. However at l3months PDO1/l le had white crystals at 4°C. From this it appears that at least 15% ethanol in an aqueous solution is required to maintain methadone solubility.

PDO1/20 was prepared which has a higher (3 8.9%) level of ethanol and used a phosphate buffer. It was stored at 4°C and was a clear colourless solution at 3 months but had white crystals at 1 year.

PDO1/22 a & b, ethanol/water and ethanol/aqueous citrate buffer respectively formulations with propylene glycol were examined after 4 weeks storage at 4°C and found not to have degraded. Methadone was 11%. Physically the solutions when stored at 4°C were clear and colourless at 2 weeks, 10 weeks and 11 months.

PDO1/36a -d were 60 and 10mg formulations based on aqueous/ethanolic solvent containing blackeurrant flavour with either sodium saccharin or glycerol. The sodium saccharin formulations also contained propylene glycol. The formulations were filled into spray devices as described above. The devices stored at 5, 25, 30 and 40°C ICH conditions were examined after 1, 2 and 6 months and were found not to have degraded. Assay, delivered dose and ethanol content resuhs were all satisfactory.

After three months storage some units at 5°C across all formulations and placebos were discoloured pale orange/brown. The stored solutions were clear and colourless.

At six months the discolouration was noted again. The discoloration was attributed to the blackcurrant flavour.

The glycerol formulations outlined in the previous paragraph were repeated with the blackeurrant flavour omitted; PD01/049 & 51(60 and 10mg) and filled into the spray devices. The devices stored at 5, 25, and 40°C ICH conditions were examined after 1, 2 and 6 months and were found not to have degraded. All solutions were clear and colourless. Assay, delivered dose and ethanol content results were all satisfactory.

It was concluded that the discolouration issue had been resolved and that these formulations formed the basis for formulations suitable to be taken into a Phase I study. The study would, for safety reasons, have an escalating dose of 10, 20 and 30 is mg only. It was decided that an 8% overage would be applied to the methadone HC1 concentration to allow for material left in the device ie the devices would deliver 10, & 30 mg methadone HC1.

The clinical trial batches were prepared in a GMP facility as; 08-212, 08-213 & 08- 214 for the 10, 20 & 30mg batches respectively. Samples were placed on stability storage at 5, 25, 30 and 40°C ICH conditions, half the samples were packed in heat sealed aluminium pouches. Units have been examined at 1, 3 and 6 months. No changes in physical appearance have been found at any temperature. Assay, delivered dose, methadone HCI concentration and ethanol content results were all satisfactory.

No significant degradation has been observed at any temperature.

Stability at 9months was completed for units from 5, 25 and 30°C ICH conditions and all results for content by HPLC and ethanol content by GC were in limits and no colour change or solubility issues were seen at this time point. Due to contractual problems stability at 12 months was not possible therefore stability at 16 months was completed. The units were tested at 5, 25 and 30°C; all HPLC results were within limits and GC results (with the exception of one sample) were within limits. No colour change or solubility issues were seen at this time point. No degradation was observed and this product has a shelf life of 2 years.

Stability Results Definitions: Description -conforms if clear, colourless solution Degradation -As ICH guidelines; Reporting threshold 0.1% Identification threshold = 0.2% Qualification threshold = 0.5% Uniformity of content -The preparation complies with the test if not more than one individual content is outside the limits of 85 per cent to 115 per cent of the average content and none is outside the limits of 75 per cent to 125 per cent of the average content. The preparation fails to comply with the test if more than three individual contents are outside the limits of 85 per cent to 115 per cent of the average content or if one or more individual contents are outside the limits of 75 per cent to 125 per cent of the average content. If 2 or 3 individual contents are outside the limits of 85 per cent to per cent but within the limits of 75 per cent to 125 per cent, determine the individual contents of another 20 dosage units taken at random. The preparation complies with the test if not more than three of the individual contents of the 30 units are outside the limits of 85 per cent to 115 per cent of the average content and none is outside the limits of 75 per cent to 125 per cent of the average content.

Uniformity of mass -Determine the individual masses of 10 containers emptied as completely as possible, and calculate the average mass. Not more than 2 of the individual masses deviate by more than 10 per cent from the average mass and none deviates by more than 20 per cent.

