EP3328386A1

EP3328386A1 - A prolonged release dosage form comprising oxycodone or a pharmaceutically acceptable salt thereof and naloxone or a pharmaceutically acceptable salt thereof in the treatment of bladder pain syndrome (bps)

Info

Publication number: EP3328386A1
Application number: EP16754417.0A
Authority: EP
Inventors: Michael Hopp; Wolfram KREMERS
Original assignee: Euro Celtique SA
Current assignee: Euro Celtique SA
Priority date: 2015-07-31
Filing date: 2016-07-29
Publication date: 2018-06-06
Also published as: AU2016301861A1; BR112018001504A2; WO2017021304A1; PH12018500221A1

Abstract

The present invention provides a pharmaceutical dosage form comprising oxycodone and naloxone (or pharmaceutically acceptable salts thereof) for use in the treatment of Bladder Pain Syndrome (BPS) and/or at least one, preferably at least two symptoms thereof.

Description

A prolonged release dosage form comprising oxycodone or a pharmaceutically acceptable salt thereof and naloxone or a pharmaceutically acceptable salt thereof in the treatment of Bladder Pain Syndrome (BPS)

FIELD OF THE INVENTION

The present invention is concerned with an oral prolonged release dosage form comprising oxycodone or a pharmaceutically acceptable salt thereof and naloxone or a pharmaceutically acceptable salt thereof for use in the treatment of Bladder Pain Syndrome (PBS).

BACKGROUND OF THE INVENTION

The term "Bladder Pain Syndrome" (BPS) was recently introduced as nomenclature by the European Association of Urology (EAU) and European Society for the Study of Interstitial Cystitis (ESSIC) for a disease previously referred to as interstitial cystitis (IC) or painful bladder syndrome (PBS). Sometimes, reference was also made to this disease in the combined term of "IC/PBS". According to the ESSIC, BPS is defined as the complaint of suprapubic pain related to bladder filling, accompanied by other symptoms such as increased daytime and night-time frequency, in the absence of proven urinary infection or other obvious pathology (Abrams et al, 2002; van de Merwe et al, 2008).

LE The pathophysiology of this disease is unknown. It is expected that BPS is caused by a multifactorial process that starts with one of several insults (often urological but not inevitably so), such as immune-mediated injury, chronic inflammation, deficient bladder defences, or obstruction of vascular or lymphatic vessels (Campbell- Walsh, 9th edition). It has been suggested that the pathophysiology of BPS involves a cascade of events, in which bladder insult leads to epithelial layer dysfunction, the proliferation of mast cells and C-nerve fibre activation (Sant, 2002). Without appropriate treatment, these processes become aggravated over time, eventually leading to a vicious cycle of progressively worsening tissue damage, scarring, and fibrosis (Evans, 2002).

Currently neither an evidence based treatment algorithm nor a standardised treatment for BPS is available (van Ophoven et al., 2008). Available treatment options can be divided into oral, intravesical, surgical and physical procedures. There are also meaningful supplementary therapy procedures beyond the boundaries of classical school medicine. The WHO recommendations provide the basis for basic pain therapy. For oral therapeutic procedures currently in use the following compounds with different levels of evidence have been recommended: amitriptylin, hydroxyzin, pentosan polysulfate. Many other orally administered drugs have also been used although in many cases, including anticonvulsants, L-arginine and various immunomodulators and immunosuppressants evidence of efficacy is lacking.

Intravesical treatments include botulinum toxin A, dimethyl sulfoxide, heparin and glycosaminoglycan substitutes.

When conventional therapeutic methods fail, surgical (partial) removal of the urinary bladder or urinary diversion procedures are considered, mainly for small capacity bladder. Currently only limited data regarding the use of opioid agonists in BPS is available. In the literature there are in vivo data on cystitis as well as clinical data available on BPS demonstrating a beneficial effect of opioid agonists. In an in vivo mouse model producing cystitis based on administration of cyclophosphamide (CP), serving as a surrogate for IC, it could be demonstrated that morphine (1 - 10 mg/kg), ketorolac (1 - 5.6 mg/kg) as well as duloxetine (3 - 30 mg/kg) significantly reversed the pain behavior (Wantuch et al., 2007).

There is an ongoing need to provide an effective treatment for BPS.

OBJECTS AND SUMMARY OF THE INVENTION

The above need is solved by the aspects of the invention mentioned in the following. Initially, embodiments for the indicated use are described in several aspects, followed by a section on the dosage form according to the present invention.

Aspects of the present invention relating to the medical use It is the first aspect of the present invention to provide an oral prolonged release dosage form comprising oxycodone or a pharmaceutically acceptable salt thereof and naloxone or a pharmaceutically acceptable salt thereof for use in the treatment of Bladder Pain Syndrome (BPS) and/or at least one symptom thereof. In one embodiment thereof, the dosage form is for use in the treatment of BPS.

Preferably, the treatment of BPS is expressed by a lower score in the interstitial cystitis symptoms index (ICSI) and/or the interstitial cystitis problem index (ICPI) compared to the score in the interstitial cystitis symptoms index (ICSI) and/or the interstitial cystitis problem index (ICPI) prior to the treatment by said dosage form. More preferably, the treatment of BPS is expressed by a lower score in the interstitial cystitis symptoms index (ICSI) and the interstitial cystitis problem index (ICPI) compared to the score in the interstitial cystitis symptoms index (ICSI) and the interstitial cystitis problem index (ICPI) prior to the treatment by said dosage form. In another embodiment, the dosage form is for use in the treatment of at least one symptom of BPS. Said at least one symptom may be selected from the group consisting of pain, urinary urgency, urinary frequency, nocturia, dyspareunia and combinations thereof. Preferably, said at least one symptom is selected from the group consisting of pain, urinary urgency, urinary frequency, nocturia and combinations thereof. Said at least one symptom may be pain, preferably chronic pain. Alternatively, said at least one symptom is selected from the group consisting of urinary urgency, urinary frequency, nocturia and combinations thereof.

In a preferred embodiment, the dosage form is for use in the treatment of at least two symptoms of BPS. Said at least two symptoms may be selected from the group consisting of pain, urinary urgency, urinary frequency and nocturia. Preferably, said at least two symptoms are (i) pain and (ii) at least one symptom selected from the group consisting of urinary urgency, urinary frequency, dyspareunia and nocturia. Most preferably, said at least two symptoms are (i) pain and (ii) at least one symptom selected from the group consisting of urinary urgency, urinary frequency and nocturia.

Preferably, said treatment is carried out in a human, more preferably in a female. In another embodiment, said treatment is carried out in a human suffering from BPS who had a surgery as treatment of BPS prior to the treatment by the oral prolonged release dosage form comprising oxycodone or a pharmaceutically acceptable salt thereof and naloxone or a pharmaceutically acceptable salt thereof.

In yet another embodiment, said treatment is carried out in a human suffering from BPS who receives further BPS treatment. Said further BPS treatment may be selected from the group consisting of non-steroidal antiinflammatory and antirheumatic agents, urologicals including antispasmodics, and non-opioid analgesics and antipyretics. In still another embodiment, said treatment is carried out in a human suffering from BPS who is constipated, wherein said constipation is not opioid-induced and wherein said constipation is present at the beginning of the treatment by said dosage form.

In all of the above embodiments, said pain may be visceral pain or chronic pain or visceral chronic pain. Furthermore, in all of the above embodiments, it is most preferred that said pain is suprapubic pain / suprapubic chronic pain. Bladder pain is of course also included herein when referring to pain and also applies to the embodiments listed herein. Further, in all of the above embodiments, said treatment is preferably a long-term treatment and/or said dosage form is preferably

administered on a chronic basis.

In a second aspect, the present invention relates to an oral prolonged release dosage form comprising oxycodone or a pharmaceutically acceptable salt thereof and naloxone or a pharmaceutically acceptable salt thereof for use in the long-term treatment of (i) pain, preferably suprapubic pain, and (ii) at least one symptom selected from the group consisting of urinary urgency, urinary frequency and nocturia, wherein (i) and (ii) are symptoms of BPS. Preferably, said pain is chronic pain / chronic suprapubic pain. Additionally, if present, constipation may be treated, wherein said constipation is then not opioid-induced and present at the beginning of the treatment by said dosage form.

In a third aspect, the present invention relates to an oral prolonged release dosage form comprising oxycodone or a pharmaceutically acceptable salt thereof and naloxone or a pharmaceutically acceptable salt thereof for use in the long-term treatment of (i) chronic pain, preferably chronic suprapubic pain, and (ii) at least one symptom selected from the group consisting of urinary urgency, urinary frequency and nocturia, wherein (i) and (ii) are symptoms of BPS in a patient suffering from BPS, and for use in the prevention of opioid-induced constipation in said patient. Accordingly, said patient is not constipated at the beginning of the treatment by said dosage form.

