PHARMACEUTICAL DELIVERY DEVICE

FIELD OF THE INVENTION

The present invention relates to a method of making a pharmaceutical delivery device as well as pharmaceutical delivery devices made by such methods. The pharmaceutical delivery devices described herein enable the sustained delivery of a pharmaceutically active agent to a patient. The delivery device comprises a polyurethane matrix loaded with the active agent. The pharmaceutical delivery device has good storage stability with minimal degradation of the active agent.

BACKGROUND OF THE INVENTION

Pharmaceutical delivery devices are generally used to provide a controlled release of a pharmaceutically active agent to a patient. Such devices can take a variety of different forms, including implants, inserts and patches. Many different materials have been used to form the basis of pharmaceutical delivery devices and polymeric materials have been found to be particularly useful.

Once an active agent has been loaded into or onto a delivery device, the device may be stored for a period of time prior to use. Consequently, it is desirable that the active agent should show minimal or substantially no degradation when loaded into or onto the pharmaceutical delivery device. As will be appreciated, the compatibility of the material forming the delivery device with the active agent may affect the storage stability of the active agent. However, the presence of contaminants or impurities in the material (e.g. polymeric material) forming the pharmaceutical delivery device may also affect the stability of the active agent loaded thereon. For example, the presence of even low levels of contaminants may impact the stability of the active agent. It is therefore desirable to ensure that the levels of contaminants/impurities in the materials forming the pharmaceutical delivery devices are kept to a minimum to assist in providing devices with good and reproducible storage stability.

Prostaglandins are a known class of pharmaceutically active agents, which have been used to treat reproductive health disorders and disorders linked to inflammatory response. These reproductive health disorders include obstetrical and gynaecological indications. For example, active agents such as prostaglandins have been used in the induction of labour.

There are benefits in releasing such active agents in a controlled sustained manner to a patient. Vaginal pessaries (or “inserts”) have been commercially available for a number of years under the Trade Marks Propess® and Cervidil®. These products comprise a lozenge-shaped pessary formed of a water-swellable polyurethane polymer matrix, which is loaded with the prostaglandin dinoprostone (a PGE ₂ analogue), which is released into the vagina in a sustained manner. The prostaglandin typically has the effect of softening the cervix during childbirth. The vaginal pessary is contained within a retrieval system, which allows the pessary to be withdrawn from the patient during labour, when the clinical circumstances dictate that the required amount of drug has been delivered to the patient. However, the prostaglandin active agent tends to be somewhat unstable and the pessary is generally stored under sub-ambient conditions. For example, pessaries containing prostaglandin PGE ₂ analogues, such as dinoprostone, are typically stored under frozen conditions, e.g. temperatures between - 10 °C and -30 °C.

Patent specification W02004/029125 discloses a prostaglandin-containing vaginal pessary, where the prostaglandin in this case is misoprostol. Misoprostol also suffers from degradation on storage. Pessaries containing prostaglandin PGEi analogues, such as misoprostol, are therefore generally stored under refrigerated conditions, e.g. at temperatures between 2 and 8°C.

Patent publication W02006/013335 discloses improvements in stability of a misoprostol-containing vaginal pessary when the water content is kept below 1%, particularly below 0.2% by weight in the final product. Thus, the drug-loaded vaginal pessary is dried, for example by pan drying in the presence of dry air, down to a moisture level around 1%. The pessary is then packaged together with a desiccant, which reduces the water level down to below 0.2% typically. Patent specification W02006/013335 discloses enhanced stability results after 12 months storage at 25 ^e C.

However, subsequent investigations have shown an unexpected variability in the storage stability of such misoprostol-containing vaginal pessaries.

This has led the present inventors to conduct further investigations aimed at providing methods which yield delivery devices having improved and reproducible storage stability.

SUMMARY OF THE INVENTION

The present invention resides in the unexpected discovery that certain contaminants and/or trace impurities in reactants used to produce polyurethane based pharmaceutical delivery devices, critically determine the stability of pharmaceutically active agents loaded therein. The inventors have also identified methods to minimise the presence of contaminants and/or trace impurities in these reactants prior to polyurethane formation. These methods enable the production of pharmaceutical delivery devices showing good storage stability with minimal degradation of the active agent.

In particular, a first aspect of the present invention provides a method of making a pharmaceutical delivery device, the method comprising: purifying a poly(alkylene glycol); reacting the purified poly(alkylene glycol) with an alkane or alkene polyol and diisocyanate to produce a polyurethane matrix; and incorporating a pharmaceutically active agent in the polyurethane matrix.

In a second aspect, the invention provides a pharmaceutical delivery device obtainable by a method according to the first aspect of the invention.

Features of both the method according to the first aspect of this invention and the pharmaceutical delivery devices (“delivery device” or “device”) of the second aspect of this invention will now be described. It should be understood that references to the “polymer”, “polyurethane”, “polyurethane matrix” and/or “pharmaceutical delivery device” of this invention encompass not only these products per se, but products obtained by the methods according to the first aspect of the invention.

Additionally, as used herein, the term “matrix” may mean the polymeric material formed by a polymerisation reaction and accordingly encompasses both linear and cross-linked polymers. For example, as used herein, the term “polyurethane matrix” is used to denote the polymeric material formed by the reaction between the purified poly(alkylene glycol), the alkane or alkene polyol and the diisocyanate. As used herein, a cross-linked polymer is one which comprises bonds (or cross links) between polymer chains. In particular, as used herein, a cross-linked polymer is one which comprises covalent bonds between polymer chains.

As used herein, a linear polymer is one which is substantially free of cross-links between individual polymer chains.

It should also be appreciated that references to the term “polyol” mean an alcohol comprising more than one hydroxyl group. For instance, a polyol may mean any alcohol that is not mono-functional. By way of further example, a polyol may be an organic compound having two or more hydroxyl groups. For example, a polyol may mean a diol or triol.

Moreover, throughout this specification the term “comprising” is used to denote that embodiments of the invention “comprise” the noted features and as such, may also include other features. Flowever, in the context of this invention, the term “comprising” may also encompass embodiments in which the invention “consists essentially of” the relevant features or “consists of” the relevant features.

Poly(alkylene glycol) is purified to remove contaminants and other impurities which affect the stability of pharmaceutically active agents loaded into devices prepared therefrom. As such, the methods of this invention are specifically adapted to purify a poly(alkylene glycol) of impurities or contaminants which may be present in trace amounts. Indeed, the inventors have discovered that reducing the impurity/contaminant content of a poly(alkylene glycol) unexpectedly enhances the stability of the active agent within the polyurethane matrix produced by reaction thereof. The contaminants or impurities may be present in the poly(alkylene glycol) as a result of the manufacturing process. Thus, the impurities or contaminants may comprise “synthesis impurities” or “synthesis contaminants”. It should be understood that poly(alkylene glycol) may comprise one or more different types of (synthesis) impurity or contaminant.

The step of purifying the poly(alkylene glycol) may comprise treating or processing the poly(alkylene glycol) to remove impurities/contaminants or to minimise/reduce the amount of any impurities or contaminants present, for example, as a result of a poly(alkylene glycol) manufacturing process.

As will be appreciated, poly(alkylene glycols) may be made by a number of different manufacturing processes. In many cases, poly(alkylene glycols) may be made via a catalysed process, For example, a poly(alkylene glycol) may be made via a ring opening polymerisation process using a catalyst, such as an anionic or cationic ring opening polymerisation process. As will be understood by one skilled in the art, poly(alkylene glycols) may therefore contain synthesis impurities/contaminants derived from the catalyst, reagents used in the manufacturing reaction, reagents used at the termination of the reaction and/or reagents used in the treatment of the final poly(alkylene glycol) product.

As such, the methods of this invention may comprise determining the impurities/contaminants present in the poly(alkylene glycol) prior to the purification step. The nature and level of such contaminants may be readily determined using standard analytical techniques. The step of purifying the poly(alkylene glycol) may then comprise selecting an agent capable of increasing the solubility of the identified impurities/contaminants and adding this agent to the poly(alkylene glycol) as is described in further detail hereinafter.

