(10) United States
`
`
`
`
`
`
`
`
`(12) Patent Application Publication (10) Pub. No.: US 2006/0062812 A1
`Ross et al.
`
`
`
`
`
`
`
`(43) Pub. Date:
`Mar. 23, 2006
`
`US 20060062812Al
`
`
`
`
`(54) NOVEL COMPOSITIONS
`
`
`
`
`
`(76)
`
`
`
`Inventors: Calvin Ross, Essex (GB); Clive Boolcs,
`
`
`
`
`
`
`
`Essex (GB); Alistair Campbell, Essex
`
`
`
`
`
`(GR); Paul William Woodcock, Essex
`
`
`
`
`
`(GB); Scott Andrew Davis, Essex (GB)
`
`
`
`
`
`
`
`
`Correspondence Address:
`
`
`SA]/IWANCHIK I/I/OYD & SAI/IWANCHIK
`
`
`A PR()Fl<lSSl()NALASS()ClA'l‘l()N
`
`
`PO BOX 142950
`
`
`
`GAINESVILLE, FL 32614-2950 (US)
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`Appl. No.:
`
`
`
`11/224,383
`
`
`Filed:
`
`
`Sep. 12, 2005
`
`
`
`
`
`Related U.S. Application Data
`
`
`
`
`
`Contin1Iation—in—part of application No. PCT/GBO4/
`
`
`
`
`01037, filed on Mar. 11, 2004.
`
`
`
`
`
`
`
`
`(30)
`
`Foreign Application Priority Data
`
`
`
`
`
`Mar. 11,2003
`(GB) ....................................... .. 03055705
`
`
`
`
`
`
`Dec. 3, 2003
`(GR) ..
`.. 03280237
`
`
`
`
`
`Sep. 10, 2004
`(GR) .....................................
`04201737
`
`
`
`
`
`
`Publication Classification
`
`
`
`
`(51)
`
`
`
`Int. Cl.
`
`
`A61K 31/445
`
`A61K 31/045
`
`A61K 9/00
`
`(52) U.S.Cl.
`
`
`
`
`
`
`(2006.01)
`
`(2006.01)
`
`(2006.01)
`
`424/400; 514/317; 514/729
`
`
`
`
`
`
`
`
`(57)
`
`ABSTRACT
`
`
`
`Compositions and method are provided, for the treatment of
`
`
`
`
`
`
`
`pain, e.g. acute breakthrough pain, by means of a systemic,
`
`
`
`
`
`
`
`non-invasive mode of administration. Specifically,
`the
`
`
`
`
`
`
`invention relates to a snblingnal presentation of an opioid
`
`
`
`
`
`
`
`analgesic, such as fentanyl, or its salts, in amounts that are
`
`
`
`
`
`
`
`
`
`sullicienl to treat the pain.
`
`
`
`
`
`Page 1 of 12
`
` Insys Exhibit 2012
`CFAD v. Insys
`IPR2015-01799
`
`

`
`
`
`
`
`
`
`
`Patent Application Publication Mar. 23, 2006 Sheet 1 of 2
`
`
`
`US 2006/0062812 A1
`
`lnto mixing vessel, add
`
`
`
`
`Sodium saccharin, ethanol,
`
`
`
`and menthol.
`
`
`
`Into separate mixing vessel, add
`
`
`
`
`
`citric acid, sodium citrate, and
`
`
`
`
`
`sodium hydroxide. Add de-ionised
`
`
`
`watcr.
`
`
`
`
`Record \X'/cights
`
`
`
`
`
`
`
`
`Mix until complete
`
`
`dissolution.
`
`
`
`Check pH
`
`
`Q
`
`
`
`Adjust pH to pH 8.2 with the
`
`
`
`addition of aqueous sodium
`
`
`
`hydroxide (IM) or citric acid
`
`
`
`
`
`
`
`
`Record W/cights
`
`
`
`Mix until complete
`
`
`
`dissolution.
`
`
`
`
`
`
`Mix until complete
`
`
`dissolution.
`
`
`
`
`
`Add citrate buffer to
`
`
`
`mixing vessel, continue
`
`
`
`
`mixing
`
`
`
`Page 2 of 12
`
`

`
`
`
`
`
`
`
`Patent Application Publication Mar. 23, 2006 Sheet 2 of 2
`
`
`
`US 2006/0062812 A1
`
`Check pl-I
`
`
`
`
`Adjust pH to pll 8.2
`
`
`
`
`
`
`
`Add remaining water
`
`
`
`
`
`Filter through a 0.2pm
`
`
`
`membrane filter
`
`
`
`Air
`Purgard
`clean
`
`
`
`bottles
`and place
`the
`
`
`
`
`pumps on the bottles.
