(12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT) (19) World Intellectual Property Organization International Bureau (10) International Publication Number (43) International Publication Date 29 July 2010 (29.07.2010) WO 2010/083843 Al (51) International Patent Classification: Dyssegard (DK). HOILUND-JENSEN, Jacob Aas [DK/ A61K 9/22 (2006.01) A61K 9/28 (2006.01) DK]; Engbovej 6, DK-3600 Frederikssund (DK). A61K 9/36 (2006.01) A61K 31/485 (2006.01) (74) Agent: HOIBERG AJS; St. Kongensgade 59A, DK- 1264 A61K 9/20 (2006.01) Copenhagen K (DK). (21) International Application Number: (81) Designated States (unless otherwise indicated, for every PCT/DK20 10/0500 16 kind of national protection available): AE, AG, AL, AM, (22) International Filing Date: AO, AT, AU, AZ, BA, BB, BG, BH, BR, BW, BY, BZ, 26 January 2010 (26.01 .2010) CA, CH, CL, CN, CO, CR, CU, CZ, DE, DK, DM, DO, DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, GT, English (25) Filing Language: HN, HR, HU, ID, IL, IN, IS, JP, KE, KG, KM, KN, KP, (26) Publication Language: English KR, KZ, LA, LC, LK, LR, LS, LT, LU, LY, MA, MD, ME, MG, MK, MN, MW, MX, MY, MZ, NA, NG, NI, (30) Priority Data: NO, NZ, OM, PE, PG, PH, PL, PT, RO, RS, RU, SC, SD, PA 2009 00127 26 January 2009 (26.01 .2009) DK SE, SG, SK, SL, SM, ST, SV, SY, TH, TJ, TM, TN, TR, 61/147,1 5 1 26 January 2009 (26.01 .2009) US TT, TZ, UA, UG, US, UZ, VC, VN, ZA, ZM, ZW. PA 2009 00782 24 June 2009 (24.06.2009) DK (84) Designated States (unless otherwise indicated, for every (71) Applicant (for all designated States except US): kind of regional protection available): ARIPO (BW, GH, EGALET AJS [-/DK]; Lejrvej 37-41, Kirke Vsrløse, GM, KE, LS, MW, MZ, NA, SD, SL, SZ, TZ, UG, ZM, DK-35OO Vsrløse (DK). ZW), Eurasian (AM, AZ, BY, KG, KZ, MD, RU, TJ, (72) Inventors; and TM), European (AT, BE, BG, CH, CY, CZ, DE, DK, EE, (75) Inventors/Applicants (for US only): ANDERSEN, ES, FI, FR, GB, GR, HR, HU, IE, IS, IT, LT, LU, LV, Christine [DK/DK]; Ellefolden 14, DK-2950 Vedbsk MC, MK, MT, NL, NO, PL, PT, RO, SE, SI, SK, SM, (DK). JESPERSEN, Lillian [DK/DK]; Randvolden 12, TR), OAPI (BF, BJ, CF, CG, CI, CM, GA, GN, GQ, GW, DK-2730 Herlev (DK). LINDHARDT, Karsten ML, MR, NE, SN, TD, TG). [DK/DK]; Slettehavevej 77, DK-4690 Haslev (DK). Published: OVERG λ RD, Jan Martin [DK/DK]; Marienlystvej 8, — with international search report (Art. 21(3)) DK-3600 Frederikssund (DK). LYHNE-IVERSEN, Louise Inoka [DK/DK]; Vangedevej 4, st. th, DK-2820 — before the expiration of the time limit for amending the Gentofte (DK). OLSEN, Martin Rex [DK/DK]; Regn- claims and to be republished in the event of receipt of buen 34, DK-4300 Holbsk (DK). CHRISTENSEN, amendments (Rule 48.2(h)) Lars Hedevang [DK/DK]; Munkegardsvej 8, DK-2870 (54) Title: CONTROLLED RELEASE FORMULATIONS WITH CONTINUOUS EFFICACY (57) Abstract: The present invention relates to pharmaceutical compositions, which provide controlled release of a drug. The compositions are suitable for continuous administration as they remain effective throughout the treatment regimen. The present in- vention also relates to the use of the compositions for preparation of a medicament for continuous treatment of an individual. Controlled release formulations with continuous efficacy All patent and non-patent references cited in the application are hereby incorporated by reference in their entirety. Field of invention The present invention relates to the field of controlled release formulations, and in particular to formulations useful for once daily administration. Background of invention Steady state concentrations are an important aspect for a controlled release formulation, which cannot be determined based on single dosage studies. Efficacy may be dependent on the steady state Cmin and a small difference in steady state Cmax and steady state Cmin may be advantageous, to provide maximal possible time in the therapeutic window, (higher than minimal effective concentration and lower than a level giving rise to side effects). In relation to analgesics, the minimal effective concentration is referred to as "minima effective analgesic concentration (MEAC). Accordingly, a given Cmin for a given active drug substance may be desirable. However, for many drug substances a preferred Cmin is not easy to achieve. For opioids a concern is that the mu receptor (m OR) can show tolerance. This kind of tolerance development always carries a risk that repeated dose studies provide unexpected results in efficacy (i.e. tachyphylaxis). As it appears from the section from Raehhal and Bohn (Mu Opioid Receptor Regulation and Opiate Responsiveness The AAPS Journal 2005;7(3):Article 60) below m OR can be differently regulated in different cellular environment, and any regulations on receptor level