By way of example, the process of forming a poly(alkylene glycol) may require an acidic or basic catalyst. During the manufacturing process, the catalyst is generally removed and/or deactivated by a neutralising agent which forms a salt of the catalyst. The neutralising agent may be added in excess. For instance, when a desired molecular weight of the poly(alkylene glycol) has been reached, a neutralising agent may be added to neutralise the catalyst. Consequently, residual amounts of unreacted neutralising agent (acid or base) and/or residual amounts of salt (e.g. neutralised catalyst), can remain in the poly(alkylene glycol) as a synthesis contaminant or impurity. Therefore, impurities or contaminants of poly(alkylene glycol) may comprise neutralisers of the catalyst used in the poly(alkylene glycol) manufacturing process. The synthesis impurities or contaminants may include acidic, basic and/or salt impurities.

The impurity present in a poly(alkylene glycol) may be an organic acid, such as benzoic acid, acetic acid, lactic acid, maleic acid, propionic acid, formic acid, fumaric acid or citric acid, or a mineral acid, such as phosphoric acid, or mixtures thereof. For example, benzoic acid may be present as an acidic impurity.

The impurity present in a poly(alkylene glycol) may be a base such as sodium hydroxide, potassium hydroxide or sodium carbonate, or mixtures thereof.

In some cases, there may be more than one impurity present in the poly(alkylene glycol). For example, the poly(alkylene glycol) may comprise sodium hydroxide and benzoic acid. In other examples, the poly(alkylene glycol) may comprise potassium hydroxide and lactic acid, or may comprise potassium hydroxide and acetic acid.

The impurity present in a poly(alkylene glycol) may be a salt resulting from a neutralisation reaction at the end of the manufacturing process. The impurity may be a salt derived from the neutralisation reaction occurring between any of the acidic and basic catalysts and neutralising agents defined herein. Representative examples of such salts include, but are not limited to, potassium benzoate, potassium acetate, potassium lactate, potassium citrate, sodium benzoate, sodium acetate, sodium lactate or sodium citrate, or mixtures thereof.

The impurity may be present in amounts of 400 ppm by weight and above, depending on the source of the poly(alkylene glycol). According to the present invention (and depending on the level of impurity present initially), is the amount of impurity present may be reduced to below 300 ppm, preferably below 200 ppm, more preferably below 100 ppm, advantageously below 50 ppm, desirably below 30 ppm, especially below 20 ppm, and more especially below 10 ppm by weight of the impurity in the poly(alkylene glycol) through purification. In some cases, the purification steps described herein may reduce the impurity level to below 5 ppm, or even below 1 ppm by weight of the impurity in the poly(alkylene glycol).

In view of the above, this invention provides methods of preparing a pharmaceutical delivery device, wherein the level of impurity in the poly(alkylene glycol) reactant and/or the final polyurethane matrix is kept to a low level. The level of impurity may be kept low by the poly(alkylene glycol) purification procedures described herein. The poly(alkylene glycol) is typically polyethylene glycol (PEG), polypropylene glycol (PPG) or polytetramethylene oxide (PTMO). The poly(alkylene glycol) may be a block copolymer comprising PEG units. The poly(alkylene glycol) may be a block copolymer comprising PEG and PPG units, such as a PPG-PEG-PPG block copolymer or a PEG-PPG-PEG block copolymer.

The poly(alkylene glycols) used in the polyurethane matrices of the present invention are generally linear having a number average molecular weight of 1000 to 40,000, 2000 to 20,000 and especially 4000 to 10,000. The methods of this invention may exploit poly(alkylene glycols), for example polyethylene glycol (PEG), having a number average molecular weight between 1000 and 20,000, or between 7000 and 9000. For example, a polyethylene glycol used in the methods of this invention may have a number average molecular weight of about 8000.

As used herein, the number average molecular weight of a polymer is the mean molecular weight of the polymer. The number average molecular weight may be calculated by summing the molecular weights of n polymer molecules and dividing by n. A variety of techniques may be used to determine the number average molecular weight of a polymer. Representative examples of such techniques include, but are not limited to, gel permeation chromatography, viscometry, and proton-NMR.

Purification of a poly(alkylene glycol) to remove impurities such as, for example, (benzoic) acid impurities, may be achieved by any suitable means including, for example, by Soxhlet extraction, deionization (by for example deashing using ion- exchange resins) or with the use of solvents. Where purification is achieved using solvents, these may include alcohols such as, for example, ethanol and/or methanol. Purification of a poly(alkylene glycol) to remove impurities may exclude purification by subjecting the poly(alkylene glycol) to charcoal column chromatography.

A poly(alkylene glycol) may also be purified by extraction using superheated water (SHW).

One of skill will appreciate that the term superheated water (SHW: which may also be referred to as subcritical water or pressurized hot water) refers to liquid water under pressure at a temperature between its boiling point (100°C) and its critical temperature (374°C). In other words, the term superheated water refers to water that has been heated to temperatures within the range of approx. 100°C to 374°C while maintaining sufficient pressure to maintain the water in a liquid state.

Various properties of subcritical or superheated water are described in US 6,352,644 (Hawthorne et a/; the contents of which are incorporated herein by reference). It is also generally described in that document that subcritical water can be used to clean contaminated material, e.g. to remove contaminants from polymers.

In view of the above, a method of this invention may comprise: purifying a poly(alkylene glycol) to remove impurities by treatment with superheated water (SHW) ; reacting the purified poly(alkylene glycol) with an alkane or alkene polyol and diisocyanate to produce a polyurethane matrix; and incorporating a pharmaceutically active agent in the polyurethane matrix. In the superheated temperature range, the hydrogen bonds in water break which results in SHW having different physicochemical properties to water. In particular, the SHW may act as a suitable solvent for organic compounds. For larger organic compounds, particularly those with polar groups or compounds which are polarisable like aromatic compounds, SHW is an effective solvent. Under SHW conditions, impurities in a poly(alkylene glycol) may partition into the water and so may be removed from the poly(alkylene glycol). For example, impurities may be removed continuously from the poly(alkylene glycol) due to water circulation in a SHW apparatus (as described hereinafter). As a consequence, SHW can be used as an alternative to organic solvents to purify a poly(alkylene glycol).

Batches of purified or cleaned poly(alkylene glycol) may be prepared using SHW in an apparatus designated hereinafter, the term “SHW apparatus”. A SHW apparatus for use in this invention may comprise one or more vessels and where the apparatus comprises a plurality of vessels, it may further comprise one or more pumps adapted to pump fluid into, out of and/or between the vessels. A SHW process for purifying poly(alkylene glycol) is carried out at a pressure sufficient to maintain superheated water as a liquid.

Once a suitable pressure has been attained within a SHW apparatus the water may be heated. For example, water circulating through the vessel(s) of a SHW apparatus may be heated. Immediately prior to heating the water, the pressure may be between about 5 bar and about 8 bar, e.g. the pressure may be approximately 6.5 bar.

The water may be heated to above about 140°C, e.g. to approximately 175°C. The water may be heated by any suitable means including, for example, through the use of oil heaters. To purify poly(alkylene glycol), a poly(alkylene glycol) may be brought into contact with superheated water. For example, the poly(alkylene glycol) may be fed or pumped into a SHW purification apparatus described herein. Where the SHW apparatus comprises two vessels, water to be superheated may be fed into one of the vessels and the poly(alkylene glycol) may be fed into the other vessel. The water and poly(alkylene glycol) may be circulated through the apparatus such that their flow paths form a counter current; in other words, the superheated water may circulate through the apparatus in one direction and the poly(alkylene glycol) in another, opposite, direction. During the SHW process, the water and poly(alkylene glycol) may be passed through packing material contained within the one or more vessels. The use of packing material may increase the surface area and/or facilitate agitation of the water and poly(alkylene glycol). In this way, the mixing of the water and poly(alkylene glycol) may be facilitated. Consequently, the packing material may take any form that increases the surface area and/or that facilitates agitation or mixing of the water and poly(alkylene glycol). In some examples, the packing material takes the forms of a plurality of rings (e.g. perforated rings).

The packing material may comprise or be made of any material that can withstand the temperatures and pressures involved in the SHW process. Such materials may include plastics, ceramics or metals, or combinations thereof. By way of example, the packing material may comprise or be composed of stainless steel.

However, in other examples, the packing material may be absent from the one or more vessels. In such cases, it has been found that sufficient levels of purification may be achieved without the need for a packing material in the vessel. The purification methods described herein can be further improved according to methods known in the art. For example, those methods described in US 6,352,644 (Hawthorne et al; the contents of which are incorporated herein by reference).

In a SHW process of the type described above, a mixture of superheated water and poly(alkylene glycol) splits into two phases of nearly pure water and poly(alkylene glycol). Impurities (for example, synthesis impurities) contained within the poly(alkylene glycol) can be washed out and substantially pure poly(alkylene glycol) obtained.