`
`
`
`Number each unit
`
`
`
`
`
`Record weights of the
`
`
`
`
`pumps and bottles
`
`
`
`
`
`
`Pipette 7.084g of the
`
`
`
`formulation into each
`
`
`
`
`Crimp on the pumps
`
`
`
`
`Record weights of the
`
`
`
`pumps and bottles
`
`
`
`
`
`
`Page 3 of 12
`
`

`
`US 2006/0062812 A1
`
`
`
`
`
`Mar. 23, 2006
`
`
`
`
`
`
`NOVEL COMPOSITIONS
`
`
`CROSS-REFERENCE TO EARLIER
`
`
`APPLICATION
`
`[0001] This application is a continuation—in—part applica-
`
`
`
`
`
`tion of International Application PCT/GB04/01037, filed
`
`
`
`
`
`
`Mar. 11, 2004; which claims priority to GB 0305579.5, filed
`
`
`
`
`
`
`
`
`Mar. 11, 2003 and GB 0328023.7, filed Dec. 3, N03. The
`
`
`
`
`
`
`
`
`
`subject application further claims priority to GB 0420173.7,
`
`
`
`
`
`
`filed Sep. 10, 2004, all of which are hereby incorporated by
`
`
`
`
`
`
`
`
`reference herein in their entirety.
`
`
`
`
`EIEID OF‘ THE INVENTION
`
`
`
`[0002] This invention relates to formulations of opioid
`
`
`
`
`
`
`
`analgesics and in particular fentanyl, especially pump spray
`
`
`
`
`
`
`formulations suitable for sublingual delivery.
`
`
`
`
`
`BACKGROUND OF THE INVENTION
`
`
`
`[0003] Opioid analgesics are useful in the treatment of
`
`
`
`
`
`
`
`
`pain, such as breakthrough pain. When treating pain, it is
`
`
`
`
`
`
`
`
`particularly attractive for the patient
`to be able to self-
`
`
`
`
`
`
`
`
`
`
`medicate, enabling specific pain episodes to be treated, as
`
`
`
`
`
`
`
`
`opposed to ongoing treatment when there may be no pain to
`
`
`
`
`
`
`
`treat. It is highly desirable for the onset of analgesia to occur
`
`
`
`
`
`
`
`
`as soon after administration of the opioid analgesic as
`
`
`
`
`
`
`
`
`
`possible, especially where the patient is self-medicating.
`
`
`
`
`
`
`This not only provides pain relief as soon as possible but it
`
`
`
`
`
`
`
`
`
`can also reduce the risk of overdosage. A delay in the onset
`
`
`
`
`
`
`
`
`
`of the therapeutic effect may prompt the patient to take a
`
`
`
`
`
`
`
`
`
`further dose, with the consequent risk of the serious side-
`
`
`
`
`
`
`
`
`
`
`effects associated with overdosage.
`
`
`
`
`[0004]
`In the case of breakthrough pain, the onset of pain
`
`
`
`
`
`
`
`
`
`is relatively quick, usually between just a few seconds and
`
`
`
`
`
`
`
`
`
`10 to 15 minutes, the median being approximately 3 min-
`
`
`
`
`
`
`
`
`utes. The duration of breakthrough pain episodes tends to be
`
`
`
`
`
`
`
`anywhere between 5 minutes and 2 hours, the median being
`
`
`
`
`
`
`
`
`between 20 and 60 minutes.
`
`
`
`[0005] Thus, for the most e ective treatment of pain, and
`
`
`
`
`
`
`
`
`
`in particular, breakthrough pain, the analgesic effect should
`
`
`
`
`
`
`
`
`have a rapid onset. V»7hat is more, the analgesic effect should
`
`
`
`
`
`
`
`
`
`last for the duration of the pain episode. That said, admin-
`
`
`
`
`
`
`
`
`
`
`istration of a second or furtier dose may be acceptable,
`
`
`
`
`
`
`
`provided that these additional doses have a rapid onset of
`
`
`
`
`
`
`
`
`elfect, so that the pain is not left untreated [or too long.