PDO1/07 & 08a _______________ PDO1IO7 PDO1IOSa PDO1IOSb __________ g %w/w g %w/w g %w/w Methadone HC1 5 9.03 5.00 9.47 5.00 8.95 Sodium 0.4 0.72 0.40 0.76 0.40 0.72 Saccharin _________ _________ _________ _________ _________ _________ 9.88 18.71 Propykne 12.95 23.19 Purified Water 50 90.25 37.50 71.06 37.50 67.14 ______________ 55.4 100.00 52.78 100.00 55.85 100.00 PDO 1/07 Assay Appearance of Degradation % methadone solution _________ tgImI _______________ ________________________________ Initial _____________ Clear, colourless ____________ _______________ ______________ 4°C _________ ______________ ________ __________ __________ 1 week ____________ Clear, colourless ________________________________________ 4 weeks ____________ Clear, colourless ________________________________________ 6 weeks ____________ Clear, colourless ________________________________________ 14 weeks 93.7 Clear, colourless No significant degradation was found 6 months Clear, colourless ____________ ____________ plus white crystals ____________ ______________ _____________ 25°C ___________ __________________ ___________ _____________ _____________ 1 week ____________ Clear, colourless ________________________________________ 4 weeks ____________ Clear, colourless ________________________________________ 6 weeks ____________ Clear, colourless ________________________________________ 14 weeks 93.2 Clear, colourless No significant degradation was found 6 months Clear, colourless ____________ _____________ plus white crystals ____________ ______________ ______________ 40°C ____________ __________________ ___________ _____________ ____________ 1 week ____________ Clear, colourless ________________________________________ 4 weeks ____________ Clear, colourless ________________________________________ 6 weeks ____________ Clear, colourless ________________________________________ 14 weeks 96.0 Clear, colourless No significant degradation was found 6 months ____________ Clear, colourless ________________________________________ PDO1/08a Assay Appearance of Degradation % methadone solution _________ jig/mI _______________ _______________________________ Initial _____________ Clear, colourless ____________ ______________ ______________ 4°C _________ ______________ ________ __________ __________ 1 week _____________ Clear, colourless ________________________________________ 14 weeks 94.0 Clear, colourless No significant degradation was found 6 months _____________ Clear, colourless ____________ _____________ _____________ 14 months Clear, colourless ____________ _____________ plus white crystals ____________ _____________ _____________ 25°C ____________ __________________ ___________ ____________ ____________ 1 week _____________ Clear, colourless _________________________________________ 14 weeks 92.8 Clear, colourless No significant degradation was found 6 months ____________ Clear, colourless ___________ _____________ _____________ 14 months ____________ Clear, colourless ___________ _____________ _____________ 40°C ____________ __________________ ___________ ____________ ____________ 1 week ____________ Clear, colourless ________________________________________ 14 weeks 95.5 Clear, colourless No significant degradation was found 6 months ____________ Clear, colourless ___________ _____________ _____________ 14 months ____________ Clear, colourless ___________ _____________ _____________ PDO1/08b Assay Appearance of Degradation % methadone solution _________ jig/mI ________________ ______________________________ Initial _____________ Clear, colourless ___________ ______________ ______________ 4°C _________ _______________ _______ __________ __________ 1 week Clear, colourless ____________ _____________ plus white crystals __________ ___________________________ 14 weeks Clear, colourless No significant degradation was found ____________ _____________ plus white crystals __________ _____________ _____________ 6 months Clear, colourless ____________ _____________ plus white crystals __________ _____________ _____________ 25°C ____________ ___________________ __________ ____________ ____________ 1 week ____________ Clear, colourless _______________________________________ 14 weeks ____________ Clear, colourless No significant degradation was found 6 months Clear, colourless ____________ _____________ plus white crystals ___________ ______________ ______________ 40°C ____________ ___________________ __________ ____________ ____________ 1 week ____________ Clear, colourless _______________________________________ 14 weeks ____________ Clear, colourless No significant degradation was found 6 months _____________ Clear, colourless __________ _____________ _____________ PDO1/lta, b & c _______________ PDO1/lla PDO1/llb IPDO1/llc ________ g %w/w g %w/w g %w/w Methadone HC1 5.00 9.2 5.00 9.3 5.00 9.4 Sodium 0.40 0.7 0.40 0.7 0.40 0.7 Saccharin _________ _________ _________ _________ _________ _________ Ethanol, 3.16 5.8 5.53 10.3 7.90 14.8 anhydrous _________ _________ _________ ________ ________ ________ Purified Water 46.00 84.3 43.00 79.7 40.00 75.1 ______________ 54.56 100.00 53.93 100.00 53. 