Pharmaceutical compositions for nasal delivery

Abstract

According to the present invention, there is provided a solid pharmaceutical composition formulation for nasal delivery of an opioid antagonist, comprising a pharmacologically effective amount of an opioid antagonist and a pharmaceutically acceptable carrier. The composition is preferably in the form of a powder produced by spray drying, which is then loaded into a disposable nasal applicator. Preferred pharmaceutically acceptable carriers in this regard include disaccharides (e.g., lactose or trehalose) and dextrins (e.g., cyclodextrin or maltodextrin), preferably spray dried in combination. The composition may further comprise an alkyl sugar, preferably a sucrose ester, such as sucrose monolaurate. The composition and applicator can be used to treat an opioid overdose in a subject.

Description

[0001] The present invention relates to novel pharmaceutical compositions containing opioid antagonists, which are useful for treating opioid / opiate overdose, etc. The present invention also relates to methods of making such compositions and formulating them into dosage forms, and their use in treating opioid / opiate overdose.

[0002] Prior Art and Background

[0003] The listing or discussion of an apparently prior published document in this specification should not necessarily be taken as an admission that the document is part of the prior art or common general knowledge.

[0004] Drug addiction is a worldwide problem, of which opioid dependence is a major component. Opioids and opiates are highly addictive. People often start using illegal opioids, such as heroin (demorphine), for recreational purposes, but this often leads to dependence.

[0005] That said, over the past decade or so, particularly in the United States, a new class of opioid-dependent individuals has emerged, the so-called 'white collar' addicts, who rely on prescription opioids, often initiated for the treatment of pain.

[0006] This is due to the increasingly widespread use of pharmaceutical opioids as analgesics for the treatment of moderate to severe, chronic cancer pain as well as acute pain (e.g., during surgical recovery and during breakthrough pain). In addition, their use in the treatment of chronic, non-malignant pain is increasing.

[0007] People who become addicted to prescription opioids sometimes turn to illegal ('street') drugs such as heroin. This may be because heroin is cheaper and (relatively speaking) easier to obtain than prescription opioids.

[0008] In 2010, it was estimated that there were 15.5 million people with opioid dependence worldwide. Prevalence rates in Australasia, Western Europe, and North America are higher than the global prevalence. According to the 2017 European Monitoring Centre for Medicines and Drug Addiction report, there were an estimated 1.3 million high-risk opioid users in Europe in 2016. The opioid crisis has particularly affected the United States, and the situation has escalated in recent years.

[0009] Opioid dependence is therefore a major health problem, with long-term opioid use significantly increasing the risk of premature death from drug overdose, violence and suicide, and a variety of other well-known health problems, along with exponentially increasing socioeconomic impacts in terms of health care costs, lost productivity, addiction treatment, and criminal activity (see Florence et al, Med. Care., 54, 901 (2016)).

[0010] Opioid addicts often satisfy their addiction by purchasing opioids in the form of opioid powders (e.g., heroin) directly 'on the street'. Heroin is often mixed (or 'cut') with additives before being sold by drug dealers, and the amount and composition are almost always unknown to the abuser. In addition, more and more addicts are sold and abused more potent opioids intended for the treatment of, for example, pain, such as fentanyl and its analogs (see, e.g., Prekupec et al, J. Addict. Med., 11, 256-265 (2017)).

[0011] Even without these additional issues, opioids are extremely dangerous drugs if not delivered under medical supervision. Since there is no quality control on the illegal drugs sold, especially in terms of purity and strength issues discussed above, the whole process is a bit of a 'lottery' which increases the danger and likelihood of overdose.

[0012] An overdose of opioids causes a decrease in heart rate and breathing, which leads to hypoxia. Hypoxia can lead not only to short-term and long-term effects on the central nervous system, including coma and permanent brain damage, but often to death. Overdose from opioids, especially heroin, is common. In 2015, drug overdoses killed 52,404 people in the United States, of which 33,091 (63.1%) involved opioids (see Rudd et al, MMWR, 65, 1445 (2016)). It's not like people are new to overdoses when they first start using heroin.

[0013] Subjects who have overdosed on opioids require urgent medical attention. The only medications available to effectively treat opioid overdose are opioid receptor antagonists, which work by binding to opioid receptors, displacing opioid agonists (such as heroin) without causing their own opioid effects, either intended (e.g., euphoria) or unintentional and / or potentially dangerous (including respiratory depression). Emergency administration of opioid antagonists can reduce (sometimes completely reduce) the extent of opioid intoxication and, in essence, 'reverse' an opioid overdose.

[0014] Opioid antagonists are administered as intravenous solutions by medically qualified staff in hospital emergency departments. However, relatively few treatments are available to treat opioid overdose (or suspected overdose) outside of the hospital setting.

[0015] Two such treatments available commercially include the opioid antagonist naloxone, which is delivered in a single dose as a liquid nasal spray ( spray directly into one nostril), or as an auto-injector These treatments are often administered by first responders (i.e., non-medically qualified personnel such as ambulance crews, paramedics, police, family, friends, or other caregivers) to buy time until more qualified medical assistance arrives.

[0016] These products are undoubtedly effective and help save lives. Naloxone and other opioid antagonists are highly water-soluble drugs, and products such as Narcan are able to dissolve an effective dose of naloxone in a small amount of liquid (100 μL) to treat opioid overdose. This allows it to be taken quickly in emergency situations.

[0017] However, in about one-third of cases, Narcan is known to require two or more doses to reverse an overdose. Additionally, Narcan has the disadvantage of not allowing freezing (otherwise it cannot be dispensed). This is a problem in cold climates, for example, if the product is left in a first responder's car overnight.

[0018] On the other hand, Evzio is a parenteral product that requires a needle, which presents significant difficulties and / or problems for some first responders during emergency situations.

[0019] Due to the substantial increase in overdose deaths due to opioid misuse, there is a considerable need for opioid overdose prevention medications, and there is a clear clinical need for alternative medications and / or improvements in strength, onset, and duration of action, as well as reproducibility and reliability as medications in emergency situations, which is certainly the case for the treatment of opioid overdose.

[0020] In addition to the commercial product Narcan, liquid intranasal sprays are also disclosed in international patent application WO 2018 / 064672 and U.S. patent applications US 2018 / 0092839A and US 2019 / 0070105A.

[0021] Dry powder formulations comprising opioid antagonists that can be administered by inhalation or intranasally are known from international patent applications WO 2010 / 142696 and WO 2019 / 038756 and US patent application US 2018 / 0092839A, among others.

[0022] Russo et al (J. Pharm. Sci., 95, 2253 (2006)) disclosed spray-dried opioid analgesic compound morphine and various excipients. Vengerovich et al., Bulletin of Experimental Biology and Medicine, 163, 737 (2017) also disclosed a spray-dried preparation, in which an attempt was made to microencapsulate naloxone in various substances including 2-hydroxypropyl-β-cyclodextrin in order to develop a sustained-release preparation for emergency treatment based on a polymer carrier.

[0023] Sugar esters are a class of natural and biodegradable nonionic surfactants consisting of a hydrophilic sugar 'head group' esterified with fatty acids. The properties of sugar esters depend on the nature of the sugars and fatty acids used, as well as the degree of esterification of the sugars. They are made from natural products, sugars and edible fats, are tasteless, odourless and biodegradable, and are relatively non-toxic, with a recommended acceptable daily intake of up to 30 mg / kg (Joint FAO / WHO Expert Committee on Food Additives (JECFA)). Sugar esters, especially sucrose esters, are widely used in the food and cosmetics industries, but have been relatively underutilized in pharmaceutical formulations to date (see, for example, and Szabó-Révész in Int. J. Pharm., 433, 1 (2012)).

[0024] Sucrose esters are known to be excellent oil-in-water emulsifiers. For example, emulsion-based compositions comprising sucrose esters are described in International Patent Application WO 2005 / 065652. See also International Patent Application WO 2003 / 061632.

[0025] Sucrose esters have also been used to increase the bioavailability of poorly water-soluble drugs such as cyclosporine in oral dosage forms (see Hahn and Sucker, Pharm. Res., 6, 958 (1989)). (It should be noted that naloxone and other opioid antagonists are highly water-soluble.)

[0026] Other oral dosage forms comprising sucrose esters are described in international patent application WO 2016 / 016431 and the like.

[0027] International patent applications WO 2015 / 095389 and WO 2018 / 089709 and U.S. Patent No. US 9,895,444 also disclose that related compounds, sugar ethers, especially alkyl glycosides, can improve the bioavailability of opioid compounds in liquid nasal sprays. Sucrose esters are also mentioned in these documents. Similar drug delivery carriers are disclosed in U.S. patent application US 2016 / 0045474. In addition, Kürti et al. studied the effect of sucrose esters on epithelial permeability in a culture model (see Toxicology in Vitro, 26, 445 (2012)), and Li et al. studied the effects of various surfactants (including sucrose laurate) in in vivo absorption studies in rats, using sumatriptan as a model drug substance (see Drug Delivery, 23, 2272 (2016)).

[0028] However, to the applicant's knowledge, there are no reports of the use of sucrose esters in solid (eg, powder) formulations for intranasal delivery.

[0029] We have now unexpectedly discovered that opioid antagonists can be formulated in the form of dry powder compositions that provide surprising and substantial improvements in the bioavailability of the opioid antagonists, and even more surprisingly, an increase in the rate of absorption of the opioid antagonists compared to commercially available products. In particular, we have discovered that compositions produced by a spray drying process using specific combinations of carrier materials disclosed below, and / or similar dry powder compositions comprising alkyl sugars, such as sucrose esters, are able to produce these unexpected effects. Summary of the invention

[0030] According to a first aspect of the present invention, there is provided a solid pharmaceutical formulation / composition suitable for nasal delivery of an opioid antagonist, comprising a pharmacologically effective amount of an opioid antagonist and a pharmaceutically acceptable carrier material.

[0031] According to a second aspect of the present invention, there is provided a solid pharmaceutical formulation / composition in powder form suitable for nasal delivery of an opioid antagonist, comprising a pharmacologically effective amount of an opioid antagonist, optionally an alkyl sugar, and a pharmaceutically acceptable carrier material.

[0032] Preferably, the powder is produced by a spray drying process. According to a third aspect of the present invention, there is provided a solid pharmaceutical formulation / composition in the form of a spray-dried powder suitable for nasal delivery of an opioid antagonist, comprising a pharmacologically effective amount of an opioid antagonist and a pharmaceutically acceptable carrier material, more preferably a carrier material comprising a combination of at least two pharmaceutically acceptable carrier materials, wherein at least one carrier material is a disaccharide and at least one carrier material is a dextrin.

[0033] The compositions of the first, second and third aspects of the invention are hereinafter collectively referred to as 'compositions of the invention'.

[0034] The term 'solid' will be well understood by those skilled in the art to encompass any form of matter which retains its shape and density when unrestrained and / or in which the molecules are generally packed as tightly as the repulsive forces therebetween permit.

[0035] Opioid antagonists useful in the compositions of the present invention include any compound that has little to no opioid activity but is capable of displacing an opioid agonist from an opioid receptor, thereby reversing or preventing the pharmacological effects of the opioid agonist, whether such effects are intended (euphoria, sedation and / or reduced craving), or unintentional (unconsciousness, decreased heart rate, decreased lung function, hypoxia, etc.). In this regard, the term 'opioid receptor agonist' includes both exogenous opioid receptor ligands (i.e., those mentioned above) and endogenous opioid receptor ligands (e.g., endorphins).