`
`
`
`
`
`
`
`
`
`
`
`[0006] 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 treat-
`
`
`
`
`
`
`
`
`
`
`ments, there are a number of issues of clinical management
`
`
`
`
`
`
`
`associated with the use of fentanyl in therapy.
`
`
`
`
`
`
`[0007] 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 estab-
`
`
`
`
`
`
`
`
`
`lished therapeutically effective range and to monitor patients
`
`
`
`
`
`
`
`for evidence of self-medication at greater than the recom-
`
`
`
`
`
`
`
`mended amount. Overdosage with fentanyl can lead to a
`
`
`
`
`
`
`
`
`number of undesirable and indeed life-threatening side-
`
`
`
`
`
`
`effects, predominantly hypoventilation and respiratory
`
`
`
`
`
`depression.
`
`
`[0008] A number of routes of administration of a medica-
`
`
`
`
`
`ment can be associated with rapid onset of action. For
`
`
`
`
`
`
`
`
`
`
`example, W090/07333 describes aerosol formulations of
`
`
`
`
`
`
`fentanyl, which are adapted for inhalation. However, these
`
`
`
`
`
`
`
`
`formulations su er disadvantages such as their use of
`
`
`
`
`
`
`
`
`hydrofluorocarbon propellants and delivery effected by
`
`
`
`
`
`
`metered dose inhalers. In the case of the former, the disad-
`
`
`
`
`
`
`
`
`
`
`vantages include high velocity which results in “bounce-
`
`
`
`
`
`
`
`
`back” on administration to the front of the mouth, cold
`
`
`
`
`
`
`
`
`
`
`sensations on administration and the risk of inhalation; for
`
`
`
`
`
`
`
`the latter, careful co—ordination of breath and actuation by
`
`
`
`
`
`
`
`
`the patient. When metered dose inhalers are used, a signifi-
`
`
`
`
`
`
`
`
`
`cant 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
`
`
`
`
`
`
`
`b11lk formulation involves the preparation of large quantities
`
`
`
`
`
`
`
`of pressurised volatile propellant containing a potent nar-
`
`
`
`
`
`
`
`cotic analgesic. Accordingly,
`the precautions required to
`
`
`
`
`
`
`ensure safe manufacture are onerous and expensive.
`
`
`
`
`
`
`
`[0009] W095/31182 describes solution formulations of
`
`
`
`
`
`
`fentanyl in aerosol propellants intended for administration to
`
`
`
`
`
`
`patients by the pulmonary route.
`
`
`
`
`[0010] W001/97780 describes solution formulations of
`
`
`
`
`
`
`fentanyl free base in propellants, typically HFA134a, for
`
`
`
`
`
`
`
`sublingual aerosol administration.
`
`
`
`[0011] W000/47203 describes fomiulations of fentanyl
`
`
`
`
`
`
`citrate for intra-oral administration employing oral absorp-
`
`
`
`
`
`
`
`tion enhancers.
`
`
`[0012] Certain aqueous formulations of fentanyl for intra-
`
`
`
`
`
`
`
`nasal administration employing water and phosphate buffer
`
`
`
`
`
`
`
`have been described; see Paech, M. J., Lim, C. B., Banks, S.
`
`
`
`
`
`
`
`
`L., Rucklidge, M. W. M. & Doherty, D. A. (2003) Anaes-
`
`
`
`
`
`
`thesia 58 (8), 740-744, and Lin1 et al (2003) J Pl1arn1 Practice
`
`
`
`
`
`
`
`
`Research 33, 59-63. Such formulations can su er problems
`
`
`
`
`
`
`
`
`of nasal irritation associated with medium to long term
`
`
`
`
`
`
`
`
`usage via this route which is undesirable. Weinberg et al
`
`
`
`
`
`
`
`
`(1988) Clin Phannacol Therap 44 335-342, discloses for-
`
`
`
`
`
`
`
`mulations of fentanyl employing water and phosphate buffer
`
`
`
`
`
`
`
`for sublingual administration, but these formulations are not
`
`
`
`
`
`
`
`
`advocated for use as a spray.
`
`
`
`
`[0013]
`It is well known that the application of carefully
`
`
`
`
`
`
`
`
`
`
`chosen medicaments to the sublingual mucosa offers a route
`
`
`
`
`
`
`
`of administration which is capable of resulting in very rapid
`
`
`
`
`
`
`
`transmission of medicament to the bloodstream with con-
`
`
`
`
`
`
`
`sequent fast onset of effect. A number of ways of adminis-
`
`
`
`
`
`
`
`tering 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 [or 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 loz-
`
`
`
`
`
`
`enge, cause increased salivation, which facilitates the
`
`
`
`
`
`
`
`unwanted swallowing of drug substance.