Following the SHW process, synthesis impurities may be contained within waste water that is extracted from the apparatus. The waste water may be recirculated, reintroduced and/or reused in the SHW process. Optionally, the waste water may have been purified prior to being recirculated, reintroduced and/or reused in the SHW process.

Prior to subjecting a poly(alkylene glycol) to a purification process, including the SHW processes described herein, the poly(alkylene glycol) may be prepared as an aqueous solution.

An aqueous poly(alkylene glycol) solution may be prepared using purified and/or de-mineralised water.

The aqueous poly(alkylene glycol) solution may comprise between about 5 to about 30% w/w poly(alkylene glycol). For example, the aqueous poly(alkylene glycol) solution may comprise about 10% w/w poly(alkylene glycol). For example, approximately 90 litres of water (de-mineralised and/or purified) may be mixed with about 10kg of poly(alkylene glycol).

The aqueous solution of the poly(alkylene glycol) may optionally be further treated with an agent to increase the solubility of any impurity or contaminant therein. The aqueous solution of the poly(alkylene glycol) may be treated with a solubilising agent that would be apparent to someone skilled in the art. The addition of the solubilising agent to the aqueous solution of the poly(alkylene glycol) may be prior to or during the purification process, such as the SHW processes described herein. Thus, the solubilising agent may be added before, during or after preparation of the aqueous poly(alkylene glycol) solution. For example, where a SHW process is used to purify the poly(alkylene glycol), the solubilising agent may be added with the water into the SHW apparatus. Alternatively, the solubilising agent may be added to the aqueous solution of the poly(alkylene glycol) prior to introduction into the SHW apparatus.

The solubilising agent may enhance the aqueous solubility of impurities in the poly(alkylene glycol). For example, the solubilising agent may facilitate and/or promote the formation of ionic species from any impurities in the poly(alkylene glycol). By way of example, the solubilising agent may comprise counter ions that react with any acidic or basic impurities in the poly(alkylene glycol) to form ionic salts. Thus, in some instances, the addition of the solubilising agent may be considered as an ionisation process - promoting the formation of ionic forms of the impurities with an increased aqueous solubility.

As described previously, the manufacture of a poly(alkylene glycol) may require an acidic or basic catalyst. At the end of the manufacturing process, a first neutralising agent may be added to deactivate the catalyst. The first neutralising agent may be added in excess. Residual amounts of acid or base can remain in the poly(alkylene glycol) as a synthesis contaminant or impurity due to unreacted first neutralising agent and/or catalyst. Prior to or during purification of the poly(alkylene glycol), a solubilising agent may be added to increase the solubility of the residual amounts of acid or base. For example, the solubilising agent may be a second neutralising agent that reacts with residual acidic or basic impurities in the poly(alkylene glycol) to form an ionic salt. In those cases, where a second neutralising agent is used as the solubilising agent, the second neutralising agent may be added in a neutralising amount. Alternatively, the second neutralising agent may be added in excess. In this case, the second neutralising agent may have been selected such that any excess acid or base remaining in the poly(alkylene glycol) at the end of the second neutralisation step has an increased aqueous solubility than the residual acid or basic impurities initially present in the poly(alkylene glycol). A single solubilising agent may be added or, alternatively a combination of different solubilising agents may be added. The precise solubilising agent (or combination of agents) to be added may be determined by the synthesis impurity of the poly(alkylene glycol).

Where the synthesis contaminant comprises an acidic impurity, the solubilising agent may be a basic agent. The basic agent may comprise a chemical base such as, for example, an alkali metal oxide or hydroxide. The basic agent may comprise, for example, sodium hydroxide. For example, where the acid impurity of the poly(alkylene glycol) comprises benzoic acid, the basic agent may comprise sodium hydroxide. In this case, the neutralisation reaction between the added sodium hydroxide and the benzoic acid contaminant present in the poly(alkylene glycol) results in the formation of the salt, sodium benzoate.

Where the synthesis contaminant comprises a basic impurity, the solubilising agent may be an acidic agent. The acidic agent may comprise an organic acid such as, for example, citric acid or lactic acid. Alternatively, the solubilising agent may be a buffered solution or buffer system. The buffered solution may be added in such a form so as to push an equilibrium towards formation of the salt form of any acidic or basic impurities. For example, a buffered solution may comprise a weak acid and conjugate base, or may comprise a weak base and conjugate acid.

One example of such a buffered solution is a benzoic acid and sodium benzoate solution. For example, where the poly(alkylene glycol) comprises benzoic acid as a synthesis impurity, the solubilising agent may be a buffered solution comprising benzoic acid and sodium benzoate. The addition of this buffered solution may drive the equilibrium towards the formation of the salt, sodium benzoate.

Once the solubility of any impurity or contaminant in the poly(alkylene glycol) is increased (e.g. through the addition of a second neutralising agent such as sodium hydroxide), the resulting salt impurity (e.g. formed as a consequence of the neutralisation reaction) may be removed during subsequent purification procedures, including procedures which exploit SFIW.

In view of the above, a method of making a pharmaceutical delivery device according to this invention may comprise: providing a poly(alkylene glycol) and preparing an aqueous solution therefrom; treating the aqueous poly(alkylene glycol) solution with an agent to increase the solubility of an impurity; subjecting the treated aqueous poly(alkylene glycol) solution to a purification procedure; reacting the purified poly(alkylene glycol) with a polyol and diisocyanate to produce a polyurethane matrix; and incorporating a pharmaceutically active agent in the polyurethane matrix. Moreover, the invention provides a method of providing poly(alkylene glycol) for use in the manufacture of a pharmaceutical delivery device, said method comprising treating poly(alkylene glycol) with an agent to increase the solubility of an impurity and then further treating the poly(alkylene glycol) to remove or extract the impurity. It should be understood that poly(alkylene glycol) provided by this method may have a reduced impurity/contaminant content as compared to poly(alkylene glycol) not subjected to this method. Prior to treatment with the agent which increases the solubility of an impurity, the poly(alkylene glycol) may be prepared as an aqueous solution. As such, where the poly(alkylene glycol) is prepared as an aqueous solution, the agent which increases the solubility of an impurity may be contacted with the aqueous poly(alkylene glycol) solution. Moreover, the agent increasing the solubility of an impurity may be a second neutralising agent, for example an acidic agent or a basic agent as described herein.

In addition to ensuring that poly(alkylene glycol) for use in the manufacture of pharmaceutical delivery devices is substantially free of impurities, the methods of this invention (in particular the poly(alkylene glycol) purification procedures thereof and the method of preparing poly(alkylene glycol) for use) permit any source of poly(alkylene glycol) to be used. This assists in safeguarding a robust supply chain as poly(alkylene glycol) of different specifications/grades and/or from different suppliers/sources may reliably be used in the manufacture of the pharmaceutical delivery devices. For instance, differences in poly(alkylene glycol) material arising from manufacturing processes and/or variability between batches and their impact on the final polyurethane product may therefore be negated by using the methods of this invention. Thus, pharmaceutical delivery devices with good storage stability can be obtained consistently and reliably irrespective of the source of poly(alkylene glycol). Prior to reacting the purified poly(alkylene glycol) with a polyol and a diisocyanate, the poly(alkylene glycol) may be supplemented with a preservative and/or antioxidant agent/compound. The preservative and/or antioxidant agent/compound may be added in a sufficient quantity to reduce or eliminate degradation of the poly(alkylene glycol). For example, the quantity may be sufficient to reduce or eliminate oxidation of the poly(alkylene glycol). The preservative and/or antioxidant agent/compound may be added in an amount up to 500 ppm, between 50 and 200 ppm, or between 80 and 120 ppm, for example about 100 ppm.

For example, a quantity of butylated hydroxytoluene (BHT) or butylated hydroxy anisole (BHA) may be added to the purified poly(alkylene glycol). BHT or BHA may be added in a sufficient quantity to reduce or eliminate oxidation of the poly(alkylene glycol). BHT or BHA may be added in any of the amounts stated above. For instance, BHT or BHA may be added in an amount up to 500 ppm, between 50 and 200 ppm, or between 80 and 120 ppm. For example, BHT or BHA may be added in an amount of about 100 ppm. For example, BHT or BHA may be added in an amount of about 0.01% w/w of solid poly(alkylene glycol).

