WO2013164617A1

WO2013164617A1 - New sufentanil composition for the treatment of acute pain

Info

Publication number: WO2013164617A1
Application number: PCT/GB2013/051128
Authority: WO
Inventors: Anders Petterson; Sofia MOGENSEN; Barbro Johansson; Emil Schwan
Original assignee: Orexo Ab
Priority date: 2012-05-02
Filing date: 2013-05-01
Publication date: 2013-11-07

Abstract

There is provided pharmaceutical compositions for the treatment of pain e.g. breakthrough pain which compositions comprise a mixture comprising: (a) microparticles of sufentanil, or a pharmaceutically acceptable salt thereof, which microparticles are presented on the surfaces of larger carrier particles; (b) a water-soluble weak base; and (c) a compound which is a weak acid, which acid is presented in intimate mixture with the microparticles of sufentanil or salt thereof. The composition may further comprise a disintegrant. The acid is preferably citric acid.

Description

NEW SUFENTANIL COMPOSITION FOR THE TREATMENT OF ACUTE PAIN

This invention relates to new pharmaceutical compositions comprising sufentanil that are useful in the treatment of pain, particularly acute pain, such as breakthrough cancer pain, and may be administered transmucosally and in particular sublingually.

Opioids are widely used in medicine as analgesics. Indeed, it is presently accepted that, in the palliation of more severe pain, no more effective therapeutic agents exist.

Opioid agonist analgesics are used to treat moderate to severe, chronic cancer pain, often in combination with non-steroidal anti-inflammatory drugs (NSAIDs), as well as acute pain (e.g. during recovery from surgery and breakthrough pain). Further, their use is increasing in the management of chronic, non-malignant pain.

"Breakthrough" pain comprises brief but intense periods of inadequate analgesia in a patient already receiving an opioid analgesic for the treatment of chronic pain. Breakthrough (or "episodic") pain is defined as severe pain that exacerbates briefly with movement, the pain literally "breaking through" the underlying baseline analgesia (see, for example, Kunz et al, letter to the Journal of Pain and Symptom Management, 8, 189 (1993)). Although breakthrough pain may disappear of its own accord, it can nevertheless be excruciating for those patients that experience it.

There is a clinical need for effective treatments and methods of management of breakthrough pain. An effective treatment should be capable of:

(a) reliably producing a rapid onset of action; and

(b) being self-administrable, i.e. convenient and easy to use.

At the same time, because of the transient nature of breakthrough pain, to be effective, the method should also rapidly release for absorption substantially all of the drug content necessary to treat the condition quickly. Although intravenous opioid injections are known to give rise to a rapid onset of action, and therefore are useful in the treatment of breakthough pain, intravenous injections of opioids can be problematic in the terminally ill, as many patients have poor intravenous access and such administration can be stressful to patients and care-givers.

International patent applications WO 00/16751 , WO 2004/067004, WO 2006/103418 and WO 2008/068471 all disclose drug delivery systems for the treatment of existing pain by sublingual administration, applying an interactive mixture principle, in which the active ingredient in microparticulate form is adhered to the surfaces of larger carrier particles in the presence of a bioadhesive and/or mucoadhesive promoting agent.

Prior art documents, including international patent applications WO 03/005944, WO 02/067903, WO 2007/141328, WO 2010/132605, WO 01/30288 and US patent application US 2009/0263476 A1 employ pH modifying agents to promote dissolution and/or absorption of active ingredients.

European patent application EP 2114383, US patent applications US 2008/0268023, US 2009/0048237 and US 2011/0091544, and international patent applications WO 2007/081949 and WO 2008/085765 on the other hand relate to formulations comprising (specifically-stated) non-ordered mixtures of opioids, for example sufentanil, bioadhesive and stearic acid, which form a hydrogel in use (sublingual delivery). International patent application WO 2010/059504 relates to a sufentanil formulation comprising oxygen scavangers in packaging to minimise degradation. It stated in that document that the use of antioxidants, such as butylated hydroxytoluene (BHT) in solid sufentanil formulations do not stop degradation of the API. Dissolvable lozenges, in which drug is embedded in a matrix, are disclosed in US patent application US 2002/0160043 and international patent application WO 91/03237. International patent application WO 2008/106689 and US patent application US 2009/0011030 disclose powders for inhalation, but also cross- reference the fentanyl lollipop Actiq®. Layered tablets are disclosed in international patent application WO 2006/097361 and US patent application 2010/0233257. In WO 2006/097361 , a single compacted core is made from mannitol and microcrystalline cellulose (and optionally other excipients). This core is then coated with active ingredient (such as an opioid) in a solution or suspension. A pH-modifying component may be added at this stage. Spray-coated formulations are also disclosed in US 2010/0233257. Compressible interactive mixtures are neither mentioned nor suggested in either of these documents. pH dependent transport of cationic drugs has been studied (see e.g. Palm et al, J. Pharmacol. Exp. Then, 291 , 435 (1999) and Wang ef al, Eur. J. Pharm. Sci., 39, 272 (2010)). US patent application 2007/0104763 discloses a lozenge for intraoral delivery comprising micronized fentanyl dispersed in a matrix comprising dextrose. US patent application 2009/0263476 refers to opioid-containing (e.g. fentanyl) buccal tablets in which a filler is employed, which is an alkaline metal oxide or hydroxide to improve transmucosal drug absorption. The use of, for example, magnesium oxide and magnesium hydroxide to give a higher pH is stated to enhance absorption without leading to instability of drug exhibited with other bases.

