WO2009127878A1 - A liquid spray solution comprising buprenorphine, ethanol and an antioxidant - Google Patents

Abstract

There is provided according to the invention a non-pressurised pharmaceutical liquid solution spray formulation comprising: (i)buprenorphine; (ii)a solvent comprising ethanol; and (iii)one or more antioxidants each of a molar ratio of antioxidant:buprenorphine between 0.2 : 1 and 25 : 1.

Description

A LIQUID SPRAY SOLUTION COMPRISING BUPRENORPHINE, ETHANOL AND AN ANTIOXIDANT

Background

This invention relates to formulations of buprenorphine especially pump spray formulations suitable for transmucosal, particularly sublingual, delivery.

Buprenorphine, with structure shown below, is a partial agonist of opiate receptors which is widely used for the treatment of moderate to severe pain or in the treatment of opiate dependence.

Buprenorphine is often described as a partial agonist (receptor stimulator)/antagonist (prevents receptor stimulation). It has important actions on two types of opiate receptors in the brain. Many of the most common opioid effects, such as euphoria, respiratory effects and reduced pain sensation, are caused by stimulation of the mu receptor. Buprenorphine stimulates this receptor, albeit at lower intensity than other opiates such as heroin or methadone. This lower level of stimulation is of benefit clinically in people with respiratory compromise but require opioid medication, such as the elderly.

Buprenorphine is also an antagonist of the kappa opioid receptor, which is associated with some of the negative effects experienced in withdrawal, particularly depression. As buprenorphine inhibits stimulation of this receptor it may produce feelings of well-being. Finally, its disassociation from these receptors is slow, leading to a long duration of action, allowing once daily dosing and sometimes dosing every two days, making buprenorphine a versatile treatment option in treatment of drug addiction. A number of presentations of buprenorphine are currently available. Low-dose sub-lingual tablets, containing 0.2-0.4 mg of the drug as hydrochloride, are sold under the brand name Temgesic and are normally used for analgesic purposes. Temgesic brand of buprenorphine hydrochloride is also available as ampoules for intramuscular or slow intravenous injection. The most common formulation of buprenorphine used for the treatment of opiate dependence is sublingual tablets containing 0.4, 2 and 8 mg buprenorphine hydrochloride and available under the brand name Subutex. Using a combination of tablets, doses of up to 32 mg may be administered. These tablets are specifically intended for the treatment of problem drug use in patients who are being maintained in medically assisted treatment; in the case of patients undergoing withdrawal treatment, they are administered in a gradually reducing dose. Low-dose sublingual tablets are sometimes used for the treatment of opiate dependence, in which case multiple tablets are prescribed in order to achieve the desired dose.

A liquid formulation for sub-lingual administration is described in GB2100985 (Todd). Specifically, this document describes formulations containing buprenorphine or a non-toxic salt thereof, but especially buprenorphine hydrochloride, dissolved in 20-30% v/v ethanol in water buffered to a pH of between 4.5-5.5 with 0.05-0.2 molar concentration of a buffering agent selected from citric acid/disodium hydrogen phosphate, sodium citrate/hydrochloric acid, lactic acid/disodium hydrogen phosphate, lactic acid/sodium lactate, sodium citrate/citric acid and sodium acetate/acetic acid, the concentration of buprenorphine being between 0.8 and 10 mg/ml (i.e. around 0.08-1.0% w/v) of the formulation. The Examples relate to buprenorphine hydrochloride solutions containing various different concentrations of ethanol and a variety of buffers. The formulations do not appear to be sprays as the document refers to the volume of liquid that a patient can hold sublingually for a reasonable amount of time.

It is well known that the application of carefully chosen medicaments to mucosa, for example the sublingual mucosa, offers a route of administration which is capable of resulting in very rapid transmission of medicament to the bloodstream with consequent fast onset of effect. Other mucosa to which medicaments may be administered include the nasal mucosa and buccal mucosa. A number of ways of administering formulations sublingually are known. For example, tablets or liquids may be held under the tongue prior to swallowing. Another method is spray delivery. Of these various types of sublingual administration, spray delivery is preferred as it does not involve holding the formulation under the tongue for an extended period of time as, for example, with a lozenge and it reduces the amount of material which is swallowed (and may enter the blood stream in a delayed manner via the gastrointestinal tract). However it is not considered desirable to spray large volumes of liquid (eg greater than around 500 μL) to the sublingual cavity. WO01 /97780 (Ross) describes a pharmaceutical formulation comprising a solution of an opioid analgesic (especially fentanyl, although buprenorphine is referred to) and a propellant, for sublingual aerosol administration. The example formulations are pressurized and therefore require complex packaging and actuation technology. Also they employ halogenated propellants which may not be environmentally friendly.

Weinberg et al (1988) Clin Pharmacol Ther 44, 335-342 discusses the adsorption of various opioids including buprenorphine (presented in an aqueous phosphate buffer at pH 6.5) when administered by pipette in liquid form to the sublingual cavity.

WO01 /89476 (Pinney et al) discloses buffered compositions for transmucosal delivery. Buprenorphine is mentioned in a very long list of possible active agents and is not exemplified.

Presently there are no spray formulations containing buprenorphine which have been made available commercially.

Thus an object of the present invention is to provide a spray formulation containing buprenorphine for transmucosal, particularly sublingual, administration. Further objects of the invention are to provide a spray formulation containing buprenorphine for transmucosal (eg sublingual) administration with good physical and chemical properties, especially good stability and low environmental impact, and good biological properties, especially rapid onset of activity and efficacy at relatively low doses. Such a formulation would mitigate many of the disadvantages of prior art formulations containing buprenorphine.

Summary of the Invention

Thus according to a first aspect of the invention there is provided a non-pressurised pharmaceutical liquid solution spray formulation comprising:

(i) buprenorphine; (ii) a solvent comprising ethanol; and

(iii) one or more antioxidants each of a molar ratio of antioxidant : buprenorphine between 0.2 : 1 and 25 : 1 .

