WO2016146981A1 - Novel formulations - Google Patents

Abstract

A solid formulation comprising an antagonist of an opiate or opioid substance, such as naloxone or a salt or hydrate of said antagonist, in the absence of any opiate or opioid agonist, suitable for buccal administration, for use in the treatment of an opiate or opioid overdose. Novel formulations including in particular instant disintegrating tablets (IDTs) are also described and claimed.

Description

Novel Formulations

The present invention relates to novel formulations of opioid antagonists, in particular naloxone, to kits containing these, as well as to methods for preparing the formulations and their use in therapy.

Background of the Invention

The particularly high mortality amongst heroin users (even compared with users of other illicit drugs) has been recognised in recent years, with the abuse of heroin and other opiates contributing disproportionately to drug-related deaths, and now being one of the major causes of unnatural death amongst adolescents and adults.

Recent research over the last 20 years has also identified that there are specific times of particularly high risk, notably on release from prison and also similarly on release from hospital or residential rehabilitation.

A previous conceptual leap was the realisation that technology routinely used in Accident & Emergency departments, where an emergency intravenous (IV) or intramuscular (EVI) injection of naloxone is routinely administered to reverse opiate overdose such as heroin overdose, could be re-conceived as a peer/family-implemented interim emergency action to improve initial interim management of heroin overdose. The pre-provision of take-home emergency naloxone supplies, ready for family/peer- implemented IM injection in the emergency overdose resuscitation situation, was proposed initially as early as 1992, and articulated subsequently (Strang et al., BMJ. (Clinical Research Ed.) 312, 7044, p. 1435-1436).

A study of the feasibility and acceptability to the target population of this proposed approach, studying both treatment samples and non-treatment samples of heroin users (Strang et al, Addiction, 1999, 94, 4, 597-597) and also family members (Strang et al, Drugs: education, prevention and policy (DEPP), 2008, 15:2, 211 - 218) was carried out. The effectiveness of the provision of naloxone training for drug users themselves (Strang et al, Addiction, 2008, 103, 10, p. 1648 - 1657), drug workers (Mayet et al, International Journal of Drug Policy, 2011, 22, 1, p9-15) and family members has also been studied (Williams et al, Addiction. 2014, 109(2), 250-259).

It has been appreciated that the licensed injectable routes (IV, IM, subcutaneous) were far from ideal for non-medical/non-specialist use in this emergency situation (Strang, Addiction, 1999 supra). However, the oral route is not suitable for naloxone administration, owing to its extensive first-pass metabolism when absorbed from the gastro-intestinal tract.

Furthermore the overdose victim is likely to be unconscious.

Nasal administration of naloxone in detoxification methods was first mooted in

1994 and has been the subject of some subsequent studies. It is known that naloxone gets absorbed nasally, at least to some extent. Indeed, since the early 2000s, nasal naloxone has been used by some ambulance services to treat opioid overdose (Barton et al, The Journal of Emergency Medicine. 2005:29(3):265-71) and a purpose-developed naloxone spray was licenced by the FDA in the USA in November 2015. It is quick to administer and reduces risk of needle-stick injury; furthermore, if this fails, an IM or IV dose can be administered from the stock in the ambulance.

CN1565451 describes a naloxone hydrochloride nasal powder formulation.

However, there is uncertainty about how adequately and reliably naloxone is absorbed. A small ambulance-based randomised control trial in Australia compared intranasal (IN) to IM naloxone: the IN group was less likely to restore normal breathing (63% vs 82%) and more likely to require a 'rescue' naloxone injection (26% vs 13%). The group difference of a higher proportion of IN recipients needing a 'rescue' injection (18%) vs 5%> FM) was also sustained in a replication trial with a more concentrated nasal spray formulation (2mg/mL). This rate is broadly consistent with 16%> of opiate overdose victims who did not respond to the initial ΓΝ naloxone in a Denver-based observational trial.

The only published report on the pharmacokinetics of intranasal naloxone (Dowling et al. Ther Drug Monit, 2008, 4, 490-6) reported that 'intranasal naloxone had poor bioavailability compared with intramuscular' . Furthermore, they calculated an extremely disappointing bioavailability at only 4% compared with intravenous naloxone.

There is uncertainty about dose adequacy and comparability. The only

commercially available naloxone injections have concentrations of 0.4mg/mL or Img/mL (adult formulations). Drug administration via nasal spray typically involves giving O. lmL fluid per nostril, with 0.25mL considered the maximum, as any greater volume is likely lost post-nasally or by nasal drip.

This clearly gives rise to significant dosing issues. Even if a volume of 0.25mL per nostril of the most concentrated available naloxone formulation (2mg/2mL) were administered, then even assuming that 40% of naloxone is absorbed (discounting the reported nasal bioavailability of only 4%), then the effective IN dose would be 0.2mg, i.e. equivalent to only half the lower recommended injectable dose.

Furthermore, at a practical level, uncertainties about the effectiveness of a nasal spray include: the need for a spray device to function in horizontal position, the impact of compromised nasal mucosa (e.g. chronic ulceration from drug snorting, or obstruction from opiate-induced vomit). Any factors which reduce or delay the nasal absorption of naloxone may lessen the overdose victim's chance of survival.

A more reliable administration route is required, and one which was more compatible with the technical competence and willingness to commit that might reasonably be expected from family members, peer-group, or general public.

Buccal administration was tested in rats as early as 1986 (Hussain M. A. et al., International J. of Pharmacokinetics, 1987, 36 127-130), with a view to developing a suitable administration route for use in conditions such as senile dementia of the

Alzheimer's type or as an appetite suppressant in obesity. In this work, various routes of administration were investigated including IV, oral and buccal administration. Oral administration produced very low bioavailability. For buccal administration, solutions of naloxone were administered bucally to rats in which the oesophagus had been ligated. Under these circumstances, high bioavailability was noted. However, liquid formulations are not practicable for buccal administration due to the risk of swallowing or leakage from the mouth/buccal cavity etc., and this route has largely been ignored since.

