Title of Invention


Abstract An pharmaceutical formulation comprising (i) fentanyl or pharmaceutically acceptable salt thereof, (ii) water and (iii) a polar organic solvent, wherein the said polar organic solvent is available in a sufficient amount to enhance the solubility of the fentanyl or salt thereof in the water. The resulting solution is for use as a sublingual spray - preferably delivered by means of a pump spray device
Full Text Novel Compositions
This invention relates to formulations of fentanyl, especially pump spray formulations suitable for sublingual delivery.
Fentanyl is a narcotic alkaloid, which has been used for many years as an anaesthetic and an analgesic, especially in the treatment of moderate to severe pain. Whilst undoubtedly effective for pain relief, and especially in the treatment of pain which is refractive to other treatments, there are a number of issues of clinical management associated with the use of fentanyl in therapy.
Foremost amongst these issues is the potential for serious side effects with fentanyl It has a much higher potency than commonly known narcotics and therefore it is necessary to ensure that it is being used within the established therapeutically effective range and to monitor patients for evidence of self medication at greater than the recommended amount. Overdosage .with fentanyl can lead to a number of undesirable and indeed life-threatening side effects, predominantly hypoventilation and respiratory depression.
Due to the nature of the conditions being treated, it is much desired that the onset of analgesia occurs as soon after dosage as is compatible with safety parameters. Furthermore delay in onset of action may prompt the patient to take another dose with consequent risk, as already explained above, of overdosage.
A number of routes of administration of a medicament can be associated with rapid onset of action. For example, International Patent Application WO90/07333 (Riker Labs) described aerosol formulations of fentanyl, which are adapted for inhalation However Riker's formulations suffer disadvantages such as their use of hydrofluorocarbon propellants and delivery effected by metered dose inhalers. In the case of the former the disadvantages include high velocity which results in 'bounce back5 on administration to the front of the mouth, cold sensations on administration, the risk of inhalation and for the latter, careful co-ordination of
breath and actuation by the patient. When metered dose inhalers are used, a significant proportion of the delivered dose tends to impact the back of the throat from where it is swallowed rather than finding its way into the bronchial passages. Accordingly, the pharmacology of the medication may be unpredictable due to poor bioavailability following oral administration or may be characterised by a bi-phasic profile (fast initial onset as a result of the inhaled dose and a slower, late effect due to oral absorption of fentanyl). Furthermore, manufacture of the bulk formulation involves the preparation of large quantities of pressurised volatile propellant containing a potent narcotic analgesic. Accordingly the precautions required to ensure safe manufacture are onerous and expensive.
W095/31182 (Aradigm Corp) describes solution formulations of fentanylin aerosc propellants intended for administration to patients by the pulmonary route.
WOOl/97780 (Pharmasol Ltd) describes solution formulations of fentanyl free bas in propellants, typically HFA134a, for sublingual aerosol administration.
WO00/47203 (MQS Inc) describes formulations of fentanyl citrate for intra-oral administration employing oral absorption enhancers.
These prior art formulations of fentanyl employ propellants and also suffer from the aforementioned disadvantages.
Certain aqueous formulations of fentanyl for intranasal administration employing water and phosphate buffer have been described, (Paech, M.J., Lim, C.B., Banks, S.L., Rucklidge, M. W. M. & Doherty, D.A. (2003) Anaesthesia 58 (8), 740-744 am Lim et al (2003) J Phatm Practice Research 33, 59-63) but such formulations can suffer problems of nasal irritation associated with medium to long term usage via this route which is undesirable. Weinberg et al (1988) Clin Pharmacol Therap 44 335-342 discloses formulations of fentanyl employing water and phosphate buffer for sublingual administration however these formulations were not advocated for use as a spray.
It is well known that the application of carefully chosen medicaments to the subHngual 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. A number of ways of administering compositions 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 composition 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). Pharmaceutical compositions, for example a fentanyl lozenge cause increased salivation, which facilitates the unwanted swallowing of drug substance. Spray delivery, having low volume and ability to target the subHngual mucosa, largely mitigates this. No propellant free spray formulations of fentanyl which are adapted for subHngual administration have yet been described.
It is an aim of the present invention to provide a formulation, which avoids or mitigates some or all of the above-mentioned disadvantages.
Thus according to a first aspect of the invention a pharmaceutical composition is provided, the composition being a partially pressurised Hquid spray formulation, which comprises:
(a) fentanyl or a pharmaceutically acceptable salt thereof;
(b) water as carrier; and