In a fourth aspect, the present invention relates to an oral prolonged release dosage form comprising oxycodone or a pharmaceutically acceptable salt thereof and naloxone or a pharmaceutically acceptable salt thereof for use in the long-term treatment of (i) chronic pain, preferably chronic suprapubic pain, and (ii) at least one symptom selected from the group consisting of urinary urgency, urinary frequency and nocturia, wherein (i) and (ii) are symptoms of BPS in a patient suffering from BPS, and for use in the treatment of constipation in said patient. Accordingly, said patient is constipated at the beginning of the administration of said dosage form, wherein said constipation is not opioid induced. Said constipation might be linked to BPS.

In a fifth aspect, the present invention relates to an oral prolonged release dosage form comprising oxycodone or a pharmaceutically acceptable salt thereof and naloxone or a pharmaceutically acceptable salt thereof for use in the treatment of BPS in a patient suffering from (i) pain, preferably suprapubic pain, (ii) at least one symptom selected from the group consisting of urinary urgency, urinary frequency and nocturia, and (iii) constipation, wherein (i) and (ii) are symptoms of BPS in a patient suffering from BPS. Accordingly, said patient is constipation at the beginning of the administration of said dosage form. Preferably, said constipation is not opioid- induced constipation. Said constipation might be linked to BPS.

In a sixth aspect, the present invention relates to an oral prolonged release dosage form comprising oxycodone or a pharmaceutically acceptable salt thereof and naloxone or a pharmaceutically acceptable salt thereof for use in the treatment of BPS in a patient suffering from (i) pain, preferably suprapubic pain, and (ii) at least one symptom selected from the group consisting of urinary urgency, urinary frequency and nocturia, wherein (i) and (ii) are symptoms of BPS, and for use in the prevention of opioid-induced constipation. In this aspect, said patient is not constipated at the beginning of the administration of said dosage form.

In a seventh aspect, the present invention relates to an oral prolonged release dosage form comprising oxycodone or a pharmaceutically acceptable salt thereof and naloxone or a pharmaceutically acceptable salt thereof for use in the treatment of visceral pain. The visceral pain may be acute or preferably chronic visceral pain. The visceral pain may be selected from the group consisting of pancreatitis pain, labor pain, pain from abdominal surgery associated with ileus, pain in irritable bowel syndrome, abdominal pain in nonulcer dyspepsia, or in dysmenorrhoea, liver pain, kidney pain, epigastric pain, pleural pain, painful biliary colic or appendicitis pain. Visceral pain may result from diseases of the stomach, duodenum or colon, gall bladder, from severe menstruational pain or corresponding post-operative pain conditions. Visceral pain differs from typical pain in bones or muscosceletal origin.

Embodiments relating to the dosage form of the present invention

The dosage form used in all of the above mentioned aspects is an oral prolonged release dosage form comprising oxycodone or a pharmaceutically acceptable salt thereof and naloxone or a pharmaceutically acceptable salt thereof. All embodiments including of course the preferred and particularly preferred embodiments described in the following relate to all of the afore-mentioned aspects (including their embodiments) with respect to the dosage form referred to therein.

Amounts of the actives in a dosage form according to the invention Generally, the dosage form can comprise oxycodone or a pharmaceutically acceptable salt thereof in an amount range of equivalent to about 1 mg to about 160 mg oxycodone HC1 and naloxone or a pharmaceutically acceptable salt thereof in an amount range of equivalent to about 0.5 mg to about 80 mg naloxone HC1.

As exemplary amounts, the dosage form may comprise oxycodone or a

pharmaceutically acceptable salt thereof in an amount of equivalent to about 2.5 mg, to about 5 mg, to about 10 mg, to about 15 mg, to about 20 mg, to about 40 mg, to about 50 mg, to about 60 mg, to about 80 mg, to about 100 mg, to about 120 mg, to about 140 mg, or to about 160 mg oxycodone HC1. Still exemplary, naloxone or a pharmaceutically acceptable salt thereof may be present in an amount of equivalent to about 0.5 mg, to about 1 mg, to about 1.5 mg, to about 2 mg, to about 4 mg, to about 5 mg, to about 10 mg, to about 15 mg, to about 20 mg, to about 40 mg, to about 60 mg, or to about 80 mg naloxone HC1.

Weight ratio of the two actives used in a dosage form of the present invention

The dosage form can comprise oxycodone or a pharmaceutically acceptable salt thereof in excess over naloxone or a pharmaceutically acceptable salt thereof (related to the overall amounts of both active agents in the dosage form). It is preferred that a dosage form comprises the two actives in a weight ratio ranging from about 25:1 to about 1 :1, preferably from about 10:1 to about 1 : 1, more preferably from about 5: 1 to about 1 :1, wherein the weight ratio is calculated on the basis of the free bases of the two actives (free base of oxycodone: free base of naloxone). If the free bases are not comprised per se in the dosage form, but e.g. the hydrochloride salts or any other salts, the amounts actually comprised in the dosage form are thus initially converted to the corresponding amounts of the free bases, and the weight ratio is then calculated on the basis of the amounts of the free bases. The most preferred weight ratio range is the weight ratio range of about 5 : 1 to about 1 : 1 of the two actives (free base of oxycodone: free base of naloxone). It can be preferred that a dosage form comprising oxycodone or a pharmaceutically acceptable salt thereof and naloxone or a pharmaceutically acceptable salt thereof comprises the two actives in a weight ratio of about 25: 1, about 10: 1, about 5: 1, about 4.5: 1, about 4: 1, about 3.5: 1, about 3: 1, about 2.5 : 1 , about 2: 1, about 1.5 : 1 or about 1 : 1, wherein the weight ratio is calculated on the basis of the free bases of the two actives (free base of oxycodone: free base of naloxone). Preferred specific weight ratios are about 5: 1, about 4: 1, about 3:1, about 2: 1, and about 1 : 1, wherein the weight ratio is calculated on the basis of the free bases of the two actives (free base of oxycodone: free base of naloxone).

It is particularly preferred that a dosage form comprising oxycodone or a

pharmaceutically acceptable salt thereof and naloxone or a pharmaceutically acceptable salt thereof comprises the two actives in a weight ratio of about 2: 1, and most preferably of 2: 1 , wherein the weight ratio is calculated on the basis of the free bases of the two actives (free base of oxycodone: free base of naloxone).

Particularly preferred amounts of the actives in a dosage form of the invention

Since the ratio of 2: 1 of the two actives (free base of oxycodone: free base of naloxone) is particularly preferred, most preferred embodiments relate to dosage forms comprising amounts of equivalent to about 2.5 mg oxycodone HC1 and about 1.25 mg naloxone HC1; about 5 mg oxycodone HC1 and about 2.5 mg naloxone HC1; about 10 mg oxycodone HC1 and about 5 mg naloxone HC1; about 20 mg oxycodone HC1 and about 10 mg naloxone HC1; about 40 mg oxycodone HC1 and about 20 mg naloxone HC1; about 80 mg oxycodone HC1 and about 40 mg naloxone HC1; and about 160 mg oxycodone HC1 and about 80 mg naloxone HC1. Even more preferred are amounts of 2.5 mg oxycodone HC1 and 1.25 mg naloxone HC1; 5 mg oxycodone HC1 and 2.5 mg naloxone HC1; 10 mg oxycodone HC1 and 5 mg naloxone HC1; 20 mg oxycodone HC1 and 10 mg naloxone HC1; 40 mg oxycodone HC1 and 20 mg naloxone HC1; 80 mg oxycodone HC1 and 40 mg naloxone HC1; and 160 mg oxycodone HC1 and 80 mg naloxone HC1.

Release rates of the two actives from a dosage form of the present invention

It is preferred that a dosage form comprising oxycodone or a pharmaceutically acceptable salt thereof and naloxone or a pharmaceutically acceptable salts thereof releases in vitro, when measured using the Ph. Eur. Paddle Method at 100 rpm in 0.1 N hydrochloric acid, pH 1.2 at 37°C and using UV detection at 230 nm, about 5% to about 40% of oxycodone or a pharmaceutically acceptable salt thereof by weight and about 5% to about 40% of naloxone or a pharmaceutically acceptable salt thereof by weight at 15 min; about 20% to about 50% of oxycodone or a pharmaceutically acceptable salt thereof by weight and about 20% to about 50% of naloxone or a pharmaceutically acceptable salt thereof by weight at 1 hour; about 30% to about 60% of oxycodone or a pharmaceutically acceptable salt thereof by weight and about 30% to about 60% of naloxone or a pharmaceutically acceptable salt thereof by weight at 2 hours; about 50%> to about 80%> of oxycodone or a pharmaceutically acceptable salt thereof by weight and about 50% to about 80% of naloxone or a pharmaceutically acceptable salt thereof by weight at 4 hours; about 70% to about 95% of oxycodone or a pharmaceutically acceptable salt thereof by weight and about 70% to about 95% of naloxone or a pharmaceutically acceptable salt thereof by weight at 7 hours; and more than about 80% of oxycodone or a pharmaceutically acceptable salt thereof by weight and more than about 80% of naloxone or a pharmaceutically acceptable salt thereof by weight at 10 hours.