WO2014/ 144241 describes complex sublingual or buccal film formulations which may include naloxone but as a formulation in combination with an opioid agonist. In this case, the compositions are designed to provide doses of opioid agonist such as

buprenorphine, for use in the treatment of pain whilst minimizing the opportunities for abuse of the dosage form, since the naloxone would produce profound and distressing results if administered intravenously. In this case, the naloxone is included in order to cause distressing effects if the tablet were to be abused by crushing and injecting.

There has been some controversy about whether such compositions, where the main therapeutic agent is buprenophine, when administered sub-lingually, could reverse a heroin overdose (Welsh et al., Addiction, 2008, 103, 7 1226-1228; Nielsen et al.,

Addiction, 2008, 103, 12, 2065-2066).

Some sub-lingual formulations have also been described in CN1813740, CN10200037, CN10100755 and Journal of Chinese Pharmaceutical Sciences, 1996, 5 (3).

The applicants have developed a formulation which is specifically intended to address the problems of providing a rapid and readily available treatment for overdoses. Summary of the Invention

According to the present invention there is provided a solid formulation comprising an antagonist of an opiate or opioid substance or a salt or hydrate of said antagonist, in the absence of any opioid or opioid agonist, suitable for buccal administration, for use in the treatment of opiate or opioid overdose, in particular emergency treatment. In particular, the formulation is for buccal administration.

Buccal administration has advantages even over lingual or sub-lingual

administration in the case of opiate or opioid overdoses, since the mode of administration is easy to apply by a third party, even to an unconscious patient. The buccal cavity, being outside the teeth, means that the tablet can be inserted without fully opening the mouth and/or parting the teeth. Once in position, a buccal tablet can remain securely in place. The cheek surface provides a fast-absorption mucous membrane with rapid venous transfer to the brain by virtue of direct venous drainage via the main facial vein.

Furthermore, formulations present in the buccal cavity may be better protected from overdose-related vomit or mucous secretions than nasal, lingual or sub-lingual

formulations which could be compromised by such vomit or secretions.

As used herein, the term 'solid' refers to non-liquid formulations including semisolids such as gels and pastes, or amorphous materials below their glass transition temperature, as well as conventional solids.

Suitable antagonists of opiate or opioid substances include naloxone, nalmefene, or naltrexone, or pharmaceutically acceptable salts or hydrates thereof.

In a particular embodiment, the opiate or opioid antagonist is naloxone or a pharmaceutically acceptable salt thereof.

The applicants have found that opiate or opioid antagonists and in particular naloxone may be effectively and rapidly released from buccal formulations, giving rise to a useful and accessible means for treating opiate or opioid overdoses such as heroin overdoses.

The formulations of the invention allow for rapid absorption of the opiate or opioid antagonist into the bloodstream and thence across the blood-brain barrier, from the trans- buccal absorption from the oral vestibular cavity (the cheek pouch) into the facial vein or other vascular venous drainage and thence directly into the internal jugular vein. As a result, they are able to induce a rapid therapeutic effect in the event of an overdose.

Furthermore, the buccal placement of the formulation will be resilient to impediments and operational obstacles for other routes, (for example, if compared with the nasal naloxone formulations which are currently under investigation or licensed for use) since it would not be compromised by pre-existing nasal ulceration or erosion from drug use. In addition, it would not be influenced by the horizontal posture of the overdose victim, and may be easily placed in the mouth of an individual, even if they are unconscious or prone, by an untrained administrator such as a parent or peer. The administration process would be unlikely to be influenced greatly even if the overdose victim had vomited (a recognised acute opiate-induced effect).

Thus the formulations of the invention provide a useful and novel form of

'emergency' antagonist such as naloxone that is much more compatible with emergency administration by the general public (i.e. by persons not medically trained) than the current injectable forms. Any fear or stigma surrounding the use of an injectable formulation is therefore removed. This opens up, subject to regulatory approval, the option of providing emergency non-injectable antagonist such as naloxone as a medicinal product which might be obtained directly from a community treatment agency or from a community pharmacist, so as to enable wider access and supply for both family and peer group.

In particular, the opiate or opioid antagonist such as naloxone or salt thereof, is the sole active ingredient of the solid formulation, although it may be combined with other opiate or opioid antagonists if required. Suitable salts of naloxone include naloxone hydrochloride. The antagonists may also be in the form of a hydrate such as naloxone dehydrate or the hydrochloride salt, although, generally, the antagonist such as naloxone will be in an anhydrous form after drying.

In a particular embodiment, the solid formulation contains a relatively high dose of naloxone, for example from 0.4mg to 4mg per dosage unit for example from 0.8mg to 3mg per dosage unit. This can ensure that the dosages supplied to the individual are sufficient to mitigate the effect of the overdose.

The solid formulation of the invention is suitably provided in the form of a tablet, lozenge or capsule. In a particular embodiment, the solid formulation comprises a rapid- release formulation such as an instant dissolving tablet, also known as an Instant Disintegrating Tablet or "IDT", which is particularly suitable for buccal administration. Such formulations of naloxone, sometimes also known as Orally disintegrating tablets' or 'ODTs' are novel and so form a further aspect of the invention. In particular, the IDT may be shaped so that it fits snugly into a buccal cavity, as described further below.

Such formulations are readily portable and so may be more compatible with being constantly carried on the person, so that the individual who might witness the heroin overdose, or the non-medical person first summoned (e.g. mother, father, sibling, partner) would be more likely to have access to the necessary emergency supply of naloxone, to be able to give an effective dose efficiently. The more realistically portable the product, the greater the likelihood that the naloxone will be readily available for use in an overdose emergency situation.

Furthermore, repeated doses of such formulations if required can be given much more readily than, for example, nasal formulations, where additional doses may provoke further fluid loss, by nasal drip or post-nasal leakage (causing inactivation).

In addition, the solid formulations of the invention show good stability and shelf life. It is known that degradation reactions for example hydrolysis reactions, may occur in solutions including water and that that therefore, formulations such as the current naloxone formulations, IV. injections and the nasal spray, may have a lower shelf life than solid dosage forms, with much lower amounts of water present, including those of the present invention.

Such tablets are suitably formulated using pharmaceutically acceptable carriers or excipients, such as fillers, diluents, binding agents, plasticising agents, disintegrating agents, flavouring or sweetening agents, stabilisers, antimicrobial agents, cryoprotectants, lyoprotectants, antioxidants, solubilizing agents, tonicifying agents, surfactants, collapse temperature modifiers and inert storage gases for example nitrogen or helium.