(c) a polar organic solvent in sufficient amount to enhance the solubihty of the fentanyl or pharmaceutically acceptable salt thereof in the water.
The formulations of the invention are preferably administered subHngually as a spray. The formulations are well tolerated when administered to the sensitive subHngual mucosa and the subHngual spray administration will result in rapid onset of the therapeutic effect of the fentanyl.
The formulations of the present invention are also preferably free of any propellant
Amongst the advantages of these formulations is the fact that by being water based they avoid the issues associated with using pressurised hydrofluorocarbon propellants as mentioned above. The formulations are partially pressurised and are free of propellants such as volatile chlorofmorocarbons (e.g. propellant 12), volatile hydrofluoroalkanes (e.g. 1,1,1,2-tetrafiuoroethane and 1,1,1,2,3,3,3-heptafiuoro-n-propane) and volatile alkanes (e.g. propane, butane) and other substances which have significant vapour pressure at ambient temperature and pressure.
In one embodiment of the present invention, the formulation is a solution, rather than a suspension. Whilst it is possible to spray a suspension, the fact that most suspensions settle means that the amount of active agent included in the dispensed dose will be variable and this can be highly undesirable. Although the effect of the settling of the suspension can be reduced to an extent by shaking the composition prior to spraying, some suspensions can settle very rapidly, so that there is still potential for variation of active agent content between doses.
Furthermore the formulations of the present invention are characterised by good long-term physical and chemical stability.
Fentanyl may be employed in the form of a physiologically acceptable salt, which is soluble in water together with a polar organic solvent. Examples of suitable salts include hydrochloride, chloride, sulphate, tartrate and citrate. Preferably fentanyl is employed as the free base.
Preferably the fentanyl or physiologically acceptable salt thereof will be employed in the formulation at a concentration of 0.lmg/ml to l0mg/ml, preferably 0.5mg/ml to 4.4mg/ml (where weight is expressed as weight of fentanyl free base).
Examples of polar organic solvents that may be used to enhance the solubility of fentanyl, or the physiologically acceptable salt thereof in the water, include: lower alcohols (e.g. C2-4 alcohols) such as ethanol; lower polyols (e.g. C2-4 polyols) such as glycerol and propylene glycol; and polyethylene glycols such as PEG200 and PEG400.,
Mixtures of the above substances may be used. The preferred polar organic solvent is ethanol.
In another embodiment of the present invention, the formulation does not include ethanol. Indeed, the formulation may be substantially free of any alcohol, or completely free of alcohol.
Where the composition is free of alcohol, the carrier used is preferably a polyol. The preferred polyols include propylene glycol and glycerol.
Generally speaking it will be desired to employ the least amount of polar organic solvent necessary (or a modest excess over that necessary) to adequately solubilise the fentanyl, or physiologically acceptable salt thereof, and such that the fentanyl remains in solution under the conditions of likely usage or exposure.
The concentration of polar organic solvent is in the range preferably of between 6 and 50%, more preferably 20-45% especially 35-42%.
Preferably the water meets the USP (US Pharmacopoeia), EP (European Pharmacopoeia) "Purified Water" standards.
It has also been found that the properties of the claimed formulations may be improved by including therein a number of additional formulations components.
Thus, in one embodiment of the invention, the water in the formulation is present in the form of an aqueous buffer. The buffer is preferably adapted to stabilise th
pH of the formulation at pH 7.4 to 8.5, preferably at pH 8.0 to 8.5, more preferably at 8.1 to 8.3, or around 8.2. At higher pH values we have found evidence that the bioavailability of the formulation is improved relative to lower pH values (e.g. nearer pH 6). Example buffer systems include sodium acetate/acetic acid, ammonium acetate/disodium edetate, boric acid/sodium hydroxide, orthophosphoric acid/sodium hydroxide, sodium hydrogen carbonate/sodium carbonate, disodium hydrogen orthophosphate/citric acid (taken from the British Pharmacopoeia). The preference is use of a citrate buffer, e.g. a buffer comprising citric acid, sodium citrate and sodium hydroxide.
The concentration of the aqueous component (water or more preferably aqueous buffer) of the formulation of the present invention is preferably 50-94%, more preferably 55-80%, and especially 58-65%.
It may be desirable to include one or more of the folio-wing components in the formulation.
1) Sweeteners, flavouring or taste-masking agents (to improve patient acceptability), for example vanilla, pineapple extract, menthol, saccharin and sodium saccharin.
2) Moisturising agents (to improve patient comfort and overcome the drying tendency of ethanol and other polar organic solvents), for example pineapple extract, lanolin, polypropylene glycol, and polyethylene glycol.
3) Penetration enhancers (to improve therapeutic effect), for example menthol.
4) Mucoadherents (in order to increase residency time on the mucosa), for example carboxyvinyl polymers, chitosans, polyacrylic acid, gelatin and polyvinyl pyrrolidone.
5) Preservatives (to improve long term resistance to microbial contamination), for example ethanol, sodium metabisulphite, benzalkonium chloride and Nipas.