`
`
`
`
`
`Page 4 of 12
`
`

`
`US 2006/0062812 A1
`
`
`
`
`
`Mar. 23, 2006
`
`
`
`lingual presentation of an opioid analgesic, such as lentanyl,
`
`
`
`
`
`
`or its salts, in amounts that are sufficient to treat the acute
`
`
`
`
`
`
`
`
`
`
`
`pain. Advaritageously, the presentation of the opioid anal-
`
`
`
`
`
`
`
`
`gesic provides a rapid onset of action, as well as a pharma-
`
`
`
`
`
`
`
`
`cokinetic response and drug plasma profile suitable to
`
`
`
`
`
`
`
`
`achieve optimal pain relief over the duration of symptoms
`
`
`
`
`
`
`
`
`with minimized side-effects.
`
`
`
`[0024] The invention also relates to a specific drug for-
`
`
`
`
`
`
`
`
`
`mulation, dispensed using a metered pump action spray
`
`
`
`
`
`
`
`which is specifically designed for delivery via the sublingual
`
`
`
`
`
`
`
`
`route. This allords significant improvements and advantages
`
`
`
`
`
`
`
`in terms of plasma bioavailability and pharmacokinetic
`
`
`
`
`
`
`
`profile compared to similar, but rion-optiniised, propellant-
`
`
`
`
`
`
`driven aerosol formulations. These benefits relate in particu-
`
`
`
`
`
`
`
`lar to:
`
`
`[0025]
`
`[0026]
`
`[0027]
`
`[0014]
`In the past, spray devices, including pump sprays,
`
`
`
`
`
`
`
`
`
`have been proposed for sublingual administration. However,
`
`
`
`
`
`
`
`their effect has not been properly optimised. In order to
`
`
`
`
`
`
`
`
`
`reduce the amount of the dispensed composition which fails
`
`
`
`
`
`
`
`
`to contact the sublingual mucosa, the compositions tend to
`
`
`
`
`
`
`
`
`be dispensed in a focussed manner, so that the sublingual
`
`
`
`
`
`
`
`spray devices have a tendency to administer the composi-
`
`
`
`
`
`
`
`tions to a relatively small part of the sublingual mucosa. This
`
`
`
`
`
`
`
`
`means that the composition is effectively concentrated in the
`
`
`
`
`
`
`
`relatively small area, which slows down absorption and also
`
`
`
`
`
`
`
`
`
`means that some of the composition may not be absorbed,
`
`
`
`
`
`
`
`but rather may be washed away by saliva and swallowed.
`
`
`
`
`
`
`
`
`This is a particular problem in the case of lipopliilic opioid
`
`
`
`
`
`
`
`analgesics such as fentanyl. It has been shown that
`the
`
`
`
`
`
`
`
`
`
`lipophilic drugs need to be finely spread over the sublingual
`
`
`
`
`
`
`
`
`mucosa in order for them to be properly absorbed. When
`
`
`
`
`
`
`
`
`they are concentrated at a small area of the sublingual
`
`
`
`
`
`
`
`
`mucosa, absorption is reduced.
`
`
`
`[0015]
`It is an aim of the present invention to provide a
`
`
`
`
`
`
`
`
`
`formulation, which avoids or mitigates some or all of the
`
`
`
`
`
`
`
`
`above-mentioned disadvantages.
`
`
`[0016] Another aim of the present invention is to provide
`
`
`
`
`
`
`
`
`a presentation of an opioid analgesic for treating pain, and
`
`
`
`
`
`
`
`
`in particular breakthrough pain, wherein the opioid analge-
`
`
`
`
`
`
`
`
`sic is administered via the sublingual route and the presen-
`
`
`
`
`
`
`
`
`
`tation preferably exhibits improved performance compared
`
`
`
`
`
`
`to known opioid analgesic compositions, including those
`
`
`
`
`
`
`
`which may be administered sublingually and intravenously.
`
`
`
`
`
`
`In particular, it is an aim of the invention to provide fast
`
`
`
`
`
`
`
`
`
`onset of therapeutic effect, together with an advantageous
`
`
`
`
`
`
`
`pharmacokinetic response and drug plasma profile which
`
`
`
`
`
`
`
`will avoid the disadvantages associated with the fast onset
`
`
`
`
`
`
`
`
`
`observed when opioid analgesics are administered intrave-
`
`
`
`
`
`
`
`nously.