In a particularly preferred embodiment relating to the in vitro release of a prolonged release dosage form comprising oxycodone or a pharmaceutically acceptable salt thereof and naloxone or a pharmaceutically acceptable salts thereof, said dosage form releases in vitro, when measured using the Ph. Eur. Paddle Method at 100 rpm in 0.1 N hydrochloric acid, pH 1.2 at 37°C and using UV detection at 230 nm, about 10% to about 30% of oxycodone or a pharmaceutically acceptable salt thereof by weight and about 10% to about 30% of naloxone or a pharmaceutically acceptable salt thereof by weight at 15 min; about 30% to about 45% of oxycodone or a pharmaceutically acceptable salt thereof by weight and about 30% to about 45% of naloxone or a pharmaceutically acceptable salt thereof by weight at 1 hour; about 40% to about 60% of oxycodone or a pharmaceutically acceptable salt thereof by weight and about 40% to about 60% of naloxone or a pharmaceutically acceptable salt thereof by weight at 2 hours; about 55% to about 70%> of oxycodone or a pharmaceutically acceptable salt thereof by weight and about 55% to about 75% of naloxone or a pharmaceutically acceptable salt thereof by weight at 4 hours; about 75% to about 90% of oxycodone or a pharmaceutically acceptable salt thereof by weight and about 75% to about 90% of naloxone or a pharmaceutically acceptable salt thereof by weight at 7 hours; and more than about 85% of oxycodone or a pharmaceutically acceptable salt thereof by weight and more than about 85% of naloxone or a pharmaceutically acceptable salt thereof by weight at 10 hours.

Further, it is particularly preferred that a prolonged release dosage form according to the invention releases the oxycodone or a pharmaceutically acceptable salt thereof and the naloxone or a pharmaceutically acceptable salt thereof at substantially equal release rates.

The dosage form according to the present invention is preferably administered on a twice-a-day basis and thus provides its effect in vivo preferably for about 12 hours. However, it is generally also possible to adapt the release rate such that a once-a-day basis for the administration is achieved.

Pharmaceutically acceptable salts of the actives in dosage forms of the present invention The pharmaceutically acceptable salt of oxycodone and/or naloxone is/are preferably selected from the group comprising the hydrochloride, the sulphate, the bisulphate, the tartrate, the nitrate, the citrate, the bitartrate, the phosphate, the malate, the maleate, the hydrobromide, the hydroiodide, the fumerate and the succinate salt.

A particularly preferred salt for both actives is the hydrochloride salt. When the hydrochloride salt of naloxone is used, it is even more preferred to use naloxone hydrochloride dihydrate. The prolonged release dosage form of the present invention

In general, all dosage forms providing a prolonged release of the two actives may be used. Of course, a prolonged release dosage form capable of providing the aforementioned in vitro release rates is the most preferred prolonged release dosage form.

In a preferred embodiment, the prolonged release dosage form comprises a prolonged release matrix in order to achieve the prolonged release. In an alternative preferred embodiment, the prolonged release dosage form comprises a prolonged release coating in order to achieve the prolonged release of the active agents. In a further alternative preferred embodiment, the prolonged release dosage form is an osmotic prolonged release dosage form. When a prolonged release matrix dosage form is used, the matrix preferably comprises a fatty alcohol and/or a hydrophobic polymer such as an alkylcellulose with ethylcellulose being particularly preferred. Other structural components of the different prolonged release dosage forms are described below.

Further features of the dosage form of the present invention

The dosage form of the present invention may comprise further pharmaceutically acceptable ingredients and/or adjuvants, such as e.g. lubricants, fillers, binders, flowing agents, colourants, flavourants, surfactants, pH-adjusters, anti-tacking agents and/or combinations thereof.

Preferably, the dosage form is selected from the group consisting of a tablet, a capsule, a multiparticulate, a dragee, a granulate, a liquid and a powder. A particularly preferred dosage form is a tablet or a multi-particulate.

The dosage form according to the invention may comprise at least one further pharmaceutically active agent providing a further desired pharmaceutical effect in addition to the two active agents, i.e. oxycodone or a pharmaceutically acceptable salt thereof and naloxone or a pharmaceutically acceptable salt thereof. However, it is preferred that the dosage form according to the invention comprises the two actives oxycodone or a pharmaceutically acceptable salt thereof and naloxone or a pharmaceutically acceptable salt thereof as the sole pharmaceutically active agents.

Most preferred dosage form according to the present invention

It is most preferred that the dosage form used herein is an oral prolonged release dosage form comprising oxycodone or a pharmaceutically acceptable salt thereof and naloxone or a pharmaceutically acceptable salt thereof, wherein the two actives are present in a weight ratio of about 2: 1 (calculated on the basis of the free base of oxycodone: the free base of naloxone) with amounts of oxycodone ranging from equivalent to about 1 mg to 160 mg oxycodone HCl and the corresponding naloxone amounts resulting from the afore-mentioned ratio, wherein the dosage form releases in vitro, when measured using the Ph. Eur. Paddle Method at 100 rpm in 0.1 N hydrochloric acid, pH 1.2 at 37°C and using UV detection at 230 nm, about 5% to about 40% of oxycodone or a pharmaceutically acceptable salt thereof by weight and about 5% to about 40% of naloxone or a pharmaceutically acceptable salt thereof by weight at 15 min; about 20% to about 50% of oxycodone or a pharmaceutically acceptable salt thereof by weight and about 20% to about 50% of naloxone or a pharmaceutically acceptable salt thereof by weight at 1 hour; about 30% to about 60% of oxycodone or a pharmaceutically acceptable salt thereof by weight and about 30% to about 60% of naloxone or a pharmaceutically acceptable salt thereof by weight at 2 hours; about 50%> to about 80%> of oxycodone or a pharmaceutically acceptable salt thereof by weight and about 50% to about 80% of naloxone or a pharmaceutically acceptable salt thereof by weight at 4 hours; about 70% to about 95% of oxycodone or a pharmaceutically acceptable salt thereof by weight and about 70% to about 95% of naloxone or a pharmaceutically acceptable salt thereof by weight at 7 hours; and more than about 80% of oxycodone or a pharmaceutically acceptable salt thereof by weight and more than about 80% of naloxone or a pharmaceutically acceptable salt thereof by weight at 10 hours.

In the afore-mentioned most preferred dosage form, it is furthermore preferred that the dosage form comprises oxycodone hydrochloride and naloxone hydrochloride dihydrate.

Although all prolonged release dosage forms may be used, it is further most preferred that the dosage form in its most preferred embodiment comprises a prolonged release matrix.

The oxycodone/naloxone dosage form marketed in Germany under the tradename Targin® by Mundipharma GmbH is overall the most preferred dosage form. Targin® is a prolonged release tablet comprising oxycodone and naloxone in a 2: 1 ratio (calculated on the basis of the free bases). This ratio, when given in a prolonged release formulation, has been shown to provide sufficient analgesic activity measured by a pain scale (Numerical Analogue Scale (NAS)), similar to that of oxycodone combined with placebo naloxone, with an improved safety profile (Mueller-Lissner et al., 2007; Meissner et al., 2009). Targin® has been shown to provide effective analgesia while counteracting constipation (Meissner et al., 2009). Targin® provides an effective pain treatment together with an improved quality of life due to a reduced number of patients suffering from impeded bowel function compared to treatment with other opioids. Targin® maintains the systemic opioid effects while naloxone counteracts the bowel function disorders that are typical for opioid treatment due to the local competitive antagonism of the opioid receptor mediated oxycodone effect by naloxone in the gut.

BRIEF DESCRIPTION OF THE FIGURES

Figure 1 shows the study diagram of the study described in the example-section.

Figure 2 shows the populations of the study.

Figure 3 shows the demography of the patient populations. Figures 4 and 5 show the average pain values in the double-blind phase for the OXN and the placebo group (full analysis population).

Figure 6 shows the average pain values in the double-blind phase for the OXN and the placebo group in the per protocol population.

Figure 7 shows a more detailed analysis of sub-groups in the OXN and the placebo group for the full analysis and the per protocol populations.

Figure 8 shows the average pain scores over time in the open-label phase following the double-blind phase.

Figure 9 shows the use of rescue medication (Ibuprofen) in the double-blind phase for the full analysis population, wherein the average number and the total amount are depicted. Figure 10 and 11 shows the pain severity according to the BPI-SF for the full analysis population (Figure 10) and the per protocol population (Figure 11) in the double-blind phase.