[0036] Therefore, opioid antagonists include naloxone, nalmefene and naltrexone, or pharmacologically acceptable salts thereof. Preferred salts of these compounds include hydrochlorides. Naloxone and nalmefene (and salts thereof) are particularly preferred.

[0037] In the context of the present invention, the term 'opioid antagonist' may also include active pharmaceutical ingredients that are known to be partial antagonists of opioid receptors, such as buprenorphine. Buprenorphine may be referred to as a 'partial antagonist of opioid receptors' because it is a partial agonist of the μ-opioid receptor. It has a high binding affinity and competes with other agonists (such as methadone, heroin and morphine) for the μ-opioid receptor. The opioid agonist effect of buprenorphine is less than the maximum effect of other 'full' opioid agonists (such as morphine) and is limited by a 'ceiling' effect. Therefore, the drug produces less physical dependence than other opioid agonists (such as heroin, morphine or methadone) and can therefore be used in substitution therapy. The risk of overdose is reduced in subjects who are tolerant to opioids and the recreational value is reduced. Buprenorphine has been included in the WHO list of essential medicines for the treatment of opioid dependence. Displacement of a full agonist may make buprenorphine useful in the context of the present invention because buprenorphine is able to reverse opioid overdose and has a lower degree of inducing withdrawal than a full antagonist.

[0038] The amount of opioid antagonist used in the compositions of the present invention must be sufficient to antagonize the effects of the opioid receptor agonist (whether exogenous and / or endogenous), precipitate withdrawal symptoms and / or reversal of the pharmacological effects mentioned above. The pharmacologically suitable amount of the opioid antagonist (or its salt) can be determined by the skilled person and can vary with the type and severity of the condition to be treated and the situation that is most suitable for the individual patient. This may also vary with the nature of the formulation and the route of administration, the type and severity of the condition to be treated, and the age, weight, sex, renal function, liver function and response of the specific patient to be treated.

[0039] The total amount of opioid antagonists that can be used in the compositions of the present invention will depend on the nature of the active compounds included, but can be in the range of about 0.1%, such as about 1%, such as about 2% to about 95%. For example, based on the total weight of the composition by weight, the amount of opioid antagonists can be about 5%, such as about 10% (e.g., about 20%) to about 95%, such as about 75%, such as about 50%, such as about 40%.

[0040] Suitable doses of the opioid antagonist per unit dose (calculated as free acid / base) are in the range of about 1 mg to about 60 mg (e.g. about 40 mg), for example between about 2 mg and about 30 mg (e.g. about 20 mg, e.g. about 10 mg), depending on the opioid antagonist employed.

[0041] Suitable doses of naloxone (calculated as free base) are in the range of about 1 mg to about 20 mg (e.g. about 15 mg), for example between about 1.5 mg to about 10 mg, thus about 1.8 mg, about 5.4 mg, about 9.0 mg (e.g. about 10.8 mg), more preferably about 3.6 mg, especially about 7.2 mg.

[0042] Suitable dosages of nalmefene per unit dose (calculated as free base) may be from about 0.5 to about 10 mg, more preferably from about 1 mg to about 6 mg, including about 1.5 mg, especially about 3.0 mg.

[0043] A suitable dosage of naltrexone per unit dosage form (calculated as the free base) may be from about 1 mg to about 20 mg (eg, about 15 mg), more preferably from about 1.5 mg to about 10 mg.

[0044] With respect to any of the above aspects of the invention, suitable pharmaceutically acceptable carrier materials that can be used in the composition include any such relevant materials that are suitable (and / or approved) for pharmaceutical use and / or intranasal delivery and that are capable of maintaining their physical and / or chemical integrity in the solid state, under normal storage conditions and / or do not affect the physical and / or chemical integrity of the opioid antagonist and / or any other ingredients that may be present in the composition (e.g., alkyl sugars).

[0045] The phrase 'maintaining physical and chemical integrity' essentially refers to chemical stability and solid state stability.

[0046] By 'chemical stability' we include that any composition of the invention can be stored in isolated solid form, or when loaded into a nasal applicator or reservoir thereof (with or without appropriate pharmaceutical packaging), under normal storage conditions, with an insignificant degree of chemical degradation or decomposition.

[0047] By 'solid state stability' we include that any composition of the invention can be stored in isolated solid form, or when loaded into a nasal applicator or reservoir thereof (with or without appropriate pharmaceutical packaging), under normal storage conditions, has an insignificant degree of solid state transition (e.g. crystallization, recrystallization, loss of crystallinity, solid state phase change (e.g. between a glassy or rubbery state, or to an agglomerated form)), hydration, dehydration, solvation or desolvation.

[0048] Examples of 'normal storage conditions' for the compositions of the invention, whether packed into an applicator, device, drug reservoir (e.g., can or container) or otherwise, include a temperature of about -50°C to about +80°C (preferably about -25°C to about +75°C, e.g., about 50°C), and / or a pressure of between about 0.1 and about 2 bar (preferably atmospheric pressure), and / or exposure to UV / visible light of approximately 460 lux, and / or a relative humidity of about 5% to about 95% (preferably about 10% to about 40%), for an extended period of time (i.e., greater than or equal to about twelve months, e.g., about six months).

[0049] Under such conditions, the compositions of the present invention may be found to chemically degrade / decompose by less than about 15%, more preferably less than about 10%, and especially less than about 5%, and / or undergo solid state transformation where appropriate. The skilled person will appreciate that the above upper and lower limits for temperature and pressure represent extremes of normal storage conditions, and that certain combinations of these extremes will not be experienced during normal storage (e.g., a temperature of 50° C. and a pressure of 0.1 bar).

[0050] Such chemical stability, and especially physical stability, is critical in solid dosage forms (eg, powders) used to treat, for example, opioid overdose.

[0051] It is well known that great difficulties may be experienced when attempting to obtain chemically and physically stable solid compositions such as powders. In the present case, if the physical form of the composition of the present invention changes under normal storage conditions (e.g., from a free-flowing powder to a difficult-to-discharge mass), it may result in irreproducibility of the dose of the opioid antagonist when dispensing the composition from or through a nasal applicator (or even a complete inability to dispense the composition), which would put the life of the subject at significant risk.

[0052] For certain compositions of the invention (e.g., powders), exposure to atmospheric water may result in a composition with poor solid state stability. For example, exposure to certain (e.g., high) relative humidities may affect the physical form of the composition, for example, by deliquescing and / or by lowering the glass transition temperature of the composition and / or individual components of the composition, such as carrier materials, or in other ways.

[0053] Therefore, the compositions of the present invention and nasal applicators comprising them are preferably packaged in containers that substantially prevent the ingress of atmospheric water under normal storage conditions as defined above. Such containers may include packaging materials such as heat-sealed aluminum bags and / or thermoformed plastics.

[0054] When the composition comprises an alkyl sugar, suitable pharmaceutically acceptable solid carrier materials therefore include cellulose and its derivatives, such as sodium carboxymethylcellulose, ethylcellulose, cellulose acetate, hydroxypropyl methylcellulose (hydroxypropyl methylcellulose, HPMC), hydroxyethylcellulose (HEC), hydroxypropyl cellulose (HPC), methylcellulose (MC), ethyl hydroxyethylcellulose, carboxymethylcellulose (CMC), modified cellulose gum, microcrystalline cellulose and sodium carboxymethylcellulose; starches, such as rice starch, tapioca starch, wheat starch, more particularly, corn starch and potato starch; starch derivatives, such as pregelatinized starch, carboxymethyl starch and moderately cross-linked starch, modified starch and sodium starch glycolate; polysaccharides, including dextrins, such as dextrin, cyclodextrin and linear or branched dextrin , such as maltodextrin; tragacanth powder; malt; gelatin; talc; waxy excipients, such as cocoa butter and suppository waxes; polyols, such as solid polyethylene glycols; sugars, sugar alcohols and sugars, such as mannitol, maltitol, xylitol, sorbitol, lactose, glucose, galactose, sucrose, sucralose, trehalose, maltose, isomalt and glucose; acrylic acid polymers, such as carbomer and its derivatives; polyvinyl pyrrolidone (povidone, PVP); cross-linked polyvinyl pyrrolidone; polyethylene oxide (PEO); chitosan (poly (D-glucosamine)); natural polymers, such as gelatin, sodium alginate, pectin; scleroglucan; xanthan gum; guar gum; (methyl vinyl ether / maleic anhydride) copolymer; and cross-linked carboxymethylcellulose (e.g., cross-linked sodium carboxymethylcellulose). Mention may also be made of hydroxypropylmethylcellulose acetate succinate (HPMCAS), copovidone and polyvinyl alcohol (PVA or PVOH). Mixtures of any of the foregoing may be used.

[0055] Thus, the composition according to the first aspect of the invention may be compressed into a single unit dosage form, granulated into a pellet or a pill, but is preferably provided in the form of a dry, free-flowing powder. The composition of the second and third aspects of the invention is provided in the form of a dry, free-flowing powder. In the context of any aspect of the invention, 'dry' includes substantially free of water and other liquid solvents, comprising less than about 10%, such as less than about 5%, more preferably about 3%, such as less than about 2%, such as less than about 1% of the formulation is liquid, such as water.

[0056] The composition of the present invention can therefore be administered in the form of a plurality of particles, which can consist of and / or comprise the composition of the present invention alone and / or together. The composition of the present invention can be prepared in the form of a simple powder mixture, powder microspheres, coated powder microspheres, freeze-dried liposome dispersions or a combination thereof.

[0057] Whether in powder form or other forms, the amount of carrier material that can be used in the composition of the present invention is generally in the range of about 5% to about 99.9%, including up to about 99% (e.g., up to about 95% or about 90%), such as about 10% (e.g., about 25%, including about 35%) to about 85%, including about 50% to about 75%, based on the total weight of the composition.

[0058] In addition, whether in powder form or other forms, the composition of the present invention can be prepared by standard techniques known to technicians and using standard equipment known to technicians. In this regard, the composition of the present invention can be combined with conventional drug additives and / or excipients for related preparations in the art, and standard techniques are used to be incorporated into various pharmaceutical preparations (see, for example, Lachman et al., "Industrial Pharmacy Theory and Practice of Industrial Pharmacy", Lea and Febiger, 3rd edition (1986); "Remington: Pharmaceutical Science and Practice, Troy (ed.), University of the Sciences in Philadelphia, 21st edition (2006); and / or "Aulton's Pharmaceutics: The Design and Manufacture of Medicines", Aulton and Taylor (ed.), Elsevier Publishing Company (Elsevier), 4th edition, 2013).

[0059] Dry powders can be prepared by mixing the opioid antagonist with a pharmaceutically acceptable carrier material and (if present) an alkyl sugar and any other ingredients that may be included. Suitable techniques that may be used include simple dry mixing, granulation (including dry granulation, wet granulation, melt granulation, thermoplastic granulation, spray granulation), extrusion / spheronization or freeze drying.

[0060] Dry granulation techniques are also well known to those skilled in the art and include any technique whereby primary powder particles are agglomerated under high pressure, including slugging and roller compaction, such as described below.

[0061] Wet granulation techniques are well known to those skilled in the art and include any technique involving agglomerating a mixture of dry primary powder particles using a granulating fluid comprising a volatile inert solvent, such as water, ethanol or isopropanol, alone or in combination, and optionally in the presence of a binder or binding agent. The technique may include forcing the wet material through a sieve to produce wet granules which are then dried, preferably with a drying loss of less than about 3% by weight.