Stabilisation of drugs to oxidative degradation is discussed generally in the review article by Waterman ef al, Pharmaceutical Development and Technology, 7, 1 (2002). US patent application 201 1/0150989 also discloses specific stabilised morphinan-containing granules.

Effervescent opioid containing formulations are disclosed in inter alia US patent applications 2005/0142197, 2005/0142198, 2007/0036853 and 201 1/0071181 ,

International patent application WO 99/24023 discloses a sublingual tablet comprising an opioid, such morphine, mannitol and citric acid (in addition to sodium citrate).

We have found that, despite the fact that sufantanil is stable in solution, when attempting to formulate it into a solid state, tablet formulation, a notable instability results. This instability is unexpectedly solved by the addition of a small amount of weak acid, such as citric acid, provided that that acid is presented in intimate mixture with the API.

Further, we have found that a weak base, such as a sodium phosphate, may also be added to such formulations to enhance absorption and, even more surprisingly, that:

(a) the presence of the weak base does not, as expected, have a detrimental effect on the stability of the sufentanil in such formulations; and

(b) the enhanced absorption provided by the presence of the weak base is not, as expected, abrogated or cancelled out by the presence of the weak acid in such formulations.

According to a first aspect of the invention there is provided a pharmaceutical composition suitable for sublingual delivery which comprises a mixture comprising:

(a) microparticles of sufentanil, or a pharmaceutically acceptable salt thereof, which microparticles are presented on the surfaces of larger carrier particles;

(b) a water-soluble weak base, such as a phosphate; and

(c) a compound which is a weak acid, which acid is presented in intimate mixture with the microparticles of sufentanil or salt thereof.

Such compositions are referred to hereinafter as "the compositions of the invention". Sufentanil and pharmaceutically-acceptable salts thereof are presented in the compositions of the invention in the form of microparticles. Microparticles preferably possess a weight based mean diameter, number based mean diameter and/or a volume based mean diameter of between about 0.5 μηη and about 30 μιη, e.g. about 15 μΠΊ, such as between about 1 μηι and about 10 μπι. As used herein, the term "weight based mean diameter" will be understood by the skilled person to include that the average particle size is characterised and defined from a particle size distribution by weight, i.e. a distribution where the existing fraction (relative amount) in each size class is defined as the weight fraction, as obtained by e.g. sieving (e.g. wet sieving). As used herein, the term "number based mean diameter" will be understood by the skilled person to include that the average particle size is characterised and defined from a particle size distribution by number, i.e. a distribution where the existing fraction (relative amount) in each size class is defined as the number fraction, as measured by e.g. microscopy. As used herein, the term "volume based mean diameter" will be understood by the skilled person to include that the average particle size is characterised and defined from a particle size distribution by volume, i.e. a distribution where the existing fraction (relative amount) in each size class is defined as the volume fraction, as measured by e.g. laser diffraction. Microparticles of active ingredient may be prepared by standard micronisation techniques, such as grinding, jet milling, dry milling, wet milling, precipitation, etc. An air elutriation process may be utilised subsequently to prepare specific size fractions, if required. Preferred salts of sufentanil include citrate salts.

Weakly acidic materials that may be mentioned include those that, when dissolved in water and/or saliva, enable the provision (at the site of administration of compositions of the invention) of a pH of between about 2.0 and about 6.5. For the purpose of this invention, the term includes substances that are safe for use in mammals, and includes weak acids, weak acid derivatives and other chemicals that convert to weak acids in vivo (e.g. precursors that convert to acids in vivo, by for example being sequentially activated in accordance with properties of the local environment). Typical pKas of weak acids are in the range of between about -1.5 (e.g. about -1.74) and about 16 (e.g. about 15.74) (e.g. see Vollhardt, Organic Chemistry (1987)). A preferred range is between about 1 and about 10. More preferably, the weakly acidic material comprises a weak acid that is safe for human consumption, for example a food acid, such as citric acid, tartaric acid, malic acid, fumaric acid, adipic acid, succinic acid, lactic acid, acetic acid, oxalic acid, maleic acid, ammonium chloride or a combination thereof. Preferred acids include tartaric acid and, particularly, citric acid.

Also useful in place of (and/or in addition to) weak acids are chelating agents or sequestering agents. The term "chelating" or "sequestering" agent may be defined as any ligand that is capable of coordinating to a metal through at least two interactions. Examples of such agents include adipic acid, succinic acid, lactic acid, oxalic acid, maleic acid, and salts of any of these or, more preferably, hydroxypropylbetadex, or acetic acid, pentetic acid, glutamic acid, citric acid, tartaric acid, fumaric acid, edetic acid, malic acid, or salts of any of these, including calcium acetate, disodium edentate and, particularly, sodium citrate.

Thus, compositions of the invention may in the alternative comprise:

(b) a water-soluble weak base, such as a phosphate; and

(c) a compound which is a sequestering agent, which agent is presented in intimate mixture with the microparticles of sufentanil or salt thereof.

In such instances, all preferred features of the invention as described herein for, and all statements and/or references made in respect of, weak acid materials may be applied equally to sequestering agents.

To provide compositions of the invention, microparticles of sufentanil or pharmaceutically-acceptable salts thereof are presented in intimate mixture with particles of weakly acidic material. By "intimate mixture" we mean that some form of mixing step (simple mixing, granulation or otherwise) takes place as between the sufentanil/salt microparticles and particles of weakly acidic material, rendering them in intimate contact with each other. In this respect, as employed herein, the terms "intimate mixture" and "intimate contact" may be employed interchangeably.

Compositions of the invention are presented in the form of a mixture comprising carrier particles upon the surfaces of which are presented (e.g. adhered) microparticles of sufentanil or a pharmaceutically acceptable salt thereof. Such a mixture may be termed an interactive mixture.