`
`
`SUMMARY OF THE INVENTION
`
`
`
`[0017] The present invention is based at least in part on the
`
`
`
`
`
`
`
`understanding that spray delivery, having low volume and
`
`
`
`
`
`
`
`
`ability to target the sublingual mucosa, largely mitigates
`
`
`
`
`
`
`
`
`problems associated with other formulations, and can avoid
`
`
`
`
`
`
`
`
`the use of propellants.
`
`
`
`[0018] According to the invention, a pharmaceutical com-
`
`
`
`
`
`
`position, preferably a partially pressurised liquid spray for-
`
`
`
`
`
`
`
`mulation, comprises:
`
`
`(a) fentanyl or a pharmaceutically acceptable
`[0019]
`
`
`
`
`
`
`salt thereof;
`
`
`[0020]
`(b) water as carrier; and
`
`
`
`
`
`[0021]
`(c) a polar organic solvent in s11 icient amount to
`
`
`
`
`
`
`
`enhance the solubility of the fentanyl or pharmaceuti-
`
`
`
`
`
`
`
`cally acceptable salt thereof in the water.
`
`
`
`
`
`
`[0022] The formulations of the invention may be used in
`
`
`
`
`
`
`
`analgesia and for the treatment of pain. They are preferably
`
`
`
`
`
`
`
`
`administered sublingually as a spray. The formulations are
`
`
`
`
`
`
`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 fentanyl.
`
`
`
`
`
`
`
`
`[0023] The present invention also provides a pharmaceu-
`
`
`
`
`
`
`
`tical composition for use in the treatment of acute break-
`
`
`
`
`
`
`
`
`
`through pain by means of a systemic, non-invasive mode of
`
`
`
`
`
`
`administration. Specifically, the invention relates to a sub-
`
`
`
`
`
`
`
`
`i) a liaster rate of onset of ellect;
`
`
`
`
`
`
`ii) a faster rate of offset of e ect; and
`
`
`
`
`
`
`
`iii) a faster Tmax.
`
`
`
`[0028] According to a further aspect of the invention, an
`
`
`
`
`
`
`
`opioid analgesic pharmaceutical composition provides an
`
`
`
`
`
`
`opioid analgesic plasma concentration of 250 pg/nil within
`
`
`
`
`
`
`
`a period of no more than 2 hours, following sublingual
`
`
`
`
`
`
`
`
`
`administration using a pump spray dispensing device. The
`
`
`
`
`
`
`
`opioid analgesic is preferably fentanyl.
`
`
`
`
`[0029] Amongst the advantages of these formulations is
`
`
`
`
`
`
`the fact that, by being water-based, they avoid the issues
`
`
`
`
`
`
`
`
`
`
`associated with using pressurised hydrofluorocarbon propel-
`
`
`
`
`
`
`lants as mentioned above. The formulations may be partially
`
`
`
`
`
`
`
`pressurised and are free of propellants such as volatile
`
`
`
`
`
`
`
`
`
`chlorofluorocarbons (e.g. propellant 12), volatile hydrofluo-
`
`
`
`
`
`
`roalkanes (e.g. 1,1,1,2-tetrafluoroethane or 1,1,1,2,3,3,3-
`
`
`
`
`
`heptafluoro-n-propane) and volatile alkanes (e.g. propane or
`
`
`
`
`
`
`butane) and other substances which have significant vapour
`
`
`
`
`
`
`
`
`pressure at ambient temperature and pressure.
`
`
`
`
`
`[0030] Furthermore the formulations of the present inven-
`
`
`
`
`
`
`
`tion are characterised by good long—term physical and
`
`
`
`
`
`
`
`
`chemical stability.
`
`
`BRIEF DESCRIPTION OF THE DRAWINGS
`
`
`
`
`[0031] FIG. 1 is a flow-chart showing the first stage of a
`
`
`
`
`
`
`
`method of preparing a formulation comprising 400 ,ug
`
`
`
`
`
`
`
`fentanyl.
`
`[0032] FIG. 2 is a flow-chart showing the second stage of
`
`
`
`
`
`
`
`the method.