In a particular embodiment, the formulation is in the form of a tablet or lozenge which is of suitable size to be easily applied firmly to the inner surface of the cheek, using for example a finger or thumb. For this purpose, the tablet may be somewhat larger than conventional IDTs. For example, the tablet or lozenge may be generally range from 8- 35mm in width and length. In a particular embodiment, the tablets will be generally rectangular or square in shape, which the corners optionally rounded or cut. Thus generally rectangular tablets or lozenges may suitably be from 15-35mm long and from 8- 20mm wide, for example from 26-30mm or from 26-28mm in length and from 14- 17mm or from 14-18 mm wide, whereas generally square tablets will suitably be from 12-25mm each side.

In a particular embodiment, the tablet has at least one convex surface. For example, the tablet is generally hemispherical in shape with one of the large surfaces of the tablet being flat and the other being convex with slightly bevelled sides as illustrated in Figure 2. This shape allows the tablet to sit comfortably in the buccal area since the

hemispherical surface will fit more closely to the profile of the buccal epithelia, producing enhanced contact levels. Furthermore, the flat side makes the tablet easier to handle and apply to the buccal area, for example using a thumb or finger.

The inclusion of a flat side is also very useful as it allows 2 tablets (of the same shape) to be held together firmly and comfortably in the buccal area making a 2 sided spherical tablet of double the dose delivered to one cheek as illustrated in Figure 2B and 2C.

Tablets or lozenges of the invention are suitably relative thin in depth, for example up to 3mm for example from l-3mm to ensure rapid and complete dissolution when in contact with for example the buccal surface.

The tablet suitably has sufficient adherence properties to ensure that it remains in position throughout the dissolution process. This may be achieved by appropriate selection of excipients used in the tablet production, and in particular a binding agent.

In a particular embodiment, the tablet comprises a binding agent such as a natural polymer, like gelatine, starch, acacia, tragacanth or gum, as well as synthetic polymers such as polyvinylchloride (PVC), polyvinylpyrrolidine (PVP), hydroxypropyl

methylcellulose (UPMC), methyl cellulose, ethyl cellulose, or polyethyleneglyclol (PEG), as well as polysaccharides such as glucose, sucrose or sorbitol.

In a particular embodiment, the binding agent comprises gelatine which may be from a variety of sources including cattle, pig, fish and poultry such as chicken. The applicants have found that tablets comprising a significant proportion of gelatine adhere well to damp surfaces and so may be expected to adhere well to a buccal surface.

Furthermore, unlike other buccal formulations of the same category, it does not break down into smaller particles when introduced onto a wet surface. Instead it is held together as one part by the large content of gelatine, while at the same time dissolves rapidly from the side that is in contact with the wet surface. This lowers the chance of swallowing the formulation or, in the case of an unconscious individual, exiting the buccal/mouth area with any exiting saliva.

Suitably the binding agent is present in an amount of from 40-90%w/w for example from 55-75%w/w of the solid formulation, such as about 65%w/w.

In another particular embodiment, the solid formulation is one which dissolves rapidly, for example in less than 5 minutes and suitably less than 1 minute, when contacted with a moist or damp surface. Rapid dissolution of the tablets can be achieved by various means. For example, as far as possible, generally amorphous materials, including active ingredients or excipients are suitably used in the preparation of the tablets or lozenges. Amorphous structures are generally more prone to disruption than more ordered crystalline or partially crystalline structures. Similarly the tablet or lozenge should have a high level of porosity, which encourages disintegration and dissolution of the tablet.

The choice of excipients will affect how readily amorphous structures may be formed, as will the manufacturing method as detailed more fully below.

A further advantage of gelatine as a binding agent appears to be that, when used in significant quantities as outlined above, it can readily form a highly amorphous matrix for the tablet.

Alternatively or additionally, the formulation may further comprise a disintegrating agent, which ensures that it breaks down rapidly in the mouth. Examples of suitable disintegrating agents include those which liberate carbon dioxide in contact with water so as to actively break down the tablet. Examples of such disintegrating agents include alkali or alkaline earth metal carbonates such as sodium bicarbonate, sodium carbonate, potassium bicarbonate, potassium carbonate or calcium carbonate, as well as citric or tartaric acid or combinations thereof. A particular example of a disintegrating agent is sodium bicarbonate. However, other components such as sugars including mannitol may act as disintegrating agents.

The applicants have found that a particularly preferred combination of agents for use in the formulation is sodium bicarbonate and mannitol. It appears that the sodium bicarbonate or carbonate derived therefrom, for example after freeze drying, inhibits or prevents the crystallisation of mannitol, ensuring that that amorphous character of the product is high.

The amount of disintegrating agent included in the solid formulation will depend upon factors such as the precise nature of the disintegrating agent or combination of disintegrating agents, as well as the size and nature of the tablet. Typically however, the solid formulation of the invention may comprise from 0-45%w/w. For example, where the disintegrating agent comprises an alkali or alkaline earth metal carbonate such as sodium bicarbonate, it is suitably present in an amount of from 5-15%w/w, for example from 10-12%w/w and suitably about 1 l%w/w.

In a further embodiment, the formulation of the invention further comprises a filler or diluent. Suitable fillers or diluents for use in the formulations include for example, sugars such as mannitol, lactose, sucrose, trehalose, sorbitol, glucose, or raffinose, or amino acids such as arginine, glycine or histidine, as well as polymers such as dextran or polyethylene glycol (PEG).

If required, the formulation may further comprise a reagent which modulates the absorption profile of the opiate antagonist, for example to increase the speed or level of absorption. Such reagents may include accelerants which increase the speed or absorption of the naloxone or salt thereof, such as a surfactant (e.g. Brij surfactant), or decellerants, which may prolong the delivery of the naloxone, such as a polymer coating (e.g. HPMC) or enteric coating (e.g. methyl acrylate-methacrylic acid copolymers).

Alternatively or additionally, the formulation may comprise penetration enhancers such as chitosan, polyethylene oxide, polyvinyl alcohol, polyvinyl pyrrolidone and polyacrylic acid.