Carrier particles in interactive mixtures may comprise pharmaceutically- acceptable substances that are soluble in water, such as carbohydrates, e.g. sugars, such as lactose, and sugar alcohols, such as mannitol, sorbitol and xylitol; or pharmaceutically-acceptable inorganic salts, such as sodium chloride. Alternatively, carrier particles may comprise pharmaceutically-acceptable substances that are insoluble or sparingly soluble in water, such as dicalcium phosphate anhydrate, dicalcium phosphate dihydrate, tricalcium phosphate, calcium carbonate, and barium sulphate; starch and pre-gelatinised starch; bioadhesive and mucoadhesive materials, such as crosslinked polyvinylpyrrolidone and croscarmellose sodium; and other polymers, such as microcrystalline cellulose, cellulose; or mixtures thereof. By "soluble in water" we include that the material has a solubility in water that is greater than 33.3 mg/mL at atmospheric pressure (e.g. 1 bar) and room temperature (e.g. 21 °C). On the other hand, the term "sparingly soluble or insoluble in water" includes materials that have a solubility in water that is less than 33.3 mg/mL under the same conditions. Preferred carrier particle materials include carbohydrates, including sugar alcohols, such as sorbitol, xylitol and, particularly, mannitol.

In order to provide intimate mixture/contact of microparticles of sufentanil or salt thereof and particles of weakly acidic material, the latter may be presented, for example, either:

(i) within (i.e. as at least part of) said carrier particles, such that said carrier particles comprise or consist of said weak acid material, for example carrier particles may comprise a composite of weak acid material and another carrier particle material; and/or

(ii) upon the surfaces of the carrier particles, along with the microparticles of sufentanil or salt thereof (e.g. as part of an interactive mixture).

In this respect, any technique may be employed that involves forcing together weakly acidic material and carrier particles carrying microparticles of sufentanil or salt thereof, for example a compaction technique, such as compression and/or granulation.

Although weakly acidic material may also be presented between such carrier particles carrying the sufentanil/salt, we have found that it is important that at least some (e.g. about 10%, such as about 20%, for example about 30%, including about 40%, such as about 50%) of the weakly acidic material that is included in a composition of the invention is presented in intimate mixture with the sufentanil/salt, for example either as part of the interactive mixture, so that it is in contact with (e.g. adhered to) the surfaces of the carrier particles, and/or within said carrier particles, as described herein. We have found that, if weakly acidic material is only presented between such carrier particles carrying the sufentanil/salt (i.e. within the "bulk" along with the base), in the amounts mentioned herein, the stability advantages discussed herein are surprisingly not observed.

The term "interactive" mixture will be understood by those skilled in the art to include the term "ordered" mixture, and to denote a mixture in which particles do not appear as single units, as in random mixtures, but rather where smaller particles (e.g. microparticles of, for example, sufentanil) are attached to (i.e. adhered to or associated with) the surfaces of larger carrier particles. Such mixtures are characterised by interactive forces (for example van der Waals forces, electrostatic or Coulomb forces, and/or hydrogen bonding) between carrier and surface-associated particles (see, for example, Staniforth, Powder Technol., 45, 75 (1985)). In final mixtures, and compositions comprising such mixtures, the interactive forces need to be strong enough to keep the adherent particles at the carrier surface.

When interactive mixtures are employed, carrier particles may be of a size (weight and/or volume based average or mean diameter, vide supra) that is between about 30 pm and about 1000 pm (e.g. about 800 pm, such as about 750 pm), and preferably between about 50 (such as about 100 pm) and about 600 pm (such as about 500 pm, or about 450 pm), for example about 400 pm.

When employed in particulate form in intimate mixture with sufentanil or salt thereof on the surfaces of carrier particles, suitable particle sizes of weakly acidic materials that may be employed are in the ranges discussed hereinbefore for sufentanil or salt thereof.

Carrier particles comprising weakly acidic materials may comprise composites of such materials with other carrier particle materials and may be prepared by direct compression or granulation (wet or dry), for example as described hereinafter. In such instances, suitable particle sizes (weight and/or volume based average or mean diameter, vide supra) of weakly acidic materials that may be employed are higher than the ranges discussed hereinbefore and may be in the range of about 30 pm and about 400 μητι), and preferably between about 40 pm (such as about 50 pm) and about 200 μητι (such as about 150 μιη or about 100 pm).

The skilled person will appreciate that, when weak acids are employed which are not solids (and therefore not particulate) at or around room temperature and atmospheric pressure, they may be adsorbed onto a particulate carrier material (such as silica) in order to provide particles comprising the weakly acidic material. Such may then be employed in intimate mixture with the sufentanil/salt or as part of a carrier composite. Compositions of the invention further comprise a weak base, such as a water- soluble phosphate. Weak bases that may be mentioned further include those that, when dissolved in water and/or saliva, enable the provision (at the site of administration of compositions of the invention) of a pH of between about 7.5 and about 13.0. For the purpose of this invention, the term includes substances that are safe for use in mammals, and includes weak bases, weak base derivatives and other chemicals that convert to weak bases in vivo (e.g. precursors that convert to bases in vivo, by for example being sequentially activated in accordance with properties of the local environment). Typical pKbs of weak bases are in the range of between about -1.5 and about 16. A preferred range is between about 1 and about 10. More preferably, the weak base is safe for human consumption, for example a phosphate base, a carbonate base or a hydroxide base.