6) Antioxidants, for example Alkyl Gallates, Butylated Hydroxyanisole, Butylated Hydroxytoluene, Nordihydroguaiaretic acid, Tocopherols, Ascorbic acid and Sodium metabisulphite.
7) Anionic surfactants, for example Magnesium Stearate, Sodium Cetosteatyl sulphate, Sodium Lauryl sulphate, Sulphated caster oil, Sodium oleate, Sodium stearyl Fumarate and Sodium Tetradecyl Sulphate.
8) 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.
9) Foaming agents, for example Alginic Acid and salts, Propylene Glycol Alginate, Sodium Lauryl sulphate, Sodium Cetostearyl sulphate, carbomers,
Hydroxy ethylcellulo s e
Some of the components proposed above may already be included in the composition 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.
A versatile component, -which improves the acceptability and other properties of the formulation, is menthol. Menthol, as well as flavouring the formulation, has moisturising effect. It may also have effect as a penetration enhancer. Preferably menthol is employed in a concentration range of 0.25% to 7.5%.
One particular advantage of menthol is that it is compatible with fentanyl in a spray formulation unlike peppermint oil (of which menthol is one component), which causes fentanyl to degrade.
In an embodiment of the invention, the formulation contains a sweetener. The preferred sweetener is saccharin or a physiologically acceptable salt thereof such as saccharin sodium. Preferably the concentration of sodium saccharin or physiologically acceptable salt thereof is around 0.1-0.5%, e.g. around 0.28%.
Preferably the formulation contains saccharin. Surprisingly, we have found that tru-longer-term stability of formulations containing saccharin is better than die stability of those containing saccharin sodium.
It has been discovered that it is not generally necessary to include a preservative in the formulation when ethanol is present due to its preservative qualities.
Formulations of the invention are useful in analgesia and in the treatment of pain. In a further aspect of the invention, formulations according to the first aspect of the invention are provided for use in the treatment of moderate to severe pain. In a yet further aspect of the invention, the use of the formulations according to the invention in the manufacture of a medicament for analgesia or for the treatment of pain is provided. In one embodiment, a therapeutically effective amount of a formulation for the treatment of pain according to the invention is used.
Formulations according to the invention ate preferably packaged as a bulk solution containing multiple doses in a pump spray system comprising a sealed container fitted with a metering pump. Thus as an aspect of the invention we provide a sealed container containing a plurality of doses of a formulation according to the invention. The container will preferably contain between 20 to 200 doses. Example containers are those made out of plastics, glass and metal (e.g. aluminium) however glass containers are preferred. Glass containers have the advantage that the contents of the container can be seen (i.e. it is possible to determine visually when the contents are about to run out). Furthermore glass containers are less susceptible to tampering, which is an important consideration for narcotic substances.
In another embodiment, single or multiple use devices comprising a single or multiple dose of the formulation of the invention is envisaged.
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. Optionally, the interior of the containers can be coated to enhance stability of the