Brief description of the Figures Figure 1 : Mean Buprenorphine plasma concentration (ng/ml)

Figure 2: HPLC trace of comparator formulation A (Initial time point) Figure 3: HPLC trace of comparator formulation A (6 months) Figure 4: HPLC trace of comparator formulation B (Initial time point)

Figure 5: HPLC trace of comparator formulation B (6 months)

Figure 6: LCMS trace of comparator formulation A (Initial time point)

Figure 7: LCMS trace of comparator formulation A (12 months) Figure 8: LCMS trace of comparator formulation B (Initial time point)

Figure 9: LCMS trace of comparator formulation B (12 months)

Figure 10: UV-vis scan 700nm-200nm of comparator formulation B (Initial time point)

Figure 11 : UV-vis scan 700nm-200nm of comparator formulation B (6 weeks)

Figure 12: UV-vis scan 700nm-200nm of Example 1 c (Initial time point) Figure 13: UV-vis scan 700nm-200nm of Example 1 c (6 weeks)

Figure 14: Buprenorphine stability at 40°C/75% RH (UV scan at 458nm):

Blank, Examples 1 a, 1 b, 1 c, 2a, 2b and 2c

Figure 15: Buprenorphine stability at 40°C/75% RH (UV scan at 458nm):

Blank, Examples 3 and 4 Figure 16: Buprenorphine degradation at 40°C/75% RH:

Blank, Examples 1 a, 1 b, 1 c, 2a, 2b and 2c

Figure 17: Buprenorphine degradation at 40°C/75% RH:

Blank, Examples 3 and 4

Detailed description of the Invention

The formulation is non-pressurised i.e. is substantially free of any propellant. Exemplary propellants to be substantially avoided include volatile substances which develop significant vapour pressure at ambient temperature and pressure such as lower alkanes (eg propane, butane and the like) and halogenated hydrocarbons such as CFCs (P12 etc) and hydrofluorocarbons (P134a, P227 etc) as well as other propellants commonly used in aerosol presentations. Use of PH is also preferably substantially avoided. By "substantially free" or "substantially avoided" is meant that an amount of less than 5% w/w based on weight of formulation is employed, suitably less than 2% eg less than 0.1 % w/w. Preferably propellants are avoided altogether.

The w/v concentration of the buprenorphine in the formulation may typically vary between 0.05 and 12% w/v, more suitably 0.1-10% w/v, eg 0.1-6% w/v, particularly 0.1-4% w/v or especially 0.1-1 % w/v eg around 0.2% w/v (all figures being based on weight of buprenorphine base relative to total weight of formulation). Suitably the molar concentration of the buprenorphine of the formulation may typically vary between 1 mM and 257mM, more suitably 2mM and 214mM mM, eg 2-86mM or especially 2- 21 mM eg around 4.3mM.

An advantage of the invention, and in particular of use of buprenorphine in a formulation which contains at one or more antioxidants, is improved stability over time (especially at higher temperatures) of buprenorphine formulations comprising one or more antioxidant over formulations that do not comprise antioxidant.

In the absence of antioxidant, the inventors have observed degradation of buprenorphine formulations, particularly ethanolic formulations accompanied by development of a yellow colour. In the absence of antioxidant, the formulations were found to be relatively stable below 4⁰C. However, the formulations were found to be unstable, particularly at higher temperatures (such at above 8⁰C). This has obvious practical implications for storage and distribution of formulations. In the absence of antioxidant, the degradation was found to be greater at pH 5.0 than pH 8.5. (See Results and Figures 2-5).

The inventors have discovered that this discolouration is attributable to formation of a dimer in solution, involving the loss of oxygen, probably after a radical reaction. This route of degradation is substantially prevented, especially at higher temperatures, by incorporation of an antioxidant into the formulation. Moreover, levels of other degradation products formed over time, which may be observed by HPLC analysis are also reduced in the presence of antioxidant.

Antioxidants include, for example, alkyl gallates, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), nordihydroguaiaretic acid, alpha-tocopherol, ascorbic acid and sodium metabisulfite (especially ascorbic acid). In one embodiment, the antioxidant is other than propyl gallate. In one embodiment, the antioxidant is selected from butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), nordihydroguaiaretic acid, alpha-tocopherol, ascorbic acid and sodium metabisulfite (especially ascorbic acid).

Suitable antioxidants include butylated hydroxyanisole (BHA) butylated hydroxytoluene (BHT), alpha-tocopherol, and ascorbic acid, particularly alpha-tocopherol and ascorbic acid, particularly alpha-tocopherol and ascorbic acid, and most particularly ascorbic acid. In one particular embodiment, the antioxidant is butylated hydroxytoluene (BHT).

Ascorbic acid is commonly referred to as Vitamin C. Alpha-tocopherol is commonly referred to as Vitamin E. Formulations of the invention will contain one or more (e.g. one or two) antioxidants. Normally one antioxidant is suitable. In one embodiment, when the formulation contains one antioxidant, said antioxidant is other than propyl gallate.

When the formulation comprises more than one antioxidant, the formulation suitably comprises two antioxidants selected from alkyl gallates, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), nordihydroguaiaretic acid, alpha-tocopherol, ascorbic acid and sodium metabisulfite. Most suitably the two antioxidants are alpha-tocopherol and ascorbic acid. Suitably the antioxidants are in a ratio of between 1 :10 and 10:1 , more suitably between 1 :5 and 5:1 , more suitably 1 :2 and 2:1 , most suitably 1 :1.

Suitably the ratio of molar concentration of each antioxidant : molar concentration of buprenorphine is in the range 0.2 : 1 to 25 : 1 , e.g. between 1 : 1 and 10 : 1 e.g. 2 : 1 and 8 : 1 , e.g. around 4.65:1

Suitably the ratio of total molar concentration of antioxidant: buprenorphine is in the range 0.2 : 1 to 25 : 1 , e.g. between 1 : 1 and 10 : 1 , e.g. 2 : 1 and 8 : 1 , e.g. around 4.65:1

Suitable concentrations of each antioxidant range from 0.01 mM to 25OmM, e.g. 1 mM to 10OmM, e.g. 1 mM to 5OmM e.g. 1 mM to 25mM e.g. 5mM to 25mM. such as 5mM, 1 OmM and 2OmM, e.g. 1OmM and 2OmM, particularly 2OmM. In one embodiment, the concentration of each antioxidant ranges from 0.01 mM to 10mM, such as 1 mM to 5mM (e.g. 2.8mM). In an alternative embodiment, the concentration of each antioxidant ranges from 5OmM to 25OmM, such as 8OmM to 23OmM (e.g. 90.8mM or 226.9mM).

Suitable total concentration for antioxidant(s) range from 1 mM to 10OmM, e.g. 1 mM to 5OmM e.g. 1 mM to 25mM e.g. 5mM to 25mM. such as 5mM, 1 OmM and 2OmM, e.g. 1 OmM and 2OmM, particularly 2OmM. In one embodiment, the concentration of total antioxidant ranges from 0.01 mM to 1 OmM, such as 1 mM to 5mM (e.g. 2.8mM). In an alternative embodiment, the concentration of total antioxidant ranges from 5OmM to 25OmM, such as 8OmM to 23OmM (e.g. 90.8mM or 226.9mM).

