WO2013164617A1 - Nouvelle composition de sufentanil pour le traitement d'une douleur aiguë - Google Patents

Nouvelle composition de sufentanil pour le traitement d'une douleur aiguë Download PDF

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Publication number
WO2013164617A1
WO2013164617A1 PCT/GB2013/051128 GB2013051128W WO2013164617A1 WO 2013164617 A1 WO2013164617 A1 WO 2013164617A1 GB 2013051128 W GB2013051128 W GB 2013051128W WO 2013164617 A1 WO2013164617 A1 WO 2013164617A1
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Prior art keywords
composition
sufentanil
acid
pain
carrier particles
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PCT/GB2013/051128
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English (en)
Inventor
Anders Petterson
Sofia MOGENSEN
Barbro Johansson
Emil Schwan
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Orexo Ab
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Priority claimed from GBGB1207628.7A external-priority patent/GB201207628D0/en
Priority claimed from GB201304625A external-priority patent/GB201304625D0/en
Application filed by Orexo Ab filed Critical Orexo Ab
Publication of WO2013164617A1 publication Critical patent/WO2013164617A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
    • A61K9/0056—Mouth soluble or dispersible forms; Suckable, eatable, chewable coherent forms; Forms rapidly disintegrating in the mouth; Lozenges; Lollipops; Bite capsules; Baked products; Baits or other oral forms for animals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4468—Non condensed piperidines, e.g. piperocaine having a nitrogen directly attached in position 4, e.g. clebopride, fentanyl
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2013—Organic compounds, e.g. phospholipids, fats
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2072—Pills, tablets, discs, rods characterised by shape, structure or size; Tablets with holes, special break lines or identification marks; Partially coated tablets; Disintegrating flat shaped forms
    • A61K9/2077—Tablets comprising drug-containing microparticles in a substantial amount of supporting matrix; Multiparticulate tablets
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2009—Inorganic compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2013—Organic compounds, e.g. phospholipids, fats
    • A61K9/2018—Sugars, or sugar alcohols, e.g. lactose, mannitol; Derivatives thereof, e.g. polysorbates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
    • A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose

Definitions

  • 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.
  • NSAIDs non-steroidal anti-inflammatory drugs
  • 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.
  • An effective treatment should be capable of:
  • the method should also rapidly release for absorption substantially all of the drug content necessary to treat the condition quickly.
  • 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.
  • 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.
  • 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.
  • 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.
  • a filler 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.
  • Effervescent opioid containing formulations are disclosed in inter alia US patent applications 2005/0142197, 2005/0142198, 2007/0036853 and 201 1/0071181 ,
  • a weak base such as a sodium phosphate
  • a weak base such as a sodium phosphate
  • composition suitable for sublingual delivery which comprises a mixture comprising:
  • a water-soluble weak base such as a phosphate
  • compositions of the invention 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 ⁇ and about 30 ⁇ , e.g. about 15 ⁇ , such as between about 1 ⁇ and about 10 ⁇ .
  • 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.
  • 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.
  • 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.
  • 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.
  • 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)).
  • 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.
  • 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.
  • chelating agents or sequestering agents 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.
  • compositions of the invention may in the alternative comprise:
  • a water-soluble weak base such as a phosphate
  • microparticles of sufentanil or pharmaceutically-acceptable salts thereof are presented in intimate mixture with particles of weakly acidic material.
  • 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.
  • 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.
  • 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.
  • carbohydrates e.g. sugars, such as lactose, and sugar alcohols, such as mannitol, sorbitol and xylitol
  • pharmaceutically-acceptable inorganic salts such as sodium chloride.
  • 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.
  • 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).
  • 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.
  • carrier particles comprise or consist of said weak acid material
  • carrier particles may comprise a composite of weak acid material and another carrier particle material
  • 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.
  • 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.
  • 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.
  • 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)).
  • interactive forces for example van der Waals forces, electrostatic or Coulomb forces, and/or hydrogen bonding
  • the interactive forces need to be strong enough to keep the adherent particles at the carrier surface.
  • 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.
  • suitable particle sizes of weakly acidic materials 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.
  • 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 ⁇ ), and preferably between about 40 pm (such as about 50 pm) and about 200 ⁇ (such as about 150 ⁇ or about 100 pm).
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • compositions of the invention are non-effervescent.
  • 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:
  • 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.
  • 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.
  • 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.
  • the weak base e.g. water-soluble phosphate
  • 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.
  • 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.
  • the pharmaceutical composition may further comprise a weak base (such as a water-soluble phosphate).
  • a weak base such as a water-soluble phosphate
  • a weak acid such as citric acid
  • a solid state pharmaceutical composition comprising sufentanil or a pharmaceutically acceptable salt thereof.
  • a weak acid such as citric acid
  • 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.
  • suitable weight ratios 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.
  • 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.
  • a pH of between about 8.0 and about 10.0 such as about 9.0
  • 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.
  • USP United States Pharmacopeia
  • Suitable disintegrants 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.
  • HPC hydroxypropyl cellulose
  • HPC hydroxypropyl cellulose
  • HPC hydroxypropyl cellulose
  • methyl cellulose ethyl hydroxyethyl cellulose
  • carboxymethyl cellulose calcium carboxymethyl cellulose sodium, microcrystalline cellulose
  • modified cellulose gum modified cellulose gum
  • 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.
  • 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 ⁇ (e.g. about 1 and about 50 ⁇ ).
  • 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.
  • a pharmacologically effective amount 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).
  • subjective measurements of pain are conducted using numeric rating scales (NRSs) and/or visual analogue scales (VASs).
  • sufentanil or salt thereof
  • appropriate pharmacologically effective amounts of sufentanil 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).
  • 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 ⁇ g (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:
  • lubricants such as sodium stearyl fumarate or, preferably, magnesium stearate
  • flavourings e.g. lemon, peppermint powder or, preferably, menthol
  • sweeteners e.g. neohesperidin, acesulfame K or, preferably, sucralose
  • dyestuffs e.g. neohesperidin, acesulfame K or, preferably, sucralose
  • 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.
  • 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.
  • 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.
  • 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.
  • 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)).
  • compositions of the invention 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).
  • unit dosage forms e.g. tablets.
  • 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).
  • 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.
  • compositions of the invention may be administered 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 membrane.
  • 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).
  • 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.
  • compositions of the invention are useful in the treatment of pain, such as acute, and particularly breakthrough, pain.
  • 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.
  • Granulated carrier particles comprising citric acid anhydrous (fine granular 16/40 grade, DSM, Switzerland, Basel) and mannitol (PearlitolTM 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:
  • citric acid contents in final tablets of 0.1%, 0.25% and 0.5% by weight, as appropriate.
  • 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.
  • microcrystalline cellulose (107.525 g; ProsolvTM 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; AcDiSolTM, 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.
  • microcrystalline cellulose 107.525 g; ProsolvTM 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; AcDiSolTM, FMC Biopolymer, Cork, Ireland; approximate
  • 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 Example 2
  • Example 2 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.
  • Example 3 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
  • Example 1 (b) 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.
  • citric acid anhydrous fine granular 16/40 grade; DSM, Basel, Switzerland; micronized using a Pilotmill-1 , Food and Pharma Systems, Italy
  • 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.
  • microcrystalline cellulose 107.53 g
  • croscarmellose sodium 8.050 g
  • trisodium phosphate anhydrous 32.20 g
  • Magnesium stearate 4.025 g was then added to this mixture and mixing continued for a further 2 minutes.
  • Example 3 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.
  • 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 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.
  • 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.