Alternatively, a pH adjuster such as a pharmaceutically acceptable buffer may be added to enhance or delay absorption.

In a particular embodiment, where the formulation is intended to use in an emergency overdose situation, the formulation is suitably designed such that each buccal tablet produces a plasma naloxone level which is broadly similar to that of injectable formulations currently in use. For example they may produce a C_max plasma level of at least 1000 pg/mL (from 1000 to 5000 pg/mL) with rapid onset of action with Tmax of from 5 to 30 minutes, and in particular within 20 minutes. Alternatively or additionally, the formulation is designed such that the time it takes for at least 50% of the C_max to be achieved (T₅o%) is 10 minutes or less. This parameter ensures that an adequate amount of naloxone is absorbed quickly, to produce an immediate effect, even if the actual final Tmax is some time later.

However, additional formulations of the invention may be provided for administration as a supplementary dosage after the immediate emergency has passed, to ensure a longer and more sustained administration of naloxone. Such formulations will be designed to provide for a later T_max or Τ₅ο%, and/or a longer duration of action, if appropriate, and/or a lower C_max plasma level, in accordance with clinical practice.

The solid formulations of the invention are suitably prepared using drying procedures including lyophilisation techniques. In such cases, the formulations may further comprise lyophilisation aids such as cryoprotectants, lyoprotectants and/or collapse temperature modifiers.

In a particular embodiment, the formulation comprises a component such as mannitol, which may act as a lyophilisation aid, as well as a sweetening agent, a binding agent, a structure modifier, a diluent and may also act as a disintegrating agent. Mannitol in particular is known for its hydrophilic nature, bulking properties and is widely used as a cryoprotectant and therefore is usefully included in the formulations of the invention. It may introduce porosity into a formulation. The level however, is suitably selected so that it does not result in significant levels of crystallisation in the formulation. This will depend upon factors such as the nature of the binding agent. However, it is suitably present in an amount of from 10-40%w/w or from 10-50%, in particular from 10- 25%w/w and suitably at or below about 24%w/w.

Thus, in a particular embodiment, the formulation comprises a dosage amount such as from 0.4mg to 4mg of naloxone or a salt thereof, distributed throughout an IDT formulation comprising

(a) gelatine in an amount of from 65-69%w/w;

(b) mannitol in an amount of from 20-24%w/w;

(c) sodium bicarbonate in an amount of about 1 l%w/w;

wherein the formulation is in solid form, and in particular is in solid amorphous form. Such a formulation provides a rapidly available dosage of naloxone, as may be required in an overdose emergency.

The formulations described above are for use in the treatment of an opiate or opioid overdose. The opiate or opioid may be a prescription opiate, where the overdose may be administered accidentally, or an opiate or opioid that is subject to abuse such as heroin.

Certain types of formulation as described above are novel and so form a further aspect of the invention. In particular, the invention further provides a solid formulation in the form of an IDT suitable for buccal administration, and comprising an antagonist of an opiate or opioid substance, or a salt or hydrate of said antagonist. Suitable antagonists, salts or hydrates are as described above. In addition, excipients are also as described above. In particular, the IDT comprises from 40-90%w/w for example from 55-75%w/w of gelatine or suitably about 65%w/w gelatine.

Yet a further aspect of the invention provides a method for preparing a solid formulation as described above, said method comprising forming a solution of an opiate or opioid antagonist such as naloxone or a salt thereof and at least one pharmaceutically acceptable carrier or excipient, and drying said composition to form a solid formulation.

In a particular embodiment, the drying process is a freeze-drying or lyophilisation process. The lyophilisation process is suitably carried out at temperature in the range of from -20 to -60°C, for example at about -40°C.

In particular, the solution of opiate antagonist such as naloxone or a salt thereof and at least one pharmaceutically acceptable carrier or excipient is frozen before freeze drying or lyophilisation. In particular, the preliminary freezing step is carried out low

temperatures, for example at from -10 to -80°C, such as from -20 to -30°C to ensure that freezing takes place rapidly. During a rapid preliminary freezing step, any crystals forming will be quite small, and much of the material will be in an amorphous state. The applicants have found that this leads to a final dried product with high levels of porosity, meaning that the tablets or lozenges will dissolve more rapidly, as discussed above.

Suitable pharmaceutically acceptable carriers or excipients are as described above. In a particular embodiment however, to maximise the amorphous nature of the product, cryoprotectants may be omitted from the formulation.

Suitably the solution is divided into dosage units, in particular tablets or lozenges prior to drying, although if larger volumes of solution are dried, the resultant solid formulation may be formed into dosage units thereafter, for example by compression of powders.

Solid formulations in accordance with the invention and in particular, dosage units in the form of tablets, lozenges, films or capsules, are suitable packaged for storage and distribution. The dosage units may be contained within blister packs, foil packaging or the like, which are suitable for holding individual or small numbers of dosage units and keeping them sterile until required. Suitably the dosage units are packaged in an inert gas such as nitrogen, to avoid premature dissolution of the tablet.

The dosage units may form part of a kit which further comprises elements such as instructions for untrained user, and outer packaging. In a particular embodiment, the kit comprises a packaged dosage unit, held within a holder which is of the general shape and size as a credit card or other portable devices such as the SwissCard™ or PCMCIA (Personal Computer Memory Card International Association) device, which is provided with a suitable indentation to accommodate the dosage unit. Such holders may be easily kept in a purse or wallet. The holder might further include emergency instructions for the resuscitator, either in written or even voice-delivered form. In this way, it is hoped that individuals who may be susceptible to overdoses, or parents or peers of such individuals, would be able to carry the dosage units with them at all times, so as to be prepared in the event of an emergency.

In a particular embodiment, the kit may comprise one or more dosage units of a first solid formulation for use immediately in an overdose emergency, which provides a short T5o%as described above, and one or more dosage units of a second solid formulation according to the invention which provides a slower or more prolonged drug delivery for subsequent administration.

In a further aspect, the invention provides a method for treating an individual suffering from an overdose of an opioid such as heroin, said method comprising administering to said individual a solid formulation as described above, wherein the administration is by buccal administration. Suitably, the method is carried out immediately signs of an overdose are noticed in an individual. The opportunity for such rapid response whilst awaiting the arrival of the emergency services is designed/intended to improve the prognosis of the individual in such instances.