Figures 12 and 13 show the pain interference according to the BPI-SF in the blind phase for the full analysis population (Figure 12) and the per protocol population (Figure 13).

Figure 14 shows the pain relief according to the BPI-SF in the double-blind phase in a more detailed analysis of sub-groups in the OXN and placebo group for the full analysis population and the per protocol population.

Figures 15 and 17 show the ICSI-scores for the double-blind phase over 8 weeks for the full analysis population (Figure 15) and the per protocol population (Figure 17).

Figures 16 and 18 show the ICPI-scores for the double-blind phase over 8 weeks for the full analysis population (Figure 16) and the per protocol population (Figure 18).

Figures 19 and 20 show the ICSI change (Figure 19) and the ICPI change (Figure 20) to baseline for the mentioned sub-groups for the full analysis population and the per protocol population.

Figure 21 shows the PPIUS assessment for the full analysis population in the double-blind phase.

Figure 22 shows an overall summary of adverse events in the double-blind safety population.

Figure 23 lists the specific adverse events. Figures 24 and 25 show the "physical functioning" (Figure 24) and the "vitality" (Figure 25) parameters according to the SF-36 v2 index in the double-blind phase.

Figure 26 shows the ICSI and the ICPI questionnaires.

DETAILED DESCRIPTION OF THE INVENTION

The present invention partially resides in the surprising finding that an oral prolonged release pharmaceutical dosage form comprising oxycodone and naloxone (or pharmaceutically acceptable salts thereof) can be used in the treatment of BPS, preferably for use in the efficient treatment of at least two symptoms of BPS, wherein symptom (i) may be pain, preferably suprapubic pain, and symptom (ii) may be a urinary- symptom, preferably selected from the group consisting of urinary urgency, urinary frequency and nocturia.

DEFINITIONS

As used in the specification and the claims, the singular forms of "a" and "an" also include the corresponding plurals unless the context clearly dictates otherwise. Thus, e.g. the term "a symptom" may also refer to "symptoms".

The terms "about" and "approximately" in the context of the present invention denotes an interval of accuracy that a person skilled in the art will understand to still ensure the technical effect of the feature in question. The term typically indicates a deviation from the indicated numerical value of ±10% and preferably ±5%.

It needs to be understood that the term "comprising" is not limiting. For the purposes of the present invention, the term "consisting of is considered to be a preferred embodiment of the term "comprising of. If hereinafter a group is defined to comprise at least a certain number of embodiments, this is also meant to encompass a group which preferably consists of these embodiments only.

In the context of the present, the term "prolonged release" refers to pharmaceutical compositions showing a slower release of the active agents than that of a

conventional release pharmaceutical composition administered by the same route. Prolonged release is achieved by a special formulation design and/or manufacturing method. In general, "prolonged release dosage forms" in the context of the present invention means that the oxycodone and naloxone (or pharmaceutically acceptable salts thereof) are released from the pharmaceutical dosage form over an extended period of time and not in immediate release as defined below.

If reference is made herein to "oxycodone or "naloxone", this always also includes the reference to a pharmaceutically acceptable salt of the free base of this pharmaceutically active agent unless it is specifically indicated that the reference to the pharmaceutically active agent should only refer to the free base.

Pharmaceutically acceptable salts include, but are not limited to, inorganic acid salts such as hydrochloride, hydrobromide, hydroiodide, sulfate, bisulfate, phosphate and the like; organic acid salts such as formate, acetate, trifluoroacetate, malate, maleate, tartrate, bitartrate, fumerate, succinate, citrate and the like; sulfonates such as methanesulfonate, benzenesulfonate, p-toluenesulfonate, and the like; amino acid salts such as arginate, asparginate, glutamate and the like, and metal salts such as sodium salt, potassium salt, cesium salt and the like; alkaline earth metals such as calcium salt, magnesium salt and the like; organic amine salts such as triethylamine salt, pyridine salt, picoline salt, ethanolamine salt, triethanolamine salt,

dicyclohexylamine salt, Ν,Ν'-dibenzylethylenediamine salt and the like.

"BPS" as referred to herein is used according to the ESSIC's definition set out in the background of the invention section above, i.e. as the complaint of suprapubic pain related to bladder filling, accompanied by other symptoms such as increased daytime urinary frequency, increased night-time urinary frequency (nocturia) and urinary urgency, in the absence of proven urinary infection or other obvious pathology. "Pain" as referred to in the above definition is primarily understood herein as

"chronic pain" or "chronic suprapubic pain", which is often defined as pain lasting more than 12 weeks and which can persist for months or even longer. This is in contrast to "acute pain" or "breakthrough pain". Both types of pain, i.e. acute and chronic pain, can be treated inter alia with opioid agonists. It is, however, more common to use immediate release opioid agonist formulations when treating acute pain. Thus, if acute pain should be a symptom of BPS, this pain is usually treated by immediate release opioid agonist formulations, such as e.g. IR morphine or IR oxycodone, if opioid agonists are used, and not by a prolonged release dosage form comprising an opioid agonist. The focus of the present invention is not on the acute or breakthrough type of pain. Rather, the present invention focuses in terms of the treatment of pain as symptom of BPS on chronic pain as symptom of BPS, wherein doctors still tend to rather not prescribe opioid agonists such as e.g. morphine or oxycodone. A combination of oxycodone and naloxone in a prolonged release dosage form is particularly suitable for treating BPS and/or chronic pain as symptom of BPS since further positive effects were surprisingly found herein to be associated with the administration of said combination.

Accordingly, the dosage form according to the invention is usually administered on a chronic basis for at least several weeks up to months.

"Treatment of BPS" is to be understood as referring to a general improvement or even cure of the patient's BPS or to the alleviation of BPS. Such an improvement/ cure or alleviation can either be detected by the patient's subjective feeling, by external observations and preferably by suitable indices, such as e.g. the ICPI and/or ICPI indices. As is evident from the example section, lower scores (compared to the scores prior to the administration of a specific active or combination of actives) in the ICPI and ICPI indices indicate an improvement / cure or alleviation of BPS.

"Treatment of a symptom of BPS" is to be understood as referring to one or more specific symptom(s) of BPS, which can be improved, alleviated or even cured by a dosage form. An example is the US product information for ELMIRON® (pentosan polysulfate sodium), where it is stated under "Indication and usage" that

ELMIRON® is indicated for the relief of bladder pain or disco mo fort associated with interstitial cystitis. Typical symptoms are listed above and in the example section of the present application. An improvement, alleviation or cure can either be detected by the patient's subjective feeling, by external observations, particularly by clinical examination, and preferably by suitable indices, such as e.g. urinary indices (specific questions in the ICPI and/or the ICPI indices), a numerical pain intensity scale, a standard Brief Pain Inventory - Short Form (BPI-SF) or a PPIUS-scale, depending on the specific symptom. Reference is made on a general level in this respect to the example section, wherein suitable ways of determining specific parameters

(including BPS-symptoms) are listed. Clearly, more than one symptom may be improved by a dosage form of the present invention such that it may be used in the treatment of at least one symptom of BPS. Urinary retention is not a symptom of BPS.

RELEASE BEHAVIOUR OF THE DOSAGE FORM

In general, the release behavior of a dosage form can inter alia be determined by an in vitro release test.

The term "in vitro release" refers to the release rate at which a pharmaceutically active agent, e.g. oxycodone HC1, is released from the pharmaceutical composition when the in vitro release rate is tested by the paddle method according to the European Pharmacopeia as described in the Ph. Eur. 2.9.3 6^th edition. The paddle speed is set at 100 rpm in simulated gastric fluid (SGF) dissolution medium with pH 1.2. Aliquots of the dissolution media are withdrawn at the respective time points and analyzed by HPLC with a CI 8 column, eluted with 30mM phosphate buffer in acetonitrile (70:70; pH 2.9) with a flow rate of 1.0 ml/min and detected at 220 nm. The term "Simulated Gastric Fluid, pH 1.2" refers to 0.1 N HCl, pH 1.2. Usually, the mean value of six measurements is given for a specific release at a specific time point.

In contrast to an "immediate release", a "prolonged release" dosage form in accordance with the present invention refers to pharmaceutical compositions which release in vitro < 5% (by weight) of the pharmaceutically active agents, namely oxycodone and naloxone, at 45 min.

In the context of the present invention, the term "immediate release" refers to pharmaceutical compositions showing a release of the active substances which is not deliberately modified by a special formulation design and/or manufacturing methods. For oral dosage forms this means that the dissolution profile of the active substances depends essentially on their intrinsic properties. Typically, the term "immediate release" refers to pharmaceutical compositions which release in vitro >75% (by weight) of the pharmaceutically active agents at 45 min.