[0062] It is known to those skilled in the art that melt granulation includes any technique for obtaining particles by adding a molten binder or a solid binder (the binder material may contain a pharmaceutically acceptable carrier material) that melts in the process. After granulation, the binder solidifies at room temperature. It will be known that thermoplastic granulation is similar to melt granulation, but the plasticity of the binder is used. In both methods, the agglomerates (particles) obtained contain a matrix structure.

[0063] Extrusion / spheronization is well known to those skilled in the art and includes any process involving dry mixing of ingredients, wet agglomeration with a binder, extrusion, spheronization of the extrudate into uniformly sized spheres, and drying.

[0064] It is known to those skilled in the art that spray granulation includes any technology involving the drying of a liquid (solution, suspension, melt) while forming particles in a fluidized bed. Therefore, the term includes the process of providing an external seed (origin) and forming particles thereon, as well as the process of forming an inherent seed (origin) in a fluidized bed due to abrasion and / or rupture, and generally any spray coating granulation technology. The sprayed liquid covers the origin and contributes to the further agglomeration of the particles. It is then dried to form particles in the form of a matrix.

[0065] The term 'freeze drying' includes freeze drying or freeze drying, and any low temperature desolvation (eg dehydration) process in which the product is frozen, the pressure reduced and the freezing solvent (eg water) removed by sublimation.

[0066] However, we prefer to prepare the compositions of the present invention by a spray drying process.

[0067] The skilled person will appreciate that spray drying includes any method of producing a dry powder from a liquid, including a solution or suspension (including a slurry), which involves rapid drying using hot gases to convert a liquid stream into a vaporized solvent and solid particles comprising solutes previously dissolved in the solution, and / or particles previously suspended in the vaporized liquid.

[0068] Suitable spray drying equipment includes some form of atomizing device, such as a nozzle, which disperses a liquid into a spray having a relatively uniform droplet size. Such devices may include any device capable of producing a dry, free-flowing powder, and may include high-pressure vortex nozzles, rotating disks and / or atomizing wheels, high-pressure single-fluid nozzles, two-fluid nozzles, and / or ultrasonic nozzles.

[0069] The spray dryer may be a single-effect or multiple-effect spray dryer and may include an integrated and / or external vibrating fluidized bed, a particle separator and / or a collecting device, which may be a rotating drum or a cyclone separator.

[0070] Spray drying can be used to produce the compositions of the invention in powder form and in the process to encapsulate the substances in carrier materials, or to produce amorphous composites of active ingredient, carrier material and other ingredients.

[0071] In this regard, the composition of the present invention in powder form, especially if produced by spray drying, can be considered to contain multiple particles, which are themselves 'single particles' in their nature. About 'single particles', we include particles containing homogeneous or heterogeneous mixtures, in which the active ingredient is encapsulated in a carrier material in an amorphous state in the presence of other ingredients (e.g., amorphous complexes of those substances). In this regard, such compositions of the present invention do not include a mixture of discrete, separate particles of two or more different ingredients in the form of a mixture, such as an ordered or interactive mixture of smaller particles of an active ingredient associated with larger but separated and chemically different carrier material particles, as often occurs in the case of inhaled drug delivery compositions (see, e.g., Mehta, J. Drug Delivery, Art. ID 5635010, 1-19 (2018)).

[0072] Thus, the spray-dried compositions of the present invention are preferably amorphous in nature, including completely amorphous and / or predominantly amorphous (e.g., greater than about 50% by weight, such as greater than about 75% by weight, including greater than about 80% by weight, such as greater than about 90% by weight, or 95% by weight, including greater than about 99% by weight amorphous), and can produce a pharmaceutical product that exhibits excellent shelf life both physically and chemically when stored under normal storage conditions, as defined above.

[0073] According to another aspect of the present invention, there is provided a method for producing the composition of the present invention (in dry powder form), wherein the method comprises the following steps:

[0074] i) mixing together the opioid antagonist, the alkyl sugar (if present) and a pharmaceutically acceptable carrier material in a suitable volatile solvent,

[0075] ii) spray drying the mixture from step i) to form a spray dried plurality of particles.

[0076] Preferred volatile solvents include water or organic solvents, such as lower alkyl alcohols (such as ethanol), halogenated alkanes. Other solvents that may be mentioned include hydrocarbons (such as C 5-10 Alkanes), dimethylformamide, dimethyl sulfoxide, ethyl acetate, acetone, etc. Mixtures of any of the foregoing solvents may be used.

[0077] We prefer to mix the opioid antagonist, alkyl sugar (if present) and pharmaceutically acceptable carrier material with a solvent to produce a solution that can be spray dried.

[0078] Particularly preferred pharmaceutically acceptable carrier materials that can be used to prepare the spray-dried composition of the present invention (whether according to the first, second or third aspect of the present invention) and have the desired characteristics mentioned herein include sugars, more preferably disaccharides, such as maltitol, trehalose, sucralose, sucrose, isomalt, maltose, especially lactose (including β-D-lactose and α-D-lactose, especially α-D-lactose monohydrate); and / or polymers, including any of the polymeric materials mentioned above as suitable carrier materials (e.g. sodium carboxymethylcellulose, sodium starch glycolate, polyvinylpyrrolidone, dextrins, including cyclodextrins (e.g. α-, β- and γ-cyclodextrins and derivatives thereof, e.g. 2-hydroxypropyl-γ-cyclodextrin, sulfobutyl ether β-cyclodextrin sodium salt, random methylated β-cyclodextrin, branched β-cyclodextrin, etc., especially 2-hydroxypropyl-β-cyclodextrin); and linear or branched dextrins, such as maltodextrin, which can be classified by DE (dextrose equivalent), which can be between 3 and 20 (the higher the DE value, the shorter the glucose chain), especially maltodextrin, whose DE is between 6 and 15, for example between 8 and 12.

[0079] Also included within the scope of the present invention are combinations of two or more of the above preferred materials.

[0080] Preferably, the support material, whether a single support material or a combination of two or more support materials, is capable of producing a spray-dried composition of the present invention in powder form, wherein the composition has a glass transition temperature (Tg) of:

[0081] (a) enabling its manufacture in a hard and / or brittle, 'glassy', amorphous, powdery physical form which can be readily loaded into a nasal applicator or into a drug reservoir and / or container in or attached to such an applicator, as described herein; and

[0082] (b) sufficiently high that after such an applicator or reservoir is packaged as described herein, and thereafter subjected to high external temperatures (e.g., up to about 50°C to about 80°C), it remains in a glassy state rather than transforming to a more viscous or rubbery state, and / or a crystalline state.

[0083] In warm and / or sunny climates, such extreme exterior temperatures are often experienced inside vehicles (e.g., emergency personnel vehicles) that will often be parked for extended periods of time in full sunlight, and the heat gain generated in such circumstances can be substantial. If the Tg of the composition of the present invention is low, the composition may transition to such a viscous / rubbery state upon exposure to such high temperatures that this would result in inefficient discharge of the composition from the applicator or reservoir (and a low dose of the opioid antagonist) once the applicator is activated.

[0084] In this regard, we prefer that the lowest measurable Tg of the composition of the present invention is at least about 40°C, such as at least about 50°C, such as at least about 55°C, including at least about 60°C, when at a relative humidity of up to about 35%, such as up to about 30%, including up to about 25% (e.g. up to about 20%, such as less than about 15%, such as less than about 10%). With respect to 'lowest measurable Tg', we include that the composition of the present invention may comprise particles that are heterogeneous in nature. In particular, if more than one carrier material is used, the particles may comprise discrete regions of the carrier material or a composite mixture thereof, which may have separate and separate Tg values. It will be clear to those skilled in the art that the value of the lowest measurable Tg has a significant impact on the physical stability of the composition.

[0085] When the carrier material comprises a combination of one or more disaccharides (as defined above) and one or more polymer components (as defined above, but particularly when the polymer is a dextrin), the relative amounts of these components in the combination may be adjusted to ensure the required level of physical and / or chemical stability of the active ingredient while not lowering the Tg of the composition of the invention in a manner that affects its physical stability. We have found that a ratio of disaccharide:polymer (e.g., dextrin) between about 50:1 and about 1:50 by weight, based on the total weight of the composition, may work depending on the active ingredient used. Preferred ratios are in the range of about 10:1 to about 1:40 (including up to about 1:30 or up to about 1:20) by weight, based on the total weight of the composition, for example between about 2:1 and about 1:10, more preferably about 1:1 to about 1:8 disaccharide:polymer (e.g., dextrin).

[0086] In particular, and as described below, we have found that the compositions of the present invention, when produced by spray drying and:

[0087] (i) When disaccharides are used as carrier materials, the chemical stability of the opioid antagonists is greatly improved compared to monosaccharides (e.g., mannitol). This is surprising because mannitol has previously been used in physical mixtures with opioid antagonists (e.g., naloxone) without any stability issues;

[0088] (ii) Using dextrins such as cyclodextrin or maltodextrin as a carrier material provides significantly improved physical stability compared to other carrier materials.

[0089] (iii) however, the use of such dextrins resulted in unexpected chemical instability of the opioid antagonists;

[0090] (iv) This chemical instability can be addressed by spray drying the dextrin together with the disaccharide.

[0091] Thus, a particularly preferred combination of carrier materials comprises a disaccharide, especially trehalose, more preferably lactose, such as α-D-lactose monohydrate, and a dextrin, especially a cyclodextrin, such as 2-hydroxypropyl-β-cyclodextrin, or a maltodextrin, such as maltodextrin 12DE. We have found that such a combination of carrier materials can be spray dried with an opioid antagonist and an alkyl sugar in appropriate proportions to produce a composition of the invention having the desired physical and chemical stability under normal storage conditions, as defined above.

[0092] We have found that an amount of disaccharide between about 5% (particularly about 10%) and about 30%, such as between about 15% and about 25%, such as between about 17% and about 24%, by weight, based on the total weight of the composition, provides a desired level of chemical stability of an opioid antagonist such as naloxone, while not reducing the Tg of the composition of the invention in a manner that affects physical stability. Suitable amounts of dextrin are therefore between about 30% and about 90%, such as up to about 85%, including up to about 80%, especially up to about 75%, such as between about 40% and about 70%, such as between about 43% and 67%, by weight, based on the total weight of the composition.

[0093] As described below, the compositions of the present invention have been found to exhibit surprisingly good bioavailability and, compared to relevant reference products (e.g., in the case of naloxone, Narcan nasal spray), highly surprisingly more rapid absorption, which may result in a more rapid onset of action.

[0094] This was highly unexpected for several reasons, including:

[0095] (a) unlike the compositions of the present invention which are solid, in existing products such as Narcan, the opioid antagonist (in that case naloxone) is present in a pre-dissolved state, ready for absorption; and

[0096] (b) In any case, naloxone and the other opioid antagonists mentioned herein are known to be highly bioavailable drugs with rapid onset of action when administered through the nasal mucosa. Therefore, the composition represents a therapeutic improvement on something that already has high bioavailability and rapid onset of action.

[0097] As further described below, it was also found that the compositions of the invention comprising alkyl saccharides exhibited surprisingly good bioavailability and absorption rate compared to corresponding compositions not comprising alkyl saccharides and / or comprising different excipients known to act as surfactants. This is very surprising because these alkyl saccharides showed a tendency to reduce the penetration of opioid antagonists (e.g., naloxone) through mucosal membranes when tested in vitro, whereas different surfactants, including some listed below, showed a tendency to increase penetration.

[0098] Alkyl sugars useful in the compositions of the present invention include alkyl glycosides, which can be defined as any sugar attached to an alkyl group via a bond, such as C 7-18 Alkyl glycosides. Alkyl glycosides may therefore include alkyl maltosides (e.g. dodecyl maltoside), alkyl glycosides, alkyl sucrose sides, alkyl thiomaltosides, alkyl thioglucosides, alkyl thiosucrose and alkyl maltotriosides. However, we prefer that the alkyl sugar is a sugar ester.