A chelating agent such as EDTA may optionally be employed in the formulation. However, the formulation is suitably free of EDTA. In one embodiment of the invention, the formulation is characterised in that the formulation is substantially free of chloride. By "substantially free of chloride" is meant that the formulation has a substantial absence of chloride in ionised (i.e. such that Cl^" is formed in solution) or unionised form. The reason for the substantial absence of chloride in this embodiment is to avoid the precipitation of buprenorphine hydrochloride which is not highly soluble in aqueous or ethanolic solvents. Thus the amount of chloride in the formulation of this embodiment is suitably less than 3% w/w based on weight of buprenorphine eg less than 1 % w/w, eg less than 0.5% w/w for example less than 0.1 % w/w, especially when the pH of the formulation is less than 7.

Preferably the buprenorphine is employed in the form of its free base or as citrate, particularly as free base.

A further advantage of the invention, and in particular of use of buprenorphine in an embodiment which is a formulation which is substantially free of chloride, is that relatively concentrated formulations can be prepared which allows for administration of high doses of buprenorphine without using excessively large metering volumes. For example, as will be explained below, we have successfully prepared solutions of concentration 4 and 8% w/v, whereas buprenorphine hydrochloride has not proved soluble in water or ethanol at these concentrations. These higher concentrations of buprenorphine are achieved by using a solvent containing a significant amount of ethanol.

Some sprayable non-pressurised analgesic formulations are taught in the art, for example in WO02/094234 (Rabinowitz), WO 03/080022 (Birch) and WO 2004/071491 (Blondino). WO02/094234 relates to an opioid-containing aerosol formulation for administration by inhalation. The formulations are all aqueous solutions with no other solvent being suggested. WO 03/080022 relates to aqueous solutions comprising an analgesic for intranasal administration. The analgesic may be buprenorphine or a salt thereof but there is no teaching that the formulation should not contain chloride and indeed the examples all relate to formulations comprising buprenorphine hydrochloride. There is no suggestion that ethanol could be included in the solvent. WO 2004/071491 relates to liquid aerosol formulations in which the solvent may contain ethanol. There is no suggestion that it would be advantageous to provide a chloride-free formulation and all of the examples relate to formulations containing buprenorphine hydrochloride. None of the above documents suggests that buprenorphine suffers any problems with degradation in solution and specifically formation of a dimer. None of the above documents suggests that inclusion of an antioxidant would provide any specific advantage. Generally speaking it will be desired to employ the least amount of solvent necessary (or a modest excess over that necessary) to adequately solubilise the buprenorphine such that the buprenorphine remains in solution under the conditions of likely usage or exposure.

Typically the solvent is selected from ethanol and ethanol/water mixtures. In a first embodiment of the invention ethanol is substantially the only solvent. For example the concentration of ethanol in the solvent is greater than 85% w/w, such as 90% w/w eg greater than 95% w/w particularly greater than 98% w/w, for example around 100% w/w (i.e. the solvent is ethanol, the presence of any water as contaminant from the atmosphere being ignored). In this first embodiment of the invention use of water as solvent is substantially avoided, for example the water concentration is less than 10% w/w eg less than 5% w/w particularly less than 98% w/w, for example around 0% w/w (i.e. the formulation is substantially free of water). As noted below, avoidance of water can be advantageous especially in formulations of buprenorphine containing citrate since we have observed that such formulations have a tendency to turn pink on storage.

In a second embodiment of the invention the solvent comprises water as well as ethanol. For example the solvent consists of a water/ethanol mixture in which the concentration of ethanol is approximately 30-90% w/w (the balance being water) for example approximately 40-70% w/w eg around 50% w/w.

Preferably water when employed as solvent meets the USP (US Pharmacopoeia), EP (European Pharmacopoeia) "Purified Water" standards.

The pH of the solution may typically be between around 4 and 9.5, however will preferably be between around 4.5 and 9.

In a first embodiment of the invention the pH is between 4.5 and 7 e.g. between around 4.5 and

7 e.g. between around 5 and 7, e.g. around 5.

In a second embodiment of the invention, the pH is between 7 and 9 e.g. between 7 and 8.5.

Our clinical trials have shown that the bioavailability for formulations at pH 5.0 is similar to bioavailability for formulations at pH 8.5. (See Results and Figure 1 ).

We have found that in the absence of antioxidant the degradation is worse at pH 5.0 than pH 8.5. (See Results and Figures 2-5).

By "pH" is meant the pH reading that would be obtained using a conventional pH meter eg model pH 211 manufactured by Hanna Instruments Ltd and Orion 420A manufactured by Thermo Electron Corporation (i.e. in water free systems the word "pH" would be construed to mean "apparent pH").

In order to adjust the pH buffer salts can be employed, however we have found that careful attention must be paid to the concentration of these due to the insolubility of many organic and inorganic salts in substantially ethanolic solvents. If a buffer system is to be employed we have found that citrate/citric acid is preferably avoided since we have found that formulations of the invention containing citrate/citric acid and water have a tendency to turn pink on storage especially at elevated temperature.

Suitably the use of phosphate containing buffers (eg phosphate and protonated derivatives such as hydrogen and dihydrogen phosphate) is also avoided. Thus the amount of phosphate in the formulation (eg as phosphate per se or as a protonated derivative such as hydrogen or dihydrogen phosphate) is suitably less than 3% w/w based on weight of buprenorphine eg less than 1 % w/w, eg less than 0.5% w/w for example less than 0.1% w/w especially when the pH of the formulation is less than 7.

In general it should not be necessary to add buffers to formulations of the invention and therefore adding buffers is preferably avoided (ascorbic acid, sodium saccharin and saccharin are not considered to be added buffers for the purpose of this statement).

In order to address the issue of pH adjustment of buprenorphine solutions and in particular without use of conventional buffer salts or use of chloride (eg as HCI) the inventors have appreciated that it may be possible to achieve this by the use of other organic formulation components. Accordingly we undertook a careful assessment of the impact on pH on buprenorphine solutions by addition of saccharin or sodium saccharin optionally together with certain other formulation components such as menthol (eg L-menthol) or peppermint oil.

We surprisingly discovered that saccharin may be effectively employed to lower the pH of buprenorphine base formulations, and is particularly useful in achieving a pH in the range 4-6, particularly 4.5-6 eg around 5. The pH lowering effect of saccharin lessens with increased buprenorphine concentration. Addition of menthol (eg L-menthol) or peppermint oil has relatively little impact on pH when in conjunction with saccharin.

We also discovered that saccharin sodium as well as menthol (eg L-menthol) and peppermint oil all have a modest but potentially useful effect on raising the pH of buprenorphine base formulations in ethanol, and is particularly useful in achieving a pH in the range between about 8 and 9.5 eg between around 8 and 9 eg around 8.5 in the presence of antioxidants which are not acids (e.g. not ascorbic acid).