Prolonged release properties may be obtained by different means such as by a coating which is then designated as a prolonged release coating, a matrix which is then designated as a prolonged release matrix or e.g. by an osmotic structure of the pharmaceutical composition.

In order to obtain "prolonged release" properties, one typically uses materials which are known to prolong the release from a dosage form comprising e.g. a prolonged release matrix and/or prolonged release coating. Typical examples are set out further below. The nature of the "prolonged release material" may depend on whether the release properties are attained by a "prolonged release matrix" or a "prolonged release coating". The term "prolonged release materials" thus describes both types of materials. The term "prolonged release matrix material" indicates that a material is used for obtaining a prolonged release matrix. Likewise, the term "prolonged release coating material" indicate that a material is used for obtaining a prolonged release coating.

The term "prolonged release matrix formulation" refers to a pharmaceutical composition including at least one prolonged release material, and at least oxycodone and naloxone as the two pharmaceutically active agents. In a "prolonged release matrix formulation", the "prolonged release materials" are combined with the pharmaceutically active agents to form a mixture from which the pharmaceutically active agents are released over prolonged periods of time, such as e.g. 8, 10, 12, 14, 16, 18, 20, 22 or 24 hours.

It is to be understood that a material will be considered to act as prolonged release material if the dissolution profile of the pharmaceutically active agents is slowed down compared to an immediate or conventional release formulation. If a prolonged release material can be used for manufacturing a prolonged release matrix, it will be considered as a prolonged release matrix material.

Pharmaceutically acceptable excipients which are used to adjust an already prolonged release to a specific profile are not necessarily considered to be prolonged release materials.

It is to be understood that a prolonged release matrix does not necessarily consist only of the pharmaceutically active agents and the prolonged release material. The prolonged release matrix may comprise in addition pharmaceutically acceptable excipients such as fillers, lubricants, glidants, etc. Examples of such excipients are set out below. The term "prolonged release coating formulation" refers to a pharmaceutical composition including at least one prolonged release material, and oxycodone and naloxone as the two pharmaceutically active agents. In a "prolonged release coating formulation", the "prolonged release materials" are disposed on the pharmaceutically active agents to form a diffusion barrier. Other than in prolonged release matrix formulation, the actives are not intimately mixed with the prolonged release material and the prolonged release coating does not form a three dimensional structure within which the actives are distributed. As the term implies, the prolonged release material forms a layer above the actives. The pharmaceutically active agents are released from a prolonged release coating formulation over prolonged periods of time, such as e.g. 8, 10, 12, 14, 16, 18, 20, 22 or 24 hours.

It is to be understood that a material will be considered to act as prolonged release material if the dissolution profile of the pharmaceutically active agents is slowed down compared to an immediate or conventional release formulation. If a prolonged release material can be used for manufacturing a prolonged release coating, it will be considered as a prolonged release coating material. Pharmaceutically acceptable excipients which are used to adjust an already prolonged release to a specific profile are not necessarily considered to be prolonged release materials.

When it is mentioned that a prolonged release coating is disposed on

pharmaceutically active agents, this is not to be construed as meaning that such a coating will necessarily be directly layered on such active pharmaceutically agents. Of course, if the pharmaceutically active agents, oxycodone and naloxone, are layered on a carries such as nu-Pareil beads, the coating may be disposed directly thereon. However, the pharmaceutically active agents may also be first embedded in a polymer layer or e.g. a prolonged release matrix. Subsequently the prolonged release coating may be disposed on e.g. granules which comprise a prolonged release matrix or on tablets which are made from such granules by compression for example.

A pharmaceutical composition with a prolonged release coating may be obtained by combining the pharmaceutically active agents with a carries such as non-Pareil beads and disposing a prolonged release coating on said combinations. Such coating may be made from polymers such cellulose ethers with ethyl cellulose being preferred, acrylic resins, other polymers and mixtures thereof. Such prolonged release coatings may comprise additional excipients such as pore-formers, binders and the like.

It is further to be understood, that the term "prolonged release matrix formulation" does not exclude pharmaceutical compositions with a prolonged release matrix and an additional prolonged release coating being disposed on the matrix. Likewise the term "prolonged release coating formulation" does not exclude pharmaceutical compositions with a prolonged release coating which is disposed on prolonged release matrix.

The term "prolonged release dosage form" refers to the administration form of a pharmaceutical composition of the present invention comprising the two

pharmaceutically active agents, i.e. oxycodone and naloxone, in prolonged release form as e.g. in form of a "prolonged release matrix formulation", in the form of a "prolonged release coating formulation", combinations thereof or in other prolonged release formulations such as osmotic formulations. The terms "prolonged release matrix formulation" and "prolonged release dosage form" can be used

interchangeably if the prolonged release dosage form consists essentially of the prolonged release matrix formulation. This means that a prolonged release dosage form can comprise in addition to the prolonged release matrix e.g. cosmetic coatings and pharmaceutically acceptable excipients such fillers, lubricants, etc. For some embodiments, the term "prolonged release matrix dosage form" may indicate that the dosage form comprises a prolonged release matrix as the sole structure being responsible for prolonging the release. This, however, does not exclude that the dosage form may comprise an immediate release portion.

For some embodiments, the term "prolonged release coating dosage form" may indicate that the dosage form comprises a prolonged release coating as the sole structure being responsible for prolonging the release. This, however, does not exclude that the dosage form may comprise an immediate release portion.

The release rates indicated always refer to the formulation such as a monolithic tablet or multi-particulates. The release rates will be chosen such that a pharmaceutical composition can be administered e.g. on a twice a day or once a day basis, i.e. every 12 hours or every 24 hours. Typically, the release will occur by diffusion through the prolonged release matrix and/or coating, erosion of the prolonged matrix and/or coating or combinations thereof.

The term "substantially equal release rate" as used herein means that the two active agents, i.e. oxycodone and naloxone, are released from the dosage form such that their % of release does not deviate by more than about 20%, preferably by not more than about 15% and most preferably by not more that about 10%. In the most preferred embodiment, i.e. in the about 10% range, this means for example for a prolonged release dosage form comprising oxycodone and naloxone that if about 20% of oxycodone or a pharmaceutically acceptable salt are released from the dosage form in vitro after 15 minutes, naloxone will be released within a range of about 10% to about 30%, most preferably also at about 20% at 15 minutes.

RELEASE MATERIALS The following description of suitable materials is to be understood as being not limiting. Rather, the release material may be any material that is known to be capable of imparting prolonged release properties on the active agents, oxycodone and naloxone, when being formulated into a dosage form.

Prolonged release matrix materials

Suitable materials for inclusion in a prolonged release matrix in order to provide a prolonged release matrix dosage form comprising oxycodone and naloxone include:

(a) Hydrophilic or hydrophobic polymers, such as gums, cellulose ethers, acrylic resins and protein derived materials. Of these polymers, the cellulose ethers, especially alkylcelluloses are preferred. The dosage form may conveniently contain between 1% and 80% (by weight) of one or more hydrophilic or hydrophobic polymers.

(b) Substituted or unsubstituted hydrocarbons, such as fatty acids, fatty alcohols, glycerol esters of fatty acids, oils, and waxes.

Hydrocarbons having a melting point of between 25 and 90°C are preferred. The hydrocarbons may be long chain (Cs-Cso, preferably C12-C40) hydrocarbons. The hydrocarbons may be digestible. The oils and waxes may be vegetable, animal, mineral or synthetic oils and waxes. Of these hydrocarbon materials, fatty (aliphatic) alcohols are preferred. The dosage form may conveniently contain up to 60% (by weight) of at least one digestible, long chain hydrocarbon.

(c) Polyalkylene glycols. The dosage form may suitably contain up to

60%) (by weight) of one or more polyalkylene glycols. In a preferred embodiment, the pharmaceutical dosage forms as described in the present invention will use a diffusion matrix for achieving prolonged release of oxycodone and naloxone from the pharmaceutical dosage form. To this end, the diffusion matrix may be made from a hydrophobic polymer and/or a C12-C36 fatty alcohol.

As regards the hydrophobic polymer, use of a hydrophobic cellulose ether and particularly ethyl cellulose may be preferred.

As regards the fatty alcohol, use of lauryl, myristyl, stearyl, cetylstearyl, ceryl and/or cetylalcohol will be preferably considered. The use of stearyl alcohol is particularly preferred. A particularly preferred embodiment relates to pharmaceutical dosage forms in which the prolonged release properties of oxycodone and naloxone are provided by a diffusion matrix which is made from a hydrophobic polymer such as from ethyl cellulose and a fatty alcohol. The matrices of some of the preferred embodiments of the invention, which may e.g. be made from the aforementioned combination of ethyl cellulose and stearyl alcohol, will be a substantially non-swellable diffusion matrix.