[0099] Sugar esters useful in the compositions of the present invention include trisaccharide esters, such as raffinose esters, monosaccharide esters, such as glucose esters, galactose esters and fructose esters, and / or, preferably, disaccharide esters, such as maltose esters, lactose esters, trehalose esters, especially one or more sucrose esters.

[0100] The sucrose esters used in the compositions of the present invention have a hydrophilic-lipophilic balance value between 6 and 20. The term 'hydrophile-lipophile balance' (HLB) is a term of art that will be well understood by those skilled in the art (see, for example, "The HLB System: A Time-Saving Guide to Emulsifier Selection", published by ICI Americas Inc, 1976 (revised in 1980), Chapter 7 (pp. 20-21) of this document provides a method of how to determine the HLB value. The longer the fatty acid chain in the sucrose ester and the higher the degree of esterification, the lower the HLB value. Preferred HLB values ​​are between 10 and 20, more preferably between 12 and 20.

[0101] Sucrose esters therefore include C 8-22Saturated or unsaturated fatty acid esters, preferably saturated fatty acid esters and preferably C 10-18 Fatty acid esters and most preferably C 12 Fatty acid esters. Particularly suitable fatty acids from which such sucrose esters may be formed include erucic acid, behenic acid, oleic acid, stearic acid, palmitic acid, myristic acid and lauric acid. A particularly preferred fatty acid is lauric acid. Commercially available sucrose esters include those sold under the trademark and (Mitsubishi-Kagaku Foods Corporation, Japan). The sucrose ester may be a diester or a monoester of a fatty acid, preferably a monoester, such as sucrose monolaurate. The skilled person will appreciate that the term 'monolaurate' refers to a monoester of lauric acid, and that the terms 'ester of lauric acid' and 'laurate' have the same meaning and are therefore used interchangeably. Commercially available sucrose monolaurate products are sometimes also referred to as 'sucrose laurate'. Commercially available sucrose monolaurate (or sucrose laurate) products, such as sucrose monolaurate, may contain small amounts of diesters and / or higher sucrose esters as well as small amounts of other sucrose esters and free sucrose. D-1216 (Mitsubishi-Kagaku Foods Corporation, Japan) is suitable for use in the present invention. It will be understood by those skilled in the art that any reference herein to a specific sucrose ester includes commercially available products containing that sucrose ester as a major ingredient.

[0102] Preferred sucrose esters contain only one sucrose ester, which means that a single sucrose ester (e.g. a commercially available sucrose ester product) contains a single sucrose ester as the main component (commercially available products may contain impurities, e.g. a monoester product may contain small amounts of diesters and / or higher esters, in the context of the present invention, such products may be considered to 'contain only one sucrose ester'). As used herein, the term 'main component' will be understood to refer to the main component (e.g. greater than about 50%, e.g. about 70% weight / weight or volume / volume) in a mixture of sucrose esters, such as common commercially available surfactant products, which are usually sold with a range of ester compositions.

[0103] A particularly preferred sucrose ester is sucrose monolaurate.

[0104] The amount of alkyl sugar in the composition of the present invention is in the range of about 0.1% to about 50% by weight, more particularly up to about 10%, such as about 0.5% to about 5%, preferably about 0.75% to about 3% (e.g. to about 2%, such as about 1%), based on the total weight of the composition.

[0105] In addition to any alkylsaccharide component included in the compositions of the present invention, further optional additional excipients may be used.

[0106] Such additional excipients may include one or more (additional) surfactants. Surfactants that may be mentioned include polyoxyethylene esters (e.g. Myr TM ), including polyoxyl stearate 8 (Myrj TM S8), polyoxyl stearate 32 ( 48 / 16), polyoxyl stearate 40 (Myrj TM S40), polyoxyl stearate 100 (Myrj TM S100) and hydroxystearate polyoxyl 15 ( HS 15), polyoxyalkyl ethers (such as Brij TM ), including polyoxyhexadecyl octadecyl ether (e.g. Brij TM CS12, CS20 and CS25), polyoxylauryl ether (such as Brij TM L9 and L23) and polyoxy stearyl ether (such as Brij TM S10 and S20), and polyoxyglycerides (e.g. ), including lauroyl polyoxylglycerides ( 44 / 14) and Stearoyl Polyoxylglyceryl ( 50 / 13), sorbitan esters (such as Span TM ), including sorbitan monopalmitate (Span TM 40) and sorbitan monostearate (Span TM 60), polysorbate (Tweens TM ), including polysorbate 40 (polyoxyethylene (20) sorbitan monopalmitate), polysorbate 60 (polyoxyethylene (20) sorbitan monostearate) and polysorbate 20 (polyoxyethylene (20) sorbitan monolaurate) and sodium lauryl sulfate; and monoacylglycerols (monoglycerides), such as 2-oleoylglycerol, 2-arachidonoylglycerol, monolaurin, monomyristic, monopalmitin, hydroxystearin, and preferably monostearin, monoolein (e.g. ) and monoolein (e.g. ).

[0107] Other additional ingredients (excipients) that may be included in the compositions of the present invention include isotonic and / or osmotic agents (e.g., sodium chloride), sterols (or steroidal alcohols), such as cholesterol and phytosterols (e.g., campesterol, sitosterol, and stigmasterol); antioxidants (e.g., α-tocopherol, ascorbic acid, potassium ascorbate, sodium ascorbate, ascorbyl palmitate, butylated hydroxytoluene, butylated hydroxyanisole, dodecyl gallate, octyl gallate, propyl gallate, ethyl oleate, monothioglycerol, vitamin C); Vitamin E polyethylene glycol succinate or thymol); chelating (complexing) agents (e.g. edetic acid (EDTA), citric acid, tartaric acid, malic acid, maltol and galactose); preservatives (e.g. benzyl alcohol, boric acid, parabens, propionic acid, phenol, cresol or xylitol); viscosity modifiers or gelling agents (e.g. cellulose derivatives, including hydroxypropyl cellulose, methyl cellulose, hydroxypropyl methyl cellulose, carboxymethyl cellulose, etc., starch and modified starch, colloidal silicon dioxide, aluminum metasilicate, polycarbophil (e.g. ), Carbomer (e.g. ) and polyvinyl pyrrolidone); mucoadhesive polymers such as carboxymethyl cellulose, modified cellulose gum and sodium carboxymethyl cellulose (NaCMC); starch derivatives such as moderately cross-linked starch, modified starch and sodium starch glycolate; cross-linked polyvinyl pyrrolidone, acrylic acid polymers such as carbomer and its derivatives (Polycarbophyl, etc.); polyethylene oxide (PEO); chitosan (poly (D-glucosamine)); natural polymers such as gelatin, sodium alginate, pectin; scleroglucan; xanthan gum; guar gum; (methyl vinyl ether / maleic anhydride) copolymer; and cross-linked carboxymethylcellulose (e.g., cross-linked sodium carboxymethylcellulose); pH buffers (e.g., citric acid, maleic acid, malic acid, or glycine); colorants; penetration enhancers (e.g., isopropyl myristate, isopropyl palmitate, pyrrolidone, or trioctanoic acid); other lipids (neutral and polar); and aromatic carboxylic acids, such as benzoic acid, optionally substituted with one or more groups selected from methyl, hydroxyl, amino and / or nitro, such as toluic acid or salicylic acid.

[0108] The total amount of such 'additional' excipients (including surfactants other than one or more alkyl saccharides present (or possible) in the composition of the invention) may be up to about 15% (eg about 10%), for example up to about 5%, based on the total weight of the composition.

[0109] The skilled person will appreciate that if any additional optional ingredients are included in the compositions of the invention, the nature of these ingredients and / or the amount of those ingredients included should not adversely affect the Tg of the composition, for the reasons described above. In this regard, when the compositions of the invention are prepared by spray drying, these optional ingredients may be added during the spray drying process (i.e., mixed together with the opioid antagonist, optional alkyl sugar and pharmaceutically acceptable carrier material in a suitable volatile solvent and then spray dried), or may be included separately in the plurality of particles that are spray dried.

[0110] According to another aspect of the present invention, there is provided a composition of the invention for use in medicine (human and veterinary medicine), in particular for use in the treatment of overdose of substances (eg opioids, including opiates).

[0111] Overdose will be understood in the art to include the condition that occurs when a greater amount of an abusable substance (e.g., an opioid) is taken than the individual's body can tolerate, resulting in (in the case of opioids) central nervous system and respiratory depression, hypoxia, miosis, and apnea, one or more of which may result in death if not promptly treated (see above).

[0112] According to another aspect of the present invention, there is provided a method of treating overdose of a substance (eg, an opioid) comprising administering a composition of the present invention to a patient suffering from such a condition.

[0113] By 'treatment' of an overdose of a substance (e.g. an opioid), we include, in addition to therapeutic, symptomatic and palliative care, the prevention or diagnosis (i.e. if an overdose is suspected) of such an overdose. This is because, by using the compositions of the invention in the treatment of a drug overdose, they may eliminate or prevent the development of the symptoms of an opioid overdose mentioned above.

[0114] Care should be taken when administering compositions of the invention that include a partial opioid antagonist such as buprenorphine to ensure that the patient is actually overdosing on an opioid (and not, for example, a benzodiazepine). opioids), and / or the patient is physically addicted to opioids.

[0115] Opioid antagonists may also be administered to treat conditions mediated by endogenous opioid agonists (eg, endorphins), which may be collectively referred to as 'endorphin-mediated pleasure', manifesting as addictive behaviors (eg, excessive eating (bulimia), drinking (alcoholism), exercise, sex, gambling, etc.).

[0116] Therefore, according to another aspect of the present invention, there is provided a method for treating addiction and / or addictive behaviors mediated by activation of endogenous opioid agonists such as endorphins (including bulimia, alcohol dependence, and addiction to exercise, sex, gambling, etc.), the method comprising administering the composition of the present invention to a patient suffering from or susceptible to the relevant condition.

[0117] In the context of addiction and addictive behaviour, by 'treatment' we include, in particular, prophylaxis (prevention) and diagnosis of such disorders, as well as palliative and, in particular, symptomatic treatment of such disorders.

[0118] The compositions of the invention may be administered intranasally by any suitable means of intranasal administration known to the skilled person, such as by a nasal applicator or dispenser, a device capable of administering a suitable dose of the opioid antagonist in the form of a composition of the invention to the nasal cavity.

[0119] Thus, such an applicator device should be capable of containing and storing the composition of the invention itself, or be capable of being connected to a reservoir / container containing and storing the composition of the invention, for example in the form of a powder, and doing so without causing a significant loss of the physical and chemical integrity of the composition, including through the ingress of water. In this way, the composition is ready for use once the end user activates the applicator device, which then delivers the composition (e.g., powder) having an appropriate dose of an opioid antagonist as defined herein to the nasal mucosa of the subject.

[0120] Suitable applicator devices have been described in the prior art. When used with a composition of the invention, particularly a composition in powder form, such composition may be loaded into a reservoir attached to or forming part of such an applicator device, in which it is contained until the applicator device or dispenser is activated. In the following, the terms 'applicator', 'dispenser', 'device', 'applicator device', 'dispensing device', 'applicator device' and 'dispensing device' may be used interchangeably and mean the same thing.

[0121] Such an applicator device may therefore further comprise a mechanism for expelling the powder formulation from the reservoir through an outlet means, which may comprise any means sized to be placed within a human nostril, such as a nozzle of an appropriate shape.