`
`
`DESCRIPTION OF THE INVENTION
`
`
`
`[0033] The present invention provides a sublingual pre-
`
`
`
`
`
`
`
`sentation of an opioid analgesic, such as fentanyl, which
`
`
`
`
`
`
`
`
`enables pain relief to be achieved very rapidly following
`
`
`
`
`
`
`
`
`
`administration of the drug.
`
`
`
`[0034]
`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 suspen-
`
`
`
`
`
`
`
`
`
`sions 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 sus-
`
`
`
`
`
`
`
`
`
`
`pension can be reduced to an extent by shaking the compo-
`
`
`
`
`
`
`
`
`
`
`
`
`
`Page 5 of 12
`
`

`
`US 2006/0062812 A1
`
`
`
`
`
`Mar. 23, 2006
`
`
`
`sition prior to spraying, some suspensions can settle very
`
`
`
`
`
`
`
`
`rapidly, so that there is still potential for variation of active
`
`
`
`
`
`
`
`
`agent content between doses.
`
`
`
`
`[0035] Fentanyl may be employed in the form of a physi-
`
`
`
`
`
`
`
`ologically acceptable salt, which is soluble in water together
`
`
`
`
`
`
`
`with a polar organic solvent. Examples of suitable salts
`
`
`
`
`
`
`
`include hydrochloride, chloride, sulphate, tartrate and cit-
`
`
`
`
`
`
`
`rate. Preferably fentanyl is employed as the free base. It will
`
`
`
`
`
`
`
`
`nevertheless be understood that the buffer may provide some
`
`
`
`
`
`
`
`
`salt.
`
`[0036] Preferably the fentanyl or physiologically accept-
`
`
`
`
`
`
`able salt thereof will be employed in the formulation at a
`
`
`
`
`
`
`
`concentration of 0.1 n1g/ml
`to 10 mg/ml, preferably 0.5
`
`
`
`
`
`
`
`
`mg/ml to 4.4 mg/ml(wl1ere weight is expressed as weight of
`
`
`
`
`
`
`
`fentanyl free base). More preferably, fentanyl or physiologi-
`
`
`
`
`
`
`
`cally acceptable salt thereof will be employed in the com-
`
`
`
`
`
`
`
`
`position at a concentration of 0.1 mg/ml
`to 10 mg/ml,
`
`
`
`
`
`
`
`
`preferably 0.5 mg/ml
`to 4.4 mg/ml
`(where weight
`is
`
`
`
`
`
`
`
`expressed as weight of fentanyl free base).
`
`
`
`
`
`[0037] Examples of polar organic solvents that may be
`
`
`
`
`
`
`
`used to enhance the solubility of fentanyl, or the physiologi-
`
`
`
`
`
`
`
`cally 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.
`
`
`
`
`
`
`
`[0038] Mixtures of the above substances may be used. The
`
`
`
`
`
`
`
`
`preferred polar organic solvent is ethanol.
`
`
`
`
`
`[0039]
`lr1 another embodiment of the present invention,
`
`
`
`
`
`
`
`the formulation does not include ethanol. lndeed, the for-
`
`
`
`
`
`
`
`
`
`mulation may be substantially free of any alcohol, or com-
`
`
`
`
`
`
`
`
`pletely free of alcohol.
`
`
`
`
`the
`[0040] Where the composition is free of alcohol,
`
`
`
`
`
`
`
`
`carrier used is preferably a polyol. 'lhe preferred polyols
`
`
`
`
`
`
`
`include propylene glycol and glycerol.
`
`
`
`
`
`[0041] Generally 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.
`
`
`
`[0042] The concentration of polar organic solvent is in the
`
`
`
`
`
`
`
`range preferably of between 6 and 50%, more preferably
`
`
`
`
`
`
`
`
`20-45% especially 35-42%.
`
`
`
`[0043] Preferably the water meets the USP (US Pharma-
`
`
`
`
`
`
`
`
`
`copoeia) or EP European Pharmacopoeia) “Purified Water”
`
`
`
`
`
`standards.
`
`[0044]
`It l1as also been found that the properties of the
`
`
`
`
`
`
`
`
`
`
`
`claimed formulations may be improved by including therein
`
`
`
`
`
`
`one or more additional components.
`
`
`
`
`the
`[0045] Thus,
`in one embodiment of the invention,
`
`
`
`
`
`
`
`water in the formulation is present in the form of an aqueous
`
`
`
`
`
`
`
`buffer. The buffer is preferably adapted to stabilise the 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 fron1
`
`
`
`
`
`
`the British Pharmacopoeia). The preference is use of a
`
`
`
`
`
`
`
`citrate buffer, e.g. a bu er comprising citric acid, sodium
`
`
`
`
`
`
`
`
`citrate and sodium hydroxide.