Detailed Description of the Invention

The invention will now be particularly described by way of example. However, it will be apparent to one skilled in the art that the specific details are not required in order to practice the invention. The following descriptions of specific embodiments of the present invention are presented for purposes of illustration and description. They are not intended to be exhaustive of or to limit the invention to the precise forms disclosed. Many modifications and variations are possible in view of the above teachings. The

embodiments are shown and described in order to best explain the principles of the invention and its practical applications, to thereby enable others skilled in the art to best utilize the invention and various embodiments with various modifications as are suited to the particular use contemplated.

The example is illustrated by the accompanying drawing in which: Figure 1 illustrates a process for preparing an IDT;

Figure 2 illustrates a particular shape of a tablet formulation of the invention where (A) shows a single tablet and (B) and (C) illustrates how these may be held or administered together in a double dose;

Figure 3 shows schematically various formulation holders used in particular

embodiments of the invention;

Figure 4 shows the results of differential scanning calorimetry experiments to show the effect of mannitol:gelatin ratio on the thermal properties of the freeze dried instant disintegrating tablets. The tablets were composed of mannitol:gelatin in the ratios illustrated, plus sodium bicarbonate 11% w/w, with the exception of the 100% w/w mannitol sample;

Figure 5 shows the results of Powder X-ray diffraction analysis of tablet formulations in which a) shows the effect of mannitol :gelatin ratio on the solid state properties of the freeze dried instant disintegrating tablets. The tablets were composed of mannitol :gelatin in the ratios specified, plus sodium bicarbonate 11% w/w. (b) shows the powder X-ray diffraction of individual tablet excipients, plus the formulated product with and without naloxone 800 μg;

Figure 6 is a schematic diagram of apparatus used for a digital image disintegration assay, constructed from a blister sheet such as an aluminium blister sheet with a painted black background providing contrast for the tablet. Disintegration of the tablet was monitored as the mean grey value using an image analyser;

Figure 7 is a series of graphs showing the effect of (A) temperature [volume 0.7 mL; medium - phosphate buffered saline], (B) fluid volume [temperature 35°C; medium - phosphate buffered saline], (C) disintegration medium [temperature 35°C; volume 0.7 mL] on the disintegration profile of the naloxone instant dissolving tablet using a digital image disintegration assay. Data represent mean ^standard error, n=3; and

Figure 8 is a graph showing a comparison of the Naloxone instant disintegrating tablet of the invention, compared to a Zydis ® based formulation marketed as Imodium Instant®. Example 1

Preparation of Naloxone IDT

Gelatine powder BP (0.78g) was first dissolved in hot (70-80°C) water in a lOOmL volumetric flask. The solution was swirled until the gelatine was fully dissolved (10-15 minutes). More water (40mL) at room temperature (18-25°C) was added to the flask with swirling. Then mannitol (10%w/v solution, 2.93 lg) and sodium bicarbonate powder (0.132g) was added to the solution in the flask and the resultant mixture swirled until all solutes were fully dissolved (10-15 minutes). The flask was then transferred to a water bath held at a temperature of 18-25°C, and retained there until the temperature of solution, as measured by a thermometer, was also between 18 and 25°C.

Naloxone Hydrochloride Dihydrate powder BP (0.0586g) was added to the solution, and the flask swirled until dissolution was complete (5-10 minutes). Thereafter, cold water was added to bring the volume to lOOmL and the solution mixed by inverting the flask 3 times.

The resultant solution was poured into 30 individual blister wells (1.5g per well; Figure 1) and frozen in a freezer at a temperature range of -20°C to -26°C over a period of 4 hours to 4 days. The blister wells were transferred into an open polystyrene box of dry ice (<-70°C) for a period of 2-3 minutes, before individual frozen tablets were transferred from each blister well to an empty type 1 glass bottle using tweezers. The contents of the bottles were inspected to ensure that they had not broken and bottles containing intact frozen tablets were transferred to a freeze dryer.

The freeze-drying chamber was sealed and the cooling unit and vacuum pump were switched on. A temperature of <-40°C and a pressure of <0.1mbar were maintained for a period of from 96-120hours. At the end of this time, the vacuum pump was switched off and nitrogen gas fed into the freeze-drying chamber at a rate of

>50mL min^"1. Once the pressure in the freeze drying chamber exceeded lmbar, the nitrogen feed was closed and drying chamber opened.

The type 1 glass bottles were immediately sealed with rubber bungs whilst still inside the chamber. They were then removed from the chamber and placed on a workbench at room temperature for 30 minutes.

Tablets obtained using this method were of a shape illustrated in Figure 1 and showed a good physical appearance, as they were white and free from damage and erosion. They were weighed and measured and showed good tablet mass uniformity (mean +5.0%) and uniformity of dimension (length 28.86mm +5.0%; width 15.99mm ±5.0%.

The naloxone content was checked by FIPLC and found to be consistent across the tablets. A visual disintegration test was carried out by placing the tablets on a tissue, which had been wetted with 0.1M phosphate buffered saline (4mL), at 37-38°C. All tablets were fully dissolved within less than 30 seconds.

Batches were maintained at 4°C or 25°C for periods of from 1 to 6 months and the reviewed again. The results are summarised in the Tables la and lb below.

The tablets obtained showed good uniformity and stability and would be suitable for clinical evaluation.

Example 2

Packaging and Holders

In a particular embodiment, the invention provides a kit comprising one or more solid formulations of the invention packaged in a holder, for example as illustrated in Figure 3A-D.

The holder (1) is suitably constructed of a plastic or polymer such as polyvinyl chloride (PVC), polyethylene, polypropylene, polylactic acid (PLA) or polyethylene terephthaiate (PET) or copolymers thereof. However, in a particular embodiment, the holder is an aluminium blister pack as such packaging may be more robust and stable even under hot conditions. It is generally planar in shape. Suitably, the holder is generally rectangular, with a size similar to that of a conventional credit card. For example, the width of the holder is suitably in the range of from 70- 100mm, for example about 86mm, with a height of from 40-60mm, for example about 54mm.