[0122] Therefore, the applicator should be able to provide a reproducible and sufficient amount of the powder formulation in a single administration step (and in such a way that the device does not require 'priming') which will provide a therapeutic dose of the opioid antagonist.

[0123] Nasal applicators / inhalation devices that can be used to administer the compositions of the present invention in powder form may include multi-dose administration, such as metered dose inhalation devices (MDIs), dry powder inhalation devices (DPIs; including low, medium and high resistance DPIs) and soft mist inhalation devices (SMIs), which can be adapted according to techniques known in the art for delivering active ingredients to the lungs.

[0124] In MDIs, the compositions of the invention should be capable of forming a stable suspension when suspended in a solvent commonly used therein, such as a propellant having sufficient vapor pressure to form an aerosol upon activation of the delivery device (e.g., hydrocarbons, fluorocarbons, hydrofluorocarbons, or mixtures thereof).

[0125] However, we prefer that the nasal applicator be a single dose applicator from which the composition is dispensed upon actuation and then disposed of after use.

[0126] In this regard, suitable applicator devices or apparatus include those described in US 6,398,074, US 6,938,798 or US 9,724,713, all of which are incorporated herein by reference for their relevant disclosures. Figure 1 and Figure 2 Based on US 6,398,074 Figure 1 and Figure 2 , Figures 3 to 7 Based on Figures 19 to 23 of US 9,724,713 respectively. Both are examples of applicators that can be used for intranasal administration of the composition of the present invention.

[0127] exist Figure 1 In the embodiment of the present invention, the device comprises an upper body / dispenser head 1 (i.e. part of the 'outlet device' as described above) containing an outlet channel 40 and a gripping device 60 allowing a user to actuate the device. Inside the upper body / dispenser head 1 is mounted an element, indicated in its assembly by reference numeral 2, which comprises a reservoir 10 and an air chamber 22 for blasting 20. The element 2 may be made integral with the body 1. A lower body 3 is also provided so as to be able to slide relative to the upper body 1 and relative to the element 2, on which the user applies a thrust to actuate the device.

[0128] The reservoir 10 contains a single dose of the composition of the invention. The reservoir 10 has an air inlet 11 and a product outlet 15. A product retaining device 12 comprising an air-permeable mesh is provided in the air inlet 11 to retain the product in the reservoir 10 until the composition is dispensed. The product outlet 15 is preferably closed in a sealed manner by a closure ball 16 which is moved from its closed position by the air flow when the applicator is actuated and the product is dispensed.

[0129] When the user activates the device, pressure is exerted on the plunger 25 in such a way that the piston 21 compresses the air 20 contained in the chamber 22. Since the grid 12 is permeable to air, the compression of the air in the chamber 22 generates a jet of air which is conveyed to the reservoir 10 and is thus applied to the closing ball 16 which blocks the product outlet 15.

[0130] The dimensions of the closing ball 16 and its fixing at the reservoir product outlet 15 are such that the ball 16 moves from its blocking position when a minimum predetermined pressure is generated through the reservoir 10 by the injection of air 20 .

[0131] The precompression created by the closing ball 16 ensures that when it is removed from its blocking position, the energy accumulated in the user's hand causes the piston 21 integral with the plunger 25 to be propelled within the chamber 22, thereby generating a powerful air flow 20, i.e. an air flow suitable for finely spraying a dose of the composition of the invention.

[0132] When this minimum pressure is reached, the ball moves rapidly towards the outlet passage 40 of the device and the air flow 20 generated by the blast expels substantially all of the dose of the composition of the invention contained in the reservoir 10 .

[0133] Preferably, the diameter of the outlet channel 40 is greater than the diameter of the closing ball 16 to allow the product dose to be discharged through the outlet channel 40 by flowing around the ball 16. Figure 2 4 , which shows the same device after actuation, the channel 40 comprises means 41 for stopping or securing the ball 16 so as to prevent it from exiting the device when the product is being discharged.

[0134] Another embodiment of the composition of the present invention which can be used for intranasal administration is provided in US 9,724,713, column 7, lines 50 to column 8, line 61 and Figures 19 to 23, which are reproduced as herein. Figures 3 to 7 .

[0135] In this embodiment, the reservoir 10 is fixed in an upper body / dispenser head 1 (i.e. part of the 'outlet means' as described above) which includes a dispenser outlet passage 40, which has a gripping means or finger rest 60 to allow the user to activate the device. The radial shoulder 37 (see Figure 5 ) advantageously defines the assembly position of the reservoir 10 in the upper body / dispenser head 1 .

[0136] The mechanical opening system comprises a set of rods 61, 62, wherein when the device is actuated, a second rod portion 62 is pushed by said first rod portion 61. At the end of their actuation stroke, i.e. in the dispensing position, the set of rods 61, 62 cooperates with the closing element 16, which is spherical, in particular a ball as in the first embodiment described above, in order to mechanically expel it from its closed position.

[0137] In this embodiment, the piston 21 is separated from the first rod portion 61 and slides relative to the air chamber 22 and the cylindrical surface 614 fixed to the first rod portion 61 . Figure 7 yes Figures 3 to 6 Schematic perspective view of the air expeller of the device in its resting position.

[0138] The air chamber 22 can thus be cylindrical and in its rest position communicate with the ambient air at a notch or groove 615 formed in the surface 614 of said cylinder and cooperating with the piston 21, in particular in its rest position. The piston 21 thus comprises an inner lip 215 which slides on the cylindrical wall 614 in an airtight manner during actuation and which cooperates with said groove 615 in its rest position. The piston 21 also comprises an axial extension 216 which co-operates with the top edge 251 of the push element 25 (referred to as a "plunger" in the first embodiment) which moves said piston 21 in the air chamber 22 during actuation.

[0139] The retainer member 42 extends downwardly by an axial extension 43 which, during actuation, comes into contact with the top axial end 610 of the first shaft portion 61 .

[0140] In addition, in the present embodiment, there is no outer body, and only a cover 27 is assembled on the lower axial edge of the air chamber 22 .

[0141] A spring 80 is provided between the radial flange 225 of the air chamber 22 and the portion forming the first rod portion 61 and the cylindrical surface 614 so that the air expeller automatically returns to the rest position after actuation.

[0142] The working principle is as follows. Figure 3 In the rest position in , the reservoir 10 is closed in a sealing manner by the retaining member 42 and the closing element / ball 16. By the cooperation between the inner lip 215 of the piston 21 and the groove 615 of the cylindrical surface 614, the air expeller is open to the atmosphere.

[0143] When it is desired to activate the device, the user presses the push element 25. During this initial stroke, the inner lip 215 of the piston leaves the groove 615 to cooperate with the cylindrical surface 614 in an airtight manner, thereby closing the air chamber 22. At the same time, the top edge 251 of the push element 25 contacts the axial extension 216 of the piston 21, and the top axial end 610 of the first rod portion 61 contacts the axial extension 43 of the retaining member 42.

[0144] However, the top axial end 621 of the second rod portion 62 is still not in contact with the circular surface 55 of the closing element / ball 16, as shown in FIG. Figure 4 Visible in.

[0145] Thus, continued actuation simultaneously moves the piston 21 in the air chamber, compressing the air contained therein and moving the retaining member 42 away from its position closing the reservoir 10. When the second rod portion 62 contacts the circular surface 55 of the closing element / ball 16, said closing element / ball is mechanically expelled from its closed position, allowing the composition to be expelled under the action of the air compressed by the air expellor.

[0146] Assign location as Figure 5 As shown. Figure 5 As can be seen in the figure, when the composition is expelled under the action of compressed air provided by the air expeller, the retaining member 42 can become separated from the first rod portion 61. In this position, the closure element / ball is expelled from the reservoir 10 so that the fluid or powder can be dispensed under the action of compressed air. The closure element / ball 16 is thus stuck in the spline 3 of the upper body / dispenser head 1, which in particular prevents any risk of the closure element / ball 16 being expelled from the upper body dispenser head 1.

[0147] When the user relaxes the device, Figure 6 As shown, the spring 80 compressed during actuation returns the first rod portion 61 toward its resting position. This generates suction, which sucks the closing element 16 and the retaining member 42 back to or close to their closed position. This therefore blocks the path of new inhalation to avoid soiling the air expeller when the air expeller automatically returns to its resting position, while the empty reservoir is still assembled on the air expeller. However, the piston 21 is maintained in its dispensing position due to the friction with the air chamber 22 and the suction generated in the reservoir 30, so that the cylindrical surface 614 slides on the inner lip 215 of the piston until the inner lip and the groove 615 are matched again. At this point, the air chamber 22 is communicated with the ambient air again, and suction is no longer generated due to returning to the resting position. The piston 21 is therefore also brought to its resting position. This makes it possible to close the reservoir after use.

[0148] Optionally, the unit formed by the upper body / dispenser head 1 and the empty reservoir 10 can be removed from the air expeller and replaced by a new unit comprising a complete reservoir.

[0149] Suitable applicator devices that can be used include those available from Aptar Pharma, France (UDS Monopowder). Other examples of applicator devices that can be used in conjunction with the compositions of the present invention (especially those in powder form) include U.S. Patent Application US 2011 / 0045088A, U.S. Patent US 7,722,566 (see e.g. Figure 1 and Figure 7 ) and US 5,702,362 and those described in international patent application WO 2014 / 004400, the relevant disclosures of which are hereby incorporated by reference.

[0150] According to a further aspect of the present invention, there is provided a method of manufacturing an applicator device comprising a composition of the present invention, wherein the method comprises the step of loading the composition into a reservoir within or attached to the applicator device.

[0151] According to another aspect of the present invention, there is provided an applicator and / or dispenser device comprising a composition of the present invention in powder form, suitable for dispensing the powder, the applicator / dispenser device comprising:

[0152] an outlet through which the composition of the present invention is dispensed;

[0153] Devices that generate a force (such as air flow) from the outside when the user activates the device;

[0154] at least one (optionally replaceable) reservoir containing a composition of the invention, the reservoir being in direct or indirect communication with the dispenser outlet or being capable of being placed in direct or indirect communication with the dispenser outlet;

[0155] a removable sealing means in the device and / or reservoir for retaining the composition within the reservoir until the composition is dispensed; and

[0156] A mechanical opening system cooperates with said sealing means so that when the device is actuated, the composition of the invention is mechanically expelled by force-generating means.

[0157] According to a still further aspect of the present invention, there is provided an applicator and / or dispenser device comprising a composition of the present invention in powder form, suitable for dispensing the powder, the applicator / dispenser device comprising:

[0158] Distributor outlet;

[0159] an air expeller for generating an air flow when the device is actuated, the air expeller comprising a piston sliding in an air chamber between a rest position and a dispensing position;

[0160] The piston slides in a closed manner in the air chamber;

[0161] at least one reservoir containing a dose of a composition of the present invention, said reservoir comprising an air inlet connected to said air expeller;

[0162] a composition outlet connected to the dispenser outlet;

[0163] The air inlet comprises a movable sealing means (e.g., a retaining member) for retaining the composition in the reservoir until the composition is dispensed;

[0164] The composition outlet is closed by a closing member installed in the composition outlet of the reservoir;

[0165] The device further comprises a mechanical opening system cooperating with the closure element to mechanically expel it from its closed position when the device is actuated; and

[0166] The piston of the air ejector cooperates with the air chamber in a non-airtight manner in its rest position.