As well as their above mentioned useful properties in modifying the pH of the formulations, saccharin and saccharin sodium are useful as sweeteners which improve patient acceptability.

As well as their above mentioned useful properties in modifying the pH of the formulations, menthol (eg L-menthol) and/or peppermint oil are useful as flavourings and moisturing agents which may have penetration enhancing activity.

If necessary pH can be adjusted by adding a strong acid (e.g. HCI) or strong base (e.g. NaOH).

The properties of the claimed formulations may be further improved by including therein a number of additional formulation components.

It may be desirable to include one or more of the following components in the formulation

- sweeteners such as saccharin, saccharin sodium, sucrose, flavouring or taste-masking agents

(to improve patient acceptability),

-moisturising agents (to improve patient comfort and overcome the drying tendency of ethanol and other polar organic solvents) for example peppermint oil, menthol (eg L-menthol) pineapple extract, lanolin, polypropylene glycol, polyethylene glycol.

-mucoadherents (in order to increase residency time on the mucosa) for example carboxyvinyl polymers, chitosans, polyacrylic acid, gelatin, polyvinyl pyrrolidone. -preservatives (to improve long term resistance to microbial contamination) for example sodium metabisulfite, benzalkonium, Nipas.

-anionic surfactants for example magnesium stearate, sodium cetostearyl sulfate, sodium lauryl sulfate, sodium oleate, sodium stearyl fumarate, sodium tetradecyl sulfate -nonionic surfactants for example glyceryl monostearate, Macrogol cetostearyl ethers, Poloxamers, polyoxyl stearates, Polysorbates, sorbitan esters, sucrose esters, Tyloxapol, propylene glycol monostearate, Quillaia, polyoxyl, caster oils, nonoxinols, lecithins and derivatives, oleic acid and derivatives, oleyl alcohol and derivatives -foaming agents for example alginic acid and salts, propylene glycol alginate, sodium lauryl sulfate, sodium cetostearyl sulfate, carbomers, hydroxyethylcellulose

Amongst the above mentioned possible additional components, it may be remarked that a preservative should not normally be necessary in view of the ethanol content of the formulations. In accordance with best pharmaceutical principles, additional components will be avoided if not necessary.

Some of the components proposed above may already be included in the formulation of the present invention for other purposes. Suitable moisturising agents include, for example, the polar organic solvents such as glycols, especially propylene glycol, and the liquid polyethylene glycols, glycerol, methylcellulose, hypromellose, hydroxypropylcellulose, and many other substituted celluloses.

As mentioned above, a versatile component, which improves the acceptability and other properties of the formulation, is menthol especially L-menthol. Menthol (eg L-menthol), as well as flavouring the formulation, has moisturising effect. It may also have effect as a penetration enhancer. Preferably menthol (eg L-menthol) is employed in a concentration range of 0.1 % to 0.75% w/w eg around 0.2% w/w.

Peppermint oil is an alternative component which may be used in place of menthol. Peppermint is known to have incompatibilities with certain actives (eg fentanyl) however it appears to be compatible with buprenorphine. Suitably peppermint oil is employed in a concentration range of 0.1 % to 0.75% w/w eg around 0.5% w/w.

In preferred embodiments of the invention, the formulation contains a sweetener. In one embodiment of the invention, the sweetener is saccharin sodium. Suitably the concentration of saccharin sodium is around 0.1-0.9% w/w eg around 0.45% w/w.

In another embodiment of the invention, the formulation contains saccharin. Suitably the concentration of saccharin is around 0.025-0.75% w/w, for example around 0.05-0.4% w/w eg around 0.05-0.1% w/w. As pointed out above the concentration of saccharin may be varied depending on the eventual pH desired (see Figure 2).

A number of formulations of the invention are considered to be especially suitable.

A suitable example formulation comprises (or consists essentially of (eg consists of)): -buprenorphine in the form of its base; -a solvent selected from ethanol and ethanol/water mixtures;

-one or more antioxidants each of a molar ratio of antioxidant:buprenorphine between 0.2 : 1 and 25 : 1 and wherein the pH of the formulation is between 7 and 9.

The pH of the formulation may, for instance, be between around 7 and 8.5 eg around 8 or around 8.5.

Suitably none of the antioxidants is an acid (e.g. ascorbic acid). The solvent may suitably be ethanol.

Optionally (and advantageously) such formulations are substantially free of chloride. Optionally (and advantageously) such formulations comprise saccharin sodium. Optionally (and advantageously) such formulations comprise a flavouring agent selected from menthol (eg L-menthol), peppermint oil and mixtures thereof. Optionally such formulations comprise a chelating agent (eg EDTA or sodium edetate). Optionally hydroxide (eg NaOH, KOH) may be used to raise the pH if needed. Suitably the concentration of buprenorphine base is 0.1-4% w/v eg 0.1-1 % w/v.

A suitable example formulation comprises (or consists essentially of (eg consists of)): -buprenorphine in the form of its base;

-a solvent selected from ethanol and ethanol/water mixtures;

-one or more antioxidants, one or more of which is an acid (e.g. ascorbic acid), each of a molar ratio of antioxidant:buprenorphine between

0.2 : 1 and 25 : 1 and wherein the pH of the formulation is between around 4.5 and 7 eg between around 4.5 and 7 e.g. between around 5 and 7, e.g. around 5.

The solvent may suitably be ethanol.

Optionally (and advantageously) such formulations are substantially free of chloride.

Optionally (and advantageously) such formulations comprise saccharin sodium. Optionally (and advantageously) such formulations comprise a flavouring agent selected from menthol (eg L-menthol), peppermint oil and mixtures thereof.

Optionally such formulations comprise a chelating agent (eg EDTA or sodium edetate).

Optionally hydroxide (eg NaOH, KOH) may be used to raise the pH if needed.

Suitably the concentration of buprenorphine base is 0.1-4% w/v eg 0.1-1 % w/v.

Another suitable example formulation comprises (or consists essentially of (eg consists of)): -buprenorphine in the form of its base; -a solvent selected from ethanol and ethanol/water mixtures;

-one or more antioxidants, each of a molar ratio of antioxidant:buprenorphine between 0.2 : 1 and 25 : 1 ; -saccharin; wherein the pH of the formulation is between around 4.5 and 7 eg between around 4.5 and 7 e.g. between around 5 and 7, e.g. around 5. The solvent may suitably be ethanol.

Optionally (and advantageously) such formulations are substantially free of chloride. Optionally (and advantageously) such formulations comprise a flavouring agent selected from menthol (eg L-menthol), peppermint oil and mixtures thereof.