`
`
`
`
`the aqueous component
`[0046] The concentration of
`
`
`
`
`
`
`
`(water or more preferably aqueous buffer) of the formulation
`
`
`
`
`
`
`
`of the present invention is preferably 50-94%, more prefer-
`
`
`
`
`
`
`
`
`ably 55-80%, and especially 58-65%.
`
`
`
`
`
`[0047]
`It may be desirable to include one or more of the
`
`
`
`
`
`
`
`following components in the formulation.
`
`
`
`
`[0048]
`1) Sweeteners, flavouring or taste—masl<ing agents
`
`
`
`
`
`
`(to improve patient acceptability), for example vanilla, pine-
`
`
`
`
`
`
`
`
`apple extract, menthol, saccharin and sodium saccharin.
`
`
`
`
`
`
`
`[0049]
`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.
`
`
`
`
`
`[0050]
`3) Penetration enhancers (to improve therapeutic
`
`
`
`
`
`
`effect), for example menthol.
`
`
`
`
`[0051]
`4) Mucoadherents (in order to increase residency
`
`
`
`
`
`
`
`time or1 the mucosa), for example carboxyvinyl polymers,
`
`
`
`
`
`
`
`
`chitosans, polyacrylic acid, gelatin and polyvinyl pyrroli-
`
`
`
`
`
`
`
`done.
`
`[0052]
`5) Preservatives (to improve long term resistance to
`
`
`
`
`
`
`
`
`microbial contamination), for example ethanol, sodium met-
`
`
`
`
`
`
`
`abisulphite, benzalkonium chloride and Nipas.
`
`
`
`
`
`[0053]
`6) Antioxidants, for example alkyl gallates, buty-
`
`
`
`
`
`
`
`
`lated hydroxyanisole, butylated hydroxytoluene, nordihy—
`
`
`
`
`
`droguaiaretic acid, tocopherols, ascorbic acid and sodium
`
`
`
`
`
`
`
`metabisulphite.
`
`[0054]
`7) Anionic surfactants, for example magnesium
`
`
`
`
`
`
`
`stearate, sodium cetostearyl sulphate, sodium lauryl sul-
`
`
`
`
`
`
`
`phate, sulphated castor oil, sodium oleate, sodium stearyl
`
`
`
`
`
`
`
`
`fumarate and sodium tetradecyl sulphate.
`
`
`
`
`
`[0055]
`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, and oleyl alcohol and derivatives.
`
`
`
`
`
`
`
`
`
`[0056]
`9) Foaming agents, for example alginic acid and
`
`
`
`
`
`
`
`
`
`salts, propylene glycol alginate, sodium lauryl sulphate,
`
`
`
`
`
`
`
`sodium cetostearyl sulphate, earbomers and hydroxyethyl-
`
`
`
`
`
`
`cellulose.
`
`[0057] 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, polar organic solvents such as glycols,
`
`
`
`
`
`
`
`
`especially propylene glycol, and liquid polyethylene gly-
`
`
`
`
`
`
`
`cols, glycerol, methylcellulose, hypromellose, hydroxypro-
`
`
`
`
`
`pylcellulose, and many other substituted celluloses.
`
`
`
`
`
`
`[0058] Aversatile component, which improves the accept-
`
`
`
`
`
`
`
`ability and other properties of the formulation, is menthol.
`
`
`
`
`
`
`
`Menthol, as well as flavouring the formulation, has a mois-
`
`
`
`
`
`
`
`turising effect. It may also have effect, depending on its
`
`
`
`
`
`
`
`
`
`concentration, as a penetration enhancer. Preferably menthol
`
`
`
`
`
`
`Page 6 of 12
`
`

`
`US 2006/0062812 A1
`
`
`
`
`
`Mar. 23, 2006
`
`
`
`
`
`
`is employed in a concentration range of 0.25% to 7.5%,
`
`
`
`
`
`
`
`although it may be yet lower.
`
`
`
`
`[0059] 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 [entanyl to degrade.
`
`
`
`[0060]
`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%.
`
`
`
`[0061] Preferably the formulation contains saccharin. Sur-
`
`
`
`
`
`
`
`prisingly, we have found that the longer—term stability of
`
`
`
`
`
`
`
`
`
`formulations containing saccharin is better than the stability
`
`
`
`
`
`
`
`of those containing saccharin sodium.