give rise to a risk of unpredictable results. "Further, chronic morphine has been shown to induce desensitization of the m OR as measured by adenylyl cyclase inhibition in thalamus and periaqueductal gray brain regions but not in caudate putamen or nucleus accumbens. These observations suggest that while the m OR is expressed in these brain regions, it is not desensitized to the same extent following chronic morphine treatment and demonstrates that the m OR can be differentially regulated in different cellular environments." (Raehal and Bonn, 2005). Due to tolerance development / tachyphylaxia on a receptor level repeated dose efficacy cannot be predicted from a single dose PK profile. The International Association for the Study of Pain gives this definition of pain: PAIN is "an unpleasant sensory and emotional experience associated with actual or potential tissue damage, or described in terms of such damage". Pain and degree of pain may be determined using questionnaires asking afflicted individuals to evaluate their perception of pain. Even though Morphine has been known as an analgesic for a very long time, a MEAC, a concentration-effect relationship, or a therapeutic window have not been established for Morphine. However, the pharmacokinetic profile of Morphine is known to be critical as described by Camu and Vanlersberghe (Pharmacology of systemic analgesics. Best Pract Res Clin Anaesthesiol 2002;16(4):475-88): "...But in clinical practise, their [i.e. opioids, applicant's note] very steep concentration analgesic effect relationship remains a critical aspect of opioid therapy. Thus, small fluctuations in plasma concentrations of opioids may lead to profound fluctuations in analgesic effect when their plasma concentration and effect-site concentrations are near the minimum effective analgesic concentration" (Camu and Vanlersberghe 2002). Attempts have been made to estimate the MEAC for morphine. Dahlstrom et al (1982) (Patient-controlled analgesic therapy, part IV: Pharmacokinetics and analgesic plasma concentrations of morphine. Clin Pharmacokinet;7:266-79) reported in a group of 10 postoperative patients a calculated mean (SD) MEAC of 16 (9) ng/mL while Graves et a/ (1985, Relationship between plasma morphine concentrations and pharmacologic effects in postoperative patients using patient-controlled analgesia. Clin Pharm 1985;4:41-7) estimated this limit to be in the range of 20-40 ng/mL. These limits have, however, not proved useful in clinical practice. Commercially available controlled release formulations of Morphine includes MST Continus and Dolcontin, both which are for administration twice daily. Thus, there is a need for controlled release formulations for less frequent administration, which however are continuously effective. WO2003/024430 and WO2004/084868 describes Morphine polymer release systems, which are suggested for once or twice daily administration. The documents describe administration of single dosages of the systems, but do not relate to continuous administration of these systems and no information regarding efficacy is given. Example 3 in WO2003/024430, which is identical to Example 3 in WO2004/084868, mentions that therapeutic effect was achieved up to 5 hours after administration of a single dosage, but no information of efficacy over a longer period is revealed. Summary of invention There is thus a need for controlled release formulations, which are suitable for continuous administration once daily, and which remain effective throughout the treatment regimen. In particular, in relation to analgesics, it is important that the treatment remains efficient for the entire period between two administrations, i.e. for 24 hours for each administration. The present invention provides such pharmaceutical compositions. Accordingly, it is one objective of the present invention to provide pharmaceutical compositions comprising a) a matrix composition comprising i) an active drug substance which is an analgesic; and ii) at least one polyglycol said matrix composition having a cylindrical shape optionally with tapered end(s), said matrix being surrounded by b) a coating having at least one opening exposing one surface of said matrix, said coating being substantially impermeable to an aqueous medium; for continuous treatment of pain in an individual in need thereof, wherein the medicament is prepared for continuous administration once daily and wherein steady state C24 in respect of the active drug substance is at least 20%, preferably at least 25%, more preferably at least 30%, for example in the range of 30 to 90%, such as in the range of 30 to 80%, for example in the range of 30 to 70%, such as in the range of 30 to 60% of steady state Cmax in respect of the active drug substance. By