[0167] In the latter aspect of the present invention, it is preferred that:

[0168] (i) the air chamber in which the piston slides in an airtight manner is substantially cylindrical;

[0169] (ii) the closure member is forcefully mounted in the composition outlet of the reservoir;

[0170] (iii) the air chamber is vented to the atmosphere in the static position; and / or

[0171] (iv) The piston comprises an inner lip adapted to cooperate with a cylindrical surface, the cylindrical surface comprising a groove which cooperates with the inner lip of the piston in a rest position in a non-gas-tight manner.

[0172] Such an applicator or dispensing device can provide a suitable and reproducible powder spray pattern and / or plume geometry that can effectively deliver the powder to the nasal cavity (eg, nostrils).

[0173] In the composition of the present invention, the average particle size can be expressed as an average diameter based on weight, number or volume. As used herein, the term 'average diameter based on weight' will be understood by the technician to include that the average particle size is characterized and defined by a particle size distribution by weight, i.e., wherein the existing fraction (relative amount) in each size grade is defined as the distribution of the weight fraction obtained by, for example, sieving (e.g., wet sieving). The term 'average diameter based on volume' is similar to the average diameter based on weight in its meaning, but it will be understood by the technician to include that the average particle size is characterized and defined by a particle size distribution by volume, i.e., wherein the existing fraction (relative amount) in each size grade is defined as the distribution of the volume fraction measured by, for example, laser diffraction. As used herein, the term 'average diameter based on number' will be understood by the technician to include that the average particle size is characterized and defined by a particle size distribution by number, i.e., wherein the existing fraction (relative amount) in each size grade is defined as the distribution of the number fraction measured by, for example, microscopy. Particle size may be measured using other instruments well known in the art, such as those sold by, for example, Malvern Instruments, Ltd (Worcestershire, UK), Sympatec GmbH (Clausthal-Zellerfeld, Germany), and Shimadzu (Kyoto, Japan).

[0174] In the context of the present invention, the skilled person will understand that to allow intranasal administration, the powder typically has a volume-based mean diameter (VMD) in the range of about 5 μm (e.g., about 10 μm) to about 1,000 μm (e.g., up to about 500 μm). Depending on the applicator device employed, the VMD may be in the range of about 10 μm to about 100 μm, for example, about 20 μm to about 60 μm.

[0175] Preferred particle size distributions may also include those in which d10 is above about 3 μm and below about 75 μm (e.g., up to about 50 μm), such as greater than about 10 μm, and d90 is between about 80 μm and about 1,000 μm (e.g., about 500 μm), such as less than about 100 μm. The skilled person will understand that the parameter 'd10' (or 'Dv(10)') refers to the size (or diameter) in the particle size distribution below which 10% of the total volume of material in the sample is below. Similarly, 'd90' (or 'Dv(90)') represents the size below which 90% of the material is contained.

[0176] By powders having a particle size and / or VMD within the above ranges, we include bulk VMD and / or diffuse VMD, which are the particle size distributions upon initial loading into and / or discharge from the device, respectively.

[0177] Particle size can be measured by standard equipment, such as dry (or wet) particle size measurement techniques, including dry dispersion techniques available from manufacturers such as Sympatec and Malvern.

[0178] Preferred particle shapes include spherical or substantially spherical, which means that the particles have an aspect ratio of less than about 20, more preferably less than about 10, such as less than about 4, and especially less than about 2 and / or may have a radius variation (measured from the center of gravity to the surface of the particle) of no more than about 50% of the average value, such as no more than about 30% of the said value, such as no more than about 20% of the said value in at least about 90% of the particles.

[0179] However, the particles may be of any shape, including irregular shapes (eg 'raisin' shaped), needle-shaped, disc-shaped or cuboid-shaped particles. For non-spherical particles, the size may be expressed as, for example, the size of a corresponding spherical particle of the same weight, volume or surface area.

[0180] The spray angle of the powder composition of the present invention emitted (dispensed) from the applicator and / or dispenser device should preferably be less than about 90°.

[0181] The compositions of the invention may be formulated with additional active ingredients, such as those known to treat opioid withdrawal symptoms, such as lofexidine, and / or partial opioid antagonists used to treat opioid dependence, such as buprenorphine (see above).

[0182] Thus, co-administration of at least one (preferably full) opioid antagonist as described above with such opioid withdrawal symptom treatments (eg, lofexidine or buprenorphine) can be used to eliminate the intense withdrawal symptoms that may be observed in the absence of such compounds when administering the compositions of the present invention.

[0183] Thus, the compositions of the invention may be provided together with a compound useful for treating opioid withdrawal symptoms (e.g., lofexidine or buprenorphine, or a pharmaceutically acceptable salt (e.g., hydrochloride) of either compound), wherein the latter compound / treatment is contained in the composition (i.e., presented as a single pharmaceutical composition comprising both active ingredients). Alternatively, the compositions of the invention may be co-administered with a separate composition comprising a compound useful for treating opioid withdrawal symptoms (e.g., lofexidine or buprenorphine) or a salt thereof.

[0184] Thus, there is further provided a pharmaceutical formulation comprising a composition of the invention as defined above, further comprising a compound useful in treating opioid withdrawal symptoms (eg lofexidine or buprenorphine) or a pharmaceutically acceptable salt thereof, such formulation being hereinafter referred to as a 'combination formulation'.

[0185] There is also provided a method for preparing a combined preparation as defined above, which method comprises bringing an opioid antagonist as defined above and a compound suitable for treating opioid withdrawal symptoms (e.g. lofexidine, buprenorphine or a salt thereof) into association with the other ingredients of the composition of the invention and optionally filling into a container, which is administered in or used with (e.g. connected to) an applicator device as described above.

[0186] In such cases, the combined preparation may have the same or similar physical attributes as those described above for compositions of the invention that do not include a compound useful for treating opioid withdrawal symptoms, and to this extent the relevant disclosure is incorporated herein by reference.

[0187] In a further aspect of the present invention, there is also provided a kit comprising the following components (A) and (B):

[0188] (A) a composition of the present invention; and

[0189] (B) a pharmaceutical composition comprising a compound suitable for treating opioid withdrawal symptoms (e.g., lofexidine or buprenorphine) or a pharmaceutically acceptable salt thereof, in admixture with a pharmaceutically acceptable diluent or carrier,

[0190] Wherein compositions (A) and (B) are optionally loaded or provided for loading into separate containers for use in or with (e.g. attached to) the same or separate applicator devices, the applicator devices being suitable for administering the compositions to the nasal cavity, e.g. as described above.

[0191] In this case, the pharmaceutical composition comprising an opioid withdrawal symptom treatment described in (B) above may have the same or similar physical properties as those described above for the compositions of the present invention (including those in (A) above). For example, the pharmaceutical composition comprising an opioid withdrawal symptom treatment may be in the form of a powder comprising particles having a particle size similar to those mentioned above for the compositions of the present invention.

[0192] According to a further aspect of the present invention there is provided a method of making a kit of parts as defined above, the method comprising associating component (A) as defined above with component (B) as defined above such that the two components are suitable for administration in conjunction with each other.

[0193] As mentioned above, by 'associating' two components with each other we include that components (A) and (B) of the kit of parts may:

[0194] (i) are provided as separate preparations (ie independently of each other) and subsequently brought together for use in conjunction with each other in a combination therapy; or

[0195] (ii) The separate components are packaged and presented together as a 'combination pack' for use in conjunction with each other in a combination therapy.

[0196] Therefore, there is further provided a kit comprising:

[0197] (I) one of components (A) and (B) as defined herein; together with

[0198] (II) instructions for use of the component in combination with the other of the two components.

[0199] The kits described herein may contain more than one formulation including an appropriate amount / dose of an opioid antagonist / salt, and / or more than one formulation including an appropriate amount / dose of a compound suitable for treating opioid withdrawal symptoms, so as to provide repeated administration. If there is more than one formulation (including any one active compound), these formulations may be the same, or may differ in the dosage, chemical composition and / or physical form of any one compound.

[0200] For the kits described herein, by 'administering in conjunction with' we include sequential, separate and / or simultaneous administration of a corresponding formulation comprising an opioid antagonist (or a salt thereof) and a compound (or a salt thereof) useful for treating opioid withdrawal symptoms, to treat the relevant condition.

[0201] Thus, for a combination product according to the invention, the term 'administered in conjunction with' includes administration of the two components of the combination product together (optionally repeatedly), or sufficiently close in time to achieve a beneficial effect on the patient that is greater than the effect of either formulation being administered alone (optionally repeatedly) without the other component. Determining whether a combination provides a greater beneficial effect in treating a relevant condition will depend on the condition to be treated or prevented, but can be routinely accomplished by the skilled person.

[0202] After the emergency situation of treating acute opioid overdose has been addressed, a further composition comprising a compound useful for treating opioid withdrawal symptoms (e.g., lofexidine or more preferably buprenorphine or a salt thereof) may be administered as needed or desired. Such a composition may be similar in form to that of the present invention (and the relevant disclosure is incorporated herein by reference) or other aspects (e.g., sublingual formulations).

[0203] When the compound suitable for treating opioid withdrawal symptoms is buprenorphine, a suitable dosage may be in the range of about 1 mg to about 32 mg, more preferably about 5 mg to about 20 mg, calculated as the free base.

[0204] When the compound suitable for treating opioid withdrawal symptoms is lofexidine, a suitable dosage (eg, daily dosage) may be in the range of between about 0.1 mg to about 3 mg, such as about 0.5 mg to about 2 mg, calculated as the free base.

[0205] Whenever the word 'about' is used herein in the context of an amount, such as an absolute amount, e.g., dose, weight, volume, size, diameter, etc., or the relative amounts (including concentrations and ratios) of a single ingredient or components of a composition, a time frame and parameters, such as temperature, pressure, relative humidity, etc., it is to be understood that these variables are approximate and may therefore vary by ±10%, e.g., ±5%, preferably ±2% (e.g., ±1%) from the actual amount indicated herein. This is the case even if such a number is first presented as a percentage (e.g., 'about 10%' may mean ±10% about the number 10, i.e., any value between 9% and 11%).

[0206] The compositions of the present invention have the advantage that they can be stored over a wider temperature range than prior art compositions, including those commercially available (e.g., in the case of naloxone, Narcan). Thus, the compositions of the present invention can withstand low temperatures (e.g., below freezing) without affecting the amount of opioid antagonist administered to a subject. Furthermore, the compositions of the present invention have the advantage that they are physically and chemically more stable at higher temperatures than such prior art compositions.

[0207] The compositions of the present invention also have the significant advantage that they provide higher bioavailability of the opioid antagonist compared to prior art compositions, including those that are commercially available (e.g., in the case of naloxone, Narcan). The compositions of the present invention provide this higher bioavailability as well as more rapid absorption, which will likely result in a more rapid onset of action than such prior art and / or commercially available compositions, and thus meet a significant and serious medical need.

[0208] The compositions, pharmaceutical formulations, uses and methods described herein may also have the following advantages: whether for the treatment of opioid overdose (or bulimia or alcohol dependence), or otherwise, they may be more convenient for emergency personnel, physicians and / or patients, more effective, less toxic, have a broader range of activity, be more potent, produce fewer side effects, have less variability between patients, or it / they may have other useful pharmacological properties when treating the above-mentioned conditions, compared to similar formulations or methods (treatments) known in the prior art.

[0209] With reference to the accompanying drawings, the present invention is described by the following embodiments, but is by no means limited to the following embodiments, in which: Figures 1 to 7 A diagram showing an actuator device that can be used to dispense the composition of the present invention, Figure 8 and Fig. 9showed the permeation of naloxone and nalmefene, respectively, through porcine nasal tissue in an ex vivo model; Fig.10 and Fig.11 Shown are the mean naloxone plasma concentrations versus time (linear scale) obtained over different time periods through treatment in the clinical trial.