30 100.00 PDO1/lla Assay Appearance of Degradation % methadone solution _________ pg/mi ________________ _________ ___________ __________ Initial ______________ Clear, colourless ___________ ______________ _____________ 4°C __________ ______________ ________ __________ _________ 6 weeks _____________ Clear, colourless No significant degradation was found 13 weeks 99.7 Clear, colourless No significant degradation was found 4 months Clear, colourless ____________ _____________ plus white crystals ___________ _____________ _____________ 25°C _____________ __________________ __________ ____________ ____________ 6 weeks _____________ Clear, colourless No significant degradation was found 4 months ____________ Clear, colourless No significant degradation was found 40°C _____________ __________________ __________ ____________ ____________ 6 weeks _____________ Clear, colourless No significant degradation was found 13 weeks 100.5 Clear, colourless No significant degradation was found 4 months ______________ Clear, colourless _______________________________________ PDO1/l lb Assay Appearance of Degradation % methadone solution _________ gg/ml ________________ _________ ___________ __________ Initial ______________ Clear, colourless ___________ ______________ _____________ 4°C __________ ______________ ________ __________ _________ 6 weeks _____________ Clear, colourless No significant degradation was found 13 weeks 99.5 Clear, colourless No significant degradation was found 4 months Clear, colourless ____________ ______________ plus white crystals ___________ ______________ _____________ 25°C _____________ __________________ __________ ____________ ____________ 6 weeks _____________ Clear, colourless No significant degradation was found 4 months _____________ Clear, colourless ___________ _____________ _____________ 40°C _____________ __________________ __________ ____________ ____________ 6 weeks _____________ Clear, colourless No significant degradation was found 13 weeks 96.7 Clear, colourless No significant degradation was found 4 months ______________ Clear, colourless _______________________________________ PD01/llc Assay Appearance of Degradation % methadone solution _________ tg/ml _______________ _______________________________ Initial ______________ Clear, colourless ________________________________________ 4°C __________ ______________ ____________________________ 6 weeks _____________ Clear, colourless No significant degradation was found 13 weeks 100.1 Clear, colourless No significant degradation was found 4 months _____________ Clear, colourless _______________________________________ 13 months Clear, colourless ____________ _____________ plus white crystals ___________ _____________ _____________ 25°C _____________ __________________ __________ ____________ ____________ 6 weeks _____________ Clear, colourless No significant degradation was found 4 months _____________ Clear, colourless _______________________________________ 13 months _____________ Clear, colourless ___________ _____________ _____________ 40°C _____________ __________________ __________ ____________ ____________ 6 weeks _____________ Clear, colourless No significant degradation was found 13 weeks 99.4 Clear, colourless No significant degradation was found 4 months _____________ Clear, colourless ______________________________________ 13 months ______________ Clear, colourless _______________________________________ PDO1/22a&b __________________ PDO1/22a PDO1/22b _____________ _______ %wlw _______ %wlw Methadone HC1 6.000 10.96 6.000 10.96 Ethanol,anhydrous 5.530 10.10 5.530 10.10 Propylene Glycol 5.698 10.41 5.698 10.41 Purified Water 37.500 68.52 ________ Citrate Buffer..._- 37.500 68.52 __________________ 54.728 99.99 54.728 99.99 Citrate Buffer __________ __________ __________ __________ Citric Acid 2.4 ___________ ___________ ___________ Sodium Hydroxide 1.4 _________ _________ _________ Purified Water To 250m1 _________ _________ _________ pH formulation 4.8 ________ 6.7 ________ PDO1/22a Assay Appearance of Degradation % methadone solution _________ tg/mI ______________ _______________________________ ___________ Ut U2 ________________ _____________________________________ Initial _______ ________ Clear, colourless _________________________________________ 4°C _____ _____ ____________ _____________________________ 4 weeks 107.0 113.0 Clear, colourless No significant degradation was found weeks ______ _______ Clear, colourless ________________________________________ 11 months _______ ________ Clear, colourless _________________________________________ PDO1/22b Assay Appearance of Degradation % methadone solution _________ w/ml ______________ _______________________________ _______ Ut U2 ___________ _________________________ Initial _______ ________ Clear, colourless 4°C _____ _____ ____________ _____________________________ 4 weeks 114.2 114.9 Clear, colourless No significant degradation was found weeks ______ _______ Clear, colourless 11 months _______ ________ Clear, colourless _________________________________________ PDO1/36 ____________ PDO1/36a PDO1/36b PDO1/36c /PDO1/36d mg %wlw mg %wlw mg %w/w mg %w/w __________________________ unit' __________ unit' __________ unit' __________ __________ _________ Methadone HCT 60.0 13.53 60.0 12.99 10.0 2.53 10.0 2.42 Blackcurrant flavour 2.2 0.50 2.2 0.48 2.0 0.51 2.0 0.48 Na Saccharin 1.1 0.25 _--1.0 0.25 _-Ethanol, anhydrous 90.0 20.29 90.0 19.48 80.0 20.22 80.0 19.40 Propyleneglycol 110.0 24.80 _--100.0 25.28 _____ Glycerol 115.0 24.89 _--105.0 25.46 Water 180.3 40.64 194.8 42.16 202.6 51.21 215.4 52.23 __________________ 443.6 100.01 462.0 100.00 395.6 100.00 412.4 99.99 After standing at room temperature for 8 days prior to testing all the propylene glycol formulations had gained weight. Additional peaks were found in the chromatograms which were also observed identically in the placebos. These were therefore concluded to be from the excipients and are not degradents and thus were not reported.