Purification of the poly(alkylene glycol) may comprise the removal of synthesis impurities or contaminants other than water. Any residual water in the poly(alkylene glycol) may be removed via a drying process. For example, once purified, the optionally preservative/antioxidant (e.g. BHT) supplemented poly(alkylene glycol) may then be subjected to a drying procedure. The purified poly(alkylene glycol) may be dried under vacuum, optionally with heating and/or mechanical agitation. For example, the purified poly(alkylene glycol) may be dried under vacuum at a temperature of between 100°C and 120°C using mechanical agitation. To produce a polyurethane matrix, the purified poly(alkylene glycol) may be reacted with a polyol and diisocyanate.

The polyurethane matrix may be a polyurethane hydrogel. As used herein, the term hydrogel may mean a network of polymer chains that form a gel with water as the dispersion medium.

The polyurethane matrix may be a cross-linked polyurethane such as, for example, a cross-linked polyurethane of the type disclosed in GB 2047093 and GB 2047094. Cross-linking may be obtained by using a poly-functional alkane or alkene polyol compound comprising more than two hydroxy groups. For example, a cross- linked polyurethane may be provided by reacting poly(alkylene glycol) with a triol (as the alkane or alkene polyol) and diisocyanate.

A cross-linked polyurethane matrix may be prepared from a long chain polyethylene glycol (e.g. PEG 2000, 4000, 6000 and 8000, which has optionally been extensively dried), a triol (for example, hexanetriol) as cross-linking agent and a diisocyanate (such as dicyclohexyl methane diisocyanate).

A suitable triol for use in preparing cross-linked polyurethane matrices may include 1 ,2,6-hexanetriol.

The ratio of the components poly(alkylene glycol) to polyol to diisocyanate of the polyurethane (in terms of equivalent weights) in the cross-linked polyurethane is generally in the range 1 to 0.5-1.5 to 2-3.5, or 1 to 1-1.4 to 2.5-3.1. For example, the ratio may be about 1 to 1.2 to 2.8. For example, the polyurethane may be prepared from PEG 8000, 1 ,2,6-hexanetriol and DMDI in the ratio of 1 :1.2:2.8. Alternatively, the polyurethane matrix may be a linear polyurethane matrix. For example, a linear polyurethane matrix of the type disclosed in W02004/029125 and W02008/003932. Such linear polyurethane matrices may be obtained by reacting a poly(alkylene glycol) and a diol (or other difunctional compound) with a difunctional isocyanate.

For such linear polyurethanes, diols in the range C ₅ to C20, preferably Cs to C15 are preferred. Thus, decane diol has been found to produce particularly good results. The diol may be an alkane or alkene diol. Branched diols may be used but straight chain diols are preferred. The two hydroxy groups are generally on terminal carbon atoms. Thus, suitable diols include 1 ,5-pentanediol, 1 ,6-hexanediol, 1 ,8-octanediol, 1 ,10-decanediol, 1 ,12-dodecanediol and 1 ,16-hexadecanediol.

The difunctional isocyanate is generally one of the conventional diisocyanates, such as dicyclohexylmethane-4, 4-diisocyanate (DMDI), diphenylmethane-4,4- diisocyanate, 1 ,6-hexamethylene diisocyanate, 1 ,4-butane diisocyanate (BDI) etc.

The ratio of the components poly(alkylene glycol) to polyol to diisocyanate of the polyurethane (in terms of equivalent weights) in the linear polyurethane is generally in the range 0.01-1.5 to 1 to 1.01-2.5, particularly 0.1 -1.5 to 1 to 1.1 -2.5, more particularly 0.2-0.9 to 1 to 1.2-1.9. A preferred range is 0.5-0.9 to 1 to 1.5-1.9. The amount of diisocyanate is generally equal to the combined amounts of poly(alkylene glycol) plus diol in equivalent weights to provide the correct stoichiometry. Generally, the ratio of poly(alkylene glycol) to polyol in the linear polyurethane is 0.1 -1.5 to 1 , preferably 0.2-0.9 to 1. The inventors have noted that the extent of the polymer reaction may further affect the properties of the pharmaceutical delivery device product and/or the stability of pharmaceutically active agents loaded therein. As such, the ratio of the components poly(alkylene glycol) to polyol to diisocyanate of the polyurethane may be adjusted to ensure that the polymer reaction is complete. In particular, the ratios may be adjusted to ensure that once the polymer reaction is complete, the polyurethane matrix contains low amounts of or no unreacted difunctional isocyanate. For example, the amount of difunctional isocyanate used may be at least about ±2.5%-3% of the amount calculated to provide the correct stoichiometry.

In any event, without wishing to be bound by theory and unless otherwise stated herein, it should be understood that the properties and variables of the polyurethane matrices as described in GB 2047093, GB 2047094, WO 2004/029125 and WO 2008/003932 (the contents of which are incorporated herein by reference) may be applicable to the present invention.

The polyurethane matrices are generally produced by melting the (optionally previously dried) poly(alkylene glycol) together with the polyol and diisocyanate at a temperature of between about 70 and 100°C, e.g. a temperature of around 85°C. A catalyst may be used. In some cases, two or more catalysts may be used in the reaction to form the polyurethane matrix. Suitable catalysts may include, for example, ferric chloride.

However, it has been found that the removal of impurities from the poly (alkylene glycol) (e.g. acidic impurities) through execution of the methods according to the present invention, in particular the purification procedures, reduces the effectiveness of the conventional ferric chloride catalyst. It is, therefore, preferred to use alternate catalysts which are not sensitive or susceptible to the reduced impurity content of the purified poly(alkylene glycol). For example the methods of this invention may exploit a bismuth alkanoate catalyst (such as bismuth neodecanoate (BiCat 8106 Shepherd Chemical Co.)). Other types of catalyst may also be used in the methods of this invention. For example, other bismuth catalysts, such as bismuth chloride, tin- based catalysts, such as stannous alkanoate, or amine-based catalysts, such as triethylenediamine (TEDA) or 1 ,4-diazabicyclo[2.2.2]octane (DABCO).

Any suitable catalyst for the preparation of a polyurethane matrix may be directly added to one or more (for example all of) the poly(alkylene glycol), polyol and diisocyanate reactants. The catalyst may be added neat, in the form of a solution or suspension and/or may be pre-mixed with one or more of the reactants prior to adding the remaining reactants.

For example, the methods of this invention may require the preparation of a polyol/catalyst mix. The polyol/catalyst mix may be added to the purified and optionally dried poly(alkylene glycol) prior to contact with a diisocyanate.

Polyol/catalyst mixes for use in this invention may comprise any of the diols/triols described above. For example, a suitable polyol/catalyst mix may comprise a hexanediol such as 1 ,6-hexanediol or a hexanetriol such as 1 ,2,6-hexanetriol. A suitable polyol/catalyst mix may comprise or further comprise bismuth alkanoate as a catalyst.

To prepare a polyol/catalyst mix for use in this invention, the required quantity of catalyst, for example bismuth alkanoate, may be dissolved in a suitable solvent such as, for example, ethanol, so as to prepare a catalyst stock solution. The required amount of the catalyst/ethanol stock solution may then be added to the appropriate quantity of polyol. The solvent may be removed by rotary evaporation.

The purified poly(alkylene glycol) may be reacted with the polyol/catalyst mix and a diisocyanate to provide the polyurethane matrix.

Alternatively, by way of further example, making the polyurethane matrix may comprise the preparation of a solution of catalyst which is added to the purified poly(alkylene glycol). This mixture may then be reacted with the polyol and diisocyanate to provide the polyurethane matrix.

The reaction mixture may be poured or injected into billet moulds and cured for a specified time. The reaction mixture may be injected into the billet mould via one or more mixing head(s) which combine the required quantities of purified (dried) poly(alkylene glycol), polyol and diisocyanate for injection into the mould. This process may be referred to as injection moulding. As stated, a catalyst may be added as a supplement to the reaction mix and the polyol may be added as a polyol/catalyst mix.

Alternatively, the methods of this invention may involve the use of a reactive extrusion process. In such a process, the reactants (the poly(alkylene oxide), the polyol and the difunctional isocyanate) are generally dispensed into an extruder using a liquid feed system. In these instances, the catalyst or the catalyst dispersion may be simultaneously dispensed into the extruder from volume calibrated syringes using a syringe pump. Using methods that would be known to persons skilled in the art, the rate of flow of each of the individual liquid streams into the extruder may be fixed to ensure the final polymer contains the appropriate proportion of each of the reactants. The polyurethane matrix may be discharged from the extruder as a strand, which may optionally be pelletised prior to further processing.