Optionally such formulations comprise a chelating agent (eg EDTA or sodium edetate). Suitably the concentration of buprenorphine base is 0.1-4% w/v eg 0.1-1 % w/v.

A process for preparation of formulations of the invention comprises:

(a) taking buprenorphine in the form of its base and antioxidant and a solvent comprising ethanol optionally containing the other formulation ingredients (eg saccharin, saccharin sodium, menthol, peppermint oil etc) and dissolving the buprenorphine and antioxidant in the solvent; or

(b) taking buprenorphine in the form of its base and antioxidant and a solvent comprising ethanol and dissolving the buprenorphine and antioxidant in the solvent, then adding the other formulation ingredients (eg saccharin, saccharin sodium, menthol, peppermint oil etc); or

(c) taking buprenorphine in the form of its base and a solvent comprising ethanol containing antioxidant and optionally containing the other formulation ingredients (eg saccharin, saccharin sodium, menthol, peppermint oil etc) and dissolving the buprenorphine in the solvent; or (d) taking buprenorphine in the form of its base and a solvent comprising ethanol and dissolving the buprenorphine in the solvent, then adding the other formulation ingredients (antioxidant and eg saccharin, saccharin sodium, menthol, peppermint oil etc); or

(e) the process of (a), (b), (c) or (d) in which the pH of the solvent is adjusted once all the other formulation ingredients are mixed together. Process (b) is preferred.

Amongst the advantages of the claimed formulations is the fact that by being non-pressurised they avoid the issues associated with using propellant, such as their manufacturing disadvantages and their potential environmental impact (many propellants are "greenhouse gasses"). The solution formulations of the invention are homogenous and have limited or no susceptibility to dose-to-dose variation. Furthermore formulations of the present invention are characterised by good long-term physical and chemical stability.

The formulations of the invention are preferably administered transmucosally (particularly sublingually) as a spray. The formulations are expected to be well tolerated when administered to the sensitive sublingual mucosa and the sublingual spray administration will result in rapid onset of the therapeutic effect of the buprenorphine. Thus according to a second aspect of the invention there is provided a metered dose dispensing system comprising a sealed container containing a formulation of the invention fitted with a metering pump, an actuator and a channelling device. The metered dose dispensing system is preferably adapted for transmucosal (particularly sublingual) administration.

Although in principle the container for the pharmaceutical liquid formulation may contain a single dose of buprenorphine (which may, nevertheless be a divided dose), preferably the container will contain a plurality of doses (eg 20 to 200 doses) of buprenorphine.

Although the formulation could be packaged in a suitable pharmaceutical grade, plastics container, such a container would be relatively easy to open for abuse of the product. Therefore a glass container would be more suitable. Glass would shatter if attempts were made to open the pack, rendering the contents either lost or unusable due to glass fragments. Preferably the glass container will be coated on the exterior with a suitable moulded film of plastic to protect against shattering. For example the film may be of polypropylene. The material may be coloured and contain a UV absorber. The container glass may be colourless or more suitably may be provided with a UV protective colouring, for example amber colouring. Optionally, the interior of the container can be coated to enhance stability of the product. Coatings include polymers and lacquers but also silicone dioxide as an unreactive coating can be used to line the inside of the container.

Since the formulation is non-pressurised, it is suitably administered to the patient by pump action. Thus the metering dose dispensing system suitably contains a metering pump permitting a metered dose of the formulation to be administered as a spray.

Suitable metering pumps include those adapted for dispensation with the container in the upright or inverted orientation. Preferably the metering chamber is adapted for dispensation with the container in the upright orientation since this facilitates administration under the tongue. Accordingly the metering chamber will be in communication with the formulation by means of a dip-tube.

The metering pump is suitably a non-venting type. Suitable materials of construction include polypropylene and polyethylene. Example metering pumps are those manufactured by Valois (eg VP3, VP6, VP7 and VP7D) and for example those illustrated in International Patent Application No. WO01/66089. Other conventional pumps include those from Rexam (eg SP270) and Calmar (eg Accupump or Mistette Mk II). Preferably the actuator will be designed to deliver a transmucosally (particularly a sublingually) effective dose. The pump may suitably be manually actuated, although assisted actuation using stored energy (eg spring or gas) may be contemplated.

For a secure seal, the pump is suitably crimped onto the container neck. Suitable sealing materials eg thermo plastic crimp gaskets suitable for the purpose will be employed. In addition, a suitable aluminium ferrule purposely designed for crimping on to glass containers may suitably be employed. Suitable grade stainless steel springs will preferably be adopted.

The metering pump will administer a metered volume of formulation. Suitable metering volumes are 10-1000 μl_, more suitably 50-250 μl_, eg 100μl_ or 200 μl_, particularly 200 μl_.

A channelling device is provided to direct the liquid sprayed from the metered dose dispensing area to the appropriate part of the mouth e.g. to the sublingual cavity or if desired to the nose. Channelling devices are suitably fabricated from moulded plastics. A number of channelling devices adapted to administer sprays to the mouth or nose are known to persons skilled in the art eg

Formulations of the invention are useful in treatment or prevention of opiate dependency and abuse, particularly in the treatment or prevention of dependency on opiates such as heroin and for analgesic purposes eg for the treatment of moderate to severe pain. Thus in a further aspect of the invention there is provided a method of treatment or prevention of opiate dependency and abuse or pain which comprises administering to a subject in need thereof an effective amount of a formulation of the invention. In a further aspect of the invention, there is provided the use of a formulation according to the invention in the manufacture of a medicament for the treatment or prevention of opiate dependency and abuse or pain. In a further aspect, there is provided a formulation of the invention for use in the treatment or prevention of opiate dependency and abuse or pain.

In order to lessen the risk of abuse with the product, suitably the container or the dispensing system may be provided with features to prevent tampering. In particular, the container or the dispensing system may suitably be provided with features to prevent or discourage access to the reservoir and/or to prevent administration of more than one dose of buprenorphine at one time.

The dispensing system, in particular the actuator, may, for example, be provided with a lock-out feature to prevent administration of a second dose within a specified time interval of the first. Lock-out features are, for example, described in US2006191532, WO03097141 and WO0232487.

Typically a patient is treated by administration transmucosally (eg sublingually) of 1 to 4 actuations eg 1 or 2 actuations from the spray pump. Another advantage of mucosal spray delivery is the ability to easily titrate patients by 1 or 2 doses as required by a single actuation. This is not the case with other forms of drug delivery (patches, lozenges, tablets, suppositories).