PDO1/36a Delivered Ethanol Methadone Delivered dose as Content PDO1/36a ______ (mg/dose) dose (mg) % of fill Degradation %w/w Initial (n=3) 58.1 ND _________ _________________ _________ 5°C ____ ________ _______ _______ _____________ ______ 1 month ____ N/A N/A N/A N/A ______ No significant 2 month (n=1) 59.2 374.7 95.1 degradation ________ No significant 6 month (n2) 55.8 371.5 94.0 degradation _______ 25°C/60%RH ______ ___________ __________ __________ __________________ _________ No significant 1 month (n=2) 57.1 359.9 91.0 degradation 21.0 No significant 2 month (n=3) 58.9 372.2 94.8 degradation 17.8 No significant 6 month (n2) 59.6 377.8 94.6 degradation _________ 30°C/65%RH ______ ____________ __________ __________ __________________ _________ No significant 1 month (n=3) 59.2 372.3 95.3 degradation 20.7 No significant 2 month (n=2) 59.3 363.7 91.1 degradation 19.0 No significant 6 month (n=2) 60.6 369.5 94.3 degradation ________ 40°C/75%RH ______ ___________ _________ _________ ________________ ________ No significant 1 month (n=3) 59.7 372.6 94.9 degradation 20.2 No significant 2 month (n=3) 57.6 363.5 93.8 degradation 17.3 No significant 6 month (n2) 56.8 368.0 93.5 degradation ________ PDO1/36b Delivered Ethanol Methadone Delivered dose as Content PDO1/36b ______ (mg/dose) dose (mg) % of fill Degradation %w/w Initial (n=3) 58.7 386.4 92.5 __________________ _________ 5°C ____ ________ ________ _______ _____________ ______ 1 month ____ N/A N/A N/A N/A ______ No significant 2 month (n=3) 56.6 385.4 93.5 degradation ________ No significant 6 month (n2) 56.8 391.3 93.2 degradation ________ 25°C/60%RH ______ ____________ __________ __________ __________________ _________ No significant 1 month (n=2) 57.3 389.6 94.1 degradation 19.7 No significant 2 month (n=3) 57.6 378.3 92.0 degradation 20.4 No significant 6 month (n2) 57.2 394.8 93.8 degradation ________ 30°C/65%RH ______ ____________ ___________ __________ __________________ _________ No significant 1 month (n=3) 60.1 398.3 95.1 degradation 19.0 No significant 2 month (n=1) 59.1 392.4 93.2 degradation 19.9 No significant 6 month (n=2) 57.0 387.9 93.9 degradation ________ 40°C/75%RH ______ ___________ __________ _________ ________________ ________ No significant 1 month (n=3) 59.7 390.9 94.3 degradation 19.5 No significant 2 month (n=1) 58.4 386.9 94.1 degradation 19.9 No significant 6 month (n=2) 57.7 388.8 93.5 degradation ________ PDO1/36c Delivered Ethanol Methadone Delivered dose as Content PDO1/36c ______ (mg/dose) dose (mg) % of fill Degradation %w/w Initial (n=3) 9.7 369.1 94.3 ________________ ________ 5°C ____ ________ ________ _______ _____________ ______ 1 month ____ N/A N/A N/A N/A ______ No significant 2 month (n3) 9.5 369.5 95.0 degradation ________ No significant 6 month (n2) 9.0 359.9 91.9 degradation ________ 25°C/60%RH ______ ____________ __________ __________ __________________ _________ No significant 1 month (n3) 9.5 371.6 95.0 degradation 18.2 No significant 2 month (n=3) 9.8 371.2 95.2 degradation 19.4 No significant 6 month (n2) 9.5 367.6 93.3 degradation ________ 30°C/65%RH ______ ____________ ___________ __________ __________________ _________ No significant 1 month (n=2) 9.6 359.6 93.0 degradation 19.2 No significant 2 month (n=3) 9.9 370.9 95.0 degradation 17.0 No significant 6 month (n=2) 9.5 365.6 93.5 degradation ________ 40°C/75%RH ______ ___________ __________ _________ ________________ ________ No significant 1 month (n=2) 10.0 375.9 95.3 degradation 20.6 No significant 2 month (n=3) 9.7 364.4 94.9 degradation 18.0 No significant 6 month (n=2) 9.6 365.4 93.2 degradation ________ PDO1/36d Delivered Ethanol Methadone Delivered dose as Content PDO1/36d ______ (mg/dose) dose (mg) % of fill Degradation %w/w Initial (n=3) 10.0 391.4 95.8 ________________ ________ 5°C ____ ________ ________ _______ _____________ ______ 1 month _____ N/A N/A N/A N/A ______ No significant 2 month (n=3) 9.9 385.7 94.4 degradation ________ No significant 6 month (n=2) 9.1 377.6 93.0 degradation ________ 25°C/60%R11 ______ ____________ __________ __________ __________________ _________ No significant 1 month (n=2) 9.8 386.3 95.6 degradation 17.8 No significant 2 month (n=3) 10.0 388.1 95.5 degradation 19.2 No significant 6 month (n=2) 9.4 383.3 93.7 degradation ________ 30°C/65%RIH ______ ____________ __________ __________ __________________ _________ No significant 1 month (n=2) 10.0 393.2 95.5 degradation 19.7 No significant 2 month (n=3) 9.8 387.1 95.0 degradation 17.5 No significant 6 month (n2) 9.6 380.7 94.5 degradation ________ 40°C/75%R}I ______ ___________ __________ _________ _________________ _________ No significant 1 month (n=3) 10.2 394.1 96.3 degradation 19.7 No significant 2 month (n=2) 9.7 378.4 94.5 degradation 17.3 No significant 6 month (n2) 9.7 384.6 93.7 degradation ________ After three months storage it was observed that some of the 60mg units had leaked and had a white crystalline deposit around the base of the units and plugs. This occurred at all temperatures.