As will be appreciated, other methods of melt processing the polyurethane matrix may be used in the methods of the invention. For example, solvent casting may be used to process the polyurethane matrix. For example, in a solvent casting method, the polymer matrix may be dissolved in an appropriate solvent and cast onto a substrate, before evaporation of the solvent provides the polymer matrix in a desired form.

In view of the above, the polyurethane matrix may be formed as a moulded solid.

The polyurethane matrix product may then undergo a cleaning step. For example, the polyurethane matrix may be washed in water at ambient conditions.

A moulded polyurethane solid prepared in accordance with the methods described herein may be further processed to provide pharmaceutical delivery devices which are suppositories, pessaries for vaginal use, buccal inserts for oral administration implants and/or rings etc. For example, the moulded polyurethane solid may take the form of a sheet having a thickness of between about 0.5 and about 5mm, especially about 0.5 to about 2.5mm, particularly about 1 to about 2.5mm and more particularly about 0.8 to about 1 5mm. A moulded sheet of this type may be cut using, for example a stamp and/or die cutting process to provide individual delivery devices for use. One of skill will appreciate that a number of delivery devices may be cut or prepared from a single moulded polyurethane sheet. Alternatively, the polyurethane solid may be formed in a billet mould and sliced to form individual devices for use (e.g. pessaries). A device prepared from a moulded polyurethane solid may be in the form of a conformable unit, which is flexible enough (particularly when swollen) to be accommodated within a body cavity: for example, vaginal or buccal cavity in intimate contact with the mucosal membrane. Preferred shapes include rings, sheets, discs, ovals, kidney shapes, strips and cylinders. Generally, the smallest dimension is in the range 5-15mm and the longest dimension in the range 10-40mm. Preferred thicknesses are in the range 0.5-5mm, especially 0.5-2.5mm, particularly 1 -2.5mm and more particularly 0.8-1.5mm. It will be understood, however, that length and thickness of said delivery device may be altered and designed to preferred sizes per individual patient.

Polyurethane matrices of this invention as well as pharmaceutical delivery devices made thereof, are water-swellable having swellabilities, for example up to 500%, up to 800% or even about 1 ,000%. It should be understood that percent (%) swelling, means the increase in weight of the swollen polymer divided by the weight of the dry polymer. Usually, the polymer is swellable in the range 10% to 2000%, for example 50 to 1500% and typically 100 to 500%. The linear polyurethane matrices are also soluble in certain organic solvents, such as dichloromethane, which allows the matrix to be dissolved and cast into films or coatings. Therefore, it also allows active agents of poor water solubility but which are soluble in organic solvents to be loaded into the polymer. The polyurethane matrix of a delivery device according to this invention may exhibit a swellability of about 250% to about 325%.

Unless otherwise stated, the water swellability values described herein reflect the swellability of a polymer in water at a temperature of 25°C. The impurity level in a poly(alkylene glycol) prepared according to the methods of this invention, and which is suitable for use in the manufacture of a pharmaceutical delivery device, is generally below 100 ppm, preferably below 20 ppm and most desirably below 10 ppm. In some examples, the impurity level may be less than or equal to 5 ppm. The level of ionic impurity is generally below 100 ppm, preferably below 20 ppm and most desirably below 10 ppm. In some examples, the level of ionic impurity may be less than or equal to 5 ppm, or less than or equal to 1 ppm.

Additionally, the impurity level in a polyurethane matrix prepared according to the methods of this invention is generally below 100 ppm, preferably below 20 ppm and most desirably below 10 ppm. In some examples, the impurity level in the polyurethane matrix is less than or equal to 5 ppm. The level of ionic impurity is generally below 100 ppm, preferably below 20 ppm and most desirably below 10 ppm. In some examples, the level of ionic impurity may be less than or equal to 5 ppm, or less than or equal to 1 ppm.

Generally, the polyurethane matrix or pharmaceutical delivery device of this invention may be loaded with a pharmaceutically active agent. The step of loading a polyurethane matrix or device of this invention with pharmaceutically active agent may more generally be referred to as “loading”.

The “loading” process may comprise soaking a polyurethane matrix or device prepared therefrom in an aqueous solution of the active agent of required concentration for a time sufficient for uptake of the active agent to occur. After loading, the matrix may be dried down to the required water content. Alternatively, the loading process may be a hot melt compounding process. For example, the hot melt compounding process may be a hot melt extrusion process. Hot melt extrusion is a widely used method of loading active agents into polymers in the pharmaceutical industry. In such methods, an active agent may be added or loaded to a hot melt of the polyurethane matrix prior to extrusion. Prior to the loading step, the active agent may be formulated into granules. In such cases, the granules comprising the active agent may be compounded with pre-prepared polymer pellets using a hot melt extrusion process. During the hot melt extrusion process, the granular drug formulation and the polymer pellets may be charged into gravimetric feeders and dispensed into an extruder at a rate to provide the desired dose of active agent in the final product. An appropriate set of compounding screws, screw speed and temperature profile may be selected. As will be appreciated, the exact parameters selected may be dependent upon the nature of the polymer compositions, granules and target dose in the final product. The appropriate selection of such parameters would be well within the capabilities of the skilled person.

Prior to loading, the polyurethane matrix or device of this invention may be washed. Washing may comprise washing in water and/or washing in ethanokwater mixtures before being loaded with the pharmaceutically active agent.

A polyurethane matrix or pharmaceutical delivery device of this invention may be loaded with any pharmaceutically active agent or a combination of different agents.

The polyurethane matrix or pharmaceutical delivery devices of this invention allow the effective sustained delivery of the pharmaceutically active agent(s), from the solid state matrix. The pharmaceutical is intended to be delivered to a patient (human or animal). Generally, the active agent(s) is/are dispersed uniformly throughout the polyurethane matrix.

A delivery device prepared according to the methods of this invention may be used in medicine or therapy, e.g. as a medicament. The precise use of such devices in medicine or therapy may depend upon the pharmaceutical agent.

A delivery device prepared according to methods of this invention may find application in the treatment of obstetrical and/or gynaecological conditions. Such delivery devices may be used in the treatment and/or manipulation of the female reproductive system of both human and non-human animals. For example, a device described herein may be used in the induction of labour, particularly for cervical ripening or for the treatment of endometriosis.

Alternatively, a delivery device prepared according to methods of this invention may find application in the treatment of gastrointestinal, psychological and/or orthodontic conditions. For example, the delivery devices prepared according to the methods of this invention may be used in the treatment of schizophrenia, or in the treatment or prevention of conditions such as gastric ulcers or mucositis.

A further advantage of preparing polyurethane matrices by the methods of this invention is that agents loaded into delivery devices prepared therefrom are found to have good long-term storage stability, which is reproducible. In some embodiments, this allows the delivery device to be stored under non-frozen or non-refrigerated conditions, or even at ambient temperatures, with minimal degradation. Again, without wishing to be bound by theory, the observed good long-term storage is attributed to the purification procedures of the methods of this invention, which substantially reduce the level of impurities in the final polyurethane matrix.

Storage times of a delivery device prepared by a method of this invention are typically up to 6 months, up to 12 months, particularly up to 18 months, often up to 24 months and sometimes up to 36 months.

As used herein, the term “good stability” may mean that an active agent loaded into a polyurethane matrix prepared according to methods of the invention is substantially stable and/or exhibits minimal or no degradation in comparison to an active agent loaded into a polyurethane matrix made according to other methods. The stability of an active agent and/or its tendency to degrade is typically influenced by its chemical structure, in amongst other factors such as a surrounding environment. As such, the term “good stability” may take a different meaning when applied to different active agents. For example, “good stability” may mean an active agent loaded into the delivery device is stable when stored under frozen conditions (e.g. at a temperature between about -10°C and -30°C) for a period of 1 month, 3 months, 6 months, 12 months or 24 months. In other cases, “good stability” may mean an active agent loaded into the delivery device is stable when stored under refrigerated conditions (e.g. at temperature between about 2°C and 8°C) for a period of 1 month, 3 months, 6 months, 12 months or 24 months. In certain cases, “good stability” may mean an active agent loaded into the delivery device is stable when stored under ambient conditions (e.g. at temperature of about 25°C) for a period of 1 month, 3 months, 6 months, 12 months or 24 months. Additionally, “good stability” may mean an active agent loaded into the delivery device is stable when stored under more demanding conditions (e.g. a higher temperature of about 40°C and/or a higher relative humidity) for a period of 1 month, 3 months, 6 months, 12 months or 24 months. By way of further example, “good stability” may mean an active agent loaded into the delivery device is stable when stored under any number of different conditions, such as one or more, or all, of the conditions defined above (e.g. frozen, refrigerated, ambient and more demanding) for a period of 1 month, 3 months, 6 months, 12 months or 24 months,

As used herein, “stable” means that an active agent loaded into the delivery device may maintain at least 99%, at least 95%, at least 90%, at least 80%, at least 70% or at least 60% of an original level of pharmaceutical activity.