`
`
`
`
`
`is not generally
`[0062]
`It has been discovered that
`it
`
`
`
`
`
`
`
`
`necessary to include a preservative in the formulation when
`
`
`
`
`
`ethanol is present due to its preservative qualities.
`
`
`
`
`
`
`[0063] Formulations of the invention are useful in anal-
`
`
`
`
`
`
`
`gesia and in the treatment of pain, e.g. the treatment of
`
`
`
`
`
`
`
`
`
`moderate to severe pain, acute pain and cancer or other
`
`
`
`
`
`
`
`
`breakthrough pain. A therapeutically e ective amount of a
`
`
`
`
`
`formulation for the treatment of pain according to the
`
`
`
`
`
`
`
`
`
`invention may be used.
`
`
`
`[0064] Formulations according to the invention are pref-
`
`
`
`
`
`
`
`erably packaged as a bulk solution containing multiple doses
`
`
`
`
`
`
`
`in a pump spray system comprising a sealed container fitted
`
`
`
`
`
`
`
`
`with a metering pump. Thus a sealed container may contain
`
`
`
`
`
`
`
`
`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); 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 tam-
`
`
`
`
`
`
`
`
`pering, which is an important consideration for narcotic
`
`
`
`
`
`
`
`substances.
`
`[0065] Preferably the glass container is coated on the
`
`
`
`
`
`
`
`
`exterior with a suitable moulded film of plastics material, 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 b11t also silicone dioxide can be used
`
`
`
`
`
`
`
`
`
`to line the inside of the container with an unreactive coating.
`
`
`
`
`
`
`
`
`
`[0066]
`In another embodiment, single or multiple use
`
`
`
`
`
`
`
`
`devices comprising a single or multiple dose of the fom1u-
`
`
`
`
`
`
`
`lation of the invention are envisaged.
`
`
`
`
`
`[0067] The compositions of the invention are preferably
`
`
`
`
`
`
`
`dispensed using a pump spray device. Preferably, the pump
`
`
`
`
`
`
`
`
`consists of a metering chamber allied with efficient precom—
`
`
`
`
`
`
`
`pression qualities giving a high level of accuracy. Preferably,
`
`
`
`
`
`
`
`only pumps which are iioi1—vei1ting and are able to pass
`
`
`
`
`
`
`
`
`
`
`severe bacteriological challenge tests should be used. Suit-
`
`
`
`
`
`
`
`able pumps include VALOIS VP7 series pumps. Preferably,
`
`
`
`
`
`
`
`
`the pump spray device comprising a composition of the
`
`
`
`
`
`
`
`
`invention is capable of administering a metered dose of the
`
`
`
`
`
`
`composition to the sublingual mucosa.
`
`
`
`
`
`[0068] Also preferably, the pump spray device has fea-
`
`
`
`
`
`
`
`
`
`tures which are specifically adapted for improved sublingual
`
`
`
`
`
`
`
`delivery, as discussed in greater detail below.
`
`
`
`
`
`
`[0069] When the composition is administered to the s11b-
`
`
`
`
`
`
`lingual mucosa using such a device, the opioid analgesic has
`
`
`
`
`
`
`
`
`
`a surprisingly rapid onset of action. In addition, increased
`
`
`
`
`
`
`
`
`bioavailability is observed, compared to that observed when
`
`
`
`
`
`
`opioid analgesic formulations are administered subliiigually
`
`
`
`
`
`
`using other means (such as tablets, lozenges or elixirs) or
`
`
`
`
`
`
`
`
`devices (such as pressurised meter dose inhaler or other
`
`
`
`
`
`
`
`
`
`propellant-driven spray devices).
`
`
`
`[0070] When the compositions of the present invention are
`
`
`
`
`
`
`
`dispensed using a pump spray device, the composition will
`
`
`
`
`
`
`
`
`be dispensed at a much slower speed than is observed when
`
`
`
`
`
`
`
`
`compositions are dispensed using propellant-driven aerosol
`
`
`
`
`
`
`devices. Firstly, this will reduce the impact the composition
`
`
`
`
`
`
`
`
`
`has on the sublingual area, thereby reducing the pain which
`
`
`
`
`
`
`
`
`
`the high velocity impact can cause. This will also avoid the
`
`
`
`
`
`
`
`
`
`
`
`addi