Pharmaceutical formulations of the invention are useful in the treatment of animals, particularly non-human mammals (for example domestic or livestock animals) as well as humans. Accordingly pharmaceutical uses, for example uses in the treatment of pain, may be extended to veterinary uses. Dosages and methods of administration (eg the spray actuator design) will be adapted for the intended recipient as would be known to a skilled person.

EXAMPLES

Comparator formulations

The following example formulations were prepared for comparison with Comparator Formulation.

Example formulation 1 (Ascorbic acid, pH 5.0) a)

Material % w/w

Buprenorphine 0 253

Levomenthol 0 200

Saccharin 0 050

100% Ethanol 99.410

Ascorbic acid (5mM) 0 087

Example formulation 2 (Alpha-tocopherol, pH 5.0)

Example formulation 3 (Butylated hydroxytoluene, pH 5.0)

Example formulation 4 (Butylated hydroxyanisole, pH 5.0)

The following example formulations may be prepared for comparison with Comparator

Formulation A

Example formulation 5 (Ascorbic acid) a) pH 6.2 b) pH 5.9 c) pH 5.7

Example formulation 6 (Alph

Example formulation 7 (Butylated hydroxytoluene, pH 8.5)

Example formulation 8 (Butylated hydroxyanisole, pH 8.5)

Example formulation 9 (Butylated hydroxyanisole, pH 6.5)

Example formulation 10 (Butylated hydroxytoluene, pH 6.6)

Example formulation 11 (Butylated hydroxytoluene, pH 6.5)

Compositions were prepared as follows:

Comparator formulation A

2.9729kg of absolute ethanol was weighed into a 7 litre stainless steel container. Buprenorphine base (0.0076kg) was added to the ethanol and mixed using a mobile stirrer until completely dissolved. Levomenthol (0.0060kg) was added to the solution and mixed using a mobile stirrer until completely dissolved. Saccharin sodium (0.0135)was added to the solution and mixed using a mobile stirrer until completely dissolved.

Comparator formulation B

2.9849kg of absolute ethanol was weighed into a 7 litre stainless steel container. Buprenorphine base (0.0076kg) was added to the ethanol and mixed using a mobile stirrer until completely dissolved. Levomenthol (0.0060kg) was added to the solution and mixed using a mobile stirrer until completely dissolved. Saccharin (0.0015) was added to the solution and mixed using a mobile stirrer until completely dissolved. Example formulation 1 c

2.9742kg of absolute ethanol was weighed into a 7 litre stainless steel container. Buprenorphine base (0.0076kg) was added to the ethanol and mixed using a mobile stirrer until completely dissolved. Ascorbic acid (0.0107Kg) was added to the solution and mixed using a mobile stirrer until completely dissolved. Levomenthol (0.0060kg) was added to the solution and mixed using a mobile stirrer until completely dissolved. Saccharin (0.0015) was added to the solution and mixed using a mobile stirrer until completely dissolved.

All of Examples 1-4 were prepared by an analogous procedure.

Example formulation 5c

2.9622kg of absolute ethanol was weighed into a 7 litre stainless steel container. Buprenorphine base (0.0076kg) was added to the ethanol and mixed using a mobile stirrer until completely dissolved. . Ascorbic acid (0.0107Kg) was added to the solution and mixed using a mobile stirrer until completely dissolved. Levomenthol (0.0060kg) was added to the solution and mixed using a mobile stirrer until completely dissolved. Saccharin Sodium (0.0135Kg) was added to the solution and mixed using a mobile stirrer until completely dissolved.

All of Examples 5-11 were prepared by an analogous procedure.

RESULTS

1. Bioavailability clinical trials data

A single dose, randomised crossover study to compare the rate and extent of absorption of three formulations of buprenorphine in healthy male volunteers was carried out.

A single dose of buprenorphine was administered sublingually to each volunteer. In each study period, 14 blood collections were made over 10 hours, at the following times: immediately before administration of the study drug (0.0 hours) and at 0.25, 0.5, 0.75, 1.0, 1.33, 1.67, 2.0, 2.5, 3.0, 4.0, 6.0, 8.0 and 10.0 hours after administration. The total volume of blood taken from each volunteer (including screening and post study) was approximately 300 ml. Plasma concentration of buprenorphine was measured.

15 healthy male volunteers participated in the study; 4 withdrew before completion and 11 completed all three periods of the study. The interval between each of the periods was one week.

The study was carried out using the following treatments:

Treatment A = Buprenorphine 0.4mg spray Formulation A (pH 8.5), 1 *0.4 mg spray,

Pharmasol Ltd., UK Treatment B = Buprenorphine 0.4mg spray Formulation B (pH 5.0), 1 *0.4 mg spray,

Pharmasol Ltd., UK Treatment C = Temgesic SL tablets, 1 *0.4 mg sub-lingual tablet, Schering Plough, UK

The results are shown graphically in Figure 1.

The two spray formulations (Treatment A, Buprenorphine spray 0.4 mg Formulation A (pH 8.5), and Treatment B, Buprenorphine spray 0.4 mg Formulation B (pH 5.0), Pharmasol Ltd., UK) have a similar rate and extent of absorption.

Treatment A and Treatment B were suprabioavailable compared to the tablet formulation (Treatment C, Temgesic® SL tablets 0.4 mg, Schering Plough, UK).

Z HPLC Comparison of degradation of comparator formulations A and B Figures 2 and 4 show the HPLC trace of comparator formulations A and B at the initial time point. As can clearly be seen from Figures 2 and 4, there an HPLC peak corresponding to buprenorphine at the initial time point.

In Figure 2, peaks at 2.64 and 3.05mins are injection peaks and the peak at 12.26mins is the buprenorphine peak. In Figure 4, peaks at 2.64 and 3.05mins are injection peaks and the peak at 12.31 mins is the buprenorphine peak.

Figures 3 and 5 show the HPLC trace of comparator formulations A and B, 6 months after the initial time point, after degradation has occurred. As can clearly be seen from Figures 3 and 5, a number of new peaks corresponding to degradation products, which were not present at the initial time point, have developed.

In Figure 3, degradation peaks are observed at 3.30, 4.19, 4.35, 5.31 , 7.09mins. In Figure 5, degradation peaks are observed at 3.25, 3.71 , 4.18, 4.66, 5.01 , 5.50, 6.22, 6.88, 9.52, 10.03, 10.98, 16.77mins.

Comparison of Figure 3 with Figure 5 clearly shows that more peaks of greater intensity are present after 6 months in the spectrum of comparator formulation B than comparator formulation A.

2. LCMS Figures 6 and 8 show the LCMS trace of comparator formulations A and B at the initial time point. As can clearly be seen from Figures 6 and 8, there is no LCMS m/z peak corresponding to the dimer or a UV-vis absorption corresponding to the dimer at the initial time point.