It was also noted that some units stored at 5°C across all formulations and placebos were discoloured pale orange/brown. The stored bulk solutions were still clear and colourless.

At six months pale orange/brown discolouration was noted in a few (2 at 40°C, 2 at 30°C & 1 at 5°C) out of 79 units assayed. Some continuing evidence of poor sealing is shown by high weight loss displayed by some units.

PDO1/049 & 51 ___________________ PDO1/049 PDO1/O51 _______________ g %w/w g %w/w Methadone HCI 15.01 14.0 2.54 2.5 Ethanol, anhydrous 20.08 18.8 20.21 19.7 Glycerol 25.00 23.4 25.08 24.4 Purified water 46.96 43.9 54.98 53.5 TOTAL 107.05 100.1 102.81 100.1 Delivered Ethanol Methadone Delivered dose as Content PDO1/049 _____ (mg/dose) dose (mg) % of fill Degradation %w/w No significant Initial n=5 55.8 390.6 93.8 degradation 17.7 5°C ____ _________ ________ _______ ___________ ________ No significant 1 month n=3 55.5 394.0 96.2 degradation 16.9 No significant 2 month n=4 56.7 393.8 92.6 degradation 17.3 No significant 3 month n4 58.1 397.4 94.4 degradation __________ No significant 6 month n=3 52.1 390.4 93.4 degradation 19.3 25°C/60%RH _____ ____________ ___________ __________ _______________ ___________ No significant 1 month n4 56.2 389.6 93.1 degradation 17.5 No significant 2 month n=4 55.9 389.6 94.0 degradation 17.8 No significant 3 month n=4 58.1 392.2 94.8 degradation __________ No significant 6 month n4 53.0 399.2 94.8 degradation 18.4 40°C/75%RH _____ ___________ __________ _________ _______________ __________ No significant 1 month n=4 55.9 387.4 95.2 degradation 17.9 No significant 2 month n4 57.7 395.9 96.3 degradation 18.0 No significant 3 month n=4 57.8 391.0 94.0 degradation __________ No significant 6 month n=4 51.8 393.3 90.7 degradation 18.9 Delivered Ethanol Methadone Delivered dose as Content PDO1/O51 ______ (mg/dose) dose (mg) % of fill Degradation %w/w No significant Initial n=5 9.6 386.3 95.7 degradation 19.3 5°C ____ ________ ________ _______ ____________ ______ No significant 1 month n=3 9.8 390.0 94.5 degradation 17.5 No significant 2 month n=4 9.6 391.5 95.9 degradation 18.7 No significant 3 month n=4 10.0 400.2 96.9 degradation ________ No significant 6 month n=4 9.1 397.9 97.1 degradation 16.8 25°C/60%RH ______ ____________ __________ __________ ________________ _________ No significant 1 month n3 9.3 393.7 93.3 degradation 18.6 n=4 No significant 2 month ______ 9.7 388.1 94.9 degradation 19.2 n=4 No significant 3 month ______ 9.8 384.6 93.7 degradation ________ n=4 No significant 6 month _____ 9.1 392.7 93.5 degradation 18.9 40°C/75%R11 ______ ___________ __________ _________ _______________ ________ No significant 1 month n=3 9.7 387.0 95.1 degradation 18.5 No significant 2 month n=4 9.7 393.0 95.2 degradation 18.3 No significant 3 month n=2 9.9 386.5 94.1 degradation ________ 6 month n4 _________ 398.1 97.7 _____________ 18.6 All solutions were clear and colourless Phase I Clinical trial Supplies 08-212, 08-2 13 & 08-214; 08-212 08-213 08-214 Batch

___________ _______ _______ _______ ESN

________________ 10mg 20mg 30mg ___________ Methadone HCT 27.Og 54.Og 81.Og 4175 Ethanol, 205Mg 205.Og 205Mg 4163 (plus anhydrous 35.5g 4180 ________________ __________ __________ __________ in 08-2 14) Glycerol 250.Og 250.Og 250.Og 4162 Water 538.Og 516.Og 486.Og 4157 _______________ 1020g 1025g 1022g __________ P = Pouched, U = Unpouched.

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Claims

CLAIMS1. A pharmaceutical composition for the sublingual delivery of an opioid, said composition comprising an opioid and ethanol, wherein the composition is comprised within a container and wherein the material of the container that is in contact with the composition is Cyclic Olefin Copolymer (COC).
2. A composition according to claim 1 that additionally comprises glycerol.
3. A composition according to claim 1 or claim 2 wherein the opioid is not fentanyl.
4. A composition according to claim 1 or claim 2 wherein said opioid is methadone.
5. A composition according to any one of the preceding claims wherein the container comprises a delivery device.
6. A composition according to claim 5 wherein the delivery device dispenses the composition in a single discharge.
7. A composition according to claim 5 or claim 6 wherein the delivery device dispenses the composition as a spray.
8. A composition according to claim 7 wherein said spray comprises liquid droplets having a mean diameter of at least 10 microns.
9. A composition according to any one of claims 5 to 8 wherein the delivery device is non-pressurised.
10. A composition according to any one of claims 5 to 9 wherein the delivery device comprises seals and/or plungers and wherein the material of said seals and/or plungers that is in contact with the composition is bromobutyl polymer.
11. A composition according to any one of the preceding claims for use in the treatment of the human or animal body by therapy.
12. A composition according to any one of claims ito 10 for use in reducing pain.
13. A composition according to any one of claims 1 to 10 for use in inducing or maintaining anaesthesia.
14. A composition according to any one of claims ito 10 for use in treating opioid dependence.
15. A composition according to any one of claims 1 to 10 for use in treating anxiety.
16. A composition according to any one of claims ito 10 for use in treating a cough.
17. A composition according to any one of claims 1 to 10 for use in treating diarrhoea.