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) - Google Patents
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 EP3328386A1 EP16754417.0A EP16754417A EP3328386A1 EP 3328386 A1 EP3328386 A1 EP 3328386A1 EP 16754417 A EP16754417 A EP 16754417A EP 3328386 A1 EP3328386 A1 EP 3328386A1
- Authority
- EP
- European Patent Office
- Prior art keywords
- pharmaceutically acceptable
- acceptable salt
- dosage form
- naloxone
- oxycodone
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Withdrawn
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Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/47—Quinolines; Isoquinolines
- A61K31/485—Morphinan derivatives, e.g. morphine, codeine
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/04—Centrally acting analgesics, e.g. opioids
Definitions
- 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)
- 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).
- PBS Bladder Pain Syndrome
- BPS Breast Pain Syndrome
- EAU European Association of Urology
- ESSIC European Society for the Study of Interstitial Cystitis
- IC interstitial cystitis
- PBS painful bladder syndrome
- 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).
- BPS BPS
- insults 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).
- C-nerve fibre activation Sant, 2002.
- these processes become aggravated over time, eventually leading to a vicious cycle of progressively worsening tissue damage, scarring, and fibrosis (Evans, 2002).
- Intravesical treatments include botulinum toxin A, dimethyl sulfoxide, heparin and glycosaminoglycan substitutes.
- 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.
- BPS Bladder Pain Syndrome
- the dosage form is for use in the treatment of BPS.
- 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.
- ICSI interstitial cystitis symptoms index
- ICPI interstitial cystitis problem index
- 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.
- 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.
- said at least one symptom is selected from the group consisting of urinary urgency, urinary frequency, nocturia and combinations thereof.
- 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.
- 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.
- 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.
- said treatment is carried out in a human, more preferably in a female.
- 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.
- 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.
- 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.
- 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
- 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.
- pain is chronic pain / chronic suprapubic pain.
- constipation may be treated, wherein said constipation is then not opioid-induced and present at the beginning of the treatment by said dosage form.
- 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.
- 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.
- 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.
- said patient is constipation at the beginning of the administration of said dosage form.
- said constipation is not opioid- induced constipation. Said constipation might be linked to BPS.
- 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.
- said patient is not constipated at the beginning of the administration of said dosage form.
- 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.
- 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.
- 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.
- the dosage form may comprise oxycodone or a
- naloxone 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.
- 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.
- 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 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).
- 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).
- 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).
- 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.
- 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
- 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 7
- 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.
- compositions of the actives in dosage forms of the present invention 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.
- the hydrochloride salt of naloxone is used, it is even more preferred to use naloxone hydrochloride dihydrate.
- the prolonged release dosage form comprises a prolonged release matrix in order to achieve the prolonged release.
- the prolonged release dosage form comprises a prolonged release coating in order to achieve the prolonged release of the active agents.
- the prolonged release dosage form is an osmotic prolonged release dosage form.
- 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.
- 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.
- lubricants such as e.g. lubricants, fillers, binders, flowing agents, colourants, flavourants, surfactants, pH-adjusters, anti-tacking agents and/or combinations thereof.
- 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.
- 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.
- 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.
- the dosage form comprises oxycodone hydrochloride and naloxone hydrochloride dihydrate.
- the dosage form in its most preferred embodiment comprises a prolonged release matrix.
- 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).
- NAS Numerical Analogue Scale
- 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.
- 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.
- 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.
- a symptom may also refer to “symptoms”.
- sustained release refers to pharmaceutical compositions showing a slower release of the active agents than that of a
- Prolonged release is achieved by a special formulation design and/or manufacturing method.
- 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.
- 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,
- 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.
- immediate release opioid agonist formulations such as e.g. IR morphine or IR oxycodone
- 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.
- 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.
- 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.
- suitable indices such as e.g. the ICPI and/or ICPI indices.
- lower scores compared to the scores prior to the administration of a specific active or combination of actives
- 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.
- 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.
- BPI-SF Brief Pain Inventory - Short Form
- PPIUS-scale depending on the specific
- BPS-symptoms are listed.