Typically, the holder (1) is slightly deeper than a conventional credit card, for example from 2-5mm deep and in particular about 3mm deep. This means that one or more wells or indentations (2) may be provided in the holders, which are adapted to hold tablets such as those produced as described in Example 1 . In the embodiment of Figure 3(A), two wells are provided, each adapted to hold a buccal naloxone tablet (2), in particular, 2 tablets formulated for rapid-naloxone delivery, as described above.

Each tablet (2) is sealed within the well, for example using a film such as a plastic or metallic film, in particular an aluminium film, which may be easily broken to access the tablet when required.

If required the film may also be provided with perforations (4), arranged to allow ready fracture of the film to facilitate access to a tablet (2) in a well.

This holder (1) could be retained by a person who may be at risk of overdosing on an opiate, or a peer or relative of such a person, and would provide a means for administering a dosage of naloxone useful in an emergency situation in the event of an overdose. If the first tablet (2) did not produce a sufficient therapeutic effect, the second tablet (2) stored within the holder may be administered also.

An alternative holder (Figure 3B) includes two wells containing rapid-onset tablets (2) as described above, together with an additional well which holds a tablet (3) formulated for slower and more prolonged release of naloxone. This provides an opportunity to continue treatment for a longer period of time, so that naloxone can continue to be administered, even after the immediate emergency has passed, to ensure that a therapeutic effect can be continued, while emergency sendees are awaited.

The tablet (3) is of a different size or shape, generally a different size to those of the tablets (2), so that it is easily distinguishable from the rapid-release naloxone formulation. As shown, the tablet (3) is larger than the tablets (2) but it may be smaller if required. It is suitably arranged in a separate section, for example a different quadrant, of the holder (1) to further ensure that the different types of tablet are readily

distinguishable, even in an emergency.

A third embodiment of the holder (1) illustrated in Figure 3C comprises a double- pack of the same combination of tablets, with 4-rapid onset tablets (2) located in wells in an upper half of the holder ( 1), and two follow-up slow release naloxone tablets (3), retained within wells in the lower half of the holder (1). A protective film or foil cover (5) (Figure 2D) is suitably provided over the entire surface of the holder (1), securing the tablets (2, 3) in the respective wells. The film suitably contains appropriately arranged perforations (4) to allow for single tablet removal as well and illustrative explanatory text, to ensure that a user can readily identify the location of the rapid-onset and slow release tablets.

Example 3

Preparation of a range of Tablets

Feed solution for tablet preparation was prepared by disintegrating 0.780 g of pre- weighed gelatin powder (Fagron Ltd, 1 10 g bloom strength), 0.132 g of sodium

bicarbonate powder (Fagron Ltd) and 2.931 g of mannitol 10 (Fresenius Kabi) in 40 mL of water for injection (WFI) held at 70°C. Once all excipients were fully dissolved, a further 40 mL WFI (room temperature) was added and the solution was allowed to cool to room temperature. Naloxone hydrochloride dihydrate (pharm-grade; Fagron Ltd) 0.0586 g was dissolved in the feed solution, which was made up to 100 ml,.

The same method was used to prepare different feed solutions with varying mannitol :gelatin ratios, as summarised in the following Table 1.

Table 1

The weights of each of the excipients were adjusted accordingly.

Empty wells of an aluminium blister were filled with 1.500 g of naloxone HC1 feed solution. The wells were designed to produce tablets which were 29mm long and 16mm wide with a convex lower surface, to provide tablets shaped for easy application to the buccal epithelium of an unconscious patient for example using a thumb.

Filled blister wells were cooled down to -20°C to allow feed solutions to freeze and then were maintained at -20°C, above its T'g, for a 2 hour annealing step. After annealing, the blisters were cooled down to -80°C. Frozen tablets where removed from the wells and placed into pre-coo!ed freeze drying vials (1 oz Clear Glass Universal Type 1) packed inside a temperature controlled freeze drying chamber, -40°C, and the drying chamber was sealed. A bench top (Lyotrap freeze dryer; LTE Scientific Ltd) was used to perform the freeze drying cycle. A 5 day freeze drying cycle was initiated to ensure all ice within the tablets was sublimed under < 0.01 mbar and < -40°C. At the end of the freeze drying cycle, the drying chamber was backfilled with nitrogen, allowing it to reach atmospheric pressure with the cooling unit on. The drying chamber was opened and the freeze drying vials were immediately sealed with rubber stoppers and screw lids while inside the drying chamber. The finished products were removed from inside the drying chamber and inspected for breakage or shrinkage.

Pure mannitol crystalline tablets (composition 6 in Table 1 above) were brittle and difficult to remove from sample vials without collapsing into powder. In contrast, pure gelatin tables (composition 1 in Table 1) had a sticky texture and lacked porosity.

Formulations containing both mannitol and gelatin successfully produced tablets.

The white hemispherical porous tablets were measured with calipers and found to be 29.4 ± 0.2 mm in length, 16.1 ± 0.5 mm in width with a depth of 3.0 ± 0.2 mm and weighed 17.7 ± 0.4 mg. Scanning electron microscopy revealed the pore size in the tablet to have an average length of 0.23 ±0.02 mm(SE) and an average width of 0.094+0.01 mm (SE), n 20.

Example 4

Solid state properties of the tablets of Example 3

The solid state properties of the tablets of Example 3 were then investigated using differential scanning calorimetry (DSC) powder X-ray diffraction (PXRD).

Differential scanning calorimetry studies were performed over a temperature range of -40 to 200°C using a DSC Q20 (TA instruments, New Castle, DE, USA ) with a refrigerated cooling accessory (RCS). The DSC cell was purged with 50 cm3/min dry nitrogen and the RCS was purged with 150 crnS/min nitrogen. The DSC cell was calibrated following the instrument manufacturer's guidelines. Experimental conditions for freeze dried tablets followed an equilibration at 25°C for 5 min, ramp to 200°C

(10°C/min), followed by a ramp to 25°C (10°C/min) and a ramp to 200°C (10°C/min).