The term "substantially non-swellable diffusion matrix" indicates that the matrix will be substantially non-erosive, i.e. that the size of the matrix will not significantly increase upon contact with fluids. Typically, the volume of a substantially non- swellable diffusion matrix will increase at maximum up to 100 %, preferably at maximum up to 75 %, more preferably at maximum up to 50 %, even more preferably at maximum up to 25% and most preferably at maximum up to 10 % or at maximum up to 5 % in volume upon contacting an aqueous solution. Pharmaceutical dosage forms which comprise a hydrophobic polymer with hydrophobic cellulose ethers such as ethyl cellulose being preferred as the sole or one of the components for providing a prolonged release (non-swellable) diffusion matrix, will use an amount of such polymer of between 5 to 20%, preferably of between 6 and 15% by weight and more preferably of between 7 to 10%> by weight. The percentages indicate the amount of the matrix- forming material with respect to the total weight of the pharmaceutical dosage form.

Pharmaceutical dosage forms, which comprise a fatty alcohol as the sole or one of the components for providing a prolonged release diffusion matrix, will use an amount of fatty alcohol in the matrix of between 10 to 40%, preferably of between 15 to 35 % and more preferably of between 17 to 25% by weight. These percentages again indicate the amount of fatty alcohol based on the total weight of the dosage form.

The person skilled in the art is further aware that such a prolonged release matrix may also contain other pharmaceutically acceptable ingredients and excipients which are conventional in the pharmaceutical art such as lubricants, fillers, binders, flowing agents, colourants, flavourants, surfactants, pH-adjusters, anti-tacking agents and granulating aids. These excipients will typically have no substantial impact on the overall release behavior of the pharmaceutical dosage form.

Typical examples of fillers (diluents) comprise lactose, preferably anhydrous lactose, glucose, saccharose, starch and their hydrolysates, microcrystalline cellulose, cellatose, sugar alcohols such as sorbitol or mannitol, calcium salts like calcium hydrogen phosphate, dicalcium- or tricalcium phosphate. Granulating aids comprise inter alia povidone. Flowing agents and lubricants comprise inter alia highly dispersed silica, talcum, magnesium oxide, calcium stearate, magnesium stearate, sodium stearyl fumarate, fast like hydrated castor oil and glyceryl dibehenate.

Binders can include hyproxypropylmethyl cellulose (hypromellose), hydroxypropyl cellulose, hydroxyethyl cellulose, polyvinyl pyrollidone (povidone), acetic acid vinyl ester (copovidone) and carboxymethycellulose sodium. Anti-tacking agents may include glycerol monostearate. Furthermore, a matrix-based dosage form may e.g. comprise a cosmetic coating.

Prolonged release coating materials

As mentioned above, prolonged release characteristics of a pharmaceutical dosage form may also be achieved by a film coating that governs the release of the active agents from the dosage form. To this end, the pharmaceutical dosage form may comprise a carrier, which is associated with the opioid agonist and the opioid antagonist. For example, one may use nonpareil beads, sugar beads etc. on and/or into which the pharmaceutically active agents are disposed. Such active-associated carriers may then be overcoated with a coating that provides prolonged release characteristics. Suitable prolonged release coating materials include hydrophobic polymers such as cellulose ethers and/or acrylic polymer resins. Ethylcellulose may be preferred. The prolonged release coatings may comprise other components such as hydrophilic substances including hydrophilic polymers such hydroxypropylmethylcellulose (HPMC), polyethylenglycols etc. These components may be used to adjust the prolonged release characteristics of the coatings. In case of e.g. HPMC, the substances may act as pore formers. The coating may, of course, also comprise additional pharmaceutically acceptable excipients, e.g. as set out above for the matrices.

The invention is now illustrated with respect to specific examples. These examples are, however, not to be construed as limiting. EXAMPLE

Study design and patient populations:

Main objective: To estimate the subjects' average pain over the last 24 hours assessed at each study visit during treatment with OXN PR (Targin®) compared with placebo.

Further objectives: To assess the frequency of pain rescue medication intake; to assess the Brief Pain Inventory - Short Form (BPI-SF) at each clinic visit during treatment with study medication; to assess the efficacy based on the O'Leary-Sant Interstitial Cystitis Symptom Index (ICSI) score/ O'Leary-Sant Interstitial Cystitis Problem Index (ICPI) score; to assess overall health based on the SF-36 v2; to assess micturition (volume and time) based on 24 hours patient diary assessing 2 days in the last week prior to visits 6, 8, 10 and 16; to assess intake of additional therapy; to assess urinary urgency using the Patients' Perception of Intensity of Urgency Scale (PPIUS); and to assess adverse events including constipation.

Determination of the afore-mentioned parameters: Average pain over the last 24 hours was determined using a numerical Pain Intensity Scale (Numerical scale of 0 - 10, 0=no pain; 10=strong pain). The frequency of pain rescue medication and the amount of pain rescue medication required were recorded, as were the adverse events and the intake of additional therapy. The standard Brief Pain Inventory - Short Form (BPI-SF) questionnaire was used, wherein pain severity and pain interference are recorded (see e.g. items 3 to 6 and 9 on the BPI-SF). The questions for determining the ICSI and ICPI scores are shown in Figure 26. The standard questionnaire of SF- 36 v2 was used to determine overall health. Micturition was assessed by recording information about the time, volume, urgency and sleep disturbance in a patient's diary. Finally, the following scores are used in the PPIUS. It is noted that the PPIUS is usually used for categorizing overactive bladder syndrome (OAB).

0 ("No"): I felt no need to empty my bladder but did so for other reasons; 1 ("Mild"): I could postpone voiding for as long as necessary without fear of wetting myself;

2 ("Moderate"): I could postpone voiding for a short while without fear of wetting myself;

3 ("Severe"): I could not postpone voiding but had to rush to the toilet in order not to wet myself

4 ("Incontinence"): I leaked before arriving at the toilet.

Overall Study Design and Plan: The study was a randomized, double-blind, placebo-controlled, parallel group study comprising a pre-randomisation phase, a double-blind phase and an open-label phase to demonstrate improvement in BPS in subjects taking OXN PR (Targin®) compared to subjects taking placebo. The study design is shown in Figure 1. Inclusion criteria: Females, 18 years of age or older; subjects with a history of severe pain due to BPS for at least 6 months (mean average BPS pain over last 6 months > 5); subjects who experienced the complaint of suprapubic pain related to bladder filling, accompanied by all of the following 3 criteria, in the absence of proven urinary infection or other obvious pathology: - a total score of > 8 on the O'Leary-Sant Interstitial Cystitis Symptom Index

(ICSI) and a score of > 0 on each of the 4 questions on the ICSI; a total score of > 8 on the O'Leary-Sant Interstitial Cystitis Problem Index (ICPI) and a score of > 0 on each of the 4 questions on the ICPI; an average of > 8 voids per day and an average of > 2 voids at night (nocturia) within the last month.

Subject's treatment of pain due to BPS was insufficient (insufficient efficacy or tolerability, based on a clinical judgment); subjects with a documented history of attempts to optimize the treatment of pain due to BPS; subject's pre-study BPS treatment was expected to remain stable throughout the duration of the study

(OXN PR or matching placebo were given as add-on therapy). BPS treatment was typically carried out with non-steroidal antiinflammatory and antirheumatic actives, other urologicals including antispasmodics, and non-opioid analgesics and antipyretics.

Treatment: All subjects started the double-blind phase on a dose of

OXN 5/2.5 mg PR or matching placebo twice daily / every 12 hours (ql2h); only ibuprofen was allowed as rescue medication for the treatment of breakthrough pain during the double-blind phase; titration up to the maximum daily dose of

OXN 20/10 mg PR twice daily was permitted; the following doses were allowed for twice daily use: OXN 5/2.5 mg PR, OXN 10/5 mg PR, OXN 15/7.5 mg PR (given as OXN 10/5 mg PR + OXN 5/2.5 mg PR) and OXN 20/10 mg PR twice daily or, in the double-blind phase, the respective matching placebo; all subjects started the open- label phase on a dose of OXN5/2.5 mg PR twice daily. Only OxylR was allowed as rescue medication for the treatment of breakthrough pain during the open- label phase.

Analysis of the populations and demography: The numbers of the different populations is given in Figure 2. Starting from 68 enrolled patients, 60 patients were randomized (FA population). The total per protocol (PP) population was 36 patients. The demography of the patient populations is depicted in Figure 3 (age, gender, race, weight, height and BMI).

Results for the average pain: The results of the pain treatment in the double-blind phase, expressed as average pain over the last 24 hours, are shown in Figures 4 to 6. As can be derived from Figure 5, the average pain scores in the double-blind phase for the full analysis population decreased over time, wherein this decrease was slightly more pronounced for OXN PR in the full analysis population. The decrease in pain scores over time in the double-blind phase for the OXN PR-group was more pronounced in the per protocol population, see Figure 6.