The term "water-soluble phosphate" is employed in the context of the present invention to denote a phosphate-containing inorganic salt that is capable of dissolving in water and/or saliva to form a solution. The term "water-soluble" is as defined above. Preferred phosphate salts include potassium and sodium phosphate salts, for example monosodium phosphate, more preferably disodium phosphate (e.g. disodium phosphate dihydrate) and, particularly, trisodium phosphate (e.g. trisodium phosphate anhydrous). Other bases, such as (e.g. water-soluble) carbonates, such as disodium carbonate, and hydroxides, may also be employed instead of, or in addition to, the phosphate. In such instances, all preferred features of the invention as described herein for, and all statements and/or references made in respect of, water-soluble phosphates may be applied equally to other weak bases, including carbonates, such as disodium carbonate.

It is preferred that compositions of the invention are non-effervescent. By "non- effervescent", we mean that, following intraoral administration, the components of the composition are not such (and/or are not present in such amounts) that they give rise to either:

(i) the perceptible (i.e. the subject does not feel); or

(ii) the measurable (i.e. by scientific instrumentation)

emission of bubbles of gas within saliva or other aqueous media with a pH in the range between about 4 and about 10, such as about 9.

The water-soluble phosphate material may be employed in solid state form in compositions of the invention. It is not necessary for the phosphate to be in intimate contact with the sufentanil or the weak acid or, for example, part of an interactive mixture. Surprisingly, it is not necessary for the weakly acidic to be in contact with the phosphate base.

As mentioned previously, although it has been found that sufentanil and salts thereof are highly stable in solution, their formulation in solid state dosage forms such as those described herein has been found to give rise to instability problems. Further, co-formulation of sufentanil and salts thereof along with water-soluble phosphates in the solid state gives rise to further enhancement of such instability problems. This problem is solved by co-formulation with the weakly acidic material in the manner described herein. We have found that the weak base (e.g. water-soluble phosphate) may enhance absorption of sufentanil/salt thereof across the mucosal surface. Furthermore, the chemical stability of the sufentanil/salt thereof in a composition of the invention may be improved if a small amount of weak acid (e.g. up to about 0.75%, such as about 0.25%, by weight of the total weight of a composition of the invention) is employed as described herein. The presence of a weakly acid material, such as citric acid, would be expected to at least partially neutralise the absorption-enhancing effect of the weak base, but, as presented in compositions of the invention, this is not the case. Even more surprisingly, the presence of an excess of weak base, as presented in compositions of the invention, does not, as would be expected, affect the stability of the sulfentanil or salt thereof.

Thus, the problem of an observation of instability of sufentanil and salts thereof in solid state formulations is in itself solved in a counter-intuitive way: the positive effects of the acid (provision of stability in the solid state) and the base (provision of enhanced absorption following administration) would be expected to be cancelled out by their respective negative effects (i.e. reduced absorption after administration due to the presence of acid and instability of sufentanil in the solid state due to the presence of base), but this is not observed. According to a further aspect of the invention there is provided a method of stabilising a solid state pharmaceutical composition (e.g. a tablet for sublingual administration) comprising sufentanil or a pharmaceutically acceptable salt thereof, which method comprises providing particles of a weak acid (such as citric acid) in intimate mixture with particles of sufentanil or salt thereof. In such a method, the pharmaceutical composition may further comprise a weak base (such as a water-soluble phosphate). Such a weak base may be present in excess (by weight relative to the weak acid).

There is further provided the use of a weak acid (such as citric acid) to stabilise a solid state pharmaceutical composition (e.g. a tablet for sublingual administration) comprising sufentanil or a pharmaceutically acceptable salt thereof. Such a use preferably comprises providing particles of said weak acid in intimate mixture with particles of sufentanil or salt thereof. Preferably, the pharmaceutical composition may further comprise a weak base (such as a water-soluble phosphate), for example in excess (by weight relative to the weak acid).

Weak base, such as phosphate, and weak acid should preferably be employed to ensure that, following administration of a formulation of the invention, the pH that is achieved e.g. sublingually is weakly basic, in the range of about 8 to about 10, such as to about 9. This will depend on the nature of the phosphate (or other weak base) that is employed and suitable weight ratios that may be employed may be no less than about 2:1 (base, e.g. phosphate, to acid), for example about 4:1 , such as about 10:1 , e.g. no less than about 50:1. If trisodium phosphate and citric acid are employed, the ratio is preferably between about 5:1 and about 40:1.

According to a further aspect of the invention, there is provided a pharmaceutical composition comprising microparticles of sufentanil or a pharmaceutically acceptable salt thereof, particles of a weak acid (which are preferably in intimate mixture with the microparticles of sufentanil or salt thereof) and a water-soluble phosphate, wherein acid and phosphate are employed in relative amounts characterized in the composition to enables the provision (at the site of administration) of a pH of between about 8.0 and about 10.0 (such as about 9.0), preferably along with the maintenance of pH within this range for an appropriate length of time (e.g. up to about 5 minutes) to facilitate dissolution of the sufentanil microparticles, and/or absorption of sufentanil across the sublingual mucosa thereafter.

Preferred amounts of trisodium phosphate (if employed) to produce a pH in the above-stated range are about 2% to about 4% by weight based upon the total weight of a composition of the invention. Preferred amounts of citric acid (if employed) are about 0.25% to about 0.75% by weight based upon the total weight of a composition of the invention.

Compositions of the invention may also comprise disintegrant and/or superdisintegrant materials. Such materials may be presented, at least in part, as particles upon the surfaces of, and/or between, carrier particles.