- 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.
- the release behavior of a dosage form can inter alia be determined by an in vitro release test.
- 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.
- SGF simulated gastric fluid
- 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.
- 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.
- 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.
- 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.
- Prolonged release 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.
- the term “prolonged release coating material” indicate that a material is used for obtaining a prolonged release coating.
- 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.
- 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.
- 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.
- compositions which are used to adjust an already prolonged release to a specific profile are not necessarily considered to be prolonged release materials.
- 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.
- the coating may be disposed directly thereon.
- 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.
- a prolonged release 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.
- 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.
- prolonged release coating formulation does not exclude pharmaceutical compositions with a prolonged release coating which is disposed on prolonged release matrix.
- sustained release dosage form refers to the administration form of a pharmaceutical composition of the present invention comprising the two
- 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.
- prolonged release matrix formulation in the form of a “prolonged release coating formulation”
- prolonged release dosage form can be used
- the prolonged release dosage form consists essentially of the prolonged release matrix formulation.
- 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.
- 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.
- 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 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.
- 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.
- substantially equal release rate 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%.
- 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.
- Suitable materials for inclusion in a prolonged release matrix in order to provide a prolonged release matrix dosage form comprising oxycodone and naloxone include:
- 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.
- 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.
- the dosage form may suitably contain up to
- 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.
- the diffusion matrix may be made from a hydrophobic polymer and/or a C12-C36 fatty alcohol.
- hydrophobic polymer use of a hydrophobic cellulose ether and particularly ethyl cellulose may be preferred.
- 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.
- 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.
- 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.
- compositions 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.
- compositions 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.
- 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.
- fillers 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.
- a matrix-based dosage form may e.g. comprise a cosmetic coating.
- 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.
- the pharmaceutical dosage form may comprise a carrier, which is associated with the opioid agonist and the opioid antagonist.
- a carrier which is associated with the opioid agonist and the opioid antagonist.
- 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 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.
- OXN PR OXN PR
- 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 ICSI and a score of > 0 on each of the 4 questions on the ICSI
- ICPI O'Leary-Sant Interstitial Cystitis Problem Index
- ICPI O'Leary-Sant Interstitial Cystitis Problem Index
- 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
- BPS treatment was typically carried out with non-steroidal antiinflammatory and antirheumatic actives, other urologicals including antispasmodics, and non-opioid analgesics and antipyretics.
- 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.
- results for the average pain are shown in Figures 4 to 6.
- 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.
- 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.
- Ibuprofen was available as rescue medication for breakthrough pain in the double- blind phase.
- 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.
- less ibuprofen was needed in the OXN PR group.
- 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).
- 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).
- FA full analysis population
- PP per protocol population
- 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.
- ICSI symptoms Index
- 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).
- ICPI problem Index
- 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.
- 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.
- Figure 22 shows an overall summary of adverse events in the double-blind safety population. There were no subjects
- 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.
- 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
- 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.
- 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 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).
- 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.
- 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.
- 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.
Abstract
Description
Claims
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EP15179285 | 2015-07-31 | ||
PCT/EP2016/068173 WO2017021304A1 (en) | 2015-07-31 | 2016-07-29 | 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) |
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EP16754417.0A Withdrawn EP3328386A1 (en) | 2015-07-31 | 2016-07-29 | 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) |
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AU (1) | AU2016301861A1 (en) |
BR (1) | BR112018001504A2 (en) |
PH (1) | PH12018500221A1 (en) |
WO (1) | WO2017021304A1 (en) |
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2016
- 2016-07-29 EP EP16754417.0A patent/EP3328386A1/en not_active Withdrawn
- 2016-07-29 AU AU2016301861A patent/AU2016301861A1/en not_active Abandoned
- 2016-07-29 WO PCT/EP2016/068173 patent/WO2017021304A1/en active Application Filing
- 2016-07-29 BR BR112018001504A patent/BR112018001504A2/en not_active Application Discontinuation
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BR112018001504A2 (en) | 2018-09-11 |
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PH12018500221A1 (en) | 2018-07-30 |
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