product. Coatings include polymers and lacquers but also silicone dioxide can be used to line the inside of the container with an unreactive coating.
Another aspect of the invention is 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 sublingual administration.
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 bulk formulation by means of a dip-tube.
Example metering pumps are those manufactured by Valois and illustrated in • International Patent Application No. WO01/66089.
The metering pump is preferably a non-venting type with a dip tube. Such non-venting metering pumps may have, for example, a l00µl metering chamber capacity The materials of construction include polypropylene and polyethylene. Suitable sealing materials, e.g. thermoplastic 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.
Preferably the actuator will be designed to deliver a sublingually effective dose. The package may be further enhanced by the fitting of a lock-out system to promote compliance by patients.
Typically a patient is treated by administtation sublingually of 1 to 4 actuations, e.s 1 or 2 actuations from the spray pump. Another advantage of sublingual spray delivery is the ability to easily titrate patients by 1 or 2 doses as required by a sing.lt-

actuation. This is not the case with other forms of drug delivery (patches, lozenges, tablets, suppositories).
One of the possible methods for preparing certain formulations and filled containers according to the invention is shown in the figures, for illustrative purposes.
Figure 1 is a flow-chart showing the first stage of the method of preparing a formulation comprising 400u,g fentanyl.
Figure 2 is a flow-chart showing the second stage of the method.
Other formulations of the invention may be prepared by analogous methods, or methods known to a skilled person.
Weight percentage values given herein are expressed as w/w.
The formulations and products of the invention have better physical and chemical stability, are more environmentally friendly, are more conveniently or safely administered to patients, ate more conveniently or safely manufactured, are more economical to manufacture, or have other advantages relative to prior art formulations and products.
The invention will now be illustrated by reference to the following examples:
Citrate buffer when employed contained:
Citric acid 2.0 %
Sodium citrate 1.0 %
Sodium Hydroxide 1.0%
water: to 100%
pH 8.2 (adjusted with NaOH).

Example 1
Formulation (per container):
Fentanyl base 0.0280g
Saccharin 0.0177g
Absolute ethanol 2.8336g
Menthol 0.0531g
Citrate buffer 4.1516g
The target dose is 400\ig per actuation.
Example 2
Formulation (per container):
Fentanyl base 0.0280g
Saccharin sodium 0.0198g (equivalent to 0.0177g saccharin)
Absolute ethanol 2.8336g
Menthol 0.0531g
Citrate buffer 4.1516g
The target dose is 400µg per actuation of 100µ1.
Example 3
Formulation (per container):
Fentanyl base 0.0280g
Saccharin 0.0177g
Absolute ethanol 2.8336g
Citrate buffer 4.2047g
The target dose is 400µg per actuation of 100µl.
Example 4
Formulation (per container):
Fentanyl base 0.0280g
Sacchatin sodium 0.0198g (equivalent to 0.0177g saccharin)
Absolute ethanol 2.8336g