The methods described herein may be particularly useful in providing delivery devices for active agents that are susceptible to degradation in the presence of an impurity (such as an acidic, basic and/or salt impurity). Such active agents may be referred to herein as “impurity-labile active agents”, e.g. acid-labile, base-labile and/or salt-labile active agents. By way of an example, the degradation of an acid-labile active agent may be initiated, promoted and/or facilitated by the presence of an acid. However, when manufactured using the methods described herein, the presence of impurities in the polyurethane matrix of the delivery device may be minimised. Consequently, the methods described herein may provide a good and/or reproducible storage of such impurity-labile active agents.

The active agent may be one which is susceptible to keto-enol tautomerisation. The keto-enol tautomerisation of such active agents may be promoted in the presence of an acid. Consequently, such active agents may also be considered as acid labile. The promotion of a keto-enol tautomerisation may lead to further reaction or reactions that result in the degradation of the active agent. Prostaglandins are one such family of active agents that may be considered susceptible to degradation via an initial step of keto-enol tautomerisation. Thus, the methods described herein may be useful in providing a good and reproducible long-term storage of prostaglandin active agents.

For example, a device of this invention may be loaded with a synthetic prostaglandin PGEi analogue, such as misoprostol or a prostaglandin PGE ₂ analogue, such as dinoprostone. Devices loaded with (synthetic) prostaglandin PGEi or PGE ₂ analogues may find particular application in the treatment and/or manipulation of the female reproductive system of both human and non-human animals. For example, a device described herein may be used in the induction of labour, particularly for cervical ripening.

The term "synthetic prostaglandin PGEi analogue" as used herein is understood to cover the compound generally known as misoprostol and any analogues or derivatives thereof. Analogues or derivatives thereof are intended to encompass structural analogues or derivatives of the synthetic prostaglandin PGEi analogue, which maintain the essential pharmaceutical activity of the synthetic prostaglandin PGEi analogue, including misoprostol; for example, prostaglandins of different chain length, or different salts or esters which maintain pharmacological activity. These may also encompass stereoisomers of the synthetic prostaglandin PGEi analogue, such as misoprostol. It will be understood that the term synthetic prostaglandin PGEi analogue (or misoprostol) is not intended to encompass naturally occurring PGEi. Synthetic PGEi analogues or derivatives may be in the form of an ester; such as a methyl ester: whereas said naturally occurring PGEi is normally in the acid form. One or more Ci- ₆ alkyl groups (particularly methyl) may be attached to the prostanoic acid carbon chain, especially at the 15-position. Typically, misoprostol PGEi analogue or derivative in its physical state is an oil, whereas naturally occurring PGEi is in a crystalline form. Synthetic prostaglandin PGEi analogues are found to be particularly stable when loaded into a device of this invention. The terms “stable” or “good stability” as applied to synthetic prostaglandin PGEi analogue refer to decreased degradation of this prostaglandin at temperatures above 4°C particularly at room temperature of around +25°C within a delivery device prepared by a method of this invention. For example, wherein the percent dose of the synthetic prostaglandin PGEi analogue present within the delivery device after storage at temperatures above 4°C (preferably room temperature of around 25°C) is within a range of 90-100% of initial dose of the synthetic prostaglandin PGEi analogue added to the delivery device. For example, a synthetic prostaglandin PGEi analogue loaded into a delivery device, may maintain at least 95% pharmaceutical activity after storage at ambient temperature for 12 months. In some instances, a synthetic prostaglandin PGEi analogue may maintain at least 95% pharmaceutical activity even when stored at an elevated temperature of around 40°C for 12 months.

Misoprostol should be understood to mean (11a,13E)-(±)-11,16-Dihydroxy-16- methyl-9-oxoprost-13-en-1-oic acid methyl ester or analogue(s) or derivative(s) thereof, as described herein. Preferably, misoprostol has the formula C ₂₂ H ₃₈ O ₅ .

Misoprostol is inherently unstable and will naturally degrade to 8-iso misoprostol and misoprostol A. When loaded into a device of this invention, the inventors have discovered that misoprostol exhibits minimal degradation, that is to say, after a period of storage at ambient temperatures, the amount of misoprostol degradation (into 8-iso misoprostol and/or misoprostol A) is low.

For example, after a period of storage at ambient temperatures (for example, up to 12 months at 25°C), a delivery device of this invention loaded with misoprostol may comprise about 0.3% to about 1.1%, or about 0.4% to about 0.8%, or about 0.6% 8-iso misoprostol. Additionally, or alternatively, such a delivery device (e.g. stored up to 12 months at 25°C) may comprise about 0.1% to about 1.5%, or about 0.2% to about 0.5%, or about 0.3% to 0.4% Misoprostol A. Moreover, after a period of storage at ambient temperatures (for example, up to 12 months at 25°C), the misoprostol component of a delivery device of this invention may exhibit a potency of at least about 95% or 97% of the initial value.

Dinoprostone should be understood to mean (5Z,11a,13E,15S)-7-[3-hydroxy-2- (3-hydroxyoct-1-enyl)-5-oxo-cyclopentyl] hept-5-enoic acid or analogue(s) or derivative(s) thereof, as described herein. Preferably, dinoprostone has the formula

C ₂ OH3 ₂ 05.

Analogues or derivatives of dinoprostone are intended to encompass structural analogues or derivatives which maintain the essential pharmaceutical activity of the prostaglandin PGE ₂ analogue; for example, prostaglandins of different chain length, or different salts or esters which maintain pharmacological activity.

Prostaglandin PGE ₂ analogues are also found to be particularly stable when loaded into a device of this invention. The terms “stable” or “good stability” as applied to prostaglandin PGE ₂ analogues refer to decreased degradation of this prostaglandin at temperatures above -30°C, or above -20°C, e.g. at temperatures about -15°C or under refrigerated conditions, within a delivery device prepared by a method of this invention. For example, wherein the percent dose of the prostaglandin PGE ₂ analogue present within the delivery device of the present invention after storage at temperatures above about -20°C is within a range of 90-100% of the initial dose of the prostaglandin PGE ₂ analogue added to the delivery device. For example, a prostaglandin PGE ₂ analogue loaded into a delivery device according to this invention, may maintain at least 95% pharmaceutical activity after storage under refrigerated conditions for 12 months.

Dinoprostone is inherently unstable and will naturally degrade to PGA ₂ , 8-iso PGE ₂ and/or 15-keto PGE ₂ . When loaded into a device of this invention, the inventors have discovered that dinoprostone exhibits minimal degradation, that is to say, after a period of storage at temperatures above about -15°C, the amount of dinoprostone degradation is low.

For example, after a period of storage at temperatures above about -20°C (for example, up to 12 months at -15°C), a delivery device of this invention loaded with dinoprostone may comprise about 0.5% to about 1%, or about 0.7% to about 0.9% PGA ₂ . Additionally, or alternatively, such a delivery device (e.g. stored up to 12 months at -15°C) may comprise about 0.4% to about 0.8%, or about 0.5% to about 0.7% 8-iso PGE ₂ . Further, the device may comprise about 0.2% or less, or about 0.1% or less 15- keto PGE ₂ . Moreover, after a period of storage at temperatures above about -20°C (for example, up to 12 months at -15°C), the dinoprostone component of a delivery device of this invention may exhibit a potency of at least about 90% or 95% of the initial value.

If necessary, penetration enhancers, as known in the art, may be employed to assist the rate of transmucosal delivery, depending on the nature of the (synthetic) prostaglandin PGEi or PGE ₂ analogues, for example, its lipophilic or hydrophilic characteristics, size and molecular weight.

The stability of a pharmaceutically active agent, including synthetic prostaglandin PGEi analogues such as misoprostol, and prostaglandin PGE2 analogues such as dinoprostone, may also depend on the water content of the matrix, which is typically below 1% by weight, preferably below 0.5% by weight and advantageously below 0.2% by weight. A polyurethane matrix or delivery device of this invention is preferably packaged with a desiccant label or in desiccant packaging in order to reduce and maintain a low water content.

