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Active Plug (B) Shell (C) Active Plug US 2010O239667A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2010/0239667 A1 Hemmingsen et al. (43) Pub. Date: Sep. 23, 2010 (54) CONTROLLED RELEASE Publication Classification PHARMACEUTICAL COMPOSITIONS FOR (51) Int. Cl. PROLONGED EFFECT A69/46 (2006.01) A6IR 9/16 (2006.01) (75) Inventors: Pernille Hoyrup Hemmingsen, A6IPI/00 (2006.01) Bagsvaerd (DK); Anders Vagno A6IP 29/00 (2006.01) Pedersen, Virum (DK); Daniel A6IP35/00 (2006.01) Bar-Shalom, Kokkedal (DK) (52) U.S. Cl. .......................... 424/466; 424/495;977/775 Correspondence Address: (57) ABSTRACT STOEL RIVES LLP - SLC Layered pharmaceutical composition Suitable for oral use in 201 SOUTH MAIN STREET, SUITE 1100, ONE the treatment of diseases where absorption takes place over a UTAH CENTER large part of the gastrointestinal tract. The composition com SALT LAKE CITY, UT 84111 (US) prising A) a solid inner layer comprising i) an active Sub stance, and ii) one or more disintegrants/exploding agents, (73) Assignee: EGALET A/S, Vaerlose (DK) one of more effervescent agents or a mixture thereof. the solid inner layer being sandwiched between two outer layers B1) (21) Appl. No.: 12/602.953 and B2), each outer layer comprisingiii) a Substantially water soluble and/or crystalline polymer or a mixture of substan (22) PCT Fled: Jun. 4, 2008 tially water soluble and/or crystalline polymers, the polymer being a polyglycol in the form of one of a) a homopolymer (86) PCT NO.: PCT/EP2008/056910 having a MW of at least about 100,000 daltons, and b) a copolymer having a MW of at least about 2,000 daltons, or a S371 (c)(1), mixture thereof, and iv) an active substance, which is the (2), (4) Date: Jun. 7, 2010 same as in said solid inner layer A), and layer Abeing differ ent from layer B, the layered composition being coated with Related U.S. Application Data a coating C) that has at least one opening exposing at least one surface of said outer layer, the coating being substantially (60) Provisional application No. 60/941,848, filed on Jun. insoluble in and impermeable to fluids and comprising a 4, 2007. polymer, and the composition having a cylindrical form optionally with one or more tapered ends, wherein the ratio (30) Foreign Application Priority Data between the surface area of one end surface of the cylinder and the length of the cylinder is in a range of from 0.02 to 45 Jun. 4, 2007 (DK) ........................... PA 2007 OO816 . Active plug (B) Active plug (A) Shell (C) Patent Application Publication Sep. 23, 2010 Sheet 1 of 24 US 2010/0239667 A1 Second burst matrix (A) First burst matrix Delay plug (B) Shell (C) Fig. 1 Patent Application Publication Sep. 23, 2010 Sheet 2 of 24 US 2010/0239667 A1 Active plug (B) Active plug (A) Shell (C) Fig. 2 Patent Application Publication Sep. 23, 2010 Sheet 3 of 24 US 2010/0239667 A1 & S S. 100 – S 80 N a-Ša Burst-Hydrocodone as a Controlled - Morphine (vst 60 9 SS S 40 - S sšS Ss S SS 20 ss Ss S O 2 4. 8 10 12 Time (h) Fig. 3 Patent Application Publication Sep. 23, 2010 Sheet 4 of 24 US 2010/0239667 A1 100 - sSSSSSSSSSS & S S r 8 O s s -- Morphine s x Sr. OxyCodone 6 O 4. O - 2 O - Time (h) Fig. 4 Patent Application Publication Sep. 23, 2010 Sheet 5 of 24 US 2010/0239667 A1 A delay.plug B (C) Center plug Shell (A) end plug (AVB) Fig. 5 Patent Application Publication Sep. 23, 2010 Sheet 6 of 24 US 2010/0239667 A1 1OO - 8O 60 D s 40 -0-buffer 7.2 2O -H buffer 6.8 -o-0.1 NHC O r r O 5O 1OO 15O 2OO 250 3OO Time (min) Fig. 6 Patent Application Publication Sep. 23, 2010 Sheet 7 of 24 US 2010/0239667 A1 Shell (C) End Plug(B) Center plug (A) Fig. 7 Patent Application Publication Sep. 23, 2010 Sheet 8 of 24 US 2010/0239667 A1 100,0 80,0 60,0 i * s - s g - 20,0 - 3 4 5 6 7 Time (h) Fig. 8 Patent Application Publication Sep. 23, 2010 Sheet 9 of 24 US 2010/0239667 A1 1 OO - 8 O 6 O 4 O 2 O Time (h) Fig. 9 Patent Application Publication Sep. 23, 2010 Sheet 10 of 24 US 2010/0239667 A1 Shell (C) End plug(B) Pellets (A) Filler (A) Fig. 10 Patent Application Publication Sep. 23, 2010 Sheet 11 of 24 US 2010/0239667 A1 100 8 O ... Phosphate-buffer && 40%. EtOH 6 O 4 O 10 15 20 Time (h) Fig.11 Patent Application Publication Sep. 23, 2010 Sheet 12 of 24 US 2010/0239667 