The disintegrant or "disintegrating agent" that may be employed may be defined as any material that is capable of accelerating to a measurable degree the disintegration/dispersion of a composition of the invention. The disintegrant may thus provide for an in vitro disintegration time of about 30 seconds or less, as measured according to e.g. the standard United States Pharmacopeia (USP) disintegration test method (see FDA Guidance for Industry: Orally Disintegrating Tablets; December 2008). This may be achieved, for example, by the material being capable of swelling, wicking and/or deformation when placed in contact with water and/or mucous (e.g. saliva), thus causing tablet formulations to disintegrate when so wetted.

Suitable disintegrants (as defined in, for example, Rowe et al, Handbook of Pharmaceutical Excipients, 6^th ed. (2009)) include cellulose derivatives such as hydroxypropyl cellulose (HPC), low substituted HPC, methyl cellulose, ethyl hydroxyethyl cellulose, carboxymethyl cellulose calcium, carboxymethyl cellulose sodium, microcrystalline cellulose, modified cellulose gum; starch derivatives such as moderately cross-linked starch, modified starch, hydroxylpropyl starch and pregelatinized starch; and other disintegrants such as calcium alginate, sodium alginate, alginic acid, chitosan, docusate sodium, guar gum, magnesium aluminium silicate, polacrilin potassium and polyvinylpyrrolidone. Combinations of two or more disintegrants may be used. Preferred disintegrants include so-called "superdisintergrants" (as defined in, for example, Mohanachandran e? al, International Journal of Pharmaceutical Sciences Review and Research, 6, 105 (2011)), such as cross-linked polyvinylpyrrolidone, sodium starch glycolate and croscarmellose sodium. Combinations of two or more superdisintegrants may be used.

Disintegrants may also be combined with superdisintegrants in compositions of the invention.

Disintegrants and/or superdisintegrants are preferably employed in an (e.g. total) amount of between 0.5 and 15% by weight based upon the total weight of a composition. A preferred range is from about 0.1 to about 5%, such as from about 0.2 to about 3% (e.g. about 0.5%, such as about 2%) by weight.

If employed in particulate form, particles of disintegrants and/or superdisintegrants may be presented with a particle size (weight and/or volume based average or mean diameter, vide supra) of between about 0.1 and about 100 μηι (e.g. about 1 and about 50 μπι).

Alternatively, disintegrants and/or superdisintegrants may also be present as a constituent in composite excipients. Composite excipients may be defined as co- processed excipient mixtures. Examples of composite excipients comprising superdisintegrants are Parteck® ODT, Ludipress® and Prosolv® EASYtab.

Bio/mucoadhesive materials may also be presented in compositions of the invention. Such materials may be presented upon (e.g. adhered to) the surfaces of carrier particles when components of compositions of the invention are presented in the form of interactive mixtures. Superdisintegrant materials mentioned herein may also function as bio/mucoadhesive materials. Compositions of the invention may be employed in the prophylaxis of severe pain, such as breakthrough pain (e.g. breakthough cancer pain), as described hereinbefore.

Sufentanil and pharmaceutically-acceptable salts thereof may be employed in a pharmacologically effective amount, which refers to an amount of an active ingredient, which is capable of conferring a desired therapeutic effect on a treated patient, whether administered alone or in combination with another active ingredient. Such an effect may be objective (i.e. measurable by some test or marker) or subjective (i.e. the subject gives an indication of, or feels, an effect). Typically, subjective measurements of pain are conducted using numeric rating scales (NRSs) and/or visual analogue scales (VASs).

Thus, appropriate pharmacologically effective amounts of sufentanil (or salt thereof) include those that are capable of producing, and/or contributing to the production of, the desired therapeutic effect, namely treatment of pain, such as breakthrough pain.

The amounts of sufentanil/salt that may be employed in compositions of the invention may thus be determined by the skilled person, in relation to what will be most suitable for an individual patient. This is likely to vary with the route of administration, the type and severity of the condition that is to be treated, as well as the age, weight, sex, renal function, hepatic function and response of the particular patient to be treated. The total amount of sufentanil/salt thereof that may be employed in a composition of the invention may be in the range of about 0.005%, such as about 0.01%, to about 0.2%, such as about 0.12%, by weight based upon the total weight of the composition. The amount of this active ingredient may also be expressed as the amount in a unit dosage form (e.g. a tablet). In such a case, the amount of sufentanil/salt that may be present may be sufficient to provide a dose per unit dosage form that is in the range of between about 5 μg (such as about 8 g) and about 100 pg (for example about 80 g, such as about 50 g). A preferred range is between about 10 g and about 40 g. One, two or more dosage units may be administered concurrently.

Compositions of the invention, once prepared, may be administered as powders for sublingual administration (e.g. in the case of compositions comprising insoluble carrier particles, in the form of a spray comprising a solvent in which the sufentanil or salt thereof is not soluble or is poorly soluble). However, they are preferably directly compressed/compacted into unit dosage forms (e.g. tablets) for administration to mammalian (e.g. human) patients, for example as described hereinafter. Compositions of the invention in the form of tablets for e.g. sublingual administration may also comprise a binder. A binder may be defined as a material that is capable of acting as a bond formation enhancer, facilitating the compression of the powder mass into coherent compacts. Suitable binders include cellulose gum and microcrystalline cellulose. If present, binder is preferably employed in an amount of between about 2% and about 20% by weight based upon the total weight of the tablet formulation. A preferred range is from about 6% to about 20%, such as from about 8% to about 17% (e.g. about 12% to about 16%) by weight. Suitable further additives and/or excipients that may be employed in compositions of the invention, in particular those in the form of tablets for e.g. sublingual administration may comprise:

(a) lubricants (such as sodium stearyl fumarate or, preferably, magnesium stearate); (b) flavourings (e.g. lemon, peppermint powder or, preferably, menthol), sweeteners (e.g. neohesperidin, acesulfame K or, preferably, sucralose) and dyestuffs; and/or

(c) other ingredients, such as colouring agents, coating materials, preservatives and gliding agents (e.g. colloidal silica).