Water 4.2026g
The target dose is 400µg per actuation of 100µl.
Example 5
Formulation (per container):
Fentanylbase 0.0140g
Saccharin sodium 0.0198g (equivalent to 0.0177g saccharin)
Absolute ethanol 2.8336g
Menthol 0.0531g
Citrate buffer 4.1656g
The target dose is 200µg per actuation of l00µl.
Packaging of formulations
The example formulations may be packaged into a suitable coated glass container and fitted -with a suitable non-venting metered dose pump. An actuator suitable for sublingual delivery may be fitted.
Test data
The formulation of Example 1 was subjected to the following tests.
Units were placed on stability storage at 5°C, 25°C/60% RH, 30°C/65% RH and
40°C/75% RH. For each test 3 replicates were assessed.
a) Appearance (including clarity). Observation be made and the results recorded.
b) Mean Weight of Expelled Dose (Shot weight)
Each unit -will be weighed before and after test sprays. From these measurements, mean shot weight will be calculated by difference calculation
c) PH
pH is measured on a single unit at each time point at each condition. The unit is opened under controlled conditions and the pH measured by use of a pH meter.

d) Degradation Products
A sample of the formulation from each unit was taken and examined for degradation products by HPLC assay. The result was recorded as 'none', The results were as follows:

(Table Removed)
The formulation of Example 2 was subjected to the same tests, with the following results:

(Table Removed)
Condition A: 2-8°C, ambient tmmidity Condition B: 25°C, 60% relative humidity
Condition C: 30°C, 60% relative humidity Condition D: 40°C, 75% relative humidity
Appearance: all samples were clear and colourless with no particles.
Shotweight: all samples were within target.
pH: stable (8.2-8.3).
Moisture content: acceptable.
Degradation products A and B: none detected.
From the test results, it was concluded that the tested formulations of the invention demonstrate excellent physical and chemical stability

1. A pharmaceutical liquid formulation comprising:
(a) fentanyl free base at a concentration of 0.1-10 mg/ml;
(b) water as carrier;
(c) 6 to 50% of a polar organic solvent such as herein described; and
(d) a buffer such as herein described,
wherein the aqueous component (water and aqueous buffer) of the formulation is 50 to 94% and
wherein the pH of the formulation is 7.4 to 8.5.
2. A formulation as claimed in claim 1, wherein the buffer is a citrate buffer.
3. A formulation as claimed in claim 2, wherein the citrate buffer comprises citric acid, sodium citrate and sodium hydroxide.
4. A formulation as claimed in any one of the preceding claims, wherein the fentanyl free base is present at a concentration of 0.5 mg/ml to 4.4 mg/ml.
5. A formulation as claimed in any one of the preceding claims, wherein the polar organic solvent is selected from ethanol, propylene glycol, glycero polyethylene glycol and mixtures thereof.

6. A formulation as claimed in claim 5, wherein the polar organic solvent s ethanol.
7. A formulation as claimed in any one of the preceding claims, wherein t^ polar organic solvent present in an amount of 20-45% w/w.
8. A formulation as claimed in any of the preceding claims, wherein the poar organic solvent is present in an amount of 35-42% w/w.
9. A formulation as claimed in any one of the preceding claims, wherein the

pH is 8.1 to 8.3.
10. A formulation as claimed in any one of claims 1 to 9 contained in a sealed container.
11. A formulation as claimed in claim 10, wherein the said container containinq the formulation is made out of glass.
12. A formulation as claimed in claim 10 or claim 11, wherein the formulation contained within said container is partially pressurised.




3409-delnp-2005-complete specification (granted).pdf



3409-DELNP-2005-Description (Complete).pdf












Patent Number 241660
Indian Patent Application Number 3409/DELNP/2005
PG Journal Number 30/2010
Publication Date 23-Jul-2010
Grant Date 19-Jul-2010
Date of Filing 01-Aug-2005
Name of Patentee ARAKIS LTD
# Inventor's Name Inventor's Address
PCT International Classification Number A61K 31/4468
PCT International Application Number PCT/GB2004/001037
PCT International Filing date 2004-03-11
PCT Conventions:
# PCT Application Number Date of Convention Priority Country
1 0305579.5 2003-03-11 U.K.
2 0328023.7 2003-12-03 U.K.