Samples were analyzed in aluminium pin-holed hermetic pans. Ail experiments were repeated three times. The sample size used was approximately 5 mg, with the mass for each experiment recorded accurately on a six-figure balance, (Micro balance: Sartorius

UK Ltd).

The results are shown in Figure 4.

PXRD analyses were performed on Rigaku MiniFlex 600 diffractometer (Rigaku, Tokyo, Japan). The samples were spread on a zero background holder and placed on a spinner stage. The instrument produces Cu Ka radiation (1 .5418 A) operated at a voltage of 40 kV and a current of 15 mA over a scan range 3-40° 2Θ with a step size of 0.01° 2Θ at a speed of 5°/min.

The results are shown in Figure 5. It is clear that addition of gelatin diminished the crystalline melting peak in the freeze-dried product. However, even with quite high gelatin content, persistent peaks were observed in the amorphous halo of the PXRD results. This indicated a crystalline fraction within the freeze-dried tablet and the unique peak at 9.7° 2Θ identified the presence of mannitol hemihydrate. These results show that tablets containing 24% mannitoi were in substantially amorphous form.

Example 5

In- vitro Disintegration Studies

A digital image or photographic disintegration assay was developed to measure tablet disintegration in small volumes of medium in temperature controlled blisters and i s shown in schematic form in Figure 6. Disintegration was quantified using a gel imager to follow tablet disappearance. The disintegration vessel was a thermal-jacketed aluminium blister sheet with black-painted wells of the same dimension as those used for

manufacturing the tablets (Figure 6). Disintegration medium was phosphate buffered distilled water (pH 7.3 ± 0.2) or a synthetic saliva adapted from the SS5 USP recipe for artificial saliva [33], which consisted of distilled water, salts (NaCi = 8 g/L, KH2P04 = 0.19 g/L and Na2HP04 = 2.38 g/L) and mucin 2.16 g/L (from porcine stomach).

Assay temperature was adjusted by placing the whole apparatus in a temperature controlled water bath at the target temperature. Disintegration medium, 0.7 mL, was pipetted into the blister wells adjacent to the test well and micro probe thermocouples connected to a data logger thermometer were used to monitor the temperature of the disintegration medium. Once the temperature of the disintegration medium in blister wells reached the target temperature the apparatus was placed inside a heat-insulting box of polystyrene and transferred into a closed box gel imager for the disintegration assay. This apparatus allowed accurate temperature logging throughout the disintegration assay to ensure the temperature of the disintegration medium was maintained ± 1°C of the target temperature.

Disintegration was measured using a GeneSnap version 6,07.03 gel imager, with the camera located above test blister well. A reference image was then taken of test blister well containing disintegration medium, after which the well was dried and an instant disintegrating tablet was placed in the blister. An image of test well was then taken (t = 0 s) and the assay initiated by adding the required volume of temperature-conditioned disintegration medium onto the tablet, (e.g. 0.7mL at 35°C) after which 100 consecutive images were taken at 0.4s intervals. Image J analysis software was used to analyse the images by determining the mean grey value (MGV) corrected for baseline at each time point and normalised to the assay range. The results are shown in Figure 7. Tablets of the optimized naloxone formulation appeared white but once the disintegration media had been added, a clear solution very rapidly developed revealing the black painted surface of the blister well beneath. For example, adding 0.7 mL of phosphate buffer to a naloxone tablet, with the temperature of the blister well held at 37°C, resulted in approximately half of the matrix remaining at 2s and by 10s the matrix had disappeared, figure 1. For the digital imaging disintegration assay the limit or target for tablet disintegration was classified as the time taken to achieve 10% of the matrix remaining or 90% disintegration. This target was met for the optimized naloxone tablets, under the conditions of 37°C and 0.7 mL, at 4.8 ± 0.6 seconds and furthermore by 10 seconds only 6% of the matrix remained, figure 7a & 7b.

It should be noted that a very small amount of white colour remained in the images recorded at the end of disintegration assay. This was attributed to small air bubbles remaining in the solution and internal reflection at the curved edge of the blister well resulting from the position of the light sources. No paniculate matter was seen when the contents of the blister well, from a typical naloxone tablet experiment, were viewed under a light microscope. Even under high magnification only air bubbles in a clear solution were observed. When the phosphate buffer was replaced with artificial saliva, the very small amount of residual white colour was further diminished at the end of the naloxone tablets' disintegration. The surface-active nature of the mucin present in the saliva dispersed the air bubbles, and thus the percentage of matrix remaining fell to a reading of approximately zero, figure 7C.

The novel digital imaging disintegration assay was used to explore the effects of temperature, solvent volume and composition on the disintegration of the tablets. Under all conditions the tablets disintegrated fully (>90%) within 30 seconds. Tablets disintegrated in < 10 seconds in 0.7 mL of phosphate buffer at 35°C (Figure 5a).

Temperature variation over the range reported to exist in the buccal cavity, 33~37°€, did not alter the disintegration rate, but the rate was 4-5 times slower at 25°C. In opiate overdose, the volume of oral fluid available in the buccal cavity may be reduced compared to 0.7 mL in a typical adult human. Reducing the amount of fluid available to the tablet progressively reduced the rate at which the tablet disintegrated, with

disintegration in 0.1 mL being 4.5 times slower than in 0,7 ml, (Figure 7b). Interestingly, when phosphate buffer was replaced with synthetic saliva, a slightly quicker disintegration rate was observed, a result of better spreading and wetting of the tablet caused by the mucin present in the disintegration medium (Figure 7c).

Evaluating the discrimination between disintegration profiles, measured at different temperatures and volumes, was performed using the similarity factor (f2) test [Shar et al. Pharmaceutical Research, 2010, 49(12) p5854-5862]. This approach was applied because of the high number of data points recorded for each disintegration profile, therefore making other common statistical approaches, for example the MANOVE analysis, impractical. This analysis confirmed that the digital imaging disintegration assay disintegration profiles were sensitive to the volume of disintegration medium used, for example the f2 value comparing between a disintegration volume of 0.7 and 0.4 mL at 35°C was 28.36, (for this statistical approach an f2 value below 50 indicates low similarity or in other words a significant difference between the two profiles of data). Interestingly the profiles at different temperatures, indicated a high similarity for disintegration between 33, 35 and 37°C, as all comparisons had f2 values equal or greater than 50, with only the profiles recorded at 25°C showing a statistical difference to the rest of the data set.