Compositions of the invention may be prepared by standard techniques, and using standard equipment, known to the skilled person. When presented in the form of interactive mixtures, particles of e.g. sufentanil/salt may be dry mixed with relevant carrier particles over a period of time that is sufficiently long to enable appropriate amounts of respective active ingredients to adhere to the surface of the carrier particles. This may also apply to other active ingredients and/or any of the relevant excipients (e.g. weak acid) defined hereinbefore.

The skilled person will appreciate that, in order to obtain a formulation in the form of an interactive mixture by dry powder mixing, larger carrier particles must be able to exert enough force to break up agglomerates of smaller particles. This ability will primarily be determined by particle density, surface roughness, shape, flowability and, particularly, relative particle sizes.

Standard mixing equipment may be used in this regard. The mixing time period is likely to vary according to the equipment used, and the skilled person will have no difficulty in determining by routine experimentation a suitable mixing time for a given combination of active ingredient and carrier particle material(s).

Interactive mixtures may also be provided using techniques other than dry mixing, which techniques will be well known to those skilled in the art. For example, certain weak acids may be sprayed as an e.g. aqueous solution or suspension onto the surfaces of carrier particles in order to provide (following evaporation of the relevant solvent) particles of that material on the surfaces of such carrier particles. Other ingredients may alternatively be incorporated by standard mixing or other formulation principles.

The compositions of the invention may be administered transmucosally, such as buccally, rectally, nasally or preferably sublingually by way of appropriate dosing means known to the skilled person. A sublingual tablet may be placed under the tongue, and the active ingredients absorbed through the surrounding mucous membranes. In this respect, the compositions of the invention may be incorporated into various kinds of pharmaceutical preparations intended for transmucosal (e.g. sublingual) administration using standard techniques (see, for example, Lachman et al, "The Theory and Practice of Industrial Pharmacy", Lea & Febiger, 3^rd edition (1986) and "Remington: The Science and Practice of Pharmacy", Gennaro (ed.), Philadelphia College of Pharmacy & Sciences, 19^th edition (1995)).

Pharmaceutical preparations for sublingual administration may be obtained by combining compositions of the invention with conventional pharmaceutical additives and/or excipients used in the art for such preparations, and thereafter preferably directly compressed/compacted into unit dosage forms (e.g. tablets). (See, for example, Pharmaceutical Dosage Forms: Tablets. Volume 1, 2^nd Edition, Lieberman et al (eds.), Marcel Dekker, New York and Basel (1989) p. 354-356 and the documents cited therein.) Suitable compacting equipment includes standard tabletting machines, such as the Kilian SP300, the Korsch EKO, the Korsch XP1 , the Korsch XL100, the Korsch PharmaPress 800 or the Manesty Betapress.

Suitable final sublingual tablet weights are in the range of about 5 to about 300 mg, such as about 10 (e.g. about 50) to about 200 mg, for example about 30 to about 175 mg, more preferably between about 30 (e.g. about 40) and about 150 (e.g. about 140 mg). Two or more tablets may be taken simultaneously. Suitable final tablet diameters are in the range of about 3 to about 12 mm, for example about 4 to about 10 mm, and more preferably about 5 to about 9 mm. Suitable final tablet thicknesses are in the range of about 0.5 mm to about 6 mm, such as about 1.5 mm to about 3 mm. Various tablet shapes are possible (e.g. circular, triangular, square, diamond, polygon or oval).

Irrespective of the foregoing, compositions of the invention comprising disintegrants, bioadhesives (or other excipients that function by swelling) should be essentially free (e.g. less than about 20% by weight based on the total weight of the formulation) of water. It will be evident to the skilled person that "premature" hydratisation will dramatically decrease the performance of a tablet formulation in use and may result in premature dissolution of active ingredients.

Wherever the word "about" is employed herein in the context of dimensions (e.g. tablet sizes and weights, particle sizes etc.), surface coverage (e.g. of carrier particles by particles of active ingredients), amounts (e.g. relative amounts of individual constituents in a composition or a component of a composition and absolute doses (including ratios) of active ingredients and/or excipients), temperatures, pressures, times, pH values, pKa values concentrations, etc., it will be appreciated that such variables are approximate and as such may vary by ± 10%, for example ± 5% and preferably ± 2% (e.g. ± 1%) from the numbers specified herein.

Compositions of the invention may be administered by way of appropriate dosing means known to the skilled person. For example, a sublingual tablet may be placed under the tongue, and the active ingredients absorbed through the surrounding mucous membrane.

In accordance with the invention, sufentanil or salts thereof may be combined with one or more other analgesic drugs, for example opioids, which may be administered sublingually (e.g. buprenorphine) or perorally, or other peroral analgesics (e.g. NSAIDs). Sufentanil may be combined with such other analgesic drugs either in compositions of the invention or in separate combination therapy.

The compositions of the invention are useful in the treatment of pain, such as acute, and particularly breakthrough, pain. By "treatment" of pain associated we include the therapeutic treatment, as well as the symptomatic, prophylactic and palliative treatment of the condition. The compositions of the invention enable the production of unit dosage forms that are easy and inexpensive to manufacture, and which enable the rapid release and/or a rapid uptake of the active ingredient employed through the mucosa, such as the oral mucosa, thus enabling rapid relief of symptoms, such as those described hereinbefore.