The full analysis population and the per protocol population were then analyzed in further detail as regards BPS therapy at the beginning of the study, i.e. at screening, and as regards BPS-related surgical procedures prior to the study. The results are shown in Figure 7. It can be derived therefrom for the OXN PR-treated group that the change to baseline was more pronounced in patients with BPS therapy at screening and in patients with preceding BPS-related surgical procedures.

Figure 8 shows the average pain scores over time in the open-label phase following the double-blind phase. The green line shows the average pain scores for the complete open label population, whereas the blue line depicts the pain scores in patients who received OXN PR in the double-blinded phase. The red line shows the average pain scores in patients who received placebo in the double-blinded phase, who were switched to OXN PR. It is noted that the pain decrease is more pronounced in the population that received placebo in the double-blind phase indicating that these patients, now treated with OXN PR instead of placebo, experienced pain relief to a larger extent than before.

Results for rescue medication in the double-blind phase:

Ibuprofen was available as rescue medication for breakthrough pain in the double- blind phase. As can be derived from Figure 9, the use of rescue medication in the double-blind phase was overall about identical in terms of the number of tablets per day but lower in terms of the amount (in mg) of ibuprofen in the OXN PR group (11948.4 mg in the OXN PR group vs. 14185.7 mg in the placebo group). This difference in amounts needed for the treatment of breakthrough pain is particularly obvious when comparing the amount needed at week 8: 1981.8 mg in the OXN PR group vs. 3072.7 mg in the placebo group. Thus, less ibuprofen was needed in the OXN PR group.

Results for BPI-SF:

Pain severity according to the BPI-SF is shown in Figure 10 for the full analysis population in the double-blind phase. The severity is lower in the OXN PR-treated group. This is more pronounced in the per protocol population in the double-blind phase, see Figure 11.

Figures 12 and 13 show pain interference according to the BPI-SF in the double- blind phase for the full analysis population (Figure 12) and the per protocol population (Figure 13). As for the severity, there is a positive effect in the OXN PR group, which is more pronounced when looking at the per protocol population.

Figure 14 shows the pain relief in % according to the BPI-SF in the double-blind phase for the full analysis population (FA) and the per protocol population (PP). As already noted for the average pain (see above), the pain relief expressed as change from baseline is particularly pronounced in patients with BPS therapy at screening and in patients with preceding BPS-related surgical procedures.

Results for the ICSI/ICPI scores in the double-blind phase:

The ICSI/ICPI scores are given in Figures 15 to 18 for the double-blind phase over 8 weeks. Figure 15 shows the ICSI-scores and Figure 16 the ICPI-scores for the full analysis population. Figure 17 shows the ICSI-scores and Figure 18 the ICPI-scores for the per protocol population. As for the symptoms Index (ICSI), OXN is superior over placebo, wherein the decrease in the overall score is more pronounced in the per protocol population (see Figures 15 and 17). This is also the case for the problem Index (ICPI), see Figures 16 and 18. As can be derived from Figure 26, the symptoms and problems evaluated therein relate to urinary urgency, urinary frequency, nocturia and pain.

Figure 19 shows the ICSI change to baseline for the two afore-mentioned subgroups, namely subjects with PBS therapy at screening and with surgical procedures. The change to baseline is more pronounced in these two sub-groups. This also applies for the ICPI change to baseline in the two sub-populations, see Figure 20.

Results of the PPIUS assessment by week in the double-blind phase:

Urinary urgency was analyzed in more detail as outlined above, namely by the PPIUS assessment, and the results are shown in Figure 21 for the full analysis population in the double-blind phase.

It can be derived from Figure 21 that there is a shift in the OXN PR-treated group from "Severe" to "Moderate" over time (i.e. from baseline, upper diagram [64.5: "Severe" vs. 32.3 : "Moderate"] to week 8, lower diagram [27.3 : "Severe" vs. 54.5 : "Moderate"]). This shift is not so explicit in the placebo-treated group.

Results of the adverse events analysis: Figure 22 shows an overall summary of adverse events in the double-blind safety population. There were no subjects

- with at least one related serious adverse event;

- who died;

- who died of a related serious adverse event. When analyzing the adverse events in more detail, there was an unexpected and interesting finding for constipation as adverse event. As can be taken from Figure 23, more than 20% of the placebo-treated group were constipated (21.4%). These patients did not receive an opioid agonist so the constipation is not opioid-induced. Since a rate of more than 20% of constipation is clearly higher than in the "normal" healthy population, it appears that there might be a link between the urogenital system and the gastrointestinal system: problems in the urogenital system might also negatively influence the gastrointestinal function resulting in constipation.

Unexpectedly, only 6.3%> of the OXN PR-treated group were constipated. This can be interpreted such that the naloxone present in addition to the opioid agonist oxycodone in OXN PR is not only able to counteract the oxycodone-induced constipation but furthermore treats and/or alleviates constipation that might be present due to the problems in the urogenital system. If the naloxone would only counteract the oxycodone-induced constipation, one would have expected that also about 20%) of the OXN PR-treated group (as in the placebo group) are constipated.

Results of overall health according to SF-36 v2:

Figures 24 and 25 show the "physical functioning" and the "vitality" parameters as deduced from the afore-mentioned index in the double-blind phase for the placebo- and the OXN PR-treated group. A stronger increase in the OXN PR-treated group over placebo is particularly visible for the parameter "vitality", see Figure 25.

Results of micturition:

At the beginning of the study, the mean frequency of micturition over 24 hours was 18.9 in the OXN PR and 18.5 in the placebo group. Of those, 10.5 in the OXN PR group and 10.8 in the placebo group occurred at night, and 15.8 in the OXN group and 15.5 in the placebo group were urgency-related micturitions. This is

approximately one micturition every 76-78 minutes per 24 hours, and one every 77- 80 minutes between 20:00 and 10:00 (which was defined as night-time per SAP), and one urgent micturition every 91-93 minutes. Mean urine volume in 24 hours at baseline was 3759.8 mL in the OXN PR group and 3912.7 mL in the placebo group, which according to the National Institute of Health (2011) is defined as polyuria, as it is well in excess of 2.5 L of urine per day.

The overall frequency of micturition in 24 hours decreased in both treatment groups from baseline to week 8. In the FA population the mean decrease was -4.1 in the OXN PR, compared to -2.0 in the placebo group. In the long term, this would add up to a decrease of 123 micturitions in one month, or 1496.5 micturitions in one year for subjects taking OXN PR. While the mean daytime micturition decreased to a similar extent by -1.4 in the OXN PR group and -1.0 in the placebo group, the mean nocturnal frequency of micturition decreased by -2.6 in the OXN PR group and -1.1 in the placebo group - which adds up to 78 less instances of night-time micturitions per month or 949 per year for patients taking OXN PR. The decrease in urgency- related frequency was also greater in the OXN PR group, where the mean decrease from baseline to week 8 was -4.1 (overall), -1.2 (daytime) and -2.5 (nocturnal) compared to placebo, were the observed decreases were -2.4 (overall), -1.5 (daytime) and -0.6 (nocturnal). The overall total volume decreased by -468.0 mL in the

OXN PR group compared to -140.5 mL in the placebo group. The decrease in mean urgency-related volume from baseline to week 8 was -832.6 in the OXN PR group and - 289.9 in the placebo group, again with a greater decease in the OXN PR group at night-time. The mean volume per micturition did increase slightly in both groups, by 25.6 mL in the OXN PR group and by 19.7 mL in the placebo group, which is not unexpected considering the decrease in micturition frequency. The improvement in micturition is also notable in the PP population, where the differences between the OXN PR group and the placebo group reached statistical significance for overall (24h) urgency-related mean frequency at week 8 (p=0.036; CI: -9.84, -0.37) and week 8 (LOCF (p=0.038; 95% CI: -8.02, -0.24), nocturnal urgency- related mean frequency at week 8 (p=0.029; 95% CI: -6.52, -0.38) and week 8 LOCF (p=0.026; 95% CI: -5.34, -0.37) overall total urgency-related volume at week 8 LOCF (p= 0.038; 95% CI: -1965.45, -57.43), overall mean urgency-related volume at week 1 (p= 0.047; 95% CI: 0.29, 49.48) and approached statistical significance in daytime mean frequency at week 8 (p=0.051; 95%> CI: -2.84, 0.01). In the open-label phase, the micturition parameters improved, however this improvement was greater in the subjects who had previously taken placebo, who now showed statistically significant improvements from the start of the open-label phase to week 4 for frequency (overall, daytime), urgency-related frequency (overall, daytime, nocturnal), total volume (overall, daytime), urgency-related volume (overall, daytime, nocturnal) and mean volume (overall and daytime). For both subgroups a statistically significant change from the start of the open-label phase to week 4 was observed in mean frequency (overall, daytime, nocturnal), urgency- related frequency (overall and nocturnal), and mean volume (overall and daytime), subjects who had received OXN PR in the double-blind phase had statistically significant changes in mean volume (overall, daytime, nocturnal) and urgency- related mean volume (overall and daytime).

