US008821928B2

(12) United States Patent (10) Patent No.: US 8,821,928 B2 Hemmingsen et al. (45) Date of Patent: Sep. 2, 2014

(54) CONTROLLED RELEASE 5,869,097 A 2/1999 Wong et al. PHARMACEUTICAL COMPOSITIONS FOR 6,103,261 A 8, 2000 Chasin et al. 2003.01.18641 A1 6/2003 Maloney et al. PROLONGED EFFECT 2003/O133976 A1* 7/2003 Pather et al...... 424/466 2004/O151772 A1 8/2004 Andersen et al. (75) Inventors: Pernille Hoyrup Hemmingsen, 2005.0053655 A1 3/2005 Yang et al. Bagsvaerd (DK); Anders Vagno 2005/O158382 A1* 7/2005 Cruz et al...... 424/468 2006, O1939 12 A1 8, 2006 KetSela et al. Pedersen, Virum (DK); Daniel 2007/OOO3617 A1 1/2007 Fischer et al. Bar-Shalom, Kokkedal (DK) 2007,0004797 A1 1/2007 Weyers et al. (73) Assignee: Egalet Ltd., London (GB) 2007. O190142 A1 8, 2007 Breitenbach et al. (Continued) (*) Notice: Subject to any disclaimer, the term of this patent is extended or adjusted under 35 FOREIGN PATENT DOCUMENTS U.S.C. 154(b) by 1052 days. DE 202006O14131 1, 2007 EP O435,726 8, 1991 (21) Appl. No.: 12/602.953 (Continued) (22) PCT Filed: Jun. 4, 2008 OTHER PUBLICATIONS (86). PCT No.: PCT/EP2008/056910 Krogel etal (Pharmaceutical Research, vol. 15, 1998, pp. 474-481).* Notification of Transmittal of the International Search Report and the S371 (c)(1), Written Opinion of the International Searching Authority issued Jul. (2), (4) Date: Jun. 7, 2010 8, 2008 in International Application No. PCT/DK2008/000016. International Preliminary Reporton Patentability issued Jul. 16, 2009 (87) PCT Pub. No.: WO2008/148798 in corresponding International Application No. PCT/DK2008/ PCT Pub. Date: Dec. 11, 2008 000016, now WO 2008/086804. Notification of Transmittal of the International Search Report and the (65) Prior Publication Data Written Opinion of the International Searching Authority issued Apr. US 2010/O239667 A1 Sep. 23, 2010 21, 2010 in International Application No. PCT/EP2010/000728. (Continued) Related U.S. Application Data (60) Provisional application No. 60/941,848, filed on Jun. Primary Examiner — Brian-Yong Kwon 4, 2007. Assistant Examiner — Mark V Stevens (74) Attorney, Agent, or Firm — Seed IP Law Group PLLC (30) Foreign Application Priority Data (57) ABSTRACT Jun. 4, 2007 (DK) ...... 2007 OO816 Layered pharmaceutical composition Suitable for oral use in (51) Int. Cl. the treatment of diseases where absorption takes place over a A6 IK9/46 (2006.01) large part of the gastrointestinal tract. The composition com A6 IK9/24 (2006.01) prising A) a solid inner layer comprising i) an active Sub A6 IK 9/14 (2006.01) stance, and ii) one or more disintegrants/exploding agents, A 6LX 9/52 (2006.01) one of more effervescent agents or a mixture thereof. the solid A6 IK 9/28 (2006.01) inner layer being sandwiched between two outer layers B1) A6 IK9/20 (2006.01) and B2), each outer layer comprisingiii) a Substantially water (52) U.S. Cl. soluble and/or crystalline polymer or a mixture of substan CPC ...... A61K9/209 (2013.01); A61 K9/2866 tially water soluble and/or crystalline polymers, the polymer (2013.01); A61 K9/2086 (2013.01); A61 K being a polyglycol in the form of one of a) a homopolymer 9/2072 (2013.01) having a MW of at least about 100,000 daltons, and b) a USPC ...... 424/466; 424/472: 424/486; 424/457 copolymer having a MW of at least about 2,000 daltons, or a (58) Field of Classification Search mixture thereof, and iv) an active substance, which is the CPC ...... A61 K9/2086; A61 K9/2072 same as in said solid inner layer A), and layer Abeing differ See application file for complete search history. ent from layer B, the layered composition being coated with a coating C) that has at least one opening exposing at least one (56) References Cited Surface of said outer layer, the coating being Substantially insoluble in and impermeable to fluids and comprising a U.S. PATENT DOCUMENTS polymer, and the composition having a cylindrical form 2,685,553 A 8, 1954 Carroll et al. optionally with one or more tapered ends, wherein the ratio 4,034,758 A 7, 1977 Theeuwes between the surface area of one end surface of the cylinder 4,449,983 A 5, 1984 Cortese et al. 4,898,733. A 2f1990 DePrince et al. and the length of the cylinder is in a range of from 0.02 to 45 5,019,396 A 5/1991 Ayer et al. . 5,213,808 A * 5/1993 Bar-Shalom et al...... 424/473 5,609,885 A 3, 1997 Rivera et al. 27 Claims, 24 Drawing Sheets US 8,821,928 B2 Page 2

(56) References Cited Response to Oct. 26, 2011 Office Action filed Feb. 21, 2012 in co-pending U.S. Appl. No. 12/523,045, now US 2010/0291205. U.S. PATENT DOCUMENTS Office Action issued May 24, 2012 in U.S. Appl. No. 12/523,045. now US 2010/0291205. 2007/0224129 A1 9, 2007 Guimberteau et al. 2007,0264.346 A1 11/2007 Guimberteau et al. First Office Action issued Apr. 11, 2012 in U.S. Appl. No. 2008. O152595 A1 6/2008 Emigh et al. 12,694,197, now US 2010/0203129. 2008. O166407 A1 7/2008 Shalaby et al. Response to First Office Action filed Jul. 11, 2012 in U.S. Appl. No. 2008/0299.199 A1 12/2008 Bar Shalom et al. 12,694,197, now US 2010/0203129. 2008/0311205 A1 12/2008 Habib et al. First Office Action issued Nov. 14, 2011 in U.S. Appl. No. 2009/0022790 A1 1/2009 Flath et al. 12/823,067, now US 2011/0159100. 2009/0202634 A1 8, 2009 Janset al. Response to Nov. 14, 2011 Office Action filed May 14, 2012 in 2010/0203129 A1 8/2010 Andersen et al. co-pending U.S. Appl. No. 12/823,067, now US 2011/0159 100. 2010/0203130 A1 8/2010 Tygesen et al. s 2010/0204259 A1 8/2010 Tygesen et al. Camu & Vanlersberghe, “‘Pharmacology of Systemic Analgesics. 2010, O291205 A1 11/2010 Downie et al. Best Practice and Research Clinical Anesthesiology, 2002; 16(4): 2011 O159100 A1 6/2011 Andersen et al. 475-88. Dahlstrom, et al., “Patient-Controlled Analgesic Therapy, Part IV: FOREIGN PATENT DOCUMENTS Pharmacokinetics and Analgesic Plasma Concentrations of Mor phine.” Clinical Pharmacokinetics, 1982; 7:266-79. EP O493513 7, 1992 Fischer, et al., “Nonmedical Use of Prescription Opioids: Furthering EP O406315 11, 1992 a Meaningful Research Agenda.” J. Pain. 9:6, 2008 490-493. EP 1213014 6, 2002 Graves et al., “Relationship Between Plasma Morphine Concentra WO WO 89,09066 10, 1989 WO WO91,040 15 4f1991 tions and pharmacologic Effects in Postoperative Patients. Using WO WO95/22962 8, 1995 Patient-Controlled Analgesia.” Clinical Pharmacology, 1985; 4:41-7. WO WO99,51208 10, 1999 Haahr, et al. (Poster—Drug Abuse Resistant, Controlled Release WO WOOOf 41704 T 2000 using Egalet Dosage Units. Proceedings of the 34th Annual Meeting WO WO 03/024426 3, 2003 Exposition of the Controlled Release Society Jul. 7-11, 2007). WO WOO3,O24429 3, 2003 Hemmingsen, et al., “Drug Abuse Resistant, Controlled Release, WO WOO3,O24430 3, 2003 Using Egalet Dosage Units' poster. Published Jun. 28, 2007. WO WOO3,O266.13 4/2003 Katikaneni, et al. Ethylcellulose Matrix controlled Release Tablets of WO WOO3,O75897 9, 2003 a Water-Soluable Drug. International Journal of Pharmaceutics 123 WO WOO3,082204 10, 2003 pp. 119-125 1995. WO WO 2004/041252 5, 2004 L. Qui, et al., “Design Core-Shelled Polymer Cylinder for Potential WO WO 2004/084869 10, 2004 WO WO 2004/093819 11, 2004 Programmable Drug Delivery.” Int. J. Pharm., 2001; 2 19:151-160. WO WO 2004/093843 11, 2004 Meyer, et al., “Awareness Topic: Mitigating the Risks of Ethanol WO WO 2005/O16313 2, 2005 Induced Dose Dumping from Oral Sustained/Controlled Release WO WO 2005,107713 11, 2005 Dosage Forms.” FDA's ACPS Meeting, Oct. 2005. WO WO 2006/026504 3, 2006 National Institute on Drug Abuse, Monitoring the Future, “National WO WO 2006O265.04 A2 * 3, 2006 Results on Adolescent Drug Use Overview of Key Findings 2009.” WO WO 2006/058249 6, 2006 http://www.monitoringthefuture.org/ (Originally Published in May WO WO 2006/106344 10, 2006 2010). WO WO 2006/128471 12/2006 National Institute on Drug Abuse, Monitoring the Future, “National WO WO 2007 131357 11, 2007 Results on Adolescent Drug Use Overview of Key Findings 2008.” WO WO 2008/O23261 2, 2008 http://www.samhsa.gov/ (Originally Published in May 2009). WO WO 2008/086804 T 2008 WO WO 2008. 148798 12/2008 National Institute on Drug Abuse, 2008 http://www.nida.nih.gov/ WO WO 2010/032128 3, 2010 dmgpages/prescription.html (Last Accessed on Jul. 15, 2008). WO WO 2010/088911 8, 2010 Raehhal & Bohn, "Mu Opioid Receptor Regulation and Opiate WO WO 2010/089132 8, 2010 Responsiveness.” The AAPS Journal 2005; 7(3): Article 60. (www.rxlist.com/miralax-drug.htm) as referenced Oct. 19, 2011. OTHER PUBLICATIONS Notification of Transmittal of the International Search Report and the Written Opinion of the International Searching Authority issued Jan. International Preliminary Reporton Patentability issued Aug. 6, 2011 28, 2009 in International Application No. PCT/US2008/056910. in corresponding International Application No. PCT/EP2010/ Supplemental Amendment filed Jul. 17, 2013 in U.S. Appl. No. 000728, now WO 2010/089132. 12/523,045, now US 2010/0291205. Notification of Transmittal of the International Search Report and the Notice of Allowance issued Jun. 11, 2013 in U.S. Appl. No. Written Opinion of the International Searching Authority issued May 12/823,067, now US 2011/0159100. 28, 2010 in International Application No. PCT/DK2010/000019. Roberts, et al. “Enterohepatic Circulation: Physiological, International Preliminary Reporton Patentability issued Aug. 6, 2011 Pharmacokinetic and Clinical Implications.” Clin. Pharmacokinet. in corresponding International Application No. PCT/DK2010/ 41(10), 751-790 (2002). 000019, now WO 2010/088911. Notice of Allowance issued Jul. 24, 2013, in U.S. Appl. No. Notification of Transmittal of the International Search Report and the 12/701,429. Written Opinion of the International Searching Authority issued Feb. Amendment after Notice of Allowance filed Aug. 26, 2013, in U.S. 6, 2010 in International Application No. PCT/DK2010/050016. Appl. No. 12/701,429. International Type Search Report issued Jun. 17, 2009 in Interna Office Action issued Dec. 17, 2012 in co-pending U.S. Appl. No. tional Application No. DK 200900 1925. 12/701,429, now US 2010/0203130. First Office Action issued Feb. 24, 2012 in co-pending U.S. Appl. No. Response to First Office Action filed Mar. 13, 2013 in in co-pending 12/701,248. U.S. Appl. No. 12/701,429, now US 2010/0203130. Response to first Office Action filed Jun. 21, 2012 in co-pending U.S. Second Office Action issued Jul. 20, 2012 in co-pending U.S. Appl. Appl. No. 12/701.248. No. 12/701.248. Preliminary Amendment filed Jul. 13, 2009 unco-pending U.S. Appl. Response to Jul. 20, 2012 Office Action filed Oct. 22, 2012 in co No. 12/523,045. pending U.S. Appl. No. 12/701.248. Office Action issued Oct. 26, 2011 in U.S. Appl. No. 12/523,045, now Interview Summary issued Dec. 12, 2012 in co-pending U.S. Appl. US 2010/0291205. No. 12/701.248. US 8,821,928 B2 Page 3

(56) References Cited Final Office Action issued Sep. 10, 2012 in U.S. Appl. No. 12/823,067, now US 2011/0159100. OTHER PUBLICATIONS Interview Summary issued Dec. 20, 2012 in U.S. Appl. No. Response to May 24, 2012 Office Action filed Aug. 7, 2012 in U.S. 12/823,067, now US 2011/0159100. Appl. No. 12/523,045, now US 2010/0291205. Response to Sep. 10, 2012 Final Office Action filed Jan. 10, 2013 in Interview Summary issued Dec. 14, 2012 in U.S. Appl. No. U.S. Appl. No. 12/823,067, now US 2011/0159100. 12/523,045, now US 2010/0291205. Brannan, et al. (Geometry 2nd Edition. Cambridge University Press: Final Office Action issued Sep. 14, 2012 in co-pending U.S. Appl. NY; 2012 p. 78). No. 12/694,197, now US 2010/0203129. Response to Final Office Action filed Mar. 13, 2013 in co-pending U.S. Appl. No. 12/694,197, now US 2010/0203129. * cited by examiner U.S. Patent Sep. 2, 2014 Sheet 1 of 24 US 8,821,928 B2

Second burst matrix (A) First burst matrix

Delay plug (B) Shell (C)

Fig. 1 U.S. Patent Sep. 2, 2014 Sheet 2 of 24 US 8,821,928 B2

Active plug (B)

Active plug (A)

Shell (C)

Fig. 2 U.S. Patent Sep. 2, 2014 Sheet 3 of 24 US 8,821,928 B2

120 sys.sysyassassississassssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssss

Š SSS SS S.

100 – & Šs

s 80 - a-Ša Burst-Hydrocodone s as a Controlled - Morphine CD 60 s S s 9 40 d s is 20 sŠ s i. Sss. SS s O Šccrecycrococci 10 12 18 20 Time (h)

Fig. 3 U.S. Patent Sep. 2, 2014 Sheet 4 of 24 US 8,821,928 B2

1 OO SSSSSSSSSSS S & S& S S

S r 8 O s s -- Morphine s x Sr. OxyCodone

6 O

4. O -

2 O -

Time (h)

Fig. 4 U.S. Patent Sep. 2, 2014 Sheet 5 of 24 US 8,821,928 B2

A delay.plug B (C) center plug Shell (A)

end plug (AVB)

Fig. 5 U.S. Patent Sep. 2, 2014 Sheet 6 of 24 US 8,821,928 B2

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 U.S. Patent Sep. 2, 2014 Sheet 7 of 24 US 8,821,928 B2

Shell (C)

End Plug(B)

Center plug (A)

Fig. 7 U.S. Patent Sep. 2, 2014 Sheet 8 of 24 US 8,821,928 B2

100,0 8-8-8-8-8-8 8-8-8-8-0-0-0--0 (s-s-s-s

80,0 s i a 60,0 i t s s C s SS 400 - g 8 * s 20,0 gs 8 9. s s 0,0 (s O 2 3 4 5 6 8 9 10 Time (h)

Fig. 8 U.S. Patent Sep. 2, 2014 Sheet 9 of 24 US 8,821,928 B2

1 OO -

80 - -* C c i s 6O is c d s SS 40 –

Fig. 9 U.S. Patent Sep. 2, 2014 Sheet 10 of 24 US 8,821,928 B2

Shell (C)

End plug(B)

Pellets (A) Filler (A)

Fig. 10 U.S. Patent Sep. 2, 2014 Sheet 11 of 24 US 8,821,928 B2

100

80 ... Phosphate-buffer N- && 40%. EtOH 60 CD 9. & 40

20

10 15 20 Time (h)

Fig.11 U.S. Patent Sep. 2, 2014 Sheet 12 of 24 US 8,821,928 B2

1 OO serkers-s-sexes-Kersex sexes

80 - r ... &..., 40% EtOH as a Phosphate-buffer 60

O 0,5 1 15 2 Time (h)

Fig. 12 U.S. Patent Sep. 2, 2014 Sheet 13 of 24 US 8,821,928 B2

120 - 100 saw's 80

6 O

Fig. 13

U.S. Patent Sep. 2, 2014 Sheet 15 of 24 US 8,821,928 B2

s Burst-lag-burst f Burst: 1 - 100% in less than 1 h is ?u Lag: less than 10% (5%) in a duration of 1 to 10h Burst: 1 - 100% in less than 1 h

Fig. 15 U.S. Patent Sep. 2, 2014 Sheet 16 of 24 US 8,821,928 B2

Aue 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 U.S. Patent Sep. 2, 2014 Sheet 17 of 24 US 8,821,928 B2

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 U.S. Patent Sep. 2, 2014 Sheet 18 of 24 US 8,821,928 B2

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 U.S. Patent Sep. 2, 2014 Sheet 19 of 24 US 8,821,928 B2

pus 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 U.S. Patent Sep. 2, 2014 Sheet 20 of 24 US 8,821,928 B2

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 U.S. Patent Sep. 2, 2014 Sheet 21 of 24 US 8,821,928 B2

S.k Acco Controlled-controlled OControlled: 0.1%/h - 30%/h (50%/h) in a duration of 1 to 10 h Controlled: 0.1%/h - 30%/h (50%/h) in a duration of 1 to 10 Time h

Fig. 21 U.S. Patent Sep. 2, 2014 Sheet 22 of 24 US 8,821,928 B2

1 ACtive A 1 - 100% in less than 12h 2 Active B 1 - 100% in less than 12h

Fig. 22 U.S. Patent Sep. 2, 2014 Sheet 23 of 24 US 8,821,928 B2

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 U.S. Patent Sep. 2, 2014 Sheet 24 of 24 US 8,821,928 B2

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 8,821,928 B2 1. 2 CONTROLLED RELEASE preferably in a procedure involving relatively few steps and PHARMACEUTICAL COMPOSITIONS FOR relatively simple equipment, and in an economical feasible PROLONGED EFFECT manner. Moreover, it is desired to obtain a technology that is Suitable for use for many different drug Substances, i.e. a The present invention relates to a technology that is espe technology that is relatively flexible with respect to how to cially suitable for designing oral pharmaceutical composi obtain a desired release pattern of the active substance. Thus, tions that are useful in the treatment of diseases whereabsorp a relatively simple technology is desired that enables combi tion e.g. takes place over a large part of the gastrointestinal nation of e.g. delayed release followed by controlled (ex tract (e.g. in stomach, the Small intestine as well as in the tended) release, delayed release followed by immediate colon). Accordingly, the present invention provides a compo 10 release, burst release followed by delayed release followed by sition that enables a first release of the active Substance (e.g. either controlled or immediate release, burst release followed a burst or a controlled release) followed by a second release of by controlled release, controlled release followed by con the same active Substance (e.g. a burstora controlled release). The design of the composition takes into account the fact that trolled release or immediate release. A further advantage different conditions are present in different parts of the gas 15 could be a technology that enables variation in the design in a trointestinal system. Thus, e.g. in the colon, the Surface area relatively easy manner Such that the composition also of the mucosal Surface through which the active Substance includes e.g. a burst dose or controlled release dose (of dif must be absorbed is much smaller than in the small intestine ferent active Substance). and, moreover, the amount of body liquid present is also much The present invention provides such a technology. The Smaller. The compositions of the present invention may also technology is a further development of the Applicant’s pro be suitable in the treatment of diseases in which circadian prietary technology described in WO 99/51208, WO rhythm or biorhythm effects can influence the condition being 03/24426, WO 03/24429, WO 03/24430, WO 2004/41252, treated or when an effective therapy is desired e.g. in the early WO 2004/84869, WO 2005/107713, WO2006/128471 that is morning before awakening or when the active Substance have based on matrix compositions comprising a substantially a narrow absorption window or the absorption is poor e.g. in 25 water soluble and/or crystalline polymer. Moreover it is a the colon or for local effect/treatment. Some physiologically further development of the technology described in WO active Substances are periodically produced in vivo at certain 2006/128471 that relates to a composition having an inner time intervals and it may accordingly be desirable to admin part of a composition that liquefies at body temperature sand ister Such substances in a controlled release formulation wiched between two matrix compositions. In this manner a which periodically releases the active substance at predeter 30 delay is obtained with respect to release of the active sub mined time intervals to obtain certain fluctuation in the drug stance contained in the inner part and once, the matrix com level which may be desirable in connection with the treatment positions are eroded away, the liquefied inner part is designed of various diseases. The present technology provides a means to flow out of the shell that surrounds the cylindrical part of a for designing Such compositions and moreover, Such compo cylindrical shaped composition (i.e. the shell (or coating) sitions may be combined with an initiated burst release and/or 35 covers the cylindrical surface, but not the end surfaces). In Zero order controlled release of the active substance. this manner the active substance in the inner part should be immediately released once the matrix parts are eroded. How BACKGROUND OF THE INVENTION ever, in some situations the present inventors have observed that the outflow of the liquefied inner part is not that easy, e.g. In the past decades many controlled release technologies 40 in situations where the composition reaches the large intes have appeared. However, for drug Substances that can be tine or the colon. In these situations, a limited amount of water absorbed through many segments of the gastrointestinal (GI) is present and, accordingly, the flow is limited and moreover, tract, there is still a need for developing compositions that in the colon lumps of feces may block the open ends of the enable sufficient absorption of the drug substance over shell leading to limited release of the active substance. broader range of segment of the gastrointestinal (GI) tract in 45 Accordingly, the present inventors have developed composi order to enable a less frequent dosage of the drug and/or in tions that substantially overcome the above-mentioned prob order to avoid excretion of unabsorbed drug via the faces. lems. Pharmacodynamics and pharmacokinetics challenges The present invention provides an extended release com might enforce the need for special release patters (such as position for prolonged effect and a way to ensure prolonged paracetamol in which the first pass metabolism makes it dif 50 effect e.g. once daily administration is to ensure optimal ficult to make a constant release unit work). Furthermore, the absorption of the active Substance though the gastrointestinal passage of material through the gastrointestinal tract is care tract i.e. from the stomach to rectum. fully controlled by several mechanisms. This “house-keep When absorption of the active substance is limited or do ing” (intestinal peristalsis) might lead to anomalies in the not proceed substantially good in the distal part of the Small effect of solid oral dosage forms which might be compensated 55 intestine and/or in colon a relatively fast release of the active by the formulation. Substance is an advantage when the controlled release com Furthermore, the active substance may exert its effect position enter this part of the tract and especially in those locally in the colon or other parts of the gastrointestinal sys cases where the active substance is poorly absorbed in the tem, such as for treatment of cancer, inflammation, gas distal part of the Small intestine or in ascending and first part trointestinal diseases and treatment with anthelmintic agents. 60 of the transverse colon. A release composition having con trolled release follow by immediate release behavior is desir DETAILED DESCRIPTION OF THE INVENTION able for optimal absorption and effect. A composition having controlled release follow by imme However, to the best of our knowledge there is still a need diate release of the active Substance is also an advantage when to develop a technology that enables preparation of pharma 65 the active substance is poorly soluble and therefore requires a ceutical compositions useful for the above-mentioned thera substantial amount of water/fluid to dissolve in the distal part pies (including chronotherapy) in a relatively simple manner, of the small intestine before it enters colon for absorption. US 8,821,928 B2 3 4 If absorption of the active substance is unchanged through vii) it is possible to use a formulation technique that poten the gastrointestinal tract a better absorption of the active tially may improve the bioavailability of at least one of the substance in the colon can be achieved if a relatively fast active substances and, preferably, of both of the active sub release of controlled release multiple units is released from stance (due to the fact that both active Substances generally the controlled release composition in the distal part of the have a low bioavailability). small intestine to prevent limited absorption of the active In one aspect, the present invention relates to a layered substance due to block of the open ends of the shell in the pharmaceutical composition comprising colon lumps of feces. A composition having controlled A) a solid inner layer comprising release follow by controlled release behavior in the shape of i) an active substance, and controlled release multiple units is desirable. 10 ii) one or more disintegrants/exploding agents, one of more The opposite is the case (i.e. a composition having burst effervescent agents or a mixture thereof. release follow by delay and/or controlled release behavior) if the solid inner layer being sandwiched between two outer there is absorption problem in the first part of the gastrointes layers B1) and B2), each outer layer comprising tinal tract e.g. the stomach. It is also the case if fast effect iii) a substantially water soluble and/or crystalline polymer follow by maintenance of the effect is desirable. 15 or a mixture of substantially water soluble and/or crystalline Controlling the release of the active substance from the polymers, the polymer being a polyglycol in the form of one composition and thereby the absorption of the active sub ofa) a homopolymer having a MW of at least about 100,000 stance, makes it possible to control the blood level of the daltons, and b) a copolymer having a MW of at least about active Substance and maintain the concentration within the 2,000 daltons, or a mixture thereof, and therapeutic range over an extended period of time without iv) an active Substance, which is the same as in said solid high peak trough fluctuation which improve the therapeutic inner layer A), and layer Abeing different from layer B. effect and reduced incidence of side effects. the layered composition being coated with a coating C) that It is an object of centian embodiments of the present inven has at least one opening exposing at least one Surface of said tion to provide bioavailable formulations suitable for once outer layer, the coating being Substantially insoluble in and daily administration which substantially improve efficiency 25 impermeable to fluids and comprising a polymer, and the and quality of the treatment. composition having a cylindrical form optionally with one or It is an object of centian embodiments of the present inven more tapered ends, wherein the ratio between the surface area tion to provide oral controlled release composition suitable of one end surface of the cylinder and the length of the for once daily administration which provide an early onset of cylinder is in a range of from 0.02 to 45 mm. therapeutic effect and which, after rising to a maximum con 30 In a specific embodiment of the present invention, layer A) centration during the dosage interval, provide a relatively flat comprises plasma profile, meaning that the plasma level of the active v) a substantially water soluble and/or crystalline polymer substance provides a peak trough ratio of about 0.5 to about or a mixture of substantially water soluble and/or crystalline 1.0, and which provides effective treatment. polymers, the polymer being a polyglycol in the from of one Another advantage relating to the present invention is the 35 of c) a homopolymer having a MW of at the most about possibility of administering the two active Substances at the 16,000 daltons, and d) a copolymer having a MW of at the same time and advantageous in the same pharmaceutical most about 30,000 daltons. composition. However, as such a combination treatment is As mentioned above, the present invention is a further expected to have optimized effect with respect to each of the development of the Applicant’s proprietary technology, two Substances at different points in time it is important to 40 namely preparation of pharmaceutical compositions based on incorporate the two active Substances in the composition in a water soluble and/or crystalline polymer or mixture of such Such a manner that polymers involving a step of melting or softening the polymer i) it is possible to incorporate a suitable amount of each by means of injection moulding, extrusion or the like. The active Substance (notably an amount corresponding to a daily injection moulding technique has the advantage of simulta dose and should be present in a specific weight ratio that is 45 neous mixing and heating the components during increased optimized with respect to therapeutic effect), pressure in a one step procedure without exposure to air and ii) it is possible to avoid any negative interaction of the two moisture because the injection moulding is performed in a active Substances in the composition, single closed compartment from the time a blend of the com iii) it is possible to avoid an excessive degree of oxidation ponents has entered the machine to the final pharmaceutical of the active Substances (however, levels corresponding to 50 units are ejected ready for packaging. More details regarding normally accepted levels are acceptable), iii) it is possible to the preparation method are given below and in the experimen obtain release patterns of both substances that are optimized tal section. with respect to therapeutic effect (see iv)-vi) for more specific As appears from the above, the invention concerns a lay details), ered pharmaceutical composition having an inner layer with iv) it is possible to control the release pattern of the two 55 the active Substance sandwiched between two lag-time pro active Substances from the composition in Such a manner that viding layers, i.e. layers that enable a delay in the release of the release of S1 is independent of the release of S2; this the active substance contained in the inner layer. The layered applies for the release mechanism as well as the release rate composition is coated in Such a manner that only a surface and time for 80-100% w/w release, layer from the outer layer(s) is free of coating material. In a V) it is possible to e.g. obtain a Zero order release for one or 60 preferred embodiment, the composition has a cylindrical both of the active substance, Zero order release for one of the shape and then the cylindrical Surface is coated leaving one or active substances and another order of release for the other two of the end Surfaces without any coating (normally both active substance or the like, end Surfaces are without coating). In order to ensure a suffi vi) it is possible to obtain e.g. a relatively slow release cient release of the active substance contained in layer A) of followed by a faster release of one of the active substance 65 the composition, the present inventor's have found that the without impact on the release of the other active substance, following two properties are important, namely the geometry and/or and dimensions of the composition and the present of a dis US 8,821,928 B2 5 6 integrant and/or an effervescent agent (or couple). The first controlled release followed by controlled release, burst parameter ensures that the distance to travel for the inner layer release followed by burst release). However, as explained is not too big compared with the size of the opening (i.e. the above one of the problems the inventors were faced with was end Surface) and the other one ensures that a driving force how to ensure that the inner layer exits the shell (coating) once activates the mobility of the active substance in layer A) when the outer layers have disappeared. As explained above, two it comes into contact with a body liquid. Moreover, as will be parameters are of importance. Firstly, incorporation of a phar explained below, a further parameter has also a positive influ maceutically acceptable excipient that aids in disintegrating ence in order to enable a release of the active substance from the inner layer seems to be of relevance. Accordingly, the layer A), namely the incorporation of the active Substance in inner layer may also contain one or more disintegration/ readily flowable multiple units. 10 exploding agents, one of more effervescent agents or a mix Geometry ture thereof. The lag-time mechanisms (and the release mechanics of It is important to note that once the inner layer is “released any active Substance contained in the outer layers) described from the shell and brought into direct contact with an aqueous above depends on the geometry of the composition. For medium (e.g. the gastrointestinal fluids after oral administra example erosion based release from a matrix depends on the 15 tion) then various types of release of the active Substance can exposed area of the matrix. In this case the area may be be obtained ranging from immediate release (e.g. the active manipulated by employment of a coat that is not subject to Substance is readily available for release such as e.g. present erosion and thus covering the areas of the matrix that hence in dissolved form in a form that is easily dissolvable) to will not be a releasing site. In particular, a cylindrical com controlled release (e.g. in the form of pellets designed to position with the two ends exposing the eroding matrix will controlled release or other well-known types of formulations give rise to Zero order release because the releasing area is including beads, flakes, mini-tablets, granules, microspheres, COnStant. nanoparticles, crystals or the like). The geometric form of the composition is very important As the shell (coating) has properties that ensure exposure for the obtainment of the above-mentioned controlled release. of a well-defined (normally constant or Substantially con Thus, in one embodiment of the invention, the pharmaceuti 25 stant) Surface area of the composition to the Surrounding cal composition has a geometric shape, which enables a Sub medium so that the outer layer(s) can be eroded with a con stantially constant Surface area to become exposed during stant rate until the layer(s) are eroded away, it is important that erosion of the matrix. As explained above, the present inven the shell remains intact until the outer layer(s) have eroded. tors have found that the proportions between the surface area This normally means that the shell is left when the inner layer of the end surface and the length of the cylinder are important 30 is the only layer left of the composition. Accordingly, the in order to ensure that the active substance (or, if relevant, of difficulty of the problem is to ensure a “release of the inner the multiple unit formulation containing the active substance) layer from the shellor, in other words, a delivery of the inner can be released from the inner part. Specific examples appear layer material from the inside of the shell to the outside. from the examples herein. In general, the following ratio Disintegrants, Swelling Agents, Exploding Agents, Effer between the surface area of one end surface and the length of 35 Vescent Agents the cylinder has been found to be suitable in order to ensure a The inner layer may beformulated such that it disintegrates proper release: from about 0.02 to about 45 mm such as, e.g., upon contact with water. The disintegration may be by a from about 0.1 to about 10 mm or from about 0.5 to about 8 mechanism of exploding, by effervescence, by Swelling, by mm. In most cases, the composition of the invention has two rapid erosion or combinations thereof. The disintegration by end Surfaces, and, if the ratio is calculated on the total Surface 40 exploding may be governed by rapid water influx into- and area of the end surfaces, then the ratio is from about 0.02 to Swelling of one or several of the matrix components leading about 85 mm such as, e.g., from about 0.1 to about 10 mm or to a collapse of the inner layer structure (normally a matrix from about 1.3 to about 14 mm. structure) Such that the active Substance may be released or In a specific example, the compositions employed are Such that e.g. multiple units, crystals etc. containing the active coated in Such a manner that the Surface has a Substantially 45 substance may be released. The multiple units may be constant or controlled surface area during release or erosion. designed as quick release (/burst releasefimmediate release) In the present context controlled Surface area relates to a multiple units or controlled release multiple units for release predetermined surface area typically predicted from the of the active Substance in the Small intestine and/or colon. shape of the coat of the unit dosage system. It may have a The disintegration may be by means of Swelling. The inner simple uniform cylindrical shape or the cylindrical form can 50 layer comprises an excipient (here a disintegrant), which have one or more tapered ends in order to decrease (or Swells rapidly upon contact with aqueous media makes it increase) the initial release period. possible to push the active Substance or active multiple units As another example, in diffusion based systems the release out of the shell. Preferably, the detachment of the active will furthermore depend on the thickness of the diffusion matrix should be in Smaller lumps with a large area-to-Vol layer and in this case the release will depend both on the 55 ume ratio. diffusion area and thickness of the diffusion system. As mentioned above, the “release' of the inner layer (or As yet another example the release mechanism of dissolv delivery of the inner layer material to the outside of the shell) ing/solubilization also depend on the releasing area and the may be aided by incorporation of e.g. a disintegrant also release rate may be controlled by covering parts of the releas called Swelling and/or exploding agent. A disintegrant typi ing matrix by a coat. Controlling the coverage of the matrix by 60 cally swells upon contact with water and enable disruption of the coat hence refers to covering from 0 to 100% of the matrix the inner layer to agglomerates or particle. Examples of Suit by a coat. able disintegrants include Sodium starch glycolate, Povi Inner Layer A) done, Sodium alginate, Alginic acid, Calcium alginate, Car The object of the present invention is to design a compo boxymethylcellulose calcium, Carboxymethylcellulose sition comprising an active Substance that is released after a 65 sodium, Powdered cellulose, Chitosan, Croscarmellose certain period of time (e.g. burst release followed by con Sodium, Crospovidone, Hydroxypropyl Starch, Hydroxypro trolled release, controlled release followed by burst release, pyl cellulose low-substituted, Magnesium aluminium sili US 8,821,928 B2 7 8 cate, Methylcellulose, Microcrystalline cellulose, pregelati “layer A polymer is used to indicate that the polymer is nized starch, Docusae sodium, Guar gum, Polacrilin Suitable for use as a dispersion medium or excipient in layer potassium. A. The disintegration may also be due to an effervescent Suitable polymers for use according to the invention typi effect, whereby gas such as CO is released from the inner 5 cally comprises a polyglycol, e.g. in the form of a homopoly layer upon contact with water and a rapid dissolving system is mer and/or a copolymer. In a specific embodiment the poly formed. The formation of gas bubbles will push the inner meris Substantially water Soluble, thermoplastic, crystalline, layer out in Small lumps and thereby manifold increase the semi-crystalline or amorphous or a mixture of Substantially exposed area of the inner layer (e.g. containing active Sub water soluble, crystalline, semi-crystalline or amorphous stance, active multiple units or the like) to the medium. For 10 polymers. Suitable polymers for use in a composition accord example sodium bicarbonate releases CO by reaction with water in an acidic environment. It is possible to develop a ing to the invention are polyethylene glycols, including more pH-robust formulation by adding an acidic excipient to derivatives such as mono and dimethoxypolyethylene glycols the formulation. The rate of which the gas formation occurs (mPEGs) polyethylene oxides and/or block copolymers of depends on the rate of hydration and diffusion of water into 15 ethylene oxide and propylene oxide. the matrix. Polyethylene glycols (PEGs) are linear polydisperse poly mers composed of repeating units of ethylene glycol. Their NaHCO(s)'s Na'(aq)+HCOs (aq) (1) chemical formula is HOCHICHOCHCH-OH where m represents the average number of repeating units. Alterna tively, the general formula HOCH2CHI.OH may be used to represent polyethylene glycol, where n is a number m in the HCO(aq) pCO(g)+HO(l) (3) previous formula +1. See the structural presentations of poly “Release of the inner layer may also take place by means ethylene glycol below. n is the average number of oxyethyl of gas formation using effervescent Substances or efferves enegroups. n equals m+1. cent couples. Examples of suitable effervescentagent include 25 Effer-Soda, Citric acid, monohydrate, Dextrates, Fumaric acid, Potassium bicarbonate, Sodium bicarbonate, Sodium citrate dehydrate, Tartaric acid. "Sun-N- 11 N-1so Disintegration may also take place by rapid erosion, which can be obtained by employing for example short chained 30 polymers in the matrix, such that the matrix is readily wetted Polyethylene oxides (PEOs) are linear polydisperse non and dissolved exposing either the active multiple units or the ionic polymers composed of repeating units of ethylene matrix component(s) containing the active Substance. oxide. Their chemical formula is HOCHCH-OH where n Furthermore, disintegration might be facilitated by facili represents the average number of oxyethylene groups. See the tating water transport through the matrix by for example open 35 structural presentation of polyethylene oxide below. n is the pores. average number of oxyethylene groups. Depending on prepa In order to ensure suitable properties of the inner layer A, ration method high molecular weigh PEO may have one the inner layer A) without B) and C) disintegrates within at the terminal methyl group. most 60 min Such as, e.g., at the most about 30 minor at the most about 15 min, when subjected to a disintegration test 40 according to Ph. Eur. Normally, the concentration of the one or more disinte I-N-1s grants, exploding agent and/or effervescent agent in the inner layer is from about 5% w/w to about 80% w/w such as, e.g., Polyethylene glycols are mixtures of addition of ethylene from about 10% w/w to about 70% w/w, from about 15% w/w 45 glycol. In general PEG refers to polymers chains with to about 60% w/w or from about 20% w/w to about 50% w/w. molecular weights below 20,000, while PEO refers to higher One or more pharmaceutically acceptable excipients or molecular weights polymers. However, because of the simi additives may also be present in inner layer A) (see the section larities between PEO and PEG, the terms are often used "Pharmaceutically acceptable excipients”) interchangeably for the same compound. The inner layer A) may also contain a polymer. The same 50 Poloxamers are copolymers or block copolymers and area applies to the outer layers B) and in the following is given a range of non-ionic Surfactants of polyethylene glycol (PEG) general description of suitable polymers for the two (three) and polypropylene glycol (PPG). layers A) and B). It is important to note that in those cases In chemical abstracts Diol EO/PO block copolymers are where the active substance in layer A) is present in the form of described under the Scientific name—hydroxy-hydroxypoly multiple units, then the multiple units may be in the form of 55 (oxyethylene)poly(oxypropylene)-poly(oxyethylene)— e.g. pellets, beads or the like, and in Such cases one or more block copolymer in combination with the CAS register num polymer may be employed in the preparation of the multiple ber. units. In Such cases, the polymers mentioned in the following In specific embodiments a suitable poloxamer for use in a are Suitable and Such polymers may appropriately be of the composition of the invention has a HLB value of at least about same nature as the polymers employed in the B) layers. In 60 18 Such as, e.g., at least about 20. The mean molecular weight contrast hereto, the layer A may also contain a polymeric of a suitable poloxamer is typically at least about 2,000. Substance (as a dispersion medium for the active Substance), Mixtures of PEO with different average molecular weights but in this case, it is important that the polymeric Substance can be used in order to obtain a PEO with a desirable average has different properties from that used in layer B). To differ molecular weight. The same applies to PEG. entiate between the individual polymers, the notation “matrix 65 The polymer has a melting point higher than the body polymer is used to indicate that the polymer is suitable for temperature of the human in which the composition is to be use in layer B) and in multiple units, whereas the notation used. Thus, the polymer(s) employed in the matrix composi US 8,821,928 B2 10 tion will suitably have a melting point of about 20-120° C. the polymer is a PEO having a molecular weight of at least such as, e.g. from about 30 to about 100° C. or from about 40 about 100,000 such as, e.g., from about 100,000 to about to about 80° C. 8,000,000, from about 100,000 to about 7,000,000, from In addition to a polymer of a polyglycol type as described about 100,000 to about 5,000,000, from about 100,000 to above other polymers may be suitable for use in a pharma about 4,000,000, from about 100,000 to about 2,000,000, ceutical composition provided that the solubility and/or from about 100,000 to about 1,000,000, form about 100,000 release rate of the active Substance from the composition in to about 900,000. When PEO is employed with a molecular water is higher than or equal to the solubility of the matrix in weight in the lower end, the PEO typically has a molecular 40% w/w ethanol in water. Thus, in other embodiments of the weight as mentioned in the preceding paragraph. Commer invention, the polymer oran additional polymer to the polyg 10 cially available PEOs with a molecular weight in the higher lycol may be selected from one or more of the following end have typically the following molecular weights: about polymers: modified or unmodified water soluble natural poly 900,000, about 1,000,000, about 2,000,000, about 4,000,000, mers such as glucomannan, galactan, glucan, polygalactur about 5,000,000, about 7,000,000, about 8,000,000. It should onic acid, polyxylane, polygalactomannans, rhanogalactur be noted that when PEO with a molecular weight of up to onan, polyxyloglycan, arabinogalactan, and starch, cellulose, 15 about 700,000 is used, it is possible to obtain a matrix com chitosan, alginate, fibrin, collagen, gelatin, hyaluronic acid, position (prepared e.g. by injection molding) that releases the amylopectin, pectin including low methylated or methoxy active Substance contained in the matrix with a Zero order lated pectins, dextran and fatty acids and alcohols; synthetic release (erosion of a constant Surface area). However, the polymers such as polyvinylpyrrolidone (PVP), PVA, PVB, applicant has indications that employment of PEO with a Eudragit L. methyl ester, Eudragit L., Eudragit RL, Eudragit E. molecular weight of 1,000,000 or higher leads to a slower Eudragit S, PHPV. PHA, PCL, PLGA and PLA; and hydro release and a different release pattern. However, Zero order gels made from the polymers or combined polymers men release may not always be required from the layer B), but a tioned above and or from polymers originated from: HEMA, slow release may be important. In such cases, the high HEEMA, MEMA, MEEMA, EDGMA, NVPVAc, AA, acry molecular weight PEOs are suitable for use in a composition lamide, MAA, HPMA, PEGA, PEGMA, PEGDMA, 25 of the invention. PEGDA, and PEGDMA. Typical block copolymers of ethylene oxide and propylene Polymers in Layer A) oxide have a molecular weight of from about 2,000 daltons, In one embodiment of the invention, layer A) comprises V) typically about 3,000 to about 30,000 daltons such as, e.g. a substantially water soluble and/or crystalline polymer or a from about 4,000 to about 15,000 daltons. If the copolymer is mixture of substantially water soluble and/or crystalline poly 30 the sole thermoplastic polymer present in the composition it mers, the polymer being a polyglycol in the from of one of c) must not bee too brittle in order to avoid abuse by crushing of a homopolymer having a MW of at the most about 16,000 the composition, i.e. it must have an HLB value of about 18 to daltons, and d) a copolymer having a MW of at the most about about 24. 30,000 daltons. Concentration of Polymers in Layer A and/or B In specific embodiments, the polymer comprises a 35 The polymer may also be a mixture of the above-men homopolymer having a MW of at least about 1,000 daltons tioned polymers. Normally, the concentration of the Such as, e.g., a homopolymer having a MW in a range from polymer(s) in layer A) when applied is from about 1 to about about 1,000 to about 15,000 daltons, from about 1,000 to 99.9% w/w dependent on the desired release properties relat about 12,000 daltons, from about 1,500 to about 10,000 dal ing to the release of the active Substance from the inner layer. tons, from about 1,500 to about 8,000 daltons. 40 In those cases where a relative fast release of the active The polymer may also comprise a co-polymer having a Substance (or multiple units e.g. a pellet composition or the MW of at the most about 25,000 daltons such as, e.g., at the like containing the active Substance) is desired or there is a most about 20,000 daltons, at the most about 15,000 daltons, relatively high concentration of active Substance in layer A), at the most about 10,000 daltons, at the most about 5,000 a relative low concentration of the polymer may be of interest daltons, at the most about 2,000 daltons. 45 Such as, e.g. from about 1 to about 30% w/w Such as, e.g., Polymers in Layers B) or Used in Multiple Units Contain from about 5 to about 25% w/w, from about 5 to about 20% ing the Active Substance and Incorporated in Layer A) wfw or from about 10 to about 20% w/w. In other cases, the Polyethylene glycols and/or polyethylene oxides, which concentration of the polymer in layer A) may be such as from are Suitable for use in the matrix composition are those having about 10 to about 95% w/w, from about 15% to about 90% a molecular weights of from about 20,000 daltons, such as, 50 w/w, such as from 20 to 85%, such as from 30% to 85% from e.g., from about 20,000 to about 700,000 daltons, from about about 30 to about 99% w/w such as, e.g., from about 35 to 20,000 to about 600,000 daltons, from about 35,000 to about about 95% w/w, from about 35 to about 90% w/w, from about 500,000 daltons, from about 35,000 to about 400,000 daltons, 35 to about 85% w/w, from about 35 to about 80% w/w, from from about 35,000 to about 300,000 daltons, from about about 40 to about 75% w/w, from about 45 to about 70% w/w, 50,000 to about 300,000 daltons, such as, e.g. about 35,000 55 from about 45 to about 65% w/w. from about 55 to about 85% daltons, about 50,000 daltons, about 75,000 daltons, about w/w or from about 60 to about 85% w/w. 100,000 daltons, about 150,000 daltons, about 200,000 dal One or more polymers are typically present in a composi tons, about 250,000 daltons, about 300,000 daltons or about tion of the invention in a concentration amount of from 5 to 400,000 daltons. 99.9% w/w such as from 10 to 95% such as from 15% to 90%, In a specific embodiment the matrix polymer is a polyeth 60 such as from 20 to 85%, such as from 30% to 85% calculated ylene oxide or a polyethylene glycol that has a molecular as w/w % of the composition. weight of about 20,000 daltons, about 35,000 daltons, about In those cases, where mixture of polymers are present in 50,000 daltons, about 100,000 daltons, about 200,000 dal the composition, the concentration of an individual polymer tons, about 300,000 daltons and about 400,000 daltons. PEG in the composition may typically be from about 0% to about is commercially available with average molecular weights up 65 95% w/w such as, e.g., from about 0.5% to about 90% w/w, to 35 000. PEO is commercially available with average from about 1% to about 90% w/w, from about 5% to about molecular weights up to 8,000,000. In specific embodiment, 90% w/w, from about 10% to about 90% w/w, from about US 8,821,928 B2 11 12 10% to about 80% w/w, from about 10% to about 70% w/w, described in the following including multiple units. In such a from about 10% to about 60%, from about 10% to about 50%, formulation, the active substance may be present in Solid or from about 15% to about 50% w/w, from about 15% to about dissolved form as well. The multiple units for use according 45% w/w, from about 15% to about 40% w/w, from about to the invention may be crystals of an active Substance, inert 20% to about 40% w/w, from about 20% to about 35% w/w or 5 cores coated with active Substance—inert cores like e.g. cal from about 20% to about 30% w/w. In specific embodiments, cium alginate beads, cellulose spheres, charged resin spheres, the concentration is even lower such as from about 1% to glass beads, polystyrene spheres, sand silica beads or units, about 15% w/w or from about 5% to about 15% w/w. Sodium hydroxide beads. Sucrose spheres. Cores containing The total concentration of the polymers (notably the sum of active Substance like e.g. beads, pellets, flake, pieces, gran homo- and copolymers of the polyglycol type) in the compo 10 ules, granulates (also denoted agglomerates), spheres, tablets, sition is typically from about 5 to about 99.9% w/w such as especially minitablets etc. from about 10 to about 95% w/w, from about 15% to about The shape of the multiple units may be any suitable shape 90% w/w, such as from 20 to 85%, such as from 30% to 85% including a rounded or oval shape as well as a polygonal or from about 30 to about 99% w/w such as, e.g., from about 35 rod-like or flake-like shape. to about 95% w/w, from about 35 to about 90% w/w, from 15 The mean particle size of the multiple units is at the most about 35 to about 85% w/w, from about 35 to about 80% w/w, about 1400 um. In particular embodiments, the particle size from about 40 to about 75% w/w, from about 45 to about 70% of the multiple units is at the most about 1200 um Such as, e.g., wfw, from about 45 to about 65% w/w. from about 55 to about at the most about 1100 um, at the most about 1000 um, at the 85% w/w or from about 60 to about 85% w/w. In specific most about 900 um, at the most about 800 um, at the most embodiments (e.g. for burst layer (may be layer A) and/or about 750 um, at the most about 700 um, at the most about 650 layer B)), the concentration is even lower such as from about um, at the most about 600 um, at the most about 550 um or at 5% to about 40% w/w or from about 5% to about 35% w/w. the most about 500 um; such as, e.g., from about 150 um to The concentration of the polyglycol homopolymer is typi about 1200 um, from about 200 um to about 1200 um, from cally from about 0.5 to about 99.9% w/w such as from 5 to about 200 um to about 1000 um, from about 250 um to about about 99.9% w/w, from about 0.5% to about 90% w/w, from 25 800 um or from about 300 um to about 750 um. In a specific about 1% to about 90% w/w, from about 5% to about 90% embodiment of the invention the particle size of the multiple wfw, from about 20 to about 90% w/w, from about 30 to about units is at the most about 500 um to about 1000 um, or from 90% w/w, and, in those cases where the homopolymer is the about 350 um to about 500 um. In some cases, the particle size only thermoplastic polymer present in the composition, then of the multiple units may be even higher. Thus, in Some cases the concentration is normally from about 50 to about 95% 30 the particle size may be at the most about 2 mm. w/w such as, e.g. from about 55 to about 90% w/w, from about The release of the active substance may take place by 60 to about 90%, from about 65 to about 90%, from about diffusion by which the rate of release depends on several 70% to about 90% or from about 70 to about 85% w/w. In mechanisms, for example: the concentration difference specific embodiments, the concentration is even lower Such as between the matrix active Substance concentration and the from about 1% to about 15% w/w or from about 5% to about 35 bulk concentration, the release surface area and the diffusion 15% W/w. constant of the drug Substance in the matrix. In special cases The concentration of the polyglycol copolymer, if present diffusion controlled release may be zero order. in combination with a polyglycol homopolymer, is typically Once the inner layer is exposed to the gastrointestinal fluids from about 1 to about 60% w/w such as, e.g. from about 2.5 to (or another aqueous medium) the release of the active Sub about 50% w/w, from about 5 to about 45% w/w. If the 40 stance may take place. In contrast to a release from a matrix copolymer is the sole thermoplastic polymer in the composi that erodes (i.e. a matrix like the one of the outer layer), the tion the concentration may be from about 5 to about 99.5% release of the active substance from the inner layer may w/w such as those ranges described above and described for follow a kinetic that is different from a zero order release. The the homopolymer. In specific embodiments, the concentra present formulation principle is designed to delay the release tion is even lower such as from about 1% to about 15% w/w 45 not necessarily to enable a zero order release or other types of or from about 5% to about 15% w/w. release kinetics that are relevant when designing controlled or In embodiments where the outer layer matrix composition modified release compositions. However, the basic formula comprises a PEO and a poloxamer the weight ratio (PEO/ tion principle of the present invention may be combined with poloxamer) is normally in a range from about 10:0.1 to about known formulation principles e.g. if an active substance also 0.1:10 such as, e.g., from about 10:1 to about 1:10, from about 50 is included in the matrix of the outer layer B), then this active 5:1 to about 1:5 or from about 3:1 to about 1:3. Substance can be released by Zero order kinetics, i.e. in a The one or more, the same or different active substance in controlled manner, and the active Substance contained in the the inner layer may be designed to various types of release first fraction is released once exposed to the gastrointestinal once the inner layer is “released from the shell. fluids (or anotheraqueous medium) or in a controlled manner, In one embodiment of the invention, the inner layer con 55 but once the release of active substance or active multiple tains the active Substance incorporated into a multiple unit units from the first fraction starts it may be relatively fast. formulation or it may be present in the form of relatively large Outer Layers B1) and B2) crystals (i.e. 100 um or more). The outer layers of a composition according to the inven Inner Layer Active Substance in Multiple Units tion are typically based on the matrix principle disclosed in As mentioned above, the active Substance may be present 60 WO99/51208, WO 03/24426, WO 03/24429, WO 03/24430, in many forms in the inner layer. Thus, it may be present in WO 2004/41252, WO 2004/84869, WO 2005/107713, dissolved form, e.g. dissolved in the ingredients of the inner WO2006/128471 (to the same applicant). Such matrices have layer Such as in the form of a solid dispersion or Solid solution. unique properties in that they erode, i.e. it does not disinte It may also be present in Solid form e.g. in the form of particles grate into Smaller particles or conglomerates of particles upon or crystals of the active substance. Moreover, the active sub 65 exposure to the gastrointestinal fluid. Simplified, erosion stance may be incorporated into a formulation before it is means that a layer is eroded from the composition into the incorporation into the inner layer. Such formulations are Surrounding medium almost as if a slice of the matrix is cut US 8,821,928 B2 13 14 off. Only the outer surface is exposed to erosion and from this In the section “Other embodiments of the invention s outer layer the active substance will be released and/or dis examples of various combinations are described. Solved provided that an active Substance is present in the Coating matrix. This means that if it is possible to control the size of As described above, the layered composition is provided the Surface area by maintaining a constant size, it is possible 5 with a coating C) that has at least one opening exposing at to control the size of the release rate and, furthermore, a zero least one Surface of said outer layer (layer B), the coating order release rate can be obtained. being substantially insoluble in and impermeable to fluids The outer layers contain the same active substance as the and comprising a polymer. inner layer A) to ensure optimal absorption of the active A composition according to the invention may be provided Substance though the gastrointestinal tract a way to prolong 10 with a coating that can be applied in Such a manner that it the effect of e.g. a once-daily dosage form. leaves a well-defined surface area free of coating while the As mentioned above, each of the outer layers B1) and B2) remaining Surface is covered and at the same time ensuring comprises iii) a Substantially water soluble and/or crystalline that the coating fulfils the requirement that no transport of polymer or a mixture of substantially water soluble and/or water into the matrix (or other parts of the composition) takes crystalline polymers, the polymer being a polyglycol in the 15 place through the coating (or, if any water should enter, then from of one of a) a homopolymer having a MW of at least it does not result in a transport of dissolved active Substance about 100,000 daltons, and b) a copolymer having a MW of at out through the coating). In other words, it has been the object least about 2,000 daltons, to develop a coating that does not leave an uncontrollable The layers B1) and B2) may have the same or different Surface area of the matrix exposed to the aqueous environ composition and in a cylindrical shaped composition they ment and that has suitable properties compared to the matrix, may have the same or different size. In a preferred embodi i.e. if the coating dissolves or otherwise disappears then it ment, the composition and size of the two B) layers are the should only take place after the matrix has eroded or dis SaC. Solved away (during the release period, the coating may of Suitable polymers for use in the outer layers are described course also partly dissolve or disappear provided that the part in detail in the section above. However, with respect to the 25 it concerns covered a part of the matrix that has already been outer layer, it is important to ensure a control of the rate with Subject to erosion or diffusion, thus, leaving the remaining which the outer layer disappears from the composition once it composition “intact with a matrix that is surrounded by the is exposed to an aqueous medium. As described above, the coating apart from the open end from which erosion or dif outer layers are composed in Such a manner that the outer fusion of the matrix takes place). layer leaves the composition with a constant rate (correspond 30 The composition may be partly or fully covered by a coat ing to a Zero order release rate in the event that a drug Sub with specific properties in Such away that the exposed area of stance was present in the layer). Such a constant rate can be the matrix may be controlled by the use of a coat. In a specific achieved by use of one or more polyglycols, but in contrast to example the coat is Substantially insoluble, non-erodable and the polymers suitable for used in the inner layer A), the non-permeable to water leaving only the exposed areas of the homopolymer should preferably have a much higher molecu 35 composition for release. Such a coat may be composed of a lar weight in order to ensure a constant erosion rate of the polymer that has thermoplastic properties. Examples of Such outer layer. Moreover, it is contemplated that when a co materials are mentioned below including cellulose derivative polymer is employed preferably one or more of another poly which has thermoplastic properties, plasticizer or plasticizers mer is included in the outer layer in order to obtain a suitable and/other functional excipients. constant erosion rate. 40 The coating may also be a coating, which is Substantially As the function of the outer layers is different from the soluble in and permeable to fluids such as body fluids during function of the inner layer, the polymer composition of the the intended release period provided that the coating dis outer layer(s) B is different from the polymer composition of Solves so much slower than the matrix composition that the the inner layer A). coating remains intact until the matrix has eroded and/or One or more pharmaceutically acceptable excipients or 45 released the inner layer containing an active Substance. additives may also be incorporated into the outer layer(s), see Examples of Suitable polymers include polyglycols as the section herein. However, it is important that such excipi described herein. ents or additives do not significantly change the manner in The coating may further comprise any of the mentioned which the outer layer disappears from the composition, i.e. it matrix materials (i.e. polymeric material Suitable for use in is important that this disappearance still is by a Substantially 50 the outer layers B) in a form, which erodes at a substantially constant rate e.g. by erosion or diffusion; addition of Such slower rate than the rest of the matrix. The coating may thus Substances may have impact on the rate (e.g. slow down or comprise a matrix of one or more Substantially water soluble increase the rate), but it must not significantly change the crystalline polymers and, optionally, a non-ionic emulsifier, properties of the outer layer B) so that the function as a the coating being one which is eroded in the aqueous phase at “controlled lag-time layer provider' is destroyed. 55 a substantially slower rate than the outer layer B, whereby a In some embodiments of the invention, the outer layer B) substantially controlled area of the outer layer B matrix com may also contain one or more second active Substances. Nor position (in some cases also comprising a second active Sub mally, such a second active substance in layer B) will be a stance) is exposed during erosion of the matrix composition different substance from that contained in layer A) in order to and/or during release of the active substance, and whereby the achieve a suitable combination treatment with two of more 60 coating is substantially eroded upon erosion of the matrix different active substance, one of which with a desired con composition and/or during release of the active Substance. trolled release following a Zero order release (the one con Such a coating will be designed so that its longitudinal ero tained in the outer layer B)) and the other one contained in the sion rate is Substantially the same as the longitudinal erosion inner layer and designed for immediate release (or, alterna rate of the matrix, whereby the matrix and the coating will tively, as detailed described under the section “Inner layer. 65 erode longitudinally towards the centre of the composition at as a controlled release composition e.g. with Zero or 1st order substantially the same rate. Thus, when the outer layer matrix release). composition has been completely eroded and/or dissolved by US 8,821,928 B2 15 16 the aqueous medium and the inner layer has been released aqueous medium in which the composition is to be used, from the shell (i.e. the coating), the coating will also be e.g. an ethylcellulose such as ethylcellulose having an Substantially completely eroded. A matrix composition hav ethoxyl content in the range of 44.5-52.5%, or cellulose ing Such a coating has the obvious advantage of being com acetate, cellulose propionate or cellulose nitrate; pletely biodegraded upon release of the active Substance. 5 and at least one of: The coating may impart delayed properties for releasing (b) a second cellulose derivative which is soluble or dis the active Substance or it may be a film-coating or a coating persible in water, e.g. a cellulose derivative selected containing the active Substance for immediate release prior to from the group consisting of methylcellulose, car the controlled release or other kinds of coatings that does not boxymethylcellulose and salts thereof, cellulose acetate delay the release but e.g. make it easier to Swallow the com 10 phthalate, microcrystalline cellulose, ethylhydroxyeth position or it may e.g. maska bad taste. Materials suitable for ylcellulose, ethylmethylcellulose, hydroxyethylcellu Such coatings are well-known for a person skilled in the art lose, hydroxyethylmethylcellulose, hydroxypropylcel and information can be found e.g. in the latest editions of lulose, hydroxypropylmethylcellulose, handbooks like Handbook of Pharmaceutical Excipients or in hydroxymethylcellulose and hydroxymethylpropylcel Remington's Pharmaceutical Sciences. 15 In an embodiment of the invention, the coating is one, lulose; which biodegrades, disintegrates crumbles or dissolves after (c) a plasticizer, e.g. selected from the group consisting of erosion of the matrix and/or during the release of the active phosphate esters; phthalate esters; amides; mineral oils; Substance. A coating applied for an erosion matrix will fatty acids and esters thereof; polyethylene glycol, glyc remain intact as long as it is supported by the matrix contain erin or Sugars; fatty alcohols and ethers thereof. Veg ing the active Substance, but it lacks the ability to remain etable oils; or a non-ionic Surfactant; and intact after erosion of the matrix, because it then biodegrades, (d) a filler, e.g. selected from conventional tablet or capsule disintegrates or crumbles, so that it will not remain in e.g. a excipients such as diluents, binders, lubricants and dis human for any significant amount of time after the complete integrants. erosion of the outer matrix layer Band the release of the inner 25 The first cellulose derivative (a) such as, e.g., ethylcellu layer A. lose is typically contained in the coating in a concentration of In an interesting embodiment, the composition of the from about 10 to about 99% w/w such as, e.g., from about 20 invention further comprises a coating having at least one to about 95% w/w, from about 30 to about 90% w/w, from opening exposing at least one Surface of the matrix, the coat about 40 to about 90% w/w, from about 45 to about 90% w/w, ing being one which crumbles and/or erodes upon exposure to 30 from about 50 to about 85% w/w or from about 50 to about the aqueous medium at a rate which is equal to or slower than 80% W/w. the rate at which the matrix erodes in the aqueous medium, In general, the concentration of the polymer in the coating allowing exposure of said Surface of the matrix to the aqueous is from about 60% w/w to about 100% w/w. 0-40% w/w of medium to be controlled. one or more of a plasticizer, a colouring agent, a stabilizer, a Polymers useful as coatings are such as e.g. cellulose 35 glidants or the like may also be present in the coating. derivative e.g. ethylcellulose, cellulose acetate, cellulose pro Moreover, in some embodiments of the invention a further pionate, cellulose nitrate, cellulose derivative selected from active Substance may be incorporated in the coating or the the group consisting of methylcellulose, carboxymethylcel composition may be provided with a second coating compris lulose and salts thereof, cellulose acetate phthalate, microc ing the further active Substance. Such a coating may be rystalline cellulose, ethylhydroxyethylcellulose, ethylmeth 40 designed to release the active Substance from the coating ylcellulose, hydroxyethylcellulose, immediately after oral administration or a composition of the hydroxyethylmethylcellulose, hydroxypropylcellulose, invention may be subject to enteric coating Such that release hydroxypropylmethylcellulose, hydroxymethylcellulose and will be pH dependent. hydroxymethylpropylcellulose, cellulose acetate, Eudragit L Such compositions wherein a coating contains an active methyl ester, Eudragit RL, Eudragit E. polyamide, polyeth 45 Substance may be of interest in those situations where a fast ylene, polyethylene terephthalate, polypropylenem polyure onset of action is desired, i.e. a fast release of an active thane, polyvinyl acetate, polyvinyl chloride, silicone rubber, Substance is desired in order to quickly obtain a therapeuti latex, polyhydroxybutyrate, polyhydroxyvalerate, teflon, cally effective plasma concentration of the active Substance. polylactic acid or polyglycolic acid and copolymers thereof, Such an active substance may be the same or different from copolymers such as ethylene vinyl acetate (EVA), styrene 50 that contained in layer B and/or the inner layer A dependent butadienestyrene (SBS) and styrene-isoprene-styrene (SIS). on the particular disease or condition to be treated. The coating may also be copolymers of polylactic acid and In Such cases where a second coating is provided on the polyglycolic acid. The coating may also be an enteric coating composition Such a coating is generally a film-coating and it employing methacrylates Eudragit L., Eudragit S, Eudragit is normally applied in a separate manufacturing step (e.g. not FS, a co-polymer of methacrylate-galactomannan etc. 55 by injection moulding, but using processes generally appli In one embodiment, the controlled release composition of cable for film-coating of tablets Such as, e.g., pan coating, the invention further comprises a coating having at least one fluid bed coating, spray coating, dip coating etc.). opening exposing at least one Surface of the matrix, the coat Dose Dumping ing being one which crumbles and/or erodes upon exposure to In one aspect, the invention is based on controlled release the aqueous medium at a rate which is equal to or slower than 60 compositions comprising polymer or a mixture of polymers, the rate at which the matrix erodes in the aqueous medium, more specifically a polyglycol, an active Substance and allowing exposure of said Surface of the matrix to the aqueous optionally one or more pharmaceutically acceptable excipi medium to be controlled. Coatings of this type are described ents in layer B. Polymers and pharmaceutically acceptable in WO95/22962, to which reference is made and which is excipients suitable for use in Such a composition as well as incorporated herein by reference. These coatings comprise: 65 relevant active Substances are described herein. Such compo (a) a first cellulose derivative which has thermoplastic sitions have proved to mitigate the risk of alcohol induced properties and which is substantially insoluble in the dose dumping. "Dose dumping is unintended, rapid drug US 8,821,928 B2 17 18 release in a short period of time of the entire amount or a Examples of specific active Substances suitable for use in a significant fraction of the active substance retained in a con composition of the invention are: trolled release dosage. Stomatological active Substances; Epinephrine, Benzy In a specific embodiment of the invention the release damine, Acetylsalicylic acid, Adrenalone, Amlexanox, mechanism is primarily erosion or diffusion from layer B 5 Sodium fluoride, Sodium monofluorophosphate, Olaflur, composed of a polymer matrix, an active Substance and if Stannous fluoride, Sodium fluoride, Hydrogen peroxide, necessary one or more excipients. The mechanism of erosion Chlorhexidine, Amphotericin B, Polynoxylin, Domiphen, enables the composition to release with a rate depending on Oxyquinoline, Neomycin, Miconazole, Natamycin, Hexeti the exposed area. Inner layer A of the invention contains dine, Tetracycline, Benzoxonium chloride, TibeZonium active Substance or active multiple units (e.g. pellets or mini 10 iodide, Mepartricin, Metronidazole, Clotrimazole, Sodium tablets) in such a form that the active substance or individual perborate, Chlortetracycline, Doxycycline, Minocycline, Tri active units will be made available upon disintegration of the amcinolone, Dexamethasone, Hydrocortisone, Prednisolone. composition in the stomach, Small intestine and/or colon after Active Substances for acid related disorders; Magnesium car erosion of layer B. The individual units are of a size, which bonate, Magnesium oxide, Magnesium peroxide, Magne allows them to be incorporated into Such a composition. 15 sium hydroxide, Magnesium silicate, Aluminium hydroxide, The matrix composition of layer B and active multiple Algeldrate, Aluminium phosphate, Dihydroxialumini units according to the invention has (in total) a lower (or Sodium carbonate, Aluminium acetoacetate, Aloglutamol. equal) solubility and/or release rate in alcohol containing Aluminium glycinate, Calcium carbonate, Calcium silicate, media (e.g. ethanol) than inacqueous media (e.g. water, buffer) Ordinary salt combinations, Magaldrate, Almagate, Hydro talcite, Almasilate, Magaldrate, Cimetidine, Ranitidine, The active Substance in the above mention matrix compo Famotidine, Nizatidine, Niperotidine, Roxatidine, Ranitidine sition optionally comprising chosen polymers and excipients bismuth citrate, Lafutidine, Cimetidine, Famotidine, Miso in a suitable ratio attains an unchanged or lower dissolution prostol, Enprostil, Omeprazole, Pantoprazole, Lansoprazole, rate when tested in alcohol containing media as compared to Rabeprazole, Esomeprazole, Carbenoxolone. Sucralfate, aqueous media. 25 Pirenzepine, Methiosulfonium chloride, Bismuth subcitrate, In principle, the use of a composition to avoid alcohol dose Proglumide, Gefarnate, Sulglicotide, Acetoxolone, Zolimi dumping can be of relevance for any active Substance. dine, Troxipide, Bismuth submitrate, Alginic acid. Active sub An easy manner to investigate whether a composition stances for functional gastrointestinal disorders; Oxyphen potentially will be subject to alcohol induced dose dumping is cyclimine, Camylofin, Mebeverine, Trimebutine, Rociverine, to Subject the composition to an dissolution test using a dis 30 Dicycloverine, Dihexyverine. Difemerine, Piperidolate, Solution medium with and without alcohol and investigate Metoclopramide, Cisapride, Domperidone, Bromopride, whether there are any differences in the release pattern under Alizapride, Clebopride. Antiemetic and antinauseant active the two different conditions. The harshest conditions are in a Substances; Serotonin (5HT3) antagonists, Ondansetron, dissolution medium containing 40% (v/v) ethanol. If the dis Granisetron, Tropisetron, Dolasetron, Palonosetron, Scopo solution rate of the composition is substantially unaffected or 35 lamine, Cerium oxalate, Chlorobutanol, Metopimazine, slower, then it is likely to assume that no alcohol induced dose Dronabinol, Nabilone, Aprepitant. Active substances for bile dumping will take place in vivo. and liver therapy; Bile acid preparations, Chenodeoxycholic Active Substances for Use in a Composition of the Inven acid, Ursodeoxycholic acid, Nicotinyl methylamide, Pipro tion Zolin, Hymecromone, Cyclobutyrol, Arginine glutamate, A composition according to the invention comprises one or 40 Silymarin, Citiolone, Epomediol, Ornithine oxoglurate, Tidi more active Substances. At least one active Substance is acic arginine. Laxative active Substances; Softeners, Emol included in the inner layer and outer layer(s) of the composi lients, Liquid paraffin, Docusate Sodium, Liquid paraffin, tion, which are the same, but the outer layer(s) may also Contact laxatives, Oxyphenisatine, Bisacodyl, Dantron, Phe contain one or more active Substances that is different from nolphthalein, Castor oil, Senna glycosides, Cascara, Sodium the active Substance contained in the inner layer. 45 picosulfate, Bisoxatin, Belladonna alkaloids, Bisacodyl, Typically, the amount of each active Substance in the com Dantron, Senna glycosides, Cascara, Sodium picosulfate, position if the same active Substance is present in the inner Ispaghula (psylla seeds), Ethulose, Sterculia, Linseed, Meth layer and/or outer layer and/or in the coating) corresponds to ylcellulose, Triticum (wheat fibre), Polycarbophil calcium, a daily or part of a daily therapeutic dose. Magnesium carbonate, Magnesium oxide, Magnesium per A pharmaceutical composition according to the invention 50 oxide, Magnesium Sulfate, Lactulose, Lactitol, Sodium Sul is suitable for use for both water soluble as well as slightly fate, Pentaerithrityl, Macrogol, Mannitol, Sodium phosphate, soluble or insoluble active substances. Sorbitol, Magnesium citrate, Sodium tartrate, Enemas, Thus, a pharmaceutical composition according to the Sodium phosphate, Bisacodyl, Glycerol, Oil, Laurilsulfate, invention may comprise one or more active Substances, i.e. Carbon dioxide producing drugs. Antidiarrheal, intestinal, Substances, which are therapeutically, prophylactically, diag 55 anti-inflammatory/antiinfective active Substances; Antibiot nostically and/or biologically active Substance. The term ics, Neomycin, Nystatin, Natamycin, Streptomycin, Poly “active substance' as used herein broadly includes any com myxin B, Paromomycin, Amphotericin B, Kanamycin, Van pound, or mixture thereof, that can be delivered from the comycin, Colistin, Rifaximin, Sulfonamides, composition to produce a beneficial result. Phthalylsulfathiazole, Sulfaguanidine, Succinylsulfathiaz The active Substance or Substances included in a pharma 60 ole, Imidazole derivatives, Miconazole, Broxyquinoline, ceutical composition of the invention may be selected from Acetarsol, Nifuroxazide, Nifurzide, Medicinal charcoal, Bis many therapeutic categories, in particular from Substances muth, Pectin, Kaolin, Crospovidone, Attapulgite, Diosmec which may advantageously be administered orally, rectally, tite, Diphenoxylate, Opium, Loperamide, Dilfenoxin, Lopera vaginally, or administered to a body cavity (e.g. the urinary mide oxide, Morphine, Prednisolone, Hydrocortisone, bladder, kidney pelvis, the gallbladder, the uterus, a central 65 Prednisone, Betamethasone, Tixocortol, Budesonide, nervous system cavity, infectious/malignant/post-operative Beclometasone, Antiallergic agents, excl. corticosteroids, cavities, etc.). Cromoglicic acid, Aminosalicylic acid and similar agents, US 8,821,928 B2 19 20 Sulfasalazine, Mesalazine, Olsalazine, Balsalazide, Antidiar chloride, Ferrous succinate, Ferrous sulfate, Ferrous tartrate, rheal microorganisms, Lactic acid producing organisms, Sac Ferrous aspartate, Ferrous ascorbate, Ferrous iodine, Ferric charomyces boulardii, Lactic acid producing organisms, sodium citrate, Saccharated iron oxide, Sodium feredetate, Albumin tannate, Ceratonia, Calcium compounds, Raceca Ferric hydroxide, Dextriferron, Ferric citrate, Chondroitin dotril. Antiobesity active substances; Phentermine, Fenflu sulfate-iron complex, Ferric acetyl transferrin, Ferric prote ramine, Amfepramone, Dexfenfluramine, Mazindol, Etilam insuccinylate, Dextriferron, Vitamin B12 (cyanocobalamin fetamine, Cathine, Clobenzorex, Mefenorex, Sibutramine, and analogues), Cyanocobalamin, Cyanocobalamin tannin Ephedrine, Orlistat, Rimonabant. Digestiveactive sub complex, Hydroxocobalamin, Cobamamide, Mecobalamin, stances; Enzyme preparations, Diastase, Multienzymes (li Folic acid and derivatives, Erythropoietin, Darbepoetin alfa, pase, protease etc.), Pepsin, Tilactase, Acid preparations, 10 Methoxy polyethylene glycol-epoetin beta. Hematological Glutamic acid hydrochloride, Betaine hydrochloride, Hydro active Substances; Fibrinolysin and desoxyribonuclease, chloric acid, Citric acid. Diabete active substances; Insulins Hyaluronidase, Chymotrypsin, Trypsin, Desoxyribonu and analogues, Biguanides, Phenformin, Metformin, clease, Bromelains, Streptokinase, combinations, Hematin. Buformin, Sulfonamides, urea derivatives, Glibenclamide, Cardiac stimulant active Substances; Cardiac glycosides, Chlorpropamide, Tolbutamide, Glibornuride, Tolazamide, 15 Digitalis glycosides, Acetyldigitoxin, Acetyldigoxin, Digi Carbutamide, Glipizide, Gliquidone, Gliclazide, Metahexa talis leaves, Digitoxin, Digoxin, Lanatoside C. Deslanoside, mide, Glisoxepide, Glimepiride, Acetohexamide, Sulfona Metildigoxin, Gitoformate, Scilla glycosides, Proscillaridin, mides (heterocyclic), Glymidine, Combinations of oral blood Strophantus glycosides, G-strophanthin, Cymarin, Peruvo glucose lowering drugs, Alpha glucosidase inhibitors, Acar side, Adrenergic and dopaminergic agents, Etilefrine, Isopre bose, Miglitol, Voglibose. Thiazolidinediones, Troglitazone, naline, Norepinephrine, Dopamine, Norfenefrine, Phenyle Rosiglitazone, Pioglitazone, Dipeptidyl peptidase 4 (DPP-4) phrine, Dobutamine, Oxedrine, Metaraminol, Methoxamine, inhibitors, Sitagliptin, Vildagliptin, Guar gum, Repaglinide, Mephentermine, Dimetofrine, Prenalterol, Dopexamine, Nateglinide, Exenatide, Aldose reductase inhibitors, Tolr Gepefrine, Ibopamine, Midodrine, Octopamine, estat. Anabolic active Substances; Androstan derivatives, Fenoldopam, Cafedrine, Arbutamine. Theodrenaline, Epi Androstanolone, Stanozolol, Metandienone, Metenolone, 25 nephrine, Phosphodiesterase inhibitors, Amrinone, Mil Oxymetholone, Quinbolone, Prasterone, Oxandrolone, rinone, Enoximone, Bucladesine. Other cardiac stimulants, Norethandrolone, Estren derivatives, Nandrolone, Ethyl Angiotensinamide, Xamoterol, Levosimendan. Antiarrhyth estrenol, Oxabolone cipionate. Metabolism active sub mics active Subtances; class la, Quinidine, Procainamide, stances; Amino acids and derivatives, Levocarnitine, Ademe Disopyramide, Sparteine, Ajmaline, Prajmaline, Lorajmine, tionine, Glutamine, Mercaptamine, Carglumic acid, Betaine, 30 Antiarrhythmics, class Ib, Lidocaine, Mexiletine, Tocainide, Enzymes, Alglucerase, Imiglucerase, Agallsidase alfa, Agal Aprindine, Antiarrhythmics, class Ic, Propafenone, Flecain sidase beta, Laronidase, Sacrosidase, Alglucosidase alfa, ide, Lorcainide, Encainide, Antiarrhythmics, class III, Amio Galsulfase, Idursulfase, Tioctic acid, Anethole trithione, darone, Bretylium tosilate, Bunaftine, Dofetilide, Ibutilide, Sodium phenylbutyrate, Nitisinone, Zinc acetate, Miglustat, Other class I antiarrhythmics, Moracizine, Cibenzoline. Sapropterin. 35 Active Substances for vasodilation; Organic nitrates, Glyceryl Antithrombotic active Substances; Vitamin Kantagonists, trinitrate, Methylpropylpropanediol dinitrate, Pentaerithrityl Dicoumarol, Phenindione, Warfarin, Phenprocoumon, tetranitrate, Propatylnitrate, Isosorbide dinitrate, Trolnitrate, Acenocoumarol, Ethyl biscoumacetate, Clorindione, Eritrity1 tetranitrate, Isosorbide mononitrate, Tenitramine, Diphenadione, Tioclomarol, Heparin, Antithrombin III, Floseduinan, Itramin tosilate, Prenylamine, Oxyfedrine, Dalteparin, Enoxaparin, Nadroparin, Parnaparin, Reviparin, 40 Benziodarone, Carbocromen, Hexobendine, Etafenone, Hep Danaparoid, Tinzaparin, Sulodexide, Bemiparin, Platelet taminol, Imolamine, Dilazep, Trapidil, Molsidomine, Eflox aggregation inhibitors excl. heparin, Ditazole, Cloricromen, ate, Cinepazet, Cloridarol, Nicorandil, Linsidomine, Nesir Picotamide, Clopidogrel, Ticlopidine, Acetylsalicylic acid, itide. Cardiac active Substances; Prostaglandins, Alprostadil, Dipyridamole, Carbasalate calcium, Epoprostenol, Other cardiac preparations, Camphora, Indometacin, Cratae Indobufen, Iloprost, Abciximab, Aloxiprin, Eptifibatide, 45 gus glycosides, Creatinolfosfate, Fosfocreatine, Fructose 1.6- Tirofiban, Triflusal, Beraprost, Treprostinil, Enzymes, Strep diphosphate, Ubidecarenone, Adenosine, Tiracizine, Tedis tokinase, Alteplase, Anistreplase, Urokinase, Fibrinolysin, amil, Acadesine, Trimetazidine, Ibuprofen, Ivabradine, Brinase, Reteplase, Saruplase, Ancrod, Drotrecogin alfa (ac Ranolazine. Antihypertensive active Substances; Rauwolfia tivated), Tenecteplase, Protein C, Direct thrombin inhibitors, alkaloids, Rescinnamine, Reserpine, Deserpidine, Methoser Desirudin, Lepirudin, Argatroban, Melagatran, Ximelagat 50 pidine, Bietaserpine, Methyldopa, Imidazoline receptor ago ran, Bivalirudin, Dabigatran etexilate, Defibrotide, Dermatan nists, Clonidine, Guanfacine, Tolonidine, Moxonidine, Ril Sulfate, Fondaparinux. Antihemorrhagics active Substances; menidine, Sulfonium derivatives, Trimetaphan, Secondary Amino acids, Aminocaproic acid, Tranexamic acid, Ami and tertiary amines, Mecamylamine, Bisquaternary ammo nomethylbenzoic acid, Proteinase inhibitors, Aprotinin, nium compounds, Alpha-adrenoreceptor antagonists, Pra Alfal antitrypsin, C1-inhibitor, Camostat, Vitamin K. Phy 55 Zosin, Indoramin, TrimaZosin, Doxazosin, Urapidil, Guani tomenadione, Menadione, Fibrinogen, Local hemostatics, dine derivatives, Betanidine, Guanethidine, Guanoxan, Absorbable gelatin sponge, Oxidized cellulose, Tetragalactu Debrisoquine, Guanoclor, GuanaZodine, Guanoxabenz. Thi ronic acid hydroxymethylester, Adrenalone, Thrombin, Col azide derivatives, Diazoxide, Hydrazinophthalazine deriva lagen, Calcium alginate, Epinephrine, Blood coagulation fac tives, Dihydralazine, Hydralazine, Endralazine, Cadralazine, tors, Coagulation factor IX, II, VII and X in combination, 60 Pyrimidine derivatives, Minoxidil, Nitroferricyanide deriva Coagulation factor VIII, Factor VIII inhibitor bypassing tives, Nitroprusside, Guanidine derivatives, Pinacidil, Ver activity, Coagulation factor IX, Coagulation factor VII, Von atrum, Tyrosine hydroxylase inhibitors, Metirosine, MAO Willebrand factor and coagulation factor VIII in combination, inhibitors, Pargyline, Serotonin antagonists, Ketanserin, Coagulation factor XIII, Eptacog alfa (activated). Nonacog Bosentan, Ambrisentan, Sitaxentan. Diuretic active sub alfa, Thrombin, Etamsylate, Carbazochrome, Batroxobin. 65 stances: Thiazides, Bendroflumethiazide, Hydroflumethiaz Antianemic active Substances; Ferrous glycine Sulfate, Fer ide, Hydrochlorothiazide, Chlorothiazide, Polythiazide, rous fumarate, Ferrous gluconate, Ferrous carbonate, Ferrous Trichlormethiazide, Cyclopenthiazide, Methyclothiazide, US 8,821,928 B2 21 22 Cyclothiazide, Mebutizide, Sulfonamides, Quinethazone, phenicol, AZidamfenicol, Hachimycin, Oxytetracycline, Clopamide, Chlortalidone, Mefruside, Clofenamide, Metola Carfecillin, Mepartricin, Clindamycin, Pentamycin, Arsenic Zone, Meticrane, Xipamide, Indapamide, Clorexolone, Fen compounds, Acetarsol, Quinoline derivatives, Diiodohydrox quizone, Mercurial diuretics, Mersalyl, Xanthine derivatives, ycuinoline, Clioquinol, Chlorquinaldol, Dequalinium, BroX Theobromine, Cicletanine, Furosemide, Bumetanide, Piret ycuinoline, Oxyquinoline, Organic acids, Lactic acid, Acetic anide, Torasemide, Aryloxyacetic acid derivatives, Etacrynic acid, Ascorbic acid, Sulfonamides, Sulfatolamide, Combina acid, Tienilic acid, Pyrazolone derivatives, Muzolimine, Eto tions of sulfonamides, Imidazole derivatives, Metronidazole, Zolin, Aldosterone antagonists, Spironolactone, Potassium Clotrimazole, Miconazole, Econazole, Ornidazole, Isocona canrenoate, Canrenone, Eplerenone, Amiloride, Triamterene. Zole, Tioconazole, Ketoconazole, Fenticonazole, AZanida Active Substances for peripheral vasodilation: 2-amino-1- 10 Zole, Propenidazole, Butoconazole, Omoconazole, Oxicona phenylethanol derivatives, ISOXSuprine, Buphenine, Bam Zole, Flutrimazole, Triazole derivatives, Terconazole, ethan, Imidazoline derivatives, Phentolamine, Tolazoline, Clodantoin, Inosine, Policresulen, Nifuratel, Furazolidone, Nicotinic acid, Nicotinyl alcohol (pyridylcarbinol), Inositol Methylrosaniline, Povidone-iodine, Ciclopirox, Protiofate, nicotinate, Ciclonicate, Purine derivatives, Pentifylline, Xan Lactobacillus fermentum, Copper usinate, Octenidine tinol nicotinate, Pentoxifylline, Etofylline nicotinate, Ergot 15 Gynecological active substances; Ergot alkaloids, Methyl alkaloids, Ergoloid mesylates, Nicergoline, Dihydroergocris ergometrine, Ergot alkaloids, Ergometrine, Oxytocin, Pros tine, Kallidinogenase, Cyclandelate, Phenoxybenzamine, taglandins, Dinoprost, Dinoprostone, Gemeprost, Carbo Vincamine, Moxisylyte, Bencyclane, Vinburnine, Suloctidil, prost, Sulprostone, Misoprostol, Ritodrine, Buphenine, Buflomedil, Naftidrofuryl, Butalamine, Visnadine, Cetiedil, Fenoterol, Prolactine inhibitors, Bromocriptine, Lisuride, Cinepazide, Ifenprodil, Azapetine, Fasudil. Vasoprotective Cabergoline, Quinagolide, Metergoline. Hormones; Norg active Substances; Heparinoid, Sodium apolate, Heparin, estrel, Gestodene, Norgestimate, Drospirenone, Norel Pentosan polysulfate Sodium, Monoethanolamine oleate, gestromin, Progestogens, Norethisterone, Lynestrenol, Polidocanol, Invert sugar, Sodium tetradecyl sulfate, Phenol, Levonorgestrel, Quingestanol, Megestrol, Medroxyprogest Glucose, Calcium dobesilate, Bioflavonoids, Rutoside, Mon erone, Norgestrienone, Etonogestrel, Desogestrel, 3-oxoan oxerutin, Diosmin, Troxerutin, Hidrosmin, Tribenoside. Beta 25 drosten (4) derivatives, Fluoxymesterone, Methyltestoster blocking active Substances; Beta blocking agents, non-selec one, Testosterone, 5-androstanon (3) derivatives, tive, Alprenolol, Oxprenolol, Pindolol, Propranolol, Timolol. Mesterolone, Androstanolone, Ethinylestradiol, Estradiol, Sotalol, Nadolol, Mepindolol, Carteolol, Tertatolol, Bopin Estriol, Chlorotrianisene, Estrone, Promestriene, Conjugated dolol, Bupranolol, Penbutolol, Cloranolol, Beta blocking estrogens, Dienestrol, Diethylstilbestrol, Methallenestril, agents, selective, Practolol, Metoprolol, Atenolol, Acebu 30 Moxestrol, Dienestrol, Methallenestril, Estrone, Diethylstil tolol, Betaxolol, Bevantolol, Bisoprolol, Celiprolol, Esmolol. bestrol, Pregnen (4) derivatives, Gestonorone, Medrox Epanolol, S-atenolol, Nebivolol, Talinolol, Alpha and beta yprogesterone, Hydroxyprogesterone, Progesterone, Pregna blocking agents, Labetalol, Carvedilol. Calium channel dien derivatives, Dydrogesterone, Megestrol, Medrogestone, blockers; Dihydropyridine derivatives, Amlodipine, Felo Nomegestrol, Demegestone, Chlormadinone, Promegestone, dipine, Isradipine, Nicardipine, Nifedipine, Nimodipine, 35 Estren derivatives, Allylestrenol, Norethisterone, Lynestre Nisoldipine, Nitrendipine, Lacidipine, Nilvadipine, Manid nol, Ethisterone, Tibolone. Etynodiol, Methylestrenolone, ipine, Barnidipine, Lercanidipine, Cilnidipine, Benidipine, Methyltestosterone, Methylnortestosterone, Noretynodrel, Mibefradil, Phenylalkylamine derivatives, Verapamil, Gallo Dienogest, Trimegeston, Gonadotropins, Urofollitropin, Fol pamil, Benzothiazepine derivatives, Diltiazem, Phenylalky litropin alfa, Follitropin beta, Lutropin alfa, Choriogonadot lamine derivatives, Fendiline, Bepridil, Lidoflazine, Perhexy 40 ropin alfa, Cyclofenil, Clomifene, Epimestrol, Cyproterone, line. Active Substances acting on the renin-angiotensin Danazol, Gestrinone, Antiprogestogens, Mifepristone, Ral system; ACE inhibitors, Captopril, Enalapril, Lisinopril, Per oxifene, Corticotropin, Tetracosactide, Thyrotropin, Thy indopril, Ramipril, Quinapril, Benazepril, Cilazapril, Fosino rotropin, Somatropin and Somatropin agonists, Somatropin, pril, Trandolapril, Spirapril, Delapril, Moexipril, Temocapril, Somatrem, Mecasermin, Sermorelin, Mecasermin rinfabate, Zofenopril, Imidapril. Other, Renin-inhibitors, Remikiren, 45 Pegvisomant, Vasopressin and analogues, Vasopressin, Des Aliskiren, Angiotensin II antagonists, Losartan, Eprosartan, mopressin, Lypressin, Terlipressin, Ornipressin, Argipressin, Valsartan, Irbesartan, Candesartan, Telmisartan, Olmesartan. Oxytocin and analogues, Demoxytocin, Oxytocin, Carbeto Lipid modifying active substances; HMG CoA reductase cin, Gonadotropin-releasing hormones, Gonadorelin, inhibitors, Simvastatin, Lovastatin, Pravastatin, Fluvastatin, Nafarelin, Histrelin, Antigrowth hormone, Somatostatin, Atorvastatin, Cerivastatin, Rosuvastatin, Pitavastatin, 50 Octreotide, Lanreotide, Vapreotide, Anti-gonadotropin-re Fibrates, Clofibrate, Bezafibrate, Aluminium clofibrate, leasing hormones, Ganirelix, Cetrorelix, Glycogenolytic hor Gemfibrozil, Fenofibrate, Simfibrate, Ronifibrate, Ciprofi mones, Glucagon, Parathyroid hormones and analogues, brate, Etofibrate, Clofibride, Bile acid sequestrants, Col Teriparatide, Parathyroid hormone, Calcitonin, Elcatonin, estyramine, Colestipol, Colextran, Colesevelam, Nicotinic Cinacalcet. Urological active substances; Acidifiers, Ammo acid and derivatives, Niceritrol, Nicofuranose, Aluminium 55 nium chloride, Calcium chloride, Urinary concrement sol nicotinate, Nicotinyl alcohol (pyridylcarbinol), Acipimox, vents, Urinary antispasmodics, Emepronium, Flavoxate, Other lipid modifying agents, Dextrothyroxine, Probucol, Meladrazine, Oxybutynin, Terodiline, Propiverine, Tolterod Tiadenol, Benfluorex, Meglutol, Omega-3-triglycerides, ine, Solifenacin, Trospium, Darifenacin, Fesoterodine, Drugs Magnesium pyridoxal 5-phosphate glutamate, Policosanol, used in erectile dysfunction, Alprostadil, Papaverine, EZetimibe 60 Sildenafil. Yohimbin, Phentolamine, Moxisylyte, Apomor Dermatological active Substances for system use; Antifun phine, Tadalafil. Vardenafil. Combinations, Papaverine, com gals, Griseofulvin, Terbinafine, Protectives against UV-radia binations, Magnesium hydroxide, Acetohydroxamic acid, tion for systemic use, Betacarotene, Antipsoriatics, Psor Phenazopyridine. Succinimide, Collagen, Phenyl salicylate, alens, Trioxysalen, MethoXSalen, Bergapten, Retinoids, Dimethylsulfoxide, Alpha-adrenoreceptor antagonists, Alfu Etretinate, Acitretin, Anti-acne, Isotretinoin, Ichtasol. Anti 65 Zosin, Tamsulosin, Terazosin, Testosterone-5-alpha reduc infective and antiseptic active Substances; Antibiotics, Nys tase inhibitors, Finasteride, Dutasteride, Pygeum africanum, tatin, Natamycin, Amphotericin B, Candicidin, Chloram Serenoa repens, Mepartricin. Corticosteroids; Mineralocorti US 8,821,928 B2 23 24 coids, Aldosterone, Fludrocortisone, Desoxycortone, Gluco Miconazole, Ketoconazole, Triazole derivatives, Flucona corticoids, Betamethasone, Dexamethasone, Fluocortolone, Zole, Itraconazole, Voriconazole, Posaconazole, Flucytosine, Methylprednisolone, Paramethasone, Prednisolone, Pred Caspofungin, Micafungin, Anidulafungin. Antimycobacte nisone, Triamcinolone, Hydrocortisone, Cortisone, Pred rial active Substances; Aminosalicylic acid and derivatives, nylidene, Rimexolone, Deflazacort, Cloprednol, Mepred Sodium aminosalicylate, Calcium aminosalicylate, Antibiot nisone, Cortivazol, Anticorticosteroids, Trilostane. Thyroid ics, Cycloserine, Rifampicin, Rifamycin, Rifabutin, Rifapen and antithyroid active Substances; Thyroid hormones, tine, Capreomycin, Hydrazides, Isoniazid, Isoniazid. Thio Levothyroxine Sodium, Liothyronine Sodium, Tiratricol, carbamide derivatives, Protionamide, Tiocarlide, Thiouracils, Methylthiouracil, Propylthiouracil, Benzylth Ethionamide, Pyrazinamide, Ethambutol, Terizidone, Mori iouracil, Sulfur-containing imidazole derivatives, Carbima 10 namide, Clofazimine, Dapsone, Aldesulfone sodium. Antivi Zole. Thiamazole, Perchlorates, Potassium perchlorate, ral active Substances. Thiosemicarbazones, MetisaZone, Diiodotyrosine, Dibromotyrosine, Iodine. Nucleosides and nucleotides, Aciclovir, Idoxuridine, Vidara Antiinfective active substances; Demeclocycline, Doxycy bine, Ribavirin, Ganciclovir, Famciclovir, Valaciclovir, Cido cline, Chlortetracycline, Lymecycline, Metacycline, Oxytet fovir, Penciclovir, Valganciclovir, Brivudine, Cyclic amines, racycline, Tetracycline, Minocycline, Rolitetracycline, Pen 15 Rimantadine, Tromantadine, Phosphonic acid derivatives, imepicycline, Clomocycline, Tigecycline, Amphenicols, Foscarnet, Fosfonet, Protease inhibitors, Saquinavir, Indi Chloramphenicol. Thiamphenicol, Ampicillin, Pivampicil navir, Ritonavir, Nelfinavir, Amprenavir, Lopinavir, Fosam lin, Carbenicillin, Amoxicillin, Carindacillin, Bacampicillin, prenavir, Atazanavir, Tipranavir, Darunavir, Zidovudine, Epicillin, Pivmecillinam, AZlocillin, Mezlocillin, Mecilli Didanosine, Zalcitabine, Stavudine, Lamivudine, Abacavir, nam, Piperacillin, Ticarcillin, Metampicillin, Talampicillin, Tenofovir disoproxil, Adefovir dipivoxil, Emtricitabine, Sulbenicillin, Temocillin, Hetacillin, Benzylpenicillin, Phe Entecavir, Telbivudine, Nevirapine, Delavirdine, Efavirenz, noxymethylpenicillin, Propicillin, Azidocillin, Pheneticillin, Zanamivir, Oseltamivir, Moroxydine, Lysozyme, Inosine Penamecillin, Clometocillin, Benzathine, benzylpenicillin, pranobex, Pleconaril, Enfluvirtide, Raltegravir, Maraviroc. Procaine benzylpenicillin, BenZathine phenoxymethylpeni Immune sera and immunoglobulin; Diphtheria antitoxin, cillin, Dicloxacillin, Cloxacillin, Meticillin, Oxacillin, Flu 25 Tetanus antitoxin, Snake Venom antiserum, Botulinum anti cloxacillin, Sulbactam, Tazobactam, Sultamicillin, Cefal toxin, Gas-gangrene Sera, Rabies serum, Immunoglobulins exin, Cefaloridine, Cefalotin, Cefazolin, Cefadroxil, from human, Anti-D (rh) immunoglobulin, Tetanus immuno Cefazedone, Cefatrizine, Cefapirin, Cefradine, Cefacetrile, globulin, Varicella/Zoster immunoglobulin, Hepatitis B Cefroxadine, Ceftezole, Cefoxitin, Cefuroxime, Cefaman immunoglobulin, Rabies immunoglobulin, Rubella immuno dole, Cefaclor, Cefotetan, Cefonicide, Cefotiam, Loracarbef, 30 globulin, Vaccinia immunoglobulin, Staphylococcus immu Cefinetazole, Cefprozil, Ceforanide, Cefotaxime, Ceftazi noglobulin, Cytomegalovirus immunoglobulin, Diphtheria dime, Cefsulodin, Ceftriaxone, Cefinenoxime, Latamoxef, immunoglobulin, Hepatitis A immunoglobulin, Encephalitis, Ceftizoxime, Cefixime, Cefodizime, Cefetamet, Ce?pira tick borne immunoglobulin, Pertussis immunoglobulin, mide, Cefoperazone, Cefpodoxime, Ceftibuten, Cefdinir, Measles immunoglobulin, Mumps immunoglobulin, Palivi Cefditoren, Ceftriaxone, Cefepime, Ce?pirome, Monobac 35 Zumab, Nebacumab. Vaccines; Bacterial vaccines, Anthrax tams, Aztreonam, Carbapenems, Meropenem, Ertapenem, vaccines, Anthrax antigen, Brucellosis vaccines, Brucella Imipenem, Trimethoprim, Brodimoprim, Sulfaisodimidine, antigen, Cholera vaccines, Diphtheria vaccines, Diphtheria Sulfamethizole, Sulfadimidine, Sulfapyridine, Sulfafurazole, toxoid, Hemophilus influenzae B vaccines, Meningococcal Sulfanilamide, Sulfathiazole, Sulfathiourea, Sulfamethox vaccines, Meningococcus A, Meningococcus B. Meningo azole, Sulfadiazine, Sulfamoxole, Sulfadimethoxine, Sul 40 coccus C. Pertussis vaccines, Plague vaccines, Pneumococcal falene, Sulfametomidine, Sulfametoxydiazine, Sul vaccines, Pneumococcus, Tetanus vaccines, Tuberculosis famethoxypyridazine, Sulfaperin, Sulfamerazine, vaccines, Typhoid vaccines, Typhus (exanthematicus) vac Sulfaphenazole, Sulfamazone, Macrollides, Erythromycin, cines. Other bacterial vaccines, viral vaccines, Encephalitis Spiramycin, Midecamycin, Oleandomycin, Roxithromycin, vaccines, Influenza vaccines, Hepatitis vaccines, Measles Josamycin, Troleandomycin, Clarithromycin, Azithromycin, 45 vaccines, Mumps vaccines, Poliomyelitis vaccines, Rabies Miocamycin, Rokitamycin, Dirithromycin, Flurithromycin, vaccines, Rota virus Vaccines, Rubella Vaccines, Varicella Telithromycin, Lincosamides, Clindamycin, Lincomycin, Zoster vaccines, Yellow fever vaccines, Papillomavirus vac Streptogramins, Pristinamycin, Quinupristin?dalfopristin, cines, Other viral vaccines. Streptomycins, Streptomycin, Streptoduocin, Other ami Antineoplastic and immunomodulating active Substances; noglycosides, Tobramycin, Gentamicin, Kanamycin, 50 Nitrogen mustard analogues, Cyclophosphamide, Chloram Azithromycin, Neomycin, Amikacin, Retapamulin, Netilmi bucil, Melphalan, Chlormethine, Ifosfamide, Trofosfamide, cin, Sisomicin, Dibekacin, Ribostamycin, Isepamicin, Fluo Prednimustine, Alkylsulfonates, Busulfan, Treosulfan, Man roquinolones, Ofloxacin, Ciprofloxacin, Pefloxacin, Enoxa nosulfan, Ethylene imines. Thiotepa, Triaziquone, Carbo cin, Temafloxacin, Norfloxacin, Lomefloxacin, Fleroxacin, quone, Nitrosoureas, Carmustine, Lomustine, Semustine, Sparfloxacin, Rufloxacin, Grepafloxacin, Levofloxacin, Tro 55 Streptozocin, Fotemustine, Nimustine, Ranimustine, vafloxacin, Moxifloxacin, Gemifloxacin, Gatifloxacin, Pruli Epoxides, Etoglucid, Other alkylating agents, Mitobronitol, floxacin, PaZufloxacin, Garenoxacin, Other quinolones, Pipobroman, Temozolomide, Dacarbazine. Antimetabolite Rosoxacin, Nalidixic acid, Piromidic acid, Pipemidic acid, active Substances; Folic acid analogues, Methotrexate, Ralti Oxolinic acid, Cinoxacin, Flumequine, Glycopeptide anti trexed, Pemetrexed, Purine analogues, Mercaptopurine, bacterials, Vancomycin, Teicoplanin, Telavancin, Polymyx 60 Tioguanine, Cladribine, Fludarabine, Clofarabine, Nelara ins, Colistin, Polymyxin B, Steroid antibacterials, Fusidic bine, Pyrimidine analogues, Cytarabine, Fluorouracil, acid, Imidazole derivatives, Metronidazole, Timidazole, Tegafur, Carmofur, Gemcitabine, Capecitabine, Vinca alka Ornidazole, Nitrofuran derivatives, Nitrofurantoin, Nifurtoi loids and analogues, Vinblastine, Vincristine, Vindesine, nol, Fosfomycin, Xibornol, Clofoctol, Spectinomycin, Meth Vinorelbine, Podophyllotoxin derivatives, Etoposide, Teni enamine, Mandelic acid, Nitroxoline, Linezolid, Daptomy 65 poside, Colchicine derivatives, Demecolcine, Taxanes, Pacli cin. Antimycotic active Substances; Antibiotics, taxel, Docetaxel. Other plant alkaloids and natural products, Amphotericin B. Hachimycin, Imidazole derivatives, Trabectedin. Cytotoxic antibiotic and related active sub US 8,821,928 B2 25 26 stances; Actinomycines, Dactinomycin, Anthracyclines and acid, Quinolines, Oxycinchophen, Gold preparations, related substances, Doxorubicin, Daunorubicin, Epirubicin, Sodium aurothiomalate, Sodium aurotiosulfate, Auranofin, Aclarubicin, Zorubicin, Idarubicin, Mitoxantrone, Pirarubi Aurothioglucose, Aurotioprol, Penicillamine and similar cin, Valrubicin, Other cytotoxic antibiotics, Bleomycin, Pli agents, Bucillamine. Muscle relaxant active Substances; camycin, Mitomycin, Ixabepilone. Antineoplastic active Sub Peripherally acting agents, Curare alkaloids, Alcuronium, stances; Platinum compounds, Cisplatin, Carboplatin, Tubocurarine, Dimethyltubocurarine, Choline derivatives, Oxaliplatin, Methylhydrazines, Procarbazine, Monoclonal Suxamethonium, Other quaternary ammonium compounds, antibodies, Edrecolomab, Rituximab, Trastuzumab, Alemtu Pancuronium, Gallamine, Vecuronium, Atracurium, Zumab, Gemtuzumab, Cetuximab, Bevacizumab, Panitu Hexafluoronium, Pipecuronium bromide, Doxacurium chlo mumab, Sensitizers used in photodynamic/radiation therapy, 10 ride, Fazadinium bromide, Rocuronium bromide, Mivacu Porfimer sodium, Methyl aminolevulinate, Aminolevulinic rium chloride, Cisatracurium, Botulinum toxin, Centrally acid, Temoporfin, Efaproxiral, Protein kinase inhibitors, Ima acting agents, Carbamic acid esters, Phenprobamate, Cariso tinib, Gefitinib, Erlotinib, Sunitinib, Sorafenib, Dasatinib, prodol, Methocarbamol, Styramate, Febarbamate, Oxazol, Lapatinib, Nilotinib. Otherantineoplastic agents, Amsacrine, thiazine, and triazine derivatives, ChlormeZanone, ChlorZOX Asparaginase, Altretamine, Hydroxycarbamide, 15 aZone, Ethers, chemically close to antihistamines, Lonidamine, Pentostatin, Miltefosine, Masoprocol, Estra Orphenadrine (citrate). Other centrally acting agents, mustine, Tretinoin, MitoguaZone, Topotecan, Tiazofurine, Baclofen, Tizanidine, Pridinol, Tolperisone. Thiocolchico Irinotecan, Alitretinoin, Mitotane, Pegaspargase, Bexaro side, Mephenesin, Tetrazepam, Cyclobenzaprine, Fenyrami tene, Arsenic trioxide, Denileukin diftitox, Bortezomib, dol, Directly acting agents, Dantrolene and derivatives. Anti Celecoxib, Anagrelide, Oblimersen, Sitimagene ceraden gout active Substances; Preparations inhibiting uric acid ovec, Combinations of antineoplastic agents. Endocrine production, Allopurinol, Tisopurine, FebuXostat, Prepara active substances; Estrogens, Diethylstilbestrol, Polyestra tions increasing uric acid excretion, Probenecid, Sulfinpyra diol phosphate, Ethinylestradiol, Fosfestrol. Progestogens, Zone, Benzbromarone, Isobromindione, Preparations with no Megestrol, Medroxyprogesterone, Medroxyprogesterone, effect on uric acid metabolism, Colchicine, Cinchophen, Gestonorone, Gonadotropin releasing hormone analogues, 25 Other antigout preparations, Urate oxidase. Active Sub Buserelin, Leuprorelin, Goserelin, Triptorelin, hormones stances affecting bone struture and mineralization; Bisphos antagonists, Anti-estrogens, Tamoxifen, Toremifene, Fulves phonates, Etidronic acid, Clodronic acid, Pamidronic acid, trant, Anti-androgens, Flutamide, Nilutamide, Bicalutamide, Alendronic acid, Tiludronic acid, Ibandronic acid, Risedronic Enzyme inhibitors, Aminogluthetimide, Formestane, Anas acid, Zoledronic acid, Bone morphogenetic proteins, Dibo trozole, Letrozole, Vorozole, Exemestane, Abarelix. Immu 30 termin alfa, Eptotermin alfa, Other drugs affecting bone nostimulant active Substances; Cytokines and immunomodu structure and mineralization, Ipriflavone, Aluminium chloro lators, Colony stimulating factors, Filgrastim, hydrate, Strontium ranelate, Quinine and derivatives, Hydro MolgramoStim, SargramoStim, Lenograstim, Ancestim, Peg quinine, Enzymes, Chymopapain, Trypsin, Hyaluronic acid. filgrastim, Interferons, Peginterferons, Interleukins, Colecalciferol. Aldesleukin, Oprelvekin, Lentinan, Roquinimex, BCG vac 35 Analgesics; Opioids, Natural opium alkaloids, Morphine, cine, Pegademase, Pidotimod, Poly I:C, Poly ICLC, Thymo Opium, Hydromorphone, Nicomorphine, Oxycodone, Dihy pentin, Immunocyanin, Tasonermin, Melanoma vaccine, drocodeine, Diamorphine, Papavereturn, Codeine, Phenylpi Glatirameracetate. Histamine dihydrochloride, Mi?amurtide. peridine derivatives, Ketobemidone, Pethidine, Fentanyl, Immunosuppressive active Substances: Ciclosporin, Diphenylpropylamine derivatives, Dextromoramide, Piritra Muromonab-CD3, Antilymphocyte immunoglobulin, Anti 40 mide, Dextropropoxyphene, Bezitramide, Methadone, Ben thymocyte immunoglobulin, Tacrolimus, Mycophenolic Zomorphan derivatives, Pentazocine, Phenazocine, Oripa acid, Daclizumab, Basiliximab, Sirolimus, Etanercept, vine derivatives, Buprenorphine, Morphinan derivatives, Infliximab, Leflunomide, Anakinra, Alefacept, Afelimomab, Butorphanol, Nalbuphine, Tilidine, Tramadol, Dezocine, Adalimumab, Everolimus, Gusperimus, Efalizumab, Abeti Salicylic acid and derivatives, Acetylsalicylic acid, Aloxiprin, mus, Natalizumab, Abatacept, Eculizumab, Certolizumab 45 Choline salicylate, Sodium salicylate, Salicylamide, Sal pegol, Other immunosuppressive agents, Azathioprine, Tha salate, Ethenzamide, Morpholine salicylate, Dipyrocetyl, lidomide, Methotrexate, Lenalidomide. Benorilate. Diflunisal, Potassium salicylate, Guacetisal, Car Antiinflammatory and antirheumatic active Substances; basalate calcium, Imidazole salicylate, Pyrazolones, Butylpyrazolidines, Phenylbutazone, Mofebutazone, PhenaZone, Metamizole sodium, AminophenaZone, Propy Oxyphenbutazone, ClofeZone, KebuZone, Acetic acid deriva 50 phenaZone, NifenaZone, Anilides, Paracetamol, Phenacetin, tives and related Substances, Indometacin, Sulindac, Tol Bucetin, Propacetamol. Other analgesics and antipyretics, metin, Zomepirac, Diclofenac, Alclofenac, Bumadizone, Rimazolium, Glafenine, Floctafenine, Viminol, Nefopam, Etodolac, Lonazolac, Fentiazac, Acemetacin, Difempiramide, Flupirtine, Ziconotide. Anesthetics: Ethers, Diethyl ether, Oxametacin, Proglumetacin, Ketorolac, Aceclofenac, Bufex Vinyl ether, Halogenated hydrocarbons, Halothane, Chloro amac. Oxicams, Piroxicam, Tenoxicam, Droxicam, Lornoxi 55 form, Methoxyflurane, Enflurane, Trichloroethylene, Isoflu cam, Meloxicam, Propionic acid derivatives, Ibuprofen, rane, Desflurane, Sevoflurane, Barbiturates, Methohexital, Naproxen, Ketoprofen, Fenoprofen, Fenbufen, Benoxapro Hexobarbital. Thiopental, Narcobarbital, Opioid anesthetics, fen, Suprofen, Pirprofen, Flurbiprofen, Indoprofen, Tiapro Fentanyl, Alfentanil, Sufentanil, Phenoperidine, Anileridine, fenic acid, Oxaprozin, Ibuproxam, Dexibuprofen, Flunox Remifentanil. Other general anesthetics, Droperidol, Ket aprofen, Alminoprofen, Dexketoprofen, Fenamates, 60 amine, Propanidid, Alfaxalone, Etomidate, Propofol, Mefenamic acid, Tolfenamic acid, Flufenamic acid, Meclofe Hydroxybutyric acid, Nitrous oxide, Esketamine, Xenon, namic acid, Coxibs, Celecoxib, Rofecoxib, Valdecoxib, Pare Esters of aminobenzoic acid, Metabutethamine, Procaine, coxib, Etoricoxib, Lumiracoxib, Nabumetone, Niflumic acid, Tetracaine, Chloroprocaine, Benzocaine, Amides, Bupiv AZapropaZone, Glucosamine, BenZydamine, Glucosami acaine, Lidocaine, Mepivacaine, Prilocalne. Butanilicaine, noglycan polysulfate, ProquaZone, Orgotein, NimeSulide, 65 Cinchocaine, Etidocaine, Articaine, Ropivacaine, Levobupi Feprazone, Diacerein, Morniflumate, Tenidap, Oxaceprol, vacaine, Esters of benzoic acid, Cocaine. Other local anes Chondroitin sulfate, Feprazone, Dipyrocetyl, Acetylsalicylic thetics, Ethyl chloride, Dyclonine, Phenol, Capsaicin. Anti US 8,821,928 B2 27 28 migraine active Substances; Ergot alkaloids, Amobarbital, Butobarbital, Barbital, Aprobarbital, Secobar Dihydroergotamine, Ergotamine, Methysergide, Lisuride, bital, Talbutal, Vinylbital, Vinbarbital, Cyclobarbital, Hept Corticosteroid derivatives, Flumedroxone, Selective seroto abarbital, Reposal, Methohexital, Hexobarbital. Thiopental, nin (5HT1) agonists, Sumatriptan, Naratriptan, Zolmitriptan, Etallobarbital, Allobarbital, Proxibarbal, Aldehydes and Rizatriptan, Almotriptan, Eletriptan, Frovatriptan, Otheranti derivatives, Chloral hydrate, Chloralodol, Acetylglycinamide migraine preparations, Pizotifen, Clonidine, Iprazochrome, chloral hydrate, Dichloralphenazone, Paraldehyde, Benzodi Dimetotiazine, Oxetorone. Antiepileptic active Substances; azepineemepronium derivatives, Flurazepam, Nitrazepam, Barbiturates and derivatives, Methylphenobarbital, Phe Flunitrazepam, Estazolam, Triazolam, Lorimetazepam, nobarbital, Primidone, Barbexaclone, Metharbital, Hydan Temazepam, Midazolam, Brotizolam, Quazepam, Lopra toinderivatives, Ethotoin, Phenyloin, Amino(diphenylhydan 10 Zolam, Doxefazepam, Cinolazepam, Piperidinedione deriva toin) valeric acid, Mephenyloin, Fosphenyloin, Oxazolidine tives, Glutethimide, Methyprylon, Pyrithyldione, Benzodiaz derivatives, Paramethadione, Trimethadione, Ethadione, epine related drugs, Zopiclone, Zolpidem, Zaleplon, Succinimide derivatives, Ethosuximide, Phensuximide, Ramelteon, Other hypnotics and sedatives, Methaqualone, Mesuximide, Benzodiazepine derivatives, Clonazepam, Car Clomethiazole, Bromisoval, Carbromal, Scopolamine, Pro boxamide derivatives, Carbamazepine, Oxcarbazepine, Rufi 15 piomazine, Triclofos, Ethchlorvynol, Valerian, Hexapropy namide, Fatty acid derivatives, Valproic acid, Valpromide, mate, Bromides, Apronal, Valnoctamide, Methylpentynol, Aminobutyric acid, Vigabatrin, Progabide, Tiagabine. Other Niaprazine, Melatonin, Dexmedetomidine, Dipiperonylami antiepileptics, Sultiame, Phenacemide, Lamotrigine, Fel noethanol. Antidepressant active Substances; Non-selective bamate, Topiramate, Gabapentin, Pheneturide, Levetirac monoamine reuptake inhibitors, Desipramine, Imipramine, etam, Zonisamide, Pregabalin, Stiripentol, Lacosamide, Bec Imipramine oxide, Clomipramine, Opipramol, Trimi lamide. Anticholinergic active Substances; Tertiary amines, pramine, Lofepramine, Dibenzepin, Amitriptyline, Nortrip Trihexyphenidyl, Biperiden, Metixene, Procyclidine, Profe tyline, Protriptyline, Doxepin, Iprindole, Melitracen, Butrip namine, Dexetimide, Phenglutarimide, Mazaticol, Bor tyline, DoSulepin, Amoxapine, Dimetacrine, Amineptine, naprine, Tropatepine, Ethers chemically close to antihista Maprotiline, Quinupramine, Selective serotonin reuptake mines, Etanautine, Orphenadrine (chloride), Ethers of tropine 25 inhibitors, Zimeldine, Fluoxetine, Citalopram, Paroxetine, or tropine derivatives, Benzatropine. Etybenzatropine. Sertraline, Alaproclate, Fluvoxamine, Etoperidone, Escitalo Dopaminergic active Substances; Dopa and dopa derivatives, pram, Monoamine oxidase inhibitors, non-selective, Isocar Levodopa, Melevodopa, Etilevodopa, Adamantane deriva boxazid, Nialamide, Phenelzine, Tranylcypromine, Iproniaz tives, Amantadine, Dopamine agonists, Bromocriptine, Per ide, Iproclozide, Monoamine oxidase A inhibitors, golide, Dihydroergocryptine mesylate, Ropinirole, Prami 30 Moclobemide, Toloxatone. Other antidepressants, Oxitrip pexole, Cabergoline, Apomorphine, Piribedil, Rotigotine, tan, Tryptophan, Mianserin, Nomifensine, Trazodone, Nefa Monoamine, oxidase B inhibitors, Selegiline, Rasagiline, Zodone, Minaprine, Bifemelane, Viloxazine, Oxaflozane, Other dopaminergic agents, Tolcapone, Entacapone, Mirtazapine, Medifoxamine, Tianeptine, Pivagabine, Ven Budipine. Antipsychotic active substances; Phenothiazines lafaxine, Milnacipran, Reboxetine, Gepirone, Duloxetine, with aliphatic side-chain, Chlorpromazine, Levomepro 35 Agomelatine, Desvenlafaxine, Centrally acting sympathomi mazine, Promazine, Acepromazine, Triflupromazine, metics, Amfetamine, Dexamfetamine, Metamfetamine, Cyamemazine, Chlorproethazine, Phenothiazines with pip Methylphenidate, Pemoline, Fencamfamin, Modafinil, Feno erazine structure, Dixyrazine, Fluphenazine, Perphenazine, Zolone, Atomoxetine, Fenetyline, Xanthine derivatives, Caf Prochlorperazine, Thiopropazate, Trifluoperazine, feine, Propentofylline. Other psychostimulants and nootro Acetophenazine. Thioproperazine, Butaperazine, Perazine, 40 pics, Meclofenoxate, Pyritinol, Piracetam, Deanol, Fipexide, Phenothiazines with piperidine structure, Periciazine. Thior Citicoline, Oxiracetam, Pirisudanol, Linopirdine, idazine, Mesoridazine, Pipotiazine, Butyrophenone deriva Nizofenone, Aniracetam, Acetylcarnitine, Idebenone, Prolin tives, Haloperidol, Trifluperidol, Melperone, Moperone, tane, Pipradrol, Pramiracetam, Adrafinil, Vinpocetine. Anti Pipamperone, Bromperidol, Benperidol, Droperidol, Flu dementia active Subtances; Anticholinesterases, Tacrine, anisone, Indole derivatives, Oxypertine, Molindone, Sertin 45 Donepezil, Rivastigmine, Galantamine. Other anti-dementia dole, Ziprasidone. Thioxanthene derivatives, Flupentixol, drugs, Memantine, Ginkgo biloba. Other nervous system Clopenthixol, Chlorprothixene, Tiotixene, Zuclopenthixol, active Substances; Parasympathomimetics, Anticholinest Diphenylbutylpiperidine derivatives, Fluspirilene, Pimozide, erases, Neostigmine, Pyridostigmine, Distigmine, Penfluridol, Diazepines, oxazepines and thiazepines, Loxap Ambenonium, Choline esters, Carbachol, Bethanechol, ine, Clozapine, Olanzapine, Quetiapine, Neuroleptics, in tar 50 Other parasympathomimetics, Pilocarpine, Choline alfoscer dive dyskinesia, Tetrabenazine, Benzamides, Sulpiride, Sul ate. Active substances used in addictive disorders; Drugs used topride, Tiapride, Remoxipride, Amisulpride, Veralipride, in nicotine dependence, Nicotine, Bupropion, Varenicline, Levosulpiride, Lithium. Other antipsychotics, Prothipendyl, Drugs used in alcohol dependence, Disulfuram, Calcium car Risperidone, Clotiapine, Mosapramine, Zotepine, Aripipra bimide, Acamprosate, Naltrexone, Drugs used in opioid Zole, Paliperidone. Anxiolytic active substances; Benzodiaz 55 dependence, Buprenorphine, Methadone, Levacetylmeth epine derivatives, Diazepam, Chlordiazepoxide, adol, Lofexidine. Antivertigo active subtances; Betahistine, Medazepam, Oxazepam, Potassium cloraZepate, Lorazepam, Cinnarizine, Flunarizine, Acetylleucine, other nervous sys Adinazolam, Bromazepam, Clobazam, Ketazolam, tem drugs, Gangliosides and ganglioside derivatives, Tir Prazepam, Alprazolam, Halazepam, Pinazepam, ilazad, Riluzole, Xaliproden, Hydroxybutyric acid, Amifam Camazepam, Nordazepam, Fludiazepam, Ethyl loflazepate, 60 pridine. Etizolam, Clotiazepam, Cloxazolam, Tofisopam, Diphenyl Active Substances against amoebiasis and other protozoal methane derivatives, Hydroxyzine, Captodiame, Carbam diseases; Hydroxyquinoline derivatives, Broxyquinoline, ates, Meprobamate, Emylcamate, Mebutamate, Dibenzo-bi Clioquinol, Chlorquinaldol, Tilbroquinol, Nitroimidazole cyclo-octadiene derivatives, BenZoctamine, derivatives, Metronidazole, Tinidazole, Ornidazole, Azanida AZaspirodecanedione derivatives, Buspirone. Other anxiolyt 65 Zole, Propenidazole, Nimorazole, Secnidazole, Dichloroac ics, Mephenoxalone, Gedocarnil, Etifoxine. Hypnotic and etamide derivatives, Diloxanide, Clefamide, Etofamide, sedative active substances; Barbiturates, Pentobarbital, Teclozan, Arsenic compounds, Arsthinol, DifetarSone, Gly US 8,821,928 B2 29 30 cobiarsol, Chiniofon, Emetine, Phanquinone, Mepacrine, Acefylline piperazine, Bufylline, Doxofylline, Zafirlukast, Atovaquone, Trimetrexate, Tenonitrozole, Dihydroemetine, Pranlukast, Montelukast, Ibudilast, Amlexanox, Eprozinol, Fumagillin, NitaZoxanide. Antimalarial active Substances; Fenspiride, Omalizumab, Seratrodast, Roflumilast. Cough Aminoquinolines, Chloroquine, Hydroxychloroquine, Pri and cold active Substances; Expectorants, Tyloxapol, Potas maquine, Amodiaquine, Biguanides, Proguanil, Cycloguanil sium iodide, Guaifenesin, Ipecacuanha, Althea root, Senega, embonate, Methanolduinolines, Quinine, Mefloquine, Antimony pentasulfide, Creosote, Guaiacolsulfonate, Levo Diaminopyrimidines, Pyrimethamine, Artemisinin and verbenone. Mucolytics, Acetylcysteine, Bromhexine, Car derivatives, Artemether, Artesunate, Artemotil, Artenimol, bocisteine, Eprazinone, Mesna, Ambroxol, Sobrerol, Domi Halofantrine. Active Substances against leishmaniasis and odol, Letosteine, Stepronin, Tiopronin, Dornase alfa trypanosomiasis; Nitroimidazole derivatives, BenZnidazole, 10 Antimony compounds, Meglumine antimonate, Sodium sti (desoxyribonuclease), Neltenexine, Erdosteine, Opium alka bogluconate, Nitrofuran derivatives, Nifurtimox, Nitrofural, loids and derivatives, Ethylmorphine, Hydrocodone, Arsenic compounds, Melarsoprol, Acetarsol, Pentamidine Codeine, Opium alkaloids with morphine, Normethadone, isethionate, Suramin sodium, Eflornithine. Antitrematodal Noscapine, Pholcodine, Dextromethorphan, Thebacon, active substances; Quinoline derivatives and related sub 15 Dimemorfan, Acetyldihydrocodeine, Benzonatate, Benpro stances, Praziquantel, Oxamniquine, Organophosphorous perine, Clobutinol, Isoaminile, Pentoxyverine, Oxolamine, compounds, Metrifonate, Bithionol, Niridazole, Stibophen, Oxeladin, Clo?edanol, Pipazetate, Bibenzonium bromide, Triclabendazole. Antinematodal active substances; Benzimi Butamirate, Fedrilate, Zipeprol, Dibunate, Droxypropine, dazole derivatives, Mebendazole, Tiabendazole, Albenda Prenoxdiazine, propropizine, Cloperastine, Meprotixol, Pip Zole, Ciclobendazole, Flubendazole, Fenbendazole, pipera eridione, Tipepidine, Morclofone, Nepinalone, Levodro Zine and derivatives, Diethylcarbamazine, propizine, Dimethoxanate. Antihistamine active Substances; Tetrahydropyrimidine derivatives, Pyrantel, Oxantel, Imida Aminoalkyl ethers, Bromazine, Diphenhydramine, Clemas Zothiazole derivatives, Levamisole, Avermectines, Ivermec tine, Chlorphenoxamine, Diphenylpyraline, Carbinoxamine, tin, Pyrvinium, Bephenium, anticestodal active Substance; Doxylamine, Substituted alkylamines, Brompheniramine, Salicylic acid derivatives, Niclosamide, Desaspidin, Dichlo 25 Dexchlorpheniramine, Dimetindene, Chlorphenamine, Phe rophen. Ectoparasiticide active Substances; Sulfur containing niramine, Dexbrompheniramine, Talastine, Substituted eth products, Dixanthogen, Potassium polysulfide, Mesulfen, ylene diamines, Mepyramine. Histapyrrodine, Chloropy Disulfuram, Thiram, Chlorine containing products, Clofeno ramine, Tripelennamine, Methapyrilene, Thonzylamine, tane, Lindane, Pyrethrines, incl. synthetic compounds, Pyre Phenothiazine derivatives, Alimemazine, Promethazine, Thi thrum, Bioallethrin, Phenothrin, Permethrin, Benzyl ben 30 ethylperazine, Methdilazine, Hydroxyethylpromethazine, Zoate, Copper oleinate, Malathion, Quassia. Insecticide and repellent active substances; Pyrethrines, Cyfluthrin, Cyper Thiazinam, Mequitazine, Oxomemazine, Isothipendyl, pip methrin, Decamethrin, Tetramethrin, Diethyltoluaide, Dim erazine derivatives, Buclizine, Cyclizine, Chlorcyclizine, ethylphthalate, Dibutylphthalate, Dibutylsuccinate, Dimeth Meclozine, Oxatomide, Cetirizine, Levocetirizine, Bami ylcarbate, Etohexadiol. 35 pine, Cyproheptadine. Thenalidine, Phenindamine, AntaZo Decongestant active Substances; Sympathomimetics, line, Triprolidine, Pyrrobutamine, AZatadine, Astemizole, Cyclopentamine, Ephedrine, Phenylephrine, Oxymetazoline, Terfenadine, Loratadine, Mebhydrolin, Deptropine, Keto Tetryzoline, Xylometazoline, Naphazoline, Tramazoline, tifen, Acrivastine, AZelastine, Tritoqualine, Ebastine, Pime Metizoline, Tuaminoheptane, Fenoxazoline, Tymazoline, thixene, Epinastine, Mizolastine, Fexofenadine, Deslorata Epinephrine, Cromoglicic acid, Levocabastine, AZelastine, 40 dine, Rupatadine. Other respiratory system active Substances; Antazoline, Spaglumic acid, Thonzylamine, Nedocromil. Lung Surfactants, Colfosceril palmitate, Natural phospholip Olopatadine, Corticosteroids, Beclometasone, Prednisolone, ids. Respiratory stimulants, Doxapram, Nikethamide, Pentet Dexamethasone, Flunisolide, Budesonide, Betamethasone, razol, Etamivan, Bemegride, Prethcamide, Almitrine, Dime Tixocortol, Fluticasone, Mometasone, Triamcinolone, Fluti fline, Mepixanox, Nitric oxide. casone furoate, Hydrocortisone, Calcium hexamine thiocy 45 Other active Substances; Antidotes, Ipecacuanha, Nalor anate, Retinol, Ipratropium bromide, Ritiometan, Mupirocin, phine, Edetates, Pralidoxime, Prednisolone and promethaz Hexamidine, Framycetin, Phenylpropanolamine, Pseu ine. Thiosulfate, Sodium nitrite, Dimercaprol, Obidoxime, doephedrine, Phenylephrine. Throat active substances; Anti Protamine, Naloxone, Methylthioninium chloride, Potas septics, Ambazone, Dequalinium, Dichlorobenzyl alcohol, sium permanganate, Physostigmine, Copper Sulfate, Potas Chlorhexidine, Cetylpyridinium, Benzethonium, Myristyl 50 sium iodide, Amyl nitrite, Acetylcysteine, Digitalis antitoxin, benzalkonium, Chlorquinaldol, Hexylresorcinol, Acrifla Flumazenil, Methionine, 4-dimethylaminophenol, Cho vinium chloride, Oxyquinoline, Povidone-iodine, Benzalko linesterase, Prussian blue, Glutathione, Hydroxocobalamin, nium, Cetrimonium, Hexamidine, Phenol, Antibiotics, Fomepizole, Iron chelating agents, Deferoxamine, Defer Neomycin, Tyrothricin, Fusafungine, Bacitracin, Gramici iprone, Deferasirox, Polystyrene sulfonate. Sevelamer, Lan din, Benzocaine, Lidocaine, Cocaine, Dyclonine. Active Sub 55 thanum carbonate, Mesna, DexraZoxane, Calcium folinate, stances for obstructive airway diseases; Orciprenaline, Salb Calcium levofolinate, Amifostine, Sodium folinate, Rasbu utamol, Terbutaline, Fenoterol, Rimiterol, Hexoprenaline, ricase, Palifermin, Glucarpidase, Sodium cellulose phos Isoetarine, Pirbuterol, Tretoquinol, Carbuterol, Tulobuterol, phate, DiaZOxide. Salmeterol, Formoterol, Clenbuterol, Reproterol, Procaterol, In specific embodiments, the active Substance is for cardiac Bitolterol, Glucocorticoids, Beclometasone, Budesonide, 60 therapy including e.g. cardiac glycosides, antiarrhythmics, Flunisolide, Betamethasone, Fluticasone, Triamcinolone, cardiac stimulants, vasodilators, antihypertensives, diuretics, MometaSone, Ciclesonide, Ipratropium bromide, vasoprotectives, beta blockers, calcium channel blockers, OXitropium bromide, Stramoni preparations, Tiotropium agents acting on the rennin-angiotensin System, lipid modi bromide, Cromoglicic acid, Nedocromil, Fenspiride, Meth fying agents. oxyphenamine, Bambuterol, Xanthines, Diprophylline, Cho 65 In specific embodiments, the active Substance is from the line theophyllinate, Proxyphylline. Theophylline, Amino therapeutic classes including antiemetics, antinauseants, phylline, Etamiphylline. Theobromine, Bamifylline, antiobesity and anabolic agents. US 8,821,928 B2 31 32 In specific embodiments, the active Substance is from the In an embodiment of the invention, the active Substance is therapeutic classes including antiinflammatory and antiinfec a pharmaceutically active crystal. The crystal typically has a tive agents, corticosteroids, non-steroids anti-inflammatory particle size of from about 0.1 um to about 1000 um such as, and antirheumatic agents. e.g., about 0.1 um to about 750 um, about 0.1 um to about 500 In specific embodiments, the active Substance is from the um, typically from about 0.5 um to about 500 um, more therapeutic classes including decongestants, adrenergics, typically from about 1 um to about 500 um, especially from expectorants, cough suppressant and antihistamines. about 5um to about 500 um. In specific embodiments, the active Substance is from the In another embodiment of the invention, a composition therapeutic classes including anesthetics, analgesics, opioids, comprises active Substance that at least partially is present in antipyretics, antimigraine agents, antiepileptics, anti-parkin 10 amorphous form with a mean particle size of at least about Son agents, dopaminergic agents, antipsychotics, anxiolytics, 0.01 um such as, e.g., from about 0.01 um to about 500 um, from about 0.05 um to about 500 um, from about 0.1 um to sedatives, antidepressants, psychoStimulants agents used for about 500 um, from about 0.5um to about 500 um, about 1 um ADHD and nootropics, agents used in addictive disorders. to about 500 um, typically from about 0.5 um to about 300 In specific embodiments, the active Substance is from the 15 um, more typically from about 1 um to about 200 um, espe therapeutic classes including anaesthetics, centrally-acting cially from about 1 um to about 100 um. analgesics, sedative-hypnotics, anxiolytics; appetite Suppres The at least one therapeutically, prophylactically and/or sants, decongestants, antitussives, antihistamines, antiemet diagnostically and/or biologically active Substance will Suit ics, antidiarrheals, and drugs used to treat narcolepsy and ably be present in an amount of up to about 80%, typically up attention deficit hyperactivity disorder. to about 70%, up to about 60% or up to about 50%, such as, In specific embodiments, the active Substance is associated e.g., from 0.1% to 80%, such as from 0.25% to 75%, such as with abuse syndromes include opioids, CNS depressants, from 0.5% to 60%, such as from 0.75% to 50%, such as from CNS stimulants, cannabinoids, nicotine-like compounds, 1% to 40%, such as from 1.5% to 35%, such as from 1.75% to glutamate antagonists and N-methyl-D-aspartate (NMDA) 30% by weight of the composition or layer. With respect to antagonists. 25 situations where one or more active Substances are contained In specific embodiments, the active Substance is buprenor in one of the layers or coat, a content of about 60-80% w/w is phine, codeine, dextromoramide, dihydrocodeine, fentanyl. contemplated to be the maximum content, which still allows hydrocodone, hydromorphone, morphine, pentazocine, oxy for a sufficient content of the polymer and, when relevant, a codeine, oxycodone, oxymorphone and tramadol. pharmaceutically acceptable excipient in the composition. The active Substance can be in various forms, such as 30 The active Substance may, on the other hand, be present in the uncharged or charged molecules, molecular complexes, crys composition in much smaller amounts, depending on the talline forms, amorphous form, polyamorphous form, poly nature and potency of the active substance in question. morphous form, complexes, Solvates, anhydrates, if relevant A composition according to the invention containing a isomers, enantiomers, racemic mixtures and pharmacologi drug Substance is typically for oral administration. Due to the cally acceptable salts such as e.g. hydrochloride, hydrobro 35 possibility of controlling the release rate of the active sub mide, Sulfate, laurylate, palmitate, phosphate, nitrite, nitrate, stance the composition may be adapted for oral administra citrate, borate, acetate, maleate, tartrate, oleate, and salicy tion 1-6 times a day, normally 1-4 times daily Such as 1-3 late. For acidic active Substance, salts of metals e.g. alkali times, 1-2 times or 1 times daily. The technology may also metal salts such as, e.g., Sodium or potassium salts, alkaline provide compositions for administration only once or twice earth metal salts such as, e.g., calcium and magnesium salts, 40 daily. In the present context the term “once daily' is intended amines amino acids or organic cations, quaternary ammoni to mean that it is only necessary to administer the pharma ums, can be used. Derivatives of active Substances such as ceutical composition once a day in order to obtain a Suitable esters, ethers and amides which have solubility characteris therapeutic and/or prophylactic response; however, any tics suitable for use herein can be used alone or mixed with administration may comprise co-administration of more than other drugs. After release of the derivative from the drug 45 one dosage unit, such as, e.g. 2-4 dosage units if the amount delivery system it may be converted by enzymes, hydrolysed of active Substance required may not be formulated in only by body pH or other metabolic processes to the parent drug or one composition or if a composition of a smaller size is to another biologically active form. preferred. A pharmaceutical composition of the invention may in The dosage of the active Substance depends on the particu addition be suitable for the delivery of peptides, polypeptides 50 lar Substance, the age, weight condition etc. of the human or or proteins, for example hormones, enzymes such as lipases, animal that will be treated with the composition etc. All such proteases, carbohydrates, amylases, lactoferrin, lactoperoxi factors are well known to a person skilled in the art. dases, lysozymes, nanoparticles, etc., and antibodies. The Stability composition may also be employed for the delivery of micro With respect to the fixed-dosed combination formulation organisms, either living, attenuated or dead, for example bac 55 stability is employed to encompass one or more of the fol teria, e.g. gastrointestinal bacteria Such as Streptococci, e.g. S. lowing: faecium, Bacillus spp. Such as B. subtilis and B. lichenifonnis, 1) Stability with respect to the physical stability of the lactobacteria, Aspergillus spp., bifidogenic factors, or viruses composition (appearance, color, strength, etc.) Such as indigenous vira, enterovira, bacteriophages, e.g. as 2) Stability with respect to in vitro dissolution behavior of vaccines, and fungi such as baker's yeast, Saccharomyces 60 the active Substance from the composition cerevisiae and fungi imperfecti. Stability of the individual components; In an embodiment of the invention, the active Substance is 3) Stability with respect to the chemical stability of the a pharmaceutically active powder. The powder typically has a active Substance (degradation of the active Substance to particle size of from about 0.1 um to about 500 um, typically other—normally—unwanted products) from about 0.5 um to about 300 um, more typically from 65 4) Stability with respect to the form the active substance about 1 um to about 200 um, especially from about 5 um to has in the composition; if the active Substance is dis about 100 um. Solved (molecularly dispersed) in the polymeras a solid US 8,821,928 B2 33 34 dispersion. In Such cases precipitation or otherwise for rogol glycerol hydroxyStearat, colloidal silicon dioxide and mation of crystals of the active Substance in the compo mixtures thereof, disintegrants such as starches, clays, cellu sition is an indication of a stability problem. lose derivatives including microcrystalline cellulose, methyl 5) Physical and chemical stability of the pharmaceutically cellulose, carboxymethylcellulose calcium, carboxymethyl acceptable polymer and excipients employed 5 cellulose Sodium, cellulose, crosscarmellose sodium, gums, In particular, the active substance or Substances maybe aligns, various combinations of hydrogencarbonates with stabilized in the dosage form in its amorphous form. The weak acids (e.g. sodium hydrogencarbonate/tartaric acid or amorphous state and/or the Solid dispersion is stabilized citric acid) crosprovidone, Sodium starch glycolate, agar, alg either by a very careful choice of the concentration of the inic acid, calcium alginate, sodium alginate, chitosan, colloi active Substance in the composition and/or by addition of 10 dal silicon dioxide, docusate sodium, guar gum, low-substi Suitable stabilizing agents acting by stabilizing one or more of tuted hydroxypropyl cellulose, hydroxypropyl Starch, the conditions mentioned above under items 1) to 5). magnesium aluminium silicate, polacrilin potassium, povi In regards to condition 4) the stability may be retrieved by done, sodium starch glycolate, pregelatinized Starch, cation several mechanisms of which the most important are exchange resins, citrus pulp, Veegum, glycolate, natural a) Physical stabilization by decreasing the molecular 15 sponge, bentonite. Sucralfate, calcium hydroxyl-apatite or mobility of the components, i.e. Suitable excipients and mixtures thereof, effervescent agents (carbonate release) the active substance of the formulation Such as citric acid, anhydrous, citric acid, monohydrate, dex b) Chemical stabilization by increasing the apparent Solu trates, fumaric acid, potassium bicarbonate, sodium bicar bility of the active substance in the matrix formulation. bonate, Sodium citrate, dehydrate, tartaric acid or mixtures Thus a stabilizing agent may serve more than one purpose, thereof. it may stabilize the amorphous state of the active Substance in Furthermore, the composition may comprise one or more the composition in order to avoid, reduce or delay any recrys agents selected from the group consisting of Sweetening tallization, it may stabilize the active Substance or otheringre agents, flavouring agents and colouring agents, in order to dients towards proteolytic or oxidative degradation or it may provide an elegant and palatable preparation. Examples are have an anti-plasticizing effect. 25 maltol, citric acid, water soluble FD&C dyes and mixtures A stabilizing agent may also contribute to an improved thereof with corresponding lakes and direct compression Sug solubility of the active substance. Without being bound to any ars such as Di-Pac from Amstar. In addition, coloured dye theory it may be assumed that the stabilizing agent together migration inhibitors such as tragacanth, acacia or attapulgite with the polyethylene glycol and/or polyethylene oxide rep talc may be added. Specific examples include Calcium car resent the dispersion medium wherein the solubility of the 30 bonate, 1,3,5-trihydroxybenzene, Chromium-cobalt-alu active Substance may be higher than in the polyethylene gly minium oxide, ferric ferrocyanide, Ferric oxide, Iron ammo col and/or polyethylene oxide alone. The same may apply nium citrate, Iron (III) oxide hydrated, Iron oxides, Carmine with respect to the stability of the amorphous form of the red, Magnesium carbonate and Titanium dioxide. active Substance. Plasticizer may be incorporated in the composition. A Suit Pharmaceutically Acceptable Excipients 35 able plasticizer is selected from Such as e.g. mono- and di The composition may also contain other excipients as well, acetylated monoglycerides, diacetylated monoglycerides, e.g. in order to improve the technical properties of the com acetylated hydrogenated cottonseed glyceride, glyceryl position so that it may be easier to produce or in order to cocoate, Polyethylene glycols or polyethylene oxides (e.g. improve the properties of the composition Such as release rate with a molecular weight of about 1,000-500,000 daltons), of the active substance, stability of the active substance or of 40 dipropylene glycol salicylate glycerin, fatty acids and esters, the composition itself etc. phthalate esters, phosphate esters, amides, diocyl phthalate, A Suitable pharmaceutically acceptable excipient for use in phthalylglycolate, mineral oils, hydrogenated vegetable oils, a composition of the invention may be selected from the Vegetable oils, acetylated hydrogenated Soybean oil glycer group consisting of fillers, diluents, disintegrants, glidants, ides, Castor oil, acetyl tributyl citrate, acetyl triethylcitrate, pH-adjusting agents, viscosity adjusting agents, Solubility 45 methyl abietate, nitrobenzene, carbon disulfide, 13-naphtyl increasing or decreasing agents, osmotically active agents salicylate, sorbitol, sorbitol glyceryl tricitrate, fatty alcohols, and solvents. cetostearyl alcohol, cetyl alcohol, Stearyl alcohol, oleyl alco Suitable excipients include conventional tablet or capsule hol, myristyl alcohol. Sucrose octaacetate, alfa-tocopheryl excipients. These excipients may be, for example, diluents polyethylene glycol succinate (TPGS), tocopheryl derivative, Such as dicalcium phosphate, calcium sulfate, lactose or 50 diacetylated monoglycerides, diethylene glycol monostear Sucrose or other disaccharides, cellulose, cellulose deriva ate, ethylene glycol monostearate, glyceryl monooleate, tives, kaolin, mannitol, dry starch, glucose or other monosac glyceryl monostearate, propylene glycol monostearate, mac charides, dextrin or other polysaccharides, Sorbitol, inositol rogol esters, macrogol Stearate 400, macrogol Stearate 2000, or mixtures thereof binders such as alginic acid, calcium polyoxyethylene 50 Stearate, macrogol ethers, cetomacrogol alginate, Sodium alginate, starch, gelatin, Saccharides (in 55 1000, lauromacrogols, nonoxinols, octocinols, tyloxapol, cluding glucose, Sucrose, dextrose and lactose), molasses, poloxamers, polyvinyl alcohols, polysorbate 20, polysorbate panwar gum, ghatti gum, mucilage ofisapolhusk, carboxym 40, polysorbate 60, polysorbate 65, polysorbate 80, polysor ethylcellulose, methylcellulose, Veegum, larch arabolactan, bate 85, sorbitan monolaurate, sorbitan monooleate, sorbitan polyethylene glycols, ethylcellulose, water, alcohols, waxes, monopalmitate, Sorbitan monostearate, Sorbitan sesqui polyvinylpyrrolidone such as, e.g., PVP K90 or mixtures 60 oleate, Sorbitan trioleate, Sorbitan tristearate and Sucrose thereof: lubricants such as talc, silicium dioxide, magnesium esters, amyl oleate, butyl oleate, butyl stearate, diethylene Stearate, calcium Stearate, Stearic acid, hydrogenated veg glycol monolaurate, glycerol tributyrate, Cumar W-1, Cumar etable oils, Sodium benzoate, Sodium chloride, leucine, car MH-1, Cumar V-1, Flexol B-400, monomeric polyethylene bowax 4000, magnesium laurylsulfate, Sodium laurilsulfate, ester, Piccolastic A-5, Piccalastic A-25, Beckolin, Clorafin Stearyl alcohol, Polysorbate 20, Polysorbate 60, Polysorbate 65 40, acetyl tributyl citrate, acetyl triethyl citrate, benzyl ben 80, Macrogol stearate, Macrogol lauryl ether, Stearoyl mac Zoate, butoxyethyl Stearate, butyl and glycol esters of fatty rogolglycerides, Sorbitan Stearate, Sorbitan laurate, Mac acids, butyl diglycol carbonate, butyl ricinoleate, butyl US 8,821,928 B2 35 36 phthalyl butyl glycolate, camphor, dibutyl sebacate, dibutyl thereof, saccharides, oligosaccharides, polysaccharides, tartrate, diphenyl oxide, glycerine, HB-40, hydrogenated polyethylene glycol derivatives and cellulose and cellulose methyl ester of rosin, methoxyethyl oleate, monoamylphtha derivatives. late, Nevillac 10, Paracril 26, technical hydroabietyl alcohol, Alternatively or additionally, a suitable pharmaceutically triethylene glycol dipelargonate, Solid aliphatic alcohols, acceptable excipient is a mono-, di-, oligo, polycarboxylic nitrobenzene, carbon disulfide, B-naphtyl salicylate, phthalyl acid or amino acids such as, e.g. acetic acid, Succinic acid, glycolate, dioctyl phthalate, and mixtures thereof. Other suit citric acid, tartaric acid, acrylic acid, benzoic acid, malic acid, able plasticizers appear from EP-B-0 746 310 to which ref maleic acid, Sorbic acid etc., aspartic acid, glutamic acid etc. erence is made. Examples of Suitable organic acids include acetic acid/ The use of a plasticizer will often be desirable in order to 10 improve the processibility of the coating. The plasticizer may ethanoic acid, adipic acid, angelic acid, ascorbic acid/vitamin also be a non-ionic Surfactant, e.g. a non-ionic Surfactant as C, carbamic acid, cinnamic acid, citramalic acid, formic acid, the one mentioned above. fumaric acid, gallic acid, gentisic acid, glutaconic acid, glu Preferred stabilizers (chemical) include TPG e.g. in the taric acid, glyceric acid, glycolic acid, glyoxylic acid, lactic form of TPGS due to surfactant properties, BHA, BHT, t-bu 15 acid, levulinic acid, malonic acid, mandelic acid, oxalic acid, tyl hydroquinone, calcium ascorbate, gallic acid, hydro oxamic acid, pimelic acid, and pyruvic acid. quinone, maltol, octyl gallate, Sodium bisulfite, Sodium met Examples of Suitable inorganic acids include pyrophos abisulfite, tocopherol and derivates thereof, citric acid, phoric, glycerophosphoric, phosphoric Such as ortho and tartaric acid, and ascorbic acid. Other stabilisers include triva metaphosphoric, boric acid, hydrochloric acid, and Sulfuric lent phosphorous like e.g. phosphite, phenolic antioxidants, acid. hydroxylamines, lactones such as Substituted benzofura Examples of Suitable inorganic compounds include alu nones. Hindered phenols, thiosynergists and/or hindered minium. amines, acids (ascorbic acid, erythorbic acid, etidronic acid, Examples of organic bases are p-nitrophenol, Succinimide, hypophosphorous acid, nordihydroguaiaretic acid, propionic benzenesulfonamide, 2-hydroxy-2cyclohexenone, imida acid etc.), phenols, dodecyl gallate, octyl gallate, 1,3,5-trihy 25 Zole, pyrrole, diethanolamine, ethyleneamine, tris (hy droxybenzene, organic and inorganic salts (calcium ascor droxymethyl)aminomethane, hydroxylamine and derivates bate, Sodium ascorbate, Sodium bisulphite, Sodium met of amines, sodium citrate, aniline, hydrazine. abisulfite, Sodium Sulfite, potassium bisulphite, potassium Examples of inorganic bases include aluminium oxide metabisulphite), esters (calcium ascorbate, dilauryl thio Such as, e.g., aluminium oxide trihydrate, alumina, Sodium dipropionate, dimyristyl thiodipropionate, distearyl thio 30 hydroxide, potassium hydroxide, calcium carbonate, ammo dipropionate), pyranon (maltol), and vitamin E (tocopherol, nium carbonate, ammonium hydroxide, KOH and the like. D-O-tocopherol, DL-C-tocopherol, tocopheryl acetate, d-C.- Suitable pharmaceutically acceptable salts of an organic tocopheryl acetate, dl-C-tocopheryl acetate. However, other acid is e.g. an alkali metal salt or an alkaline earth metal salt anti-oxidative agents known in the art may be used according Such as, e.g. sodium phosphate, Sodium dihydrogenphos to the present invention. Other suitable stabilizer is selected 35 phate, disodium hydrogenphosphate etc., potassium phos from Such as e.g. Sorbitol glyceryl tricitrate. Sucrose octaac phate, potassium dihydrogenphosphate, potassium hydro etate. genphosphate etc., calcium phosphate, dicalcium phosphate Modifier may be incorporated in the composition. A suit etc., Sodium Sulfate, potassium sulfate, calcium sulfate, able modifier is selected from Such as e.g. fatty acids and Sodium carbonate, Sodium hydrogencarbonate, potassium esters, fatty alcohols, cetyl alcohol, Stearyl alcohol, mineral 40 carbonate, potassium hydrogencarbonate, calcium carbonate, oils, hydrogenated vegetable oils, vegetable oils, acetylated magnesium carbonate etc., Sodium acetate, potassium hydrogenated soybean oil glycerides, Castor oil, phosphate acetate, calcium acetate, Sodium Succinate, potassium Succi esters, amides, phthalate esters, glyceryl cocoate oleyl alco nate, calcium Succinate, Sodium citrate, potassium citrate, hol, myristyl alcohol. Sucrose octaacetate, diacetylated calcium citrate, sodium tartrate, potassium tartrate, calcium monoglycerides, diethylene glycol monostearate, ethylene 45 tartrate etc. glycol monostearate, glyceryl monooleate, glyceryl A Suitable inorganic salt for use in a matrix composition of monostearate, propylene glycol monostearate, macrogol the invention is sodium chloride, potassium chloride, calcium esters, macrogol Stearate 400, macrogol Stearate 2000, poly chloride, magnesium chloride etc. oxyethylene 50 Stearate, macrogol ethers, cetomacrogol Saccharides such as glucose, ribose, arabinose, Xylose, 1000, lauromacrogols, poloxamers, polyvinyl alcohols, Sor 50 lyxose, Xylol, allose, altrose, inosito, glucose, Sorbitol, man bitan monolaurate, Sorbitan monooleate, Sorbitan mono nose, gulose, Glycerol, idose, galactose, talose, mannitol, palmitate, Sorbitan monostearate, Sorbitan sesquioleate, Sor erythritol, ribitol, xylitol, maltitol, isomalt, lactitol, sucrose, bitan trioleate, sorbitan tristearate, ethylcellulose, cellulose fructose, lactose, dextrin, dextran, amylose, Xylan. acetate, cellulose propionate, cellulose