[0210] Example 1

[0211] Spray-dried opioid antagonists containing multiple sugars

[0212] Naloxone hydrochloride dihydrate (1.199 g; Johnson Matthey, UK) or nalmefene hydrochloride (0.600 g; Santa Cruz Biotechnology Inc., USA) and naltrexone hydrochloride (0.600 g; Mallinckrodt Inc., USA) were mixed with different sugars (5.088 g for naloxone and 2.554 g for nalmefene and naltrexone) (which were used as carrier materials in the composition) and purified water for irrigation (56.58 g for naloxone and 28.29 g for nalmefene and naltrexone), respectively, and the mixtures were fed into a spray dryer according to the following general procedure.

[0213] The solid ingredients were weighed into a beaker equipped with a magnetic stir bar, dissolved in water and fed into a spray dryer (ProCepT, Belgium) equipped with an ultrasonic nozzle operating at 25 kHz. The feed rate of the spray dryer was set to 3.0 g / min, the inlet temperature was set to 180°C, the air flow was set to 300 L / min, and the cyclone gas was set to 1.5 bar.

[0214] The resulting spray-dried powder was collected and filled into a device suitable for nasal powder administration (disposable single-injection nasal monodose device; UDS Monopowder, Aptar Pharma, France) with a fill weight of 23 mg. (For naloxone, this constitutes a single dose of 4 mg naloxone (calculated as hydrochloride)).

[0215] The devices were placed in heat-sealed aluminum bags and then stored at 40°C and 75% relative humidity (RH) for 6 months.

[0216] The chemical composition of the spray-dried mixture after storage was determined, as was the amount of powder released from the equipment after startup.

[0217] The stability of naloxone after 6 months (6M) is summarized for different sugars in Table 1 below, where the amount of impurities is expressed as a percentage of related substances (%RS). The initial %RS values ​​for all samples were less than 0.1%.

[0218] Table 1

[0219]

[0220] Surprisingly, certain monosaccharides, such as mannitol, which had previously been used in physical mixtures with naloxone, proved to be incompatible (with respect to the chemical stability of naloxone) when used in this spray drying process. This is in contrast to disaccharides, such as lactose, which are generally compatible.

[0221] Furthermore, it is known that polysaccharides with higher Tg tend to produce higher powder emission doses. Physical changes due to low Tg lead to powder agglomeration and aggregation in the equipment.

[0222] Similar trends were observed for nalmefene and naltrexone (see Table 2 below, where initial %RS values ​​are given in parentheses).

[0223] Table 2

[0224]

[0225] Example 2

[0226] Physical stability of spray-dried powders

[0227] To assess physical stability and reduce the risk of crystallization during storage, the glass transition temperature (Tg) was determined using differential scanning calorimetry (DSC) and is listed in Table 3 below.

[0228] The compositions were generally prepared according to the procedure described above in Example 1, using mannitol, trehalose and lactose as carrier materials.

[0229] For lactose, the true Tg was measured as well as the Tg of formulations equilibrated at four different RH conditions at 25°C (10%, 20%, 30% and 40% RH) (although the 30% was not recorded). For mannitol and trehalose, the Tg was measured as received ('ambient') and after drying ('dry').

[0230] For dried samples, the DSC ampoule caps were automatically perforated immediately before the start of the DSC run, introducing a hole of approximately 0.3 mm in diameter. The purpose of this was to allow any residual moisture to evaporate before the glass transition temperature of the dried formulation was reached. Therefore, this Tg value corresponds to the true Tg without interference from available plasticizers (such as water).

[0231] For samples equilibrated at different RH values, the DSC lid was airtight throughout the DSC run. The samples were prepared as described above.

[0232] Table 3

[0233]

[0234] Using trehalose or lactose as carrier material resulted in completely amorphous compositions, whereas mannitol seemed to crystallize in the spray dryer, as no Tg was found and the water content was below 1%.

[0235] Example 3

[0236] In vitro evaluation of nasal absorption of naloxone and nalmefene

[0237] An ex vivo model of nasal mucosal absorption was established using a standard static diffusion (Franz) cell apparatus using excised porcine nasal tissue.

[0238] Solutions containing naloxone hydrochloride dihydrate, nalmefene hydrochloride, benzalkonium chloride (Sigma-Aldrich Sweden AB), sucrose monolaurate (IMCD Nordic AB) and / or polysorbate 80 (Croda Nordica AB) were prepared by standard techniques to provide formulations according to the following Table 4. Potassium phosphate buffer (Sigma-Aldrich Sweden AB) was added to obtain the pH values ​​specified in the following Table 4.

[0239] Table 4

[0240] preparation 1 2 3 4 5 6 7 8 Naloxone (mg / mL) 5 5 5 5 5 5 5 Nalmefene (mg / mL) 5 5 5 5 5 5 5 Benzalkonium chloride (mg / mL) 0.1 0.1 0.1 Sucrose monolaurate (mg / mL) 0.4 2 Polysorbate 80 (mg / mL) 2 pH 4.5 4.5 4.5 4.5 4.5 4.5 4.5 6.5

[0241] Diffusion through the tissue was measured after 7 h and the permeation is shown as Figure 8 and Fig. 9 The average (three replicates) cumulative transport of naloxone and nalmefene in 2 ; with SD).

[0242] For naloxone and nalmefene, slightly higher apparent permeability coefficients (Papp) were observed in Formulations 7 and 8, which contained polysorbate 80 and higher amounts of pH buffer, respectively. No corresponding absorption enhancement was observed with benzalkonium chloride or sucrose monolaurate.

[0243] Example 4

[0244] Composition B containing naloxone

[0245] The spray-dried composition was prepared using the general procedure described in Example 1 from naloxone hydrochloride dihydrate (1.199 g) together with α-D-lactose monohydrate (5.026 g; DFE Pharma Germany), sucrose monolaurate D-1216 (0.062 g; Mitsubishi-Kagaku Foods Corporation, Japan).

[0246] Composition B contained a single dose of 4 mg naloxone (calculated as hydrochloride).

[0247] The devices were placed in heat-sealed aluminium bags (Protective Packaging, UK) before use.

[0248] Geometric particle size distribution (PSD) was measured using a Malvern Mastersizer 2000 (Malvern Panalytical Ltd, UK) and aerodynamic particle size distribution (aPSD) was measured using a Rapid Screening Impactor (FSI, Copley Scientific, UK).PSD: d10 = 15 μm and d90 = 55 μm; aPSD < 5 μm = 0%.

[0249] General method for PSD measurement: 80 to 100 mg of sample was dispersed in 5 mL of silicone oil and mixed thoroughly, then sonicated for 20 to 30 seconds. The solution was measured three times using a Malvern Mastersizer 2000 (Malvern Panalytical Ltd., UK).

[0250] General method for aPSD measurements: The loaded device was started in a Rapid Screening Impactor (FSI, Copley Scientific, UK) equipped with a suitable adapter, expansion ball and 10 micron insert. The flow rate was adjusted to 30 ± 0.5 L / min. Results are reported as % fine particle mass (FPM) (<5 μm) recovered during the filtration stage.

[0251] Example 5

[0252] Compositions A, C and D containing naloxone

[0253] Three additional spray-dried powders were prepared following the same general procedure as described in Example 4 above and their compositions are shown in Table 5 below.

[0254] Table 5

[0255]

[0256] Compositions A and C comprised a single dose of 4 mg naloxone, and composition D comprised a single dose of 8 mg naloxone (each calculated as hydrochloride). PSD and aPSD were analyzed using the general method described in Example 4 above (results are shown in Table 6 below).

[0257] Table 6

[0258] Composition A C D d10(μm) 15 17 17 d90(μm) 44 57 58 %<5μm 0 0 0

[0259] Example 6

[0260] Intranasal naloxone-pharmacokinetic study (healthy volunteers)

[0261] A Phase I clinical study was conducted to determine the efficacy of the product relative to the reference commercial product. Bioavailability of four investigational naloxone nasal powder formulations (obtained as described in Examples 4 and 5 above) for nasal spray ('Ref'; naloxone HCl liquid nasal spray, 4 mg; Adapt Pharma, Inc., Radnor, PA, USA).

[0262] The study was a single-center, open-label, randomized, single-dose 5-treatment crossover, relative bioavailability study in healthy subjects. Each subject received each of the four naloxone-containing powders (compositions A to D) and Ref in sequence according to a pre-specified randomization schedule, with a minimum 24-hour washout interval.

[0263] Subjects were randomized immediately prior to administration of the first dose of study medication (IMP) or Ref (if used). Subject numbers were assigned using a computer-generated randomization schedule to 1 of 10 treatment sequences (according to a balanced Williams design), with 2 subjects per treatment sequence.

[0264] A total of 48 subjects were screened for inclusion in the study up to 28 days before dosing. Twenty-one eligible subjects (healthy males and non-pregnant, non-lactating, aged between 18 and 55 years, with a body mass index between 18.0 and 32.0 kg / m 2 Female subjects between 1 and 2 years old) were admitted to the clinical ward the evening before IMP administration (Day -1) and remained on-site until discharged 24 hours after the final dose (after receiving all 5 treatments).

[0265] Subjects received IMP or Ref on the morning of Days 1, 2, 3, 4, and 5, with appropriate intervals between subjects (approximately 10 minutes) based on organizational management requirements. IMP was administered to alternating nostrils on each day of dosing, beginning with the left nostril on Day 1. Follow-up phone calls were conducted 3 to 5 days after the last dose to ensure the continued well-being of the subject.

[0266] Of the 21 subjects enrolled, all received IMP. For analysis purposes, all 21 subjects were included in the safety population, safety analysis dataset, and PK population. One case was excluded from the PK analysis dataset due to dosing failure, so 20 subjects completed the study and were included in the PK analysis dataset.

[0267] Plasma concentrations of naloxone were analyzed using non-compartmental analysis to obtain estimates of standard PK parameters as listed below:

[0268]

[0269] Assessment of safety parameters included analysis of adverse events (AEs), intranasal tolerability, laboratory evaluations, vital signs, electrocardiogram (ECG), and physical examination results.

[0270] Log-transformed exposure parameters (AUC and Cmax) were compared with standard methods to assess relative bioavailability using the SAS software program PROCMIXED. A single mixed-effects model was fit for each parameter to obtain estimates of the geometric mean ratios (GMRs) and corresponding confidence intervals (CIs) for all treatment comparisons of interest. The model included terms for actual treatment received, study day (i.e., period), and planned sequence fitted as fixed effects and subject within sequence fitted as random effects. Results are shown back-transformed to a linear scale. The following comparisons were of interest:

[0271] Relative bioavailability compared to Ref: IMP:RefGMR for AUC(0-t), AUC(0-inf) and Cmax was determined

[0272] Early exposure compared to Ref: IMPs for AUC(0 0-4min), AUC(0-10min) and AUC(0-30min) were determined: Ref GMR

[0273] Dose proportionality of IMD formulations: The 8 mg:4 mg GMR for AUC(0-t), AUC(0-inf), and Cmax were determined and dose normalized.

[0274] result

[0275] The relationship between the arithmetic mean naloxone plasma concentration and time, by treatment (linear scale) is shown in Fig.10 and 11 (first five hours and first hour after administration, respectively) and are described below in Table 7. The geometric mean naloxone plasma concentrations versus time by treatment (semi-log scale) are described below in Table 7.

[0276] Table 7

[0277]

[0278] N: number of subjects in the dataset; n: number of subjects with observed outcomes.