These results show that tablets of the invention are capable of disintegrating in less than 10 seconds, which would be required for the treatment of overdoses,

ample 6

Comparison of tablet of the invention with a commercially available IDT

The methodology of Example 5 was used to compare the tablet of the invention with a marketed freeze-dried and orally disintegrating tablet, Imodium Instant® was investigated using 0.7 ml. of phosphate buffer at 37°C.

Imodium Instant© tablets showed slower disintegration compared to the naloxone tablets of the invention, producing a cloudy suspension with 46.0 ± 0.2 % of the matrix remaining after 30 seconds (Figure 8). Light microscopy aided the validation because it showed that the much higher percentage of the matrix remaining, detected in the disintegration assay, was caused by the presence of aggregated particles.

Example 7

Chemical Stabili lv of! abieis of !he Invention

The drug content of naloxone HCL/tablet of tablets obtained in Example 3 were checked using a Naloxone HCL HPLC assay (Mostafavi A. et al., Talanta 2009, 77(4) p 1415-1419. The method utilized a C-18 Gemini-NX 5 μηι reverse phase column, mobile phase of 32% v/v methanol HPLC grade and 68% 0, 1 ammonium acetate (pH 5.8), isocratic flo rate of 1 mL/min, column temp of 37°C and an injection volume of 20 .L. Absorbance was measured at 229 nm. This was confirmed to be the target 800μ§.

The tablets were stored under nitrogen at 4°C or 25°C for nine months, after which the HPLC analysis was repeated. Tablets were found to be stable in that there was less than 5% change in drug content over that time period.

Table la | Stability study conducted at 25 °C

Table lb | Stability study conducted at 4 °C

Claims

Claims

1. A solid formulation comprising an antagonist of an opiate or opioid substance, or a salt or hydrate of said antagonist, in the absence of any opiate or opioid agonist, for use by buccal administration in the treatment of an opiate or opioid overdose.

2. A solid formulation according to claim 1 wherein the said antagonist is naloxone or a pharmaceutically acceptable salt or hydrate thereof.

3. A solid formulation according to any one of the preceding claims wherein the said antagonist, is the sole therapeutically active ingredient.

4. A solid formulation according to any one of the preceding claims which is in the form of a dosage unit and which comprises 0.4mg to 4mg naloxone per dosage unit.

5. A solid formulation according to any one of the preceding claims which is in the form of a tablet, lozenge, film or capsule.

6. A solid formulation according to claim 5 which is in the form of an instant dissolvable tablet or instant disintegrating tablet (IDT).

7. A solid formulation according to any one of the preceding claims which further comprises a pharmaceutically acceptable binding agent.

8. A solid formulation according to claim 7 wherein the binding agent is gelatine and at least some of the gelatine is in amorphous solid form.

9. A solid formulation according to any one of the preceding claims which further comprises a disintegrating agent.

10. A solid formulation according to claim 9 wherein the disintegrating agent is sodium bicarbonate.

11. A solid formulation according to any one of the preceding claims which further comprises a filler or diluent.

12. A solid formulation according to any one of the preceding claims wherein the filler or diluent is mannitol, at least some of which is in amorphous solid form.

13. A solid formulation according to any one of the preceding claims which comprises a combination of sodium bicarbonate and mannitol.

14. A solid formulation in the form of an IDT suitable for buccal administration, and comprising an antagonist of an opiate or opioid substance, or a salt or hydrate of said antagonist.

15. A solid formulation according to claim 14 wherein the said antagonist is naloxone or a pharmaceutically acceptable salt or hydrate thereof.

16. A solid formulation according to claim 14 or claim 15 wherein the said antagonist is the sole therapeutically active ingredient.

17. A solid formulation according to any one of claims 14 to 16 which comprises 0.4mg to 4mg naloxone per IDT.

18. A solid formulation according to any one of claims 14 to 17 which further comprises from 40-90%w/w gelatine.

19. A solid formulation according to claim 18 wherein at least some of the gelatine is in an amorphous solid form.

20. A solid formulation according to any one of claims 14 to 19 which further comprises a disintegrating agent.

21. A solid formulation according to any one of claims 14 to 20 which further comprises mannitol, at least some of which is in amorphous solid form.

22. A solid formulation according to claim 1 or claim 14 which comprises a dosage amount such as from 0.4mg to 4mg of naloxone or a salt thereof, distributed throughout an IDT formulation comprising

(a) gelatine in an amount of from 65-69%w/w;

(b) mannitol in an amount of from 20-24%w/w;

(c) sodium bicarbonate in an amount of about 1 lw/w%;

wherein the formulation is in solid form.

23. A solid formulation according to claim 22 which is in amorphous form.

24. A method for preparing a solid formulation according to any one of the preceding claims, said method comprising forming a solution of an opiate antagonist and at least one pharmaceutically acceptable carrier or excipient, and drying the frozen composition to form a solid formulation.

25. A method according to claim 24 wherein the solution of an opiate antagonist and at least one pharmaceutically acceptable carrier or excipient is subjected to a preliminary freezing step prior to drying.

26. A method according to claim 25 wherein the freezing step is carried out at a temperature of from -10 to -80°C.

27. A method according to any one of claims 24 to 26 wherein the solution is divided into dosage units prior to drying.

28. A method according to any one of claims 24 to 27 wherein the drying process is a freeze-drying or lyophilisation process.

29. A kit comprising a solid formulation according to any one of claims 1 to 23 which is contained within a sealed package.

30. A kit according to claim 29 wherein the package is contained within a holder suitable for storage in a purse or wallet.

31. A kit according to claim 29 or claim 30 which comprises one or more dosage units of a first solid formulation for use immediately in an overdose emergency, and one or more dosage units of a second solid formulation according to any one of claims 1 to 23 which provides a slower or more prolonged drug delivery for subsequent administration.

32. A method for treating an individual suffering from an overdose of an opiate or opioid, said method comprising administering to said individual a solid formulation according to any one of claims 1 to 23, wherein the administration is by buccal administration.

33. A method according to claim 32 wherein the opiate or opioid is heroin.