Compositions of the invention may also have the advantage that they may be prepared using established pharmaceutical processing methods and employ materials that are approved for use in foods or pharmaceuticals or of like regulatory status.

Compositions of the invention may also have the advantage that they may be more efficacious than, be less toxic than, be longer acting than, be more potent than, produce fewer side effects than, be more easily absorbed than, possess a better patient acceptability than, have a better pharmacokinetic profile than, and/or have other useful pharmacological, physical, or chemical properties over, pharmaceutical compositions known in the prior art, whether for use in the treatment of pain.

The invention is illustrated by way of the following examples, with reference to the attached Figure 1 , which shows a comparison of chemical stability of various batches of sufentanil-containing sublingual tablets. Example 1

Sufentanil (40 ig dose) Sublingual Tablets - Granulated Carrier Particles, Batches A to C

(a) Granulated carrier particles comprising citric acid anhydrous (fine granular 16/40 grade, DSM, Switzerland, Basel) and mannitol (Pearlitol™ 400 DC, Roquette, Lestrem, France) were prepared as follows.

Citric acid was mortared by hand using a pestle and mortar and then sieved. The fraction with particle sizes that were less than 90 pm was employed in the granulation. The citric acid and mannitol were firstly dry mixed in a small scale intensive mixer (Philips HR 7775 mixer) for 2 minutes in approximately the following quantities:

(i) 0.740 g citric acid and 599.260 g mannitol;

(ii) 1.851 g citric acid and 598.149 g mannitol; and

(iii) 3.701 g citric acid and 596.299 g mannitol.

These amounts were selected to provide citric acid contents in final tablets of 0.1%, 0.25% and 0.5% by weight, as appropriate.

Approximately 2.5% (w/w) water was then added over approximately 2.5 minutes. The wet granulate was then dried in a heat cabinet for about 20 hours at 60°C. The dried granulate was then seived. The fraction with particle sizes greater than 710 pm was removed from the final granulate.

Two granulation runs were pooled for each batch. The final weight of the granular carrier particles employed in subsequent mixing and tableting steps was 652.51 g in each case.

(b) Sufentanil citrate (Macfarlan Smith, Edinburgh, UK) was micronized at GfM, Bremen, Germany using an air jet mill (JM 50). The volume based mean particle size (diameter) of was 4.2 pm.

Granulated carrier (652.51 g) was mixed together with micronized sufentanil citrate (0.689 g) in a tumble blender (Turbula mixer, type T2F, WAG, Switzerland) with a 2L stainless steel container for 24 hours at 49 rpm.

The resultant interactive mixture was than mixed together with microcrystalline cellulose (107.525 g; Prosolv™ S CC 90 (particle size specification limits: d(10) - 25-46 pm, d(50) - 98-146 pm, d(90) - 195-276 pm; JRS Pharma, Rosenberg, Germany), croscarmellose sodium (8.050 g; AcDiSol™, FMC Biopolymer, Cork, Ireland; approximate particle size around 50 pm) and trisodium phosphate anhydrous (fine granules; 32.20 g; Budenheim, Germany) in the tumble blender for a further 30 minutes. Magnesium stearate (vegetable origins; 4.025 g; Peter Greven, Munstereifel, Germany) was then added to this mixture and mixing continued in the tumble blender for a further 2 minutes. The final powder mixture was then compressed into tablets using a rotary press (Manesty Betapress) equipped with 23 dies, and 6 mm round, flat faced, bevelled-edged punches, to give tablets with a final tablet weight of 70 mg and a tablet crushing strength of 25 N. Three batches of tablets (one comprising citric acid by weight in the final tablets of 0.1% (Batch A), one comprising 0.25% (Batch B), and one comprising 0.5% (Batch C)) were made in this way and employed in the stability experiments discussed hereinafter. Example 2

Sufentanil (40 \ig dose) Sublingual Tablets - Granulated Carrier Particles, Batch D

Essentially the same procedure as that described in Example 1 was carried out to prepare a fourth batch of tablets containing less trisodium phosphate.

Granulated carrier (668.61 g) made as described in Example 1 (a), including an amount of citric acid that would provide final tablets with 0.1 % of citric acid by weight. The carrier particles were mixed together with micronized sufentanil citrate (0.689 g) in a tumble blender for 24 hours at 49 rpm.

The resultant interactive mixture was then mixed together with microcrystalline cellulose (107.53 g), croscarmellose sodium (8.050 g) and trisodium phosphate (16.10 g) for a further 30 minutes.

Magnesium stearate (4.025 g) was then added to this mixture and mixing continued for a further 2 minutes. The final powder mixture was then compressed into tablets as described in Example 1 to produce a tablet Batch D, which was employed in the stability experiments discussed hereinafter. Example 3

Sufentanil (40 pg dose) Sublingual Tablets - Interactive Mixture, Batches E and F

Essentially the same procedure as that described in Example 1 (b) was carried out to prepare further batches of tablets with non-granulated carrier particles, but in which, instead, citric acid is presented on the surfaces of mannitol carrier particles.

Two batches of citric acid were prepared:

(i) for Batch E, a sieved fraction of citric acid monohydrate (Merck KGaA, Darmstadt, Germany) with a particle size <63 pm was used. The volume based mean particle size was 20.04 pm; and

(ii) for Batch F, citric acid anhydrous (fine granular 16/40 grade; DSM, Basel, Switzerland; micronized using a Pilotmill-1 , Food and Pharma Systems, Italy) was used. The volume based mean particle size was 3.8 pm.

Mannitol (651.705g) was mixed together with micronized sufentanil citrate (0.689 g) and one of other of the batches of [micronized] citric acid (0.805 g), in a tumble blender for 24 hours at 49 rpm.