Results for additional therapies: 95.0%) of the subjects in the double-blind phase had received at least one previous therapy for BPS. The most frequently used treatments fell into the pharmacological subclasses of 'Non-steroidal antiinflammatory and antirheumatic products' (31

[51.7%>] subjects), Other urologicals, including antispasmodics' (29 [48.3%>] subjects), and Other analgesics and antipyretics' (29 [48.3%>] subjects). During the study 42 (70.0%>) subjects received further treatments for BPS, with substances falling into the Other urologicals, including antispasmodics' (14 [23.3%>] subjects) and Other analgesics and antipyretics' (23 [38.3%] subjects)

pharmacological subgroups being again among the most frequently used

medications. Whilst before the study Other analgesics and antipyretics' were used by slightly more subjects from the OXN PR group (16 [50.0%] subjects compared to 13 [46.4%] subjects in the placebo group), during the study slightly more subjects from the placebo group were taking concomitant Other analgesics and antipyretics' for BPS (1 1 [34.4%] subjects in the OXN PR group compared to 12 [42.9%] in the placebo group). For the placebo group, the additional therapy was thus comparable before and during the study (46.4%> vs. 42.9%), whereas the additional therapy clearly decreased in the OXN group (50.0% vs. 34.4%).

Subsequent BPS therapies were documented for 18 (30.0%>) subjects.

Main conclusion from the study:

The type of pain occurring in BPS can be classified as visceral pain. It is also referred to as suprapubic pain. In contrast to e.g. cancer pain in bones or pain from musculoskeletal origin, the present type of pain is rather linked to smooth muscles. Furthermore, the treatment of this type of pain is usually not classified as short-term, acute pain treatment, but rather as long-term, chronic pain treatment.

Pain in BPS was more efficiently treated in patients when the subjects received OXN PR compared to placebo. This is evident from the results of the average pain analysis in the double-blind phase, but also in the open-label phase, where switching the placebo-group to ONX PR resulted in a more pronounced pain relief. The amount of rescue medication needed in the double-blind phase and particularly at week 8 of the study was less in the OXN PR group, further indicating the effective pain treatment. Interestingly, subjects with BPS therapy at screening and subjects with surgical procedures showed a larger change to baseline than subjects without BPS therapy or surgical procedures, indicating that OXN PR is particularly effective in subjects suffering from very serious forms of BPS since these subjects were previously or in parallel treated by other treatment options. The BPI-SF results also support the above conclusions on pain treatment.

The efficacy of BPS treatment was assessed by two questionnaires resulting in scores: the ICSI/ICPI scores. Both scores show that the OXN PR treatment was more effective than placebo, wherein it was again observed that the effect of the treatment was better in the afore-mentioned two populations, namely subjects with BPS therapy at screening and subjects with surgical procedures. This is in line with the finding on the efficacy of pain treatment, which seems to be more pronounced in subjects suffering from very serious forms of BPS. Urinary urgency was analyzed as specific parameter using the PPIUS assessment, and also in this analysis a positive effect of the OXN PR treatment was found.

There was a surprising and unexpected finding regarding the adverse event constipation: OXN PR not only failed to induce constipation in subjects (as expected, since the naloxone counteracts the oxycodone-induced side effect constipation such that this side effect is prevented from the outset) but apparently resulted in a treatment of constipation, which is not opioid- induced and which might be higher in subjects suffering from BPS. This additional treatment effect of OXN PR was not expected.

Finally, the use of additional therapy clearly decreased in the OXN group over the course of the study, whereas it remained constant for the placebo group. This finding is surprising since one would have expected the need for additional therapy in the OXN group because of the known side effects of an opioid agonist. It appears, however, that the additional presence of naloxone not only balances the oxycodone side effects but even has positive influence on BPS / BPS-symptoms.

Claims

An oral prolonged release dosage form comprising oxycodone or a pharmaceutically acceptable salt thereof and naloxone or a pharmaceutically acceptable salt thereof for use in the treatment of Bladder Pain Syndrome (BPS) and/or at least one symptom thereof.

The dosage form for use according to claim 1 , wherein the dosage form is for use in the treatment of BPS, wherein the treatment of BPS is expressed by a lower score in the interstitial cystitis symptoms index (ICSI) and/or the interstitial cystitis problem index (ICPI) compared to the score in the interstitial cystitis symptoms index (ICSI) and/or the interstitial cystitis problem index (ICPI) prior to the treatment.

The dosage form for use according to claim 1 , wherein the dosage form is for use in the treatment of at least two symptoms of BPS.

The dosage form for use according to claim 3, wherein said at least two symptoms are selected from the group consisting of pain, urinary urgency, urinary frequency and nocturia.

The dosage form for use according to claim 3, wherein said at least two symptoms are (i) pain and (ii) at least one symptom selected from the group consisting of urinary urgency, urinary frequency and nocturia.

The dosage form for use according to any one of the preceding claims, wherein said treatment is carried out in a human suffering from BPS who had a surgery as treatment of BPS prior to the treatment by the oral prolonged release dosage form comprising oxycodone or a pharmaceutically acceptable salt thereof and naloxone or a pharmaceutically acceptable salt thereof. The dosage form for use according to any one of the preceding claims, wherein said treatment is carried out in a human suffering from BPS who receives further BPS treatment.

The dosage form for use according to any one of the preceding claims, wherein said treatment is carried out in a human suffering from BPS who is constipated, wherein said constipation is not opioid-induced.

An oral prolonged release dosage form comprising oxycodone or a pharmaceutically acceptable salt thereof and naloxone or a pharmaceutically acceptable salt thereof for use in the long-term treatment of (i) chronic pain, preferably suprapubic pain, (ii) at least one symptom selected from the group consisting of urinary urgency, urinary frequency and nocturia, and (iii) constipation, wherein (i) and (ii) are symptoms of BPS in a patient suffering from BPS who is constipated.

The oral prolonged release dosage form for use according to claim 9, wherein said constipation is not opioid-induced constipation.

The oral prolonged release dosage form for use according to any one of claims 1 to 10, wherein the dosage form comprises oxycodone or a pharmaceutically acceptable salt thereof in an amount range of equivalent to about 1 mg to about 160 mg oxycodone HC1 and naloxone or a

pharmaceutically acceptable salt thereof in an amount range of equivalent to about 0.5 mg to about 80 mg naloxone HC1 dihydrate.

The oral prolonged release dosage form for use according to any one of claims 1 to 11, wherein the dosage form comprises oxycodone or a pharmaceutically acceptable salt thereof and naloxone or a pharmaceutically acceptable salt thereof in a weight ratio range of about 5 : 1 to about 1 : 1, wherein the weight ratio is calculated on the basis of the free base of oxycodone: free base of naloxone. The oral prolonged release dosage form for use according to any one of claims 1 to 12, wherein the dosage form comprises oxycodone or a pharmaceutically acceptable salt thereof and naloxone or a pharmaceutically acceptable salt thereof in a weight ratio of about 2: 1, wherein the weight ratio is calculated on the basis of the free base of oxycodone: free base of naloxone.

The oral prolonged release dosage form for use according to any one of claims 1 to 14, wherein the dosage form releases in vitro, when measured using the Ph. Eur. Paddle Method at 100 rpm in 0.1 N hydrochloric acid, pH 1.2 at 37°C and using UV detection at 230 nm, about 5% to about 40% of oxycodone or a pharmaceutically acceptable salt thereof by weight and about 5% to about 40% of naloxone or a pharmaceutically acceptable salt thereof by weight at 15 min; about 20%> to about 50%> of oxycodone or a

pharmaceutically acceptable salt thereof by weight and about 20% to about 50% of naloxone or a pharmaceutically acceptable salt thereof by weight at 1 hour; about 30% to about 60% of oxycodone or a pharmaceutically acceptable salt thereof by weight and about 30% to about 60% of naloxone or a pharmaceutically acceptable salt thereof by weight at 2 hours; about 50% to about 80% of oxycodone or a pharmaceutically acceptable salt thereof by weight and about 50% to about 80% of naloxone or a pharmaceutically acceptable salt thereof by weight at 4 hours; about 70%> to about 95 %> of oxycodone or a pharmaceutically acceptable salt thereof by weight and about 70% to about 95% of naloxone or a pharmaceutically acceptable salt thereof by weight at 7 hours; and more than about 80%> of oxycodone or a pharmaceutically acceptable salt thereof by weight and more than about 80% of naloxone or a pharmaceutically acceptable salt thereof by weight at 10 hours.

15. The oral prolonged release dosage form for use according to any one of claims 1 to 14, wherein said dosage form is Targin®.