A delivery device prepared by the methods described herein may comprise a quantity of a pharmaceutically active agent. The quantity of pharmaceutically active agent to be loaded into the device may be dependent on the nature of the active agent and/or the condition to be treated. By way of example, the delivery device may be loaded with between about 25 micrograms (pg) up to about 1 g of a pharmaceutically active agent. For example, the delivery device may comprise about 100 pg, 200 pg, 400 pg, 800 pg, or 1200 pg, or even around 5 mg, 10 mg, 20 mg, 30 mg or 40 mg of a pharmaceutically active agent.

A delivery device prepared by the methods of this invention may comprise: synthetic prostaglandin PGEi analogue in a dose of about 25 to 400 micrograms (pg) typically 100, 200 or 400 micrograms. Further, a delivery device prepared by the methods of this invention may comprise: PGE ₂ analogue in a dose of about 2.5 mg to about 50 mg, for example, 5 mg, 10 mg, 20 mg, 30 mg or 40 mg dinoprostone.

The delivery device may have a thickness of around 0.4 to 1 .5 mm; and has a weight of around 120 to 500 milligrams (mg). Typically, a dose of misoprostol of around 200 pg is contained within a polyurethane matrix of around 241 mg weight and of around 0.8mm thickness. Typically, a dose of dinoprostone of around 10 mg is contained within a polyurethane matrix of around 241 mg weight and of around 0.8 thickness. In view of the above, this invention provides pharmaceutical delivery devices which, as a consequence of the methods and procedures outlined in this invention, exhibit one or more properties selected from the group consisting of:

(i) reduced or neutralised impurity/contaminant content;

(ii) good long-term stability of the pharmaceutically active agent;

(iii) minimal degradation of the pharmaceutically active agent;

(iv) a level of ionic impurity below about 100 ppm;

(v) a water swellability between about 250% to 325%; and

(vi) WSE (water soluble extractables) of not more than 0.5%.

In a fourth aspect, the present invention provides the use of purified poly(alkylene glycol) in the manufacture of a pharmaceutical delivery device. As stated, the pharmaceutical delivery device may comprise a polyurethane matrix. One of skill will appreciate that devices made using purified poly(alkylene glycol) have a low impurity content making them particularly suitable for loading with pharmaceutically active agents including, for example, synthetic prostaglandin PGEi analogues such as misoprostol, or a prostaglandin PGE ₂ analogue such as dinoprostone.

A fifth aspect of this invention provides use of the pharmaceutical delivery device of the present invention for controlled administration of a pharmaceutically active agent to a human or animal. For example, the pharmaceutical delivery devices may be used in the controlled administration of a synthetic prostaglandin PGE _I/ PGE ₂ analogue to a human or animal.

A sixth aspect of the invention relates to a method of storing the pharmaceutical delivery device. For example, storing the pharmaceutical delivery device under non- frozen or non-refrigerated conditions, or even at ambient temperatures. DETAILED DESCRIPTION

The present invention will now be described in detail with reference to the following Figures which show:

Figure 1 shows a schematic overview of a method for manufacturing a pharmaceutical delivery device according to one embodiment of the present invention;

Figure 2 shows a schematic diagram of a SHW apparatus for use in purifying a poly(alkylene glycol) according to one embodiment of the present invention;

Figure 3 shows the stability of misoprostol over time in a polyurethane delivery device (12) after storage at a number of different temperatures;

Figure 4 shows the stability of misoprostol over time in a polyurethane delivery device (13) after storage at a number of different temperatures; and

Figure 5 shows the stability of misoprostol over time in a polyurethane delivery device (14) after storage at a number of different temperatures.

EXAMPLES General Procedures Purification of PEG 8000

An aqueous solution of PEG 8000 was prepared by adding PEG 8000 (10 kg) to deionised water (90L). An aqueous solution of NaOH (1 M, 57g) was prepared and added to the PEG 8000 solution with mixing.

The mixed solution was then pumped into a vessel 10 of the SHW apparatus 15 shown in Figure 2 via feed inlet 20. Deionised water is also pumped into the vessel 10 of the SHW apparatus 15 via feed inlet 25.

The SHW apparatus is maintained at a pressure of approximately 6.5bar and a temperature of approximately 175°C. The mixed solution and deionised water were circulated in the vessel 10 and passed through packing material, such as rings 30. In particular, in this example, the packing material is composed of stainless steel perforated rings. However, in other examples, the packing material may take other forms and/or may be made from other materials. For example, the packing material may comprise or be made of any material that can withstand the temperatures and pressures involved in the SHW process. Such materials may include plastics, ceramics or metals, or combinations thereof. In another example, the packing material may be absent from the vessel (e.g. sufficient purification may be achieved without the need for a packing material in the vessel).

A purified solution of PEG8000 in water (ca. 50:50) was pumped out of the vessel 10 via an outlet 35 located at the bottom of the vessel. A density meter 40 was located at the outlet 35 to ensure the density of the collected product was greater than 1000kg/m ³ . If the collected product density fell below 1000kg/m ³ , the pump was automatically stopped until the density increased. Waste water was pumped from the vessel 10 via outlet 45 located at the top of vessel. In some examples, the waste water may be reintroduced, recirculated and/or reused in the process. By way of example only, the waste water may be recirculated back into the vessel 10 via feed inlet 25. Alternatively or additionally, the waste water may be used to prepare the aqueous solution of the polyalkylene oxide and so may be recirculated back into the vessel via feed inlet 20. Optionally, the waste water may have been purified prior to the recirculation step.

A 5g sample of the mixed PEG 8000 product was taken for solids content analysis. The solids content was measured using a moisture analyser (Mettler Toledo HB43-S Halogen Moisture Analyser).

The purified PEG 8000 was then dried under vacuum at a temperature of approximately 110°C using mechanical agitation. Preparation of polyurethane

A solution of the bismuth catalyst bismuth neodecanoate (0.025 mol%, BiCat 8106 Shepherd Chemical Co.) in ethanol (20% stock solution) was added to hexanetriol (1.2 mol%). This mixture was dried under vacuum at a temperature of approximately 80°C with mixing to provide a hexanetriol/bismuth mixture.

The hexanetriol/bismuth neodecanoate mixture, PEG 8000 (1 mol%) and the dicyclohexylmethane-4, 4-diisocyanate (DMDI) (supplied by Evonik, 2.8 mol%) were injected into a billet mould via a mixing head at 107°C. The mixture was cured at a temperature of approximately 110°C for 90 minutes. The billets were sliced to provide pessaries having a mean thickness of 0.8 mm and a mean weight of 0.24g.

Preparation of pharmaceutical delivery devices Drug Loading - Misoprostol

The pessaries were placed in purified water and agitated at about 19°C for approximately 16-20 hours, then the water was decanted.

An ethanolic loading solution (a 15% w/w ethanokwater mix) weighing 5 times the dry weight of the polymer containing the misoprostol and butylated hydroxy anisole (BHA) (0.055% w/w polymer) was added to the water swollen pessaries. The pessaries and drug loading solution were agitated at approximately 19°C for approximately 6-8 hours to allow the uptake of drug.

At the end of the dosing period the remaining drug solution was decanted and the swollen polymer slices were dried for 18-24 hours.

Drug Loading - Dinoprostone

The pessaries were placed in purified water and agitated at about 25°C for approximately 6-8 hours, then the water was decanted. An ethanolic loading solution (a 25% w/w ethanokwater mix) weighing 5 times the dry weight of the polymer containing the dinoprostone and butylated hydroxy anisole (BHA) (0.055% w/w polymer) was added to the water swollen pessaries. The pessaries and drug loading solution were agitated at approximately 4°C for approximately 18-24 hours to allow the uptake of drug.

At the end of the dosing period the remaining drug solution was decanted and the swollen polymer slices were dried for 18-24 hours.

Measurement of Potency and Impurity Content

Misoprostol and the quantity of the related impurities 8-iso misoprostol and misoprostol A were quantified following the methods described in WO 2006/013335 (Robertson) via the use of standard solutions and HPLC analysis (ultraviolet absorbance detector at 280 nm with 6mm pathway). A similar procedure was used to determine the potency of dinoprostone and the quantity of the related impurities PGA ₂ , 8-iso PGE ₂ and 15-keto PGE ₂ .