The resultant interactive mixture was then mixed together with microcrystalline cellulose (107.53 g), croscarmellose sodium (8.050 g) and trisodium phosphate anhydrous (32.20 g) for a further 30 minutes. Magnesium stearate (4.025 g) was then added to this mixture and mixing continued for a further 2 minutes.

The final powder mixtures were then compressed into tablets as described in Example 1 to produce tablet batches, Batch E and Batch F, respectively, which were employed in the stability experiments discussed hereinafter. Comparative Example 4

Sufentanil (40 μg dose) Sublingual Tablets - Batch G

Essentially the same procedure as that described in Example 3 was carried out to prepare a further batch of tablets with citric acid presented as part of the bulk (i.e. not presented on the surfaces of mannitol carrier particles).

Mannitol (651.705 g) was mixed together with micronized sufentanil citrate (0.689 g) in the tumble blender for 24 hours at 49 rpm.

The resultant interactive mixture was than mixed together with the citric acid (0.805 g; micronized as described in Example 3 above to a volume-base mean particle size of 12.5 pm), microcrystalline cellulose (107.53 g), croscarmellose sodium (8.050 g) and trisodium phosphate anhydrous (32.20 g) for a further 30 minutes.

Magnesium stearate (4.025 g) was then added to this mixture and mixing continued for a further 2 minutes. The final powder mixtures were then compressed into tablets as described in Example 1 to produce a tablet Batch G, which was employed in the stability experiments discussed hereinafter.

Example 5

Stability Experiments

Stability studies were performed on batches of tablets prepared as described above stored in aluminium sachets (40 tablets/sachet). Samples were subjected to the following storage conditions +25°C/60%RH and +40°C/75%RH (following ICH requirements of ± 2°C and 5% RH), with analysis conducted at 1 , 2, 3 and 6 months. Additionally, accelerated conditions (+60°C; ambient humidity) were employed, with tablets were analysed during the first month of storage with main focus on results generated after 1 and 2 weeks of storage. Impurities resulting from degradation of sufentanil were determined using HPLC analysis and UV detection at 230 nm. The principle sufentanil-derived degradation products had previously been identified as /V-phenylpropanamide and /V-oxides (cis/trans) of sufentanil. The tablets were dissolved in a mixture of water, acetonitrile and trifluoroacetic acid and analysed on a Kinetex C18 column (150*2.1 mm, 2.6 pm; Phenomenex) using a gradient mobile phase system containing water, acetonitrile and trifluoroacetic acid. Related substances were quantified as Area% of the total area of peaks corresponding to sufentanil (all non-sufentanil peaks with Area%s that were greater than 0.05% were included).

Table 1 shows a comparison of 4 batches with 0.1% citric acid added by different manufacturing processes after storage in long term and accelerated conditions. The total amount of sufentanil-derived impurities is presented as Area%.

Table 1

Table 2 shows a comparison between the 4 granulated carrier particle batches after storage in long term and accelerated conditions. The total amount of sufentanil-derived impurities is presented as Area%. Table 2

Table 3 shows a comparison between batches A, B, E, F and G after storage for several months under ambient storage. The total amount of sufentanil-derived impurities is presented as Area%. The chemical stability is also plotted in Figure 1. Table 3

Results after storage in ambient condition shows a clear difference between the batch with citric acid added by bulk mixing (Batch G) and the other batches. The differences between the other batches are very small.

It is concluded that citric acid in intimate mixture with sufentanil, either by adding during the interactive mixing step or by co-granulating with mannitol in the carrier particles, mitigates stability problems of the API discussed herein.

Claims

1. A pharmaceutical composition suitable for sublingual delivery which comprises a mixture comprising:

(b) a water-soluble weak base; and

2. A formulation as claimed in Claim 1 , wherein particles of weakly acidic material are presented within the carrier particles, such that said carrier particles comprise a composite of:

(i) said acid material; and

(ii) another carrier particle material.

3. A formulation as claimed in Claim 1 or Claim 2, wherein particles of weakly acidic material are presented upon the surfaces of the carrier particles.

4. A composition as claimed in any one of the preceding claims, wherein the acid is citric acid.

5. A composition as claimed in any one of the preceding claims, wherein the water-soluble weak base comprises a phosphate, such as trisodium phosphate.

6. A composition as claimed in any one of the preceding claims, wherein the carrier particles comprise mannitol.

7. A pharmaceutical composition as claimed in any one of the preceding claims, which further comprises a disintegrant.

8. A composition as claimed in Claim 7, wherein the disintegrant is a superdisintegrant selected from croscarmellose sodium, sodium starch glycolate, crosslinked polyvinylpyrrolidone or a mixture thereof.

9. A composition as claimed in any one of the preceding claims which is in the form of a tablet suitable for sublingual administration.

10. A process for the preparation of a composition as defined in any one of Claims 1 to 9, which comprises dry mixing carrier particles with sufentanil or salt thereof.

11. A process for the preparation of a sublingual tablet as defined in Claim 9, which comprises directly compressing or compacting a composition as defined in any one of Claims 1 to 8.

12. A method of treatment of pain, which method comprises administration of a composition as defined in any one of Claims 1 to 9 to a person suffering from, or susceptible to, pain.

13. A composition as defined in any one of Claims 1 to 9 for use in a method of treatment of pain.

14. The use of a composition as defined in any one of Claims 1 to 9 for the manufacture of a medicament for a method of treatment of pain.

15 A method as claimed in Claim 12, a composition as claimed in Claim 13, or a use as claimed in Claim 14, wherein the pain is breakthrough pain.