[0279] a Geometric mean (geometric CV%); b median (range); c Arithmetic mean (arithmetic CV%)

[0280] Analysis of relative bioavailability (GMR, 90% CI) is shown in Table 8 below.

[0281] Table 8

[0282]

[0283] All IMPs showed significantly higher total and peak plasma exposures of naloxone than the reference. Composition B showed the highest relative bioavailability of the 4 mg formulation, with an AUC on average about 84% higher than the Ref and a Cmax about 175% higher than the Ref (note that formulation D included 8 mg naloxone hydrochloride, twice that of the other formulations). The IMPs, A, B, C, and D, also showed lower inter-patient variability (CV) than the Ref for both total and peak exposure parameters (see Table 7).

[0284] Tables 9 and 10 below show descriptive statistics for the naloxone fractional AUC (as geometric mean; geometric CV %) by treatment on an absolute (Table 9) and relative (Table 10) basis.

[0285] Table 9

[0286]

[0287] Table 10

[0288]

[0289] All IMPs showed significantly higher naloxone plasma exposure than Ref within the first 4, 10 and 30 minutes after dosing. For Composition B, the early portion AUC GMR was much higher than the corresponding AUC(0-t) GMR of this IMP, indicating that the initial absorption rate of this formulation was higher than that of Ref.

[0290] The dose proportionality analysis of IMP as dose normalized GMR (90% CI; 8 mg:4 mg; D:A) is shown in Table 11 below.

[0291] Table 11

[0292]

[0293] For the scaled point estimates of D:A GMR for AUC(0-t), AUC(0-inf), and Cmax, the 90% CIs were well below 100%.

[0294] All IMPs showed significantly higher naloxone exposures than Ref. Compositions A, B, C, and D showed approximately 36%, 84%, 37%, and 112% higher total exposures, respectively, and an average of 50%, 175%, 58%, and 113% higher peak exposures (Cmax), respectively, relative to Ref (note again that composition D contained 8 mg naloxone HCl, twice the amount of the other compositions).

[0295] The inter-subject variability of the overall exposure parameters AUC(0-t), AUC(0-inf) and Cmax was lower after administration of compositions A, B, C and D compared to Ref.

[0296] from Fig.10 It can be clearly seen in Fig.11 As can be seen more clearly in the Figures, rapid absorption was observed for all formulations, with median Tmax values ​​between 0.250 h and 0.333 h. The early exposure of all IMPs (in terms of AUC (0-4 min), AUC (0-10 min) and AUC (0-30 min)) was higher than that of Ref. Composition B had the fastest absorption, with the point estimate indicating a 270% higher exposure than Ref within the first 10 minutes after dosing. This is a significant and completely unexpected result for all the reasons described above.

[0297] The elimination of naloxone was similar between all preparations, with arithmetic mean terminal T1 / 2 values ​​ranging between 1.243 and 1.471 hours.

[0298] Under the experimental conditions, naloxone nasal powder was considered safe and well tolerated at all doses administered intranasally.

[0299] No SAEs, serious AEs, or AEs leading to subject withdrawal were reported in this study, and the AE profile was similar to previous studies of the reference nasal spray in healthy subjects. The most commonly reported AEs were nasal inflammation, headache, and dizziness. All AEs were mild in severity, and overall, the safety profile of IMP was well consistent with previous experience with naloxone HCl in healthy subjects, and no findings raised any safety concerns.

[0300] Example 7

[0301] Physical stability of spray-dried powders containing dextrin

[0302] Two formulations having the following compositions were prepared using the general procedure described above in Example 1 (percentages are by weight of the total composition):

[0303] Composition X

[0304] Naloxone hydrochloride (35%), 2-hydroxypropyl-β-cyclodextrin (Cavasol W7, HP Pharma, Wacker, Germany; 53%), lactose (Merck, Germany; 10%), and Tween 20 (Croda Nordica AB, Sweden; 1%)

[0305] Composition Y

[0306] Naloxone hydrochloride (17%), maltodextrin (Glucidex IT 12DE, Roquette, France; 72%), lactose (10%), sucrose monolaurate (1%).

[0307] An experiment similar to that described in Example 2 above was set up to measure the physical stability of compositions X and Y at different RH values ​​as Tg values. The results are shown in Table 12 below.

[0308] Table 12

[0309]

[0310] Both dextrins increased the Tg compared to compositions containing only lactose as carrier material, contributing to acceptable emission doses even after storage for 24-72 hours at 80°C. The multiple Tg values ​​presented in Table 10 indicate that the compositions in question are not completely homogeneous, but rather have regions of increased concentration of higher molecular weight polysaccharides that are separate from regions of lower molecular weight compounds.

[0311] Subsequent dissolution testing also showed that high concentrations of maltodextrin did not affect the dissolution of naloxone.

[0312] Example 8

[0313] Chemical stability of spray-dried powders containing dextrin

[0314] To explore the effect of chemical stability of naloxone as a function of dextrin and lactose / dextrin mixtures, samples were prepared using the general procedure as described above in Example 1. The compositions (percentages are by weight of the total composition) are provided in Table 13.

[0315] The chemical stability of naloxone at 40°C / 75%RH after 3 and 6 months is summarized for different compositions in Table 13 below, where the amount of impurities is expressed as a percentage of related substances (%RS). All initial %RS values ​​were less than 0.1%.

[0316] Table 13

[0317]

[0318]

[0319] The numbers in parentheses in Table 13 are the %RS after removing the measured values ​​of Impurity E (Imp E), a documented impurity (dimer) associated with naloxone. In this study, Imp E appears to have been formed during sample preparation prior to analysis, which would have affected the overall %RS values ​​in an uncontrolled manner and prevented the detection of minor degradation trends.

[0320] It is clear from Table 13 that dextrin unexpectedly induced the decomposition of naloxone, but the addition of lactose mitigated this effect.

[0321] Example 9

[0322] Compositions E, F and G containing nalmefene

[0323] Essentially the same general procedure as described in Examples 1 and / or 4 above was followed to prepare three nalmefene-containing spray-dried powders, the compositions of which are shown in Table 14. In this and the next example, nalmefene was obtained from Mallinckrodt Inc., USA.

[0324] Table 14

[0325]

[0326] Compositions E and F comprised a single dose of 3 mg nalmefene, and composition G comprised a single dose of 3 mg nalmefene, but at half strength and double fill weight (each calculated as free base).PSD and aPSD were analyzed using the general method in Example 4 above (results see Table 15 below).

[0327] Table 15

[0328] Composition E F G d10(μm) 18 20 19 d90(μm) 51 66 65 %<5μm 0 0 0

[0329] Using the method described in Example 2 above, all compositions exhibited a glass transition at about 60° C. under ambient conditions. However, composition E produced a large crystallization event just above 100° C., which was not seen in the maltodextrin-containing compositions F and G. In addition, composition E experienced crystallization at room temperature at 60% RH, which was not seen in compositions F and G.

[0330] Example 10

[0331] Chemical stability of spray-dried powder containing nalmefene

[0332] The samples were prepared using the general procedure essentially as described above in Examples 1 and / or 4. The compositions (percents are by weight of the total composition) are provided in Table 16 below.

[0333] The chemical stability of nalmefene at 40°C / 75%RH for 3 and 6 months is summarized for different compositions in Table 16 below, where the amount of impurities is expressed as percentage of related substances (%RS). All initial %RS values ​​were less than 0.1%.

[0334] Table 16

[0335]

Claims

1. A solid pharmaceutical composition in the form of a spray-dried powder suitable for nasal delivery of an opioid antagonist, comprising: a pharmacologically effective amount of an opioid antagonist selected from naloxone, nalmefene or naltrexone, or a pharmaceutically acceptable salt thereof; and A pharmaceutically acceptable carrier material, the carrier material comprising a low molecular weight disaccharide and dextrin, the disaccharide comprising lactose and / or trehalose, the dextrin comprising cyclodextrin or maltodextrin. 2 . The composition of claim 1 , wherein the powder has a particle size distribution comprising a d10 greater than 3 μm±0.3 μm and less than 75 μm±7.5 μm.

3. The composition of claim 1, wherein the powder has a particle size distribution comprising a d90 between 80 μm ± 8 μm and 1000 μm ± 100 μm.

4. The composition of claim 1, wherein the powder has a particle size distribution comprising a d90 of less than 100 μm ± 10 μm. 5 . The composition of claim 1 , wherein the powder has a particle size distribution comprising a volume-based average diameter in the range of 10 μm±1 μm to 100 μm±10 μm.

6. The composition of claim 1, further comprising a sucrose ester.

7. The composition of claim 6, wherein the sucrose ester comprises sucrose monolaurate.

8. The composition according to claim 6 or 7, wherein the sucrose ester is present in an amount of 0.1 wt% to (3±0.3) wt% based on the total weight of the composition.

9. The composition of claim 1, wherein the dextrin comprises 2-hydroxypropyl-β-cyclodextrin and / or maltodextrin 12DE.

10. The composition of claim 1, wherein the disaccharide is present in an amount of (10±1) wt% to (30±3) wt% based on the total weight of the composition.

11. The composition according to claim 1, wherein the dextrin is present in an amount of 40 wt% to (70±7) wt% based on the total weight of the composition.

12. The composition according to claim 1 or 11, wherein the ratio of "disaccharide:dextrin" is in the range of (10±1):1 to (1±0.1):10 by weight based on the total weight of the composition.

13. The composition according to claim 1, wherein the composition is free of water and other liquid solvents.

14. The composition of claim 13, comprising less than (5±0.5)% water.

15. The composition of claim 13, comprising less than (2±0.2)% water.

16. The composition of claim 13, comprising less than (1 ± 0.1)% water.

17. The composition of any one of claims 13 to 16, wherein the opioid antagonist or a pharmaceutically acceptable salt thereof chemically degrades by less than 15% after 3 months at 75% relative humidity and 40°C.

18. The composition of claim 1, wherein the opioid antagonist is naloxone or a pharmaceutical salt thereof.

19. The composition of claim 1, wherein the opioid antagonist is nalmefene or a pharmaceutical salt thereof.

20. A method for making the composition of claim 1, wherein the method comprises the steps of: i) mixing together the opioid antagonist or salt thereof and the pharmaceutically acceptable carrier material and, if present, the sucrose ester in a suitable volatile solvent; and ii) spray drying the mixture from step i) to form a spray dried plurality of particles.

21. A composition obtainable by the method of claim 20.

22. A nasal applicator device suitable and / or adapted to deliver the composition of claim 1 to the nose, comprising or pertaining to and / or attached to a reservoir in which the composition is contained.

23. A method of making the nasal applicator device of claim 22 comprising the method of claim 20 followed by loading the composition so formed into a reservoir within, incidental to or attached to the nasal applicator device.

24. The method of claim 23, wherein the nasal applicator device is packaged in a container constructed of a material that prevents the ingress of atmospheric water under storage conditions of 75% relative humidity and 40°C.

25. The method of claim 24, wherein the container comprises a material selected from the group consisting of a heat-sealed aluminum bag and a thermoformed plastic.

26. The method of claim 23, comprising loading the nasal applicator device into a container constructed of a material that prevents the ingress of atmospheric water.

27. Use of the composition according to claim 1 for the manufacture of a medicament for a method of treating opioid overdose.

28. The use according to claim 27, wherein the composition is applied to the nose by means of a nasal applicator device as defined in claim 22, or a nasal applicator device manufactured by the method of claim 24 or 25.

29. The use according to claim 28, wherein prior to said application, said nasal applicator device is removed from a container containing said nasal applicator device, said container being constructed of a material that prevents the ingress of atmospheric water.

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