Figures 7 and 9 show the LCMS trace of comparator formulations A and B, 12 months after the initial time point, after degradation has occurred. As can clearly be seen from Figures 7 and 9, an m/z peak corresponding to the dimer (at m/z 941.6) and a UV-vis absorption (at 458nm) corresponding to the dimer, which were not present at the initial time point, have developed.

3. UV-vis Scan

All buprenorphine formulations were made and were initially tested for degradation, assay for buprenorphine and scanned on the UV-vis spectrometer, before being put on stability at 4O⁰C / 75%RH. At each time point, a sample was removed from each formulation and scanned on the UV-vis spectrometer. After the scan was performed, the sample was disposed of.

The UV-vis scan was performed at 458nm, as this is the optimum wavelength to detect the buprenorphine dimerisation. For the time points at 3, 4 and 6 weeks, a scan between 700-200nm was performed on the same sample in addition to the scan at 458nm.

Buprenorphine Formulations + ascorbic acid / alpha-tocopherol

Figures 10 and 12 show that at the initial time point there was no UV-vis absorption between 400nm and 500nm.

Figure 1 1 shows that for formulation B after 6 weeks, a peak between 400nm and 500nm is clearly visible. This peak corresponds to the dimerisation product.

Figure 13 shows that for Example 1 c after 6 weeks, the presence of 2OmM ascorbic acid has prevented the development of a peak between 400nm and 500nm i.e. the presence of antioxidant in Example 1 c has inhibited the dimerisation process of buprenorphine.

Below is a table summarising the UV-vis results for the formulations including ascorbic acid and alpha-tocopherol.

nd = not determined

^*These anomalous results from the scan at 458nm were abnormally high. In addition to the scan at 458nm, a scan between 700-200nm for the same sample was also performed at this time point. The scan between 700-200nm showed that there was not a peak around 458nm. The reason for the high reading in the 458nm scan is the calibration of the equipment (for the anomalous results, the lowest possible reading was considerably higher than that for the other samples). After 6 weeks the ascorbic acid formulations appear colourless to the naked eye. By contrast the alpha-tocopherol and blank formulations have a yellow tinge compared to the comparator formulation suggesting that ascorbic acid has a greater effect on enhancing stability than does alpha-tocopherol.

The results of Table 2 are shown graphically in Figure 14.

Figure 14 clearly shows that ascorbic acid and alpha-tocopherol significantly enhance stability of the buprenorphine.

Buprenorphine Formulations + BHT / BHA

Below is a table summarising the UV-vis results for the formulations including BHT and BHA

Bold = Although these results suggest that there has been no colour change, scans between 700-200nm show a peak appearing, suggesting dimerisation.

The results of Table 3 are shown graphically in Figure 15.

Figure 15 clearly shows that BHT and BHA make a significantly positive difference on the stability of the buprenorphine.

4. Degradation Assay

The degradation and assay for buprenorphine tests were carried out as per methods used for standard productions to see if the antioxidants had any effect on the buprenorphine formulation. The data for the following tables was generated from spectroscopic data.

Buprenorphine Formulations + ascorbic acid / alpha-tocopherol

Below is a table summarising the degradation results for the formulations containing ascorbic acid and alpha-tocopherol.

nd = not determined

Specification: degradent<0.0005%

Bold = Out of spec

^*thought to be an anomaly, as shown by the results in weeks 5 & 6.

The results of Table 4 are shown graphically in Figure 16.

Figure 16 clearly shows that ascorbic acid and alpha-tocopherol control the level of degradation compared to the comparator formulation of buprenorphine.

Degradation results from stability trial: Comparator Formulation A after 1 month:

The Comparator Formulation A used in this stability trial over 1 month at 3O⁰C and 4O⁰C was taken from a 3 litre manufactured batch of said formulation.

Degradation results from stability trial: Comparator Formulation B after 1 month:

The Comparator Formulation B used in this stability trial over 1 month at 3O⁰C and 4O⁰C was taken from a 3 litre manufactured batch of said formulation

Buprenorphine Formulations + BHT / BHA

Below is a table summarising the degradation results for the formulations containing BHT and BHA.

Specification: degradent<0.0005% Bold = Out of spec

The results of Table 7 are shown graphically in Figure 17.

Figure 17 clearly shows that the formulations containing BHT and BHA keep the level of degradation at a better level compared to the comparator formulation of buprenorphine.

5. Buprenorphine Assay

The data for the following tables was generated from spectroscopic data.

Buprenorphine Formulations + ascorbic acid / alpha-tocopherol Below is a table summarising the results for the assay for buprenorphine for the formulations containing ascorbic acid and alpha-tocopherol.

nd = not determined

Buprenorphine Formulations + BHT / BHA

Below is a table summarising the results for the assay for buprenorphine for the formulations containing BHT and BHA.

nd = not determined

In summary, the tables show that the antioxidants have no negative effect on the assay for buprenorphine. 6. 2 Month Stability Analysis

A 2 month stability trial was conducted at 40⁰C and at 75% relative humidity. At various time points (i.e. initial, 2 week, 1 month and 2 months), the test formulations were measured for appearance of colour and a UV scan (to detect possible dimerisation), buprenorphine assay, pH and the presence of related substances.

Buprenorphine Formulation (control)

Below is a table summarising the stability results for a formulation containing 40 mg/ml buprenorphine in the absence of antioxidant as control

Bold = out of spec

Buprenorphine Formulation + BHT

Below is a table summarising the stability results for a formulation containing 40 mg/ml buprenorphine in the presence of 2% butylated hydroxytoluene (BHT).

Bold = out of spec Below is a table summarising the stability results for a formulation containing 40 mg/ml buprenorphine in the presence of 5% butylated hydroxytoluene (BHT).

Bold = out of spec

Buprenorphine Formulation + BHA

Below is a table summarising the stability results for a formulation containing 40 mg/ml buprenorphine in the presence of 2% butylated hydroxyanisole (BHA).

Bold = out of spec

Below is a table summarising the stability results for a formulation containing 40 mg/ml buprenorphine in the presence of 5% butylated hydroxyanisole (BHA).

Bold = out of spec

In summary, the tables show that the antioxidants BHT and BHA have a positive effect upon the stability of buprenorphine when compared with the results obtained in the absence of antioxidant. In particular, BHT appeared to confer optimal stability upon buprenorphine.

7. Comparative Stability Analysis with Propyl Gallate as Antioxidant

A stability trial using propyl gallate as antioxidant was conducted in an analogous manner to that conducted in section 6 above.