Results and Discussion

Preliminary Work

During investigations in this area, a number of batches of misoprostol-loaded polyurethane delivery devices were found to show variable levels of misoprostol stability upon storage for extended periods of time. Further investigations were conducted in order to determine the cause of these results, which included studies into the manufacturing method, catalyst, final polyurethane and additives. However, one hypothesis attributed the relatively poor stability in some batches to a recent change in the supply of poly(alkylene glycol). A number of exemplary polyurethanes (batches 1 , 2 and 3) were prepared from a reaction of PEG 8000, 1 ,2,6-hexanetriol and DMDI in a molar ratio of 1 :1.2:2.8 and loaded with 100 pg misoprostol (in accordance with the general procedures "Preparation of a polyurethane” and “Drug loading sections outlined above). In this instance, the PEG 8000 was a specially commissioned grade of PEG8000 designated “Polyethylene Glycol 8000BA, Pharmaceutical Grade”, obtained from Ineos Oxide.

These batches were stored under the conditions specified in Table 1 below and stability measurements taken at a number of time periods.

Table 1 shows the stability data for pharmaceutical delivery devices loaded with misoprostol (batches 1 , 2 and 3) at various temperatures when stored for a period of up to 3 months. ND denotes that the % of Initial Potency has not been determined/measured. In all cases, a significant drop in the potency of misoprostol loaded into the device was observed when the device was stored at either 25°C or 40°C over the time period 2 weeks, 1 month and 3 months. Further investigations revealed that the batches all contained low levels of benzoic acid (as illustrated in Table 2 below).

Table 2 shows the amount of benzoic acid found in pharmaceutical delivery devices 1 , 2 and 3.

It was observed that the poorest levels of stability were observed in batch 1 which also comprised the highest levels of benzoic acid, suggesting that this impurity was detrimental to the stability of the active agent. The inventors hypothesised that the source of the benzoic acid impurity in the final polyurethane product may be the process used to manufacture the PEG 8000 and initiated investigations to improve the reproducibility and long-term storage capabilities of the polyurethane pharmaceutical delivery devices. Polyurethane Delivery Devices (made using purified PEG 8000)

Part A PEG 8000 was obtained from a number of different suppliers. Exemplary polyurethanes were made using (i) the PEG 8000 as it was obtained from the supplier or (ii) the same PEG 8000 following a SHW purification treatment. These polymer batches are shown below in Table 3.

¹ All polyurethane polymers were prepared from PEG 8000, 1 ,2,6-hexanetriol and DMDI in the ratio of 1 :1 .2:2.8, using BiCat catalyst in accordance with the procedures outlined herein. ² PEG 8000 (Clariant) had been manufactured using a sodium hydroxide catalyst and lactic acid as the neutralising agent. ³ PEG 8000 (Dow) had been manufactured using a sodium hydroxide catalyst and acetic acid as the neutralising agent. ⁴ PEG 8000 was purified using a SHW treatment process as described herein.

Table 3 shows the polyurethane batch numbers and batch details for those polyurethanes used in the subsequent stability studies (as outlined below)

The resulting polyurethane polymers were loaded with misoprostol in accordance with the “Drug Loading” section above to provide a number of misoprostol-loaded pharmaceutical delivery devices. The stability of misoprostol in these devices was monitored. The results are shown in Table 4 below.

Table 4 shows stability data for a pharmaceutical delivery device loaded with misoprostol (batches 8, 9, 10 and 11) at various temperatures when stored for a period of 1 month.

Over the period of one month, a significant drop in the potency of misoprostol loaded into the device was observed in those pharmaceutical delivery devices made from the PEG 8000 directly obtained from the supplier. In each case, the stability of misoprostol was improved when the PEG 8000 used to make the polyurethane polymer had been purified using a SHW treatment.

Part B

Further investigations were carried out to study the effect of a SHW purification treatment on a number of pharmaceutical delivery devices.

PEG 8000 obtained from a number of different suppliers was subjected to the purification treatment using SHW (as outlined above under “Purification of PEG 8000 - General Procedure”) and the results are shown in Table 5 below.

¹ Polyethylene Glycol 8000, Pharmaceutical Grade (Ineos Oxide, “off the shelf”) (Acid impurity = benzoic acid)

² Polyglykol 8000 P, Clariant (Acid impurity = lactic acid)

Table 5 shows the impurity levels in the PEG before and after purification using SHW. ND denotes that the level of acid impurity in ppm has not been determined/measured.

Following treatment with SHW, the levels of benzoic acid present in PEG 8000 were reduced to below 10 ppm for PEG 8000 obtained from Ineos Oxide.

With regards to PEG 8000 obtained from Clariant, the impurity was lactic acid rather than benzoic acid. The removal or reduction of this impurity following the SHW treatment was indirectly observed via manufacturing the final polyurethane polymers and measuring the gel time. A correlation was found between the gel time and the acid impurity concentration (either benzoic or lactic acid). This correlation was attributed to the presence of the acid decreasing the activity of the catalyst. When purified batches of PEG 8000 (Clariant) were examined, the gel time was found to be much faster than with non-SHW purified materials, thus indicating that the level of this impurity had been reduced.

A number of exemplary polyurethanes (batches 12, 13, 14, 15, 16 and 17) were prepared from a reaction of PEG 8000 (purified - various suppliers), 1 ,2,6-hexanetriol and DMDI in a molar ratio of 1 :1.2:2.8 and loaded with an active agent (in accordance with the general procedures "Preparation of a polyurethane” and “Drug loading” sections outlined above). The details of these batches are shown in Table 6 below. Table 6 shows the batch details for various polyurethane pharmaceutical delivery devices.

In all cases, the percentage swelling values remained within specification (250-325% for misoprostol-loaded pessaries and 275-325% for dinoprostone-loaded pessaries) over the 12 month study period. In addition, the water soluble extractables (WSE) remained within specification (not more than 0.5%) over the 12 month study period. Drug Stability Studies - Misoprostol

The example delivery devices were stored under the conditions specified in Tables 7.1 to 7.4 below and stability measurements taken at a number of time periods.

Table 7.1 shows stability data for a pharmaceutical delivery device loaded with misoprostol (batches 12, 13 and 14) at various temperatures when stored for a period of 3 months.

Table 7.2 shows stability data for a pharmaceutical delivery device loaded with misoprostol (batches 12, 13 and 14) at various temperatures when stored for a period of 6 months.

Table 7.3 shows stability data for a pharmaceutical delivery device loaded with misoprostol (batches 12, 13 and 14) at various temperatures when stored for a period of 9 months.

Table 7.4 shows stability data for a pharmaceutical delivery device loaded with misoprostol (batches 12, 13 and 14) at various temperatures when stored for a period of 12 months.

As can be seen from Tables 7.1 to 7.4 above, the polyurethane delivery devices made from PEG 8000 purified using a SHW process showed good stability of misoprostol even when stored at elevated temperatures of 40°C over 12 months. These results are also illustrated in Figures 3 to 5.

Druq Stabilitv Studies - Dinoprostone (PGE )

The example delivery devices loaded with dinoprostone were stored at a temperature of -15°C and stability measurements taken at a number of time periods. The results are shown in Tables 8.1 to 8.3 below.

^* As percentage of total initial content of PGE2 (dinoprostone). NMT = “not more than”; LS = label strength

Table 8.1 shows stability data for a pharmaceutical delivery device loaded with dinoprostone (batch 15).

^* As percentage of total initial content of PGE2 (dinoprostone). NMT = “not more than”; LS = label strength.

Table 8.2 shows stability data for a pharmaceutical delivery device loaded with dinoprostone and stored at -15°C (batch 16).

^* As percentage of total initial content of PGE2 (dinoprostone). NMT = “not more than”; LS = label strength.

Table 8.3 shows stability data for a pharmaceutical delivery device loaded with dinoprostone and stored at -15°C (batch 17).

As can be seen from Tables 8.1 to 8.3 above, the polyurethane delivery devices made from PEG 8000 purified using a SHW process showed good stability of dinoprostone when stored at temperatures of -15°C for 12 months. In order to reproducibly obtain such levels of stability previously had required the use of a specially commissioned high grade of PEG 8000. However, using the processes described herein, the present inventors have made it possible to use PEG8000 from a number of different suppliers and obtain polyurethane delivery devices with good and reproducible levels of long-term stability. This assists in providing a robust manufacturing process that is less vulnerable to changes in the raw material supplier or specification.