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Abstract

La présente invention concerne des compositions pharmaceutiques pour le traitement de la douleur, par exemple, une douleur paroxystique, lesdites compositions comprenant un mélange comprenant : (a) des microparticules de sufentanil, ou un sel pharmaceutiquement acceptable de celui-ci, lesdites microparticules étant présentées sur les surfaces de particules de support plus grandes ; (b) une base faible hydrosoluble ; et (c) un composé qui est un acide faible, ledit acide étant présenté en mélange intime avec les microparticules de sufentanil ou un sel de celui-ci. La composition peut comprendre en outre un délitant. L'acide est de préférence l'acide citrique.
PCT/GB2013/051128 2012-05-02 2013-05-01 Nouvelle composition de sufentanil pour le traitement d'une douleur aiguë WO2013164617A1 (fr)

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GB1207628.7 2012-05-02
GBGB1207628.7A GB201207628D0 (en) 2012-05-02 2012-05-02 New pharmaceutical composition
GB201304625A GB201304625D0 (en) 2013-03-14 2013-03-14 New pharmaceutical composition
GB1304625.5 2013-03-14

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN110325178A (zh) * 2016-12-26 2019-10-11 盐野义制药株式会社 改善含量均一性的制剂的制造方法

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20070104763A1 (en) * 2005-11-10 2007-05-10 Navinta Llc Composition of fentanyl citrate oral solid transmucosal dosage form, excipient and binding material therefore, and methods of making
WO2008068471A1 (fr) * 2006-12-04 2008-06-12 Orexo Ab Nouvelle composition pharmaceutique non susceptible d'abus comprenant des opioïdes
US20090263476A1 (en) * 2008-04-16 2009-10-22 Jobdevairakkam Christopher N Composition of Rapid Disintegrating Direct Compression Buccal Tablet
US20120035216A1 (en) * 2006-01-06 2012-02-09 Pamela Palmer Small volume oral transmucosal dosage forms containing sufentanil for treatment of pain

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20070104763A1 (en) * 2005-11-10 2007-05-10 Navinta Llc Composition of fentanyl citrate oral solid transmucosal dosage form, excipient and binding material therefore, and methods of making
US20120035216A1 (en) * 2006-01-06 2012-02-09 Pamela Palmer Small volume oral transmucosal dosage forms containing sufentanil for treatment of pain
WO2008068471A1 (fr) * 2006-12-04 2008-06-12 Orexo Ab Nouvelle composition pharmaceutique non susceptible d'abus comprenant des opioïdes
US20090263476A1 (en) * 2008-04-16 2009-10-22 Jobdevairakkam Christopher N Composition of Rapid Disintegrating Direct Compression Buccal Tablet

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN110325178A (zh) * 2016-12-26 2019-10-11 盐野义制药株式会社 改善含量均一性的制剂的制造方法
EP3560487A4 (fr) * 2016-12-26 2020-07-29 Shionogi & Co., Ltd. Méthode de production pour formulation ayant une uniformité de teneur améliorée

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