A1 100 - ser-Kršur-se&s&srêSsssssssssssss 80 - & ... &..., 40% EtOH as a Phosphate-buffer 60 0,5 15 2 Time (h) Fig. 12 Patent Application Publication Sep. 23, 2010 Sheet 13 of 24 US 2010/0239667 A1 120 - 100 saw's 80 6 O Fig. 13 Patent Application Publication Sep. 23, 2010 Sheet 14 of 24 US 2010/0239667 A1 120 ; 1OO -: &S saaSax\wax$\\\\\\\\SYSYS & 80 s 9. & 3 60 : $s' S. SS S 40 S S S8 S S s : & O Fig. 14 Patent Application Publication Sep. 23, 2010 Sheet 15 of 24 US 2010/0239667 A1 Burst-lag-burst s Burst: 1 - 100% in less than 1 h u? Lag: less than 10% (5%) in a $ duration of 1 to 10h Burst: 1 - 100% in less than 1 h Fig. 15 Patent Application Publication Sep. 23, 2010 Sheet 16 of 24 US 2010/0239667 A1 acces Burst-controlled-burst $ Burst: 1 - 100% in less than 1 h econtrolled: 0.1%/h-30%/h (50 %/h) in a duration of 1 to 10h Burst: 1 - 100% in less than 1 h Fig. 16 Patent Application Publication Sep. 23, 2010 Sheet 17 of 24 US 2010/0239667 A1 Burst-controlled Burst: 1 - 99% in leSS than 1 h controlled: 0.1%/h - 30%/h (50 %/h) in a duration of 1 to 10h Fig. 17 Patent Application Publication Sep. 23, 2010 Sheet 18 of 24 US 2010/0239667 A1 Controlled-burst Controlled: 0.1%/h - 30%/h (50%/h) in a duration of 1 to 10 h Burst: 1 - 100% in less than 1 h Fig. 18 Patent Application Publication Sep. 23, 2010 Sheet 19 of 24 US 2010/0239667 A1 c Lag-burst s Lag: less than 10% (5%) in a duration of 1 to 10h Burst: 1 - 100% in leSS than 1 h Lag-burst-lag-burst etc Fig. 19 Patent Application Publication Sep. 23, 2010 Sheet 20 of 24 US 2010/0239667 A1 OControlled-controlled : Controlled: 0.1%/h - 30%/h (50%/h) in a duration of 1 to 10 SS h X OControlled: 0.1%/h - 30%/h 4- (50%/h) in a duration of 1 to 10 Time h Fig. 20 Patent Application Publication Sep. 23, 2010 Sheet 21 of 24 US 2010/0239667 A1 S.k Acco Controlled-controlled : OControlled: 0.1%/h - 30%/h (50%/h) in a duration of 1 to 10 SS h - Controlled: 0.1%/h - 30%/h 1 (50%/h) in a duration of 1 to 10 Time h Fig. 21 Patent Application Publication Sep. 23, 2010 Sheet 22 of 24 US 2010/0239667 A1 1 ACtive A 1 - 100% in less than 12h 2 Active B 1 - 100% in less than 12h Fig. 22 Patent Application Publication Sep. 23, 2010 Sheet 23 of 24 US 2010/0239667 A1 s 1 Active A 1/ A 1 - 100% in less than 12h 2 Active B •O.1%/h - 30%/h (50%/h) in a duration of 1 to 12h 1 - 100% in less than 12h Fig. 23 Patent Application Publication Sep. 23, 2010 Sheet 24 of 24 US 2010/0239667 A1 1 Active A 1 - 100% in less than 12h 2 Active B 2 less than 10% (5%) in a duration of 1 to 12 h 1 - 100% in less than 12h Fig. 24 US 2010/0239667 A1 Sep. 23, 2010 CONTROLLED RELEASE pharmaceutical compositions useful for the above-mentioned PHARMACEUTICAL COMPOSITIONS FOR therapies (including chronotherapy) in a relatively simple PROLONGED EFFECT manner, preferably in a procedure involving relatively few steps and relatively simple equipment, and in an economical feasible manner. Moreover, it is desired to obtain a technol 0001. The present invention relates to a technology that is especially Suitable for designing oral pharmaceutical compo ogy that is Suitable for use for many different drug Substances, sitions that are useful in the treatment of diseases where i.e. a technology that is relatively flexible with respect to how absorption e.g. takes place over a large part of the gastrointes to obtain a desired release pattern of the active substance. tinal tract (e.g. in stomach, the Small intestine as well as in the Thus, a relatively simple technology is desired that enables colon). Accordingly, the present invention provides a compo combination of e.g. delayed release followed by controlled sition that enables a first release of the active Substance (e.g. (extended) release, delayed release followed by immediate a burst or a controlled release) followed by a second release of release, burst release followed by delayed release followed by the same active Substance (e.g. a burstora controlled release). either controlled or immediate release, burst release followed The design of the composition takes into account the fact that by controlled release, controlled release followed by con different conditions are present in different parts of the gas trolled release or immediate release.
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