Below is a table summarising the stability results for a formulation containing 40 mg/ml buprenorphine in the presence of 2% propyl gallate.

Bold = out of spec

Below is a table summarising the stability results for a formulation containing 40 mg/ml buprenorphine in the presence of 5% propyl gallate.

Bold = out of spec

In summary, it would be appear that propyl gallate provides a negative effect upon the stability of buprenorphine when compared with the results obtained in section 6 in the absence of antioxidant.

SUMMARY

Antioxidants have generally been shown to have a beneficial effect on the stability of buprenorphine formulations.

Ascorbic acid

Inclusion of ascorbic acid in the example formulations prevented the yellow colour from forming over six weeks, and hence stopped the dimerisation process. It also reduced the level of degradation products shown on the HPLC, with particular significance when looking at the 2OmM concentration, which keeps the degradation results in specification over a six week period.

Alpha-tocopherol Inclusion of alpha-tocopherol in example formulations prevented the yellow colour from forming over three weeks, which is better than the comparator formulation but not as good as the ascorbic acid formulations. Reduction in degradation products as determined by HPLC appears to be better in the alpha-tocopherol formulations than in the ascorbic acid formulations.

BHT and BHA

The degradation profile as determined by HPLC and the dimerisation results as determined by UV-vis are superior to those of the comparator formulation. The presence of BHT in particular was also seen to confer excellent stability results upon buprenorphine even after two months when stored at 40⁰C and at 75% relative humidity. Propyl gallate

The stability assessment demonstrated that propyl gallate provides a negative effect upon the stability of buprenorphine when present as a sole antioxidant. For example, dimerisation occurred after just 2 weeks when compared with 1 month in the absence of antioxidant.

All patents and patent applications mentioned herein are incorporated by reference in their entirety.

Throughout the specification and the claims which follow, unless the context requires otherwise, the word 'comprise', and variations such as 'comprises' and 'comprising', will be understood to imply the inclusion of a stated integer, step, group of integers or group of steps but not to the exclusion of any other integer, step, group of integers or group of steps.

All patents and patent applications referred to herein are incorporated by reference in their entirety.

Claims

Claims

1. A non-pressurised pharmaceutical liquid solution spray formulation comprising: (i) buprenorphine; (ii) a solvent comprising ethanol; and

(iii) one or more antioxidants each of a molar ratio of antioxidant:buprenorphine between 0.2 : 1 and 25 : 1.

2. A formulation according to claim 1 wherein buprenorphine is employed in the form of its free base.

3. A formulation according to claim 2 wherein the concentration of buprenorphine is between 0.1-4% w/v.

4. A formulation according to any one of claims 1 to 3 wherein the one or more antioxidants are selected from alkyl gallates, butylated hydroxyanisole, butylated hydroxytoluene, nordihydroguaiaretic acid, alpha-tocopherol, ascorbic acid and sodium metabisulfite.

5. A formulation according to any one of claims 1 to 4 wherein the one or more antioxidants are selected from butylated hydroxyanisole, butylated hydroxytoluene, alpha-tocopherol, and ascorbic acid.

6. A formulation according to any one of claims 1 to 5 which comprises only one antioxidant.

7. A formulation according claim 6 wherein the one antioxidant is butylated hydroxytoluene.

8. A formulation according to any one of claims 1 to 5 which comprises two antioxidants.

9. A formulation according to claim 8 which comprises ascorbic acid and alpha-tocopherol.

10. A formulation according to any one of claims 1 to 4, claim 8 or claim 9 wherein the molar ratio of total antioxidant:buprenorphine between 0.2 : 1 and 25 : 1.

1 1. A formulation according to any one of claims 1 to 10 characterised in that the formulation is substantially free of chloride.

12. A formulation according to any one of claims 1 to 1 1 wherein the concentration of ethanol in the solvent is greater than 90% w/w.

13. A formulation according to any one of claims 1 to 12 which is substantially free of water.

14. A formulation according to claim 12 or claim 13 wherein the concentration of ethanol in the solvent is around 100% w/w.

15. A formulation according to any one of claims 1 to 1 1 wherein the concentration of ethanol in the solvent is approximately 30- 90% w/w, the balance being water.

16. A formulation according to any one of claims 1 to 15 wherein the pH of the formulation is between around 4 and 9.5.

17. A formulation according to claim 16 wherein the pH of the formulation is between around 5 and 7.

18. A formulation according to claim 16 wherein the pH of the formulation is between around 7 and 9.

19. A formulation according to any one of claims 1 to 18 which contains saccharin.

20. A formulation according to any one of claims 1 to 18 which contains saccharin sodium.

21. A formulation according to any one of claims 1 to 20 which contains menthol.

22. A formulation according to any one of claims 1 to 21 which contains peppermint oil.

23. A formulation according to any one of the preceding claims for transmucosal administration as a spray.

24. A formulation according to claim 23 wherein the transmucosal administration is sublingual administration.

25. A formulation according to any one of the preceding claims, for use in the treatment or prevention of opiate dependency or abuse or pain.

26. Use of a formulation according to any one of claims 1 to 25 in the manufacture of a medicament for the treatment or prevention of opiate dependency or abuse or pain.

27. A sealed container containing a plurality of doses of a formulation according to any one of claims 1 to 25.

28. A container according to claim 27 which is made out of glass.

29. A metered dose dispensing system comprising a sealed container according to claim 27 or claim 38 fitted with a metering pump, an actuator and a channelling device.

30. A metered dose dispensing system according to claim 29 containing a metering chamber which is adapted for dispensation with the container in the upright orientation and wherein the metering chamber is in communication with the formulation by means of a dip-tube.

31. A metered dose dispensing system according to claim 29 or claim 30 adapted for transmucosal administration of the formulation as a spray.

32. A metered dose dispensing system according to claim 31 wherein the transmucosal administration is sublingual administration.

33. A process for preparation of formulations of the invention which comprises:

(a) taking buprenorphine in the form of its base and antioxidant and a solvent comprising ethanol optionally containing the other formulation ingredients and dissolving the buprenorphine and antioxidant in the solvent; or

(b) taking buprenorphine in the form of its base and antioxidant and a solvent comprising ethanol and dissolving the buprenorphine and antioxidant in the solvent, then adding the other formulation; or

(c) taking buprenorphine in the form of its base and a solvent comprising ethanol containing antioxidant and optionally containing the other formulation ingredients and dissolving the buprenorphine in the solvent; or

(d) taking buprenorphine in the form of its base and a solvent comprising ethanol and dissolving the buprenorphine in the solvent, then adding the other formulation ingredients; or

(e) the process of (a), (b), (c) or (d) in which the pH of the solvent is adjusted once all the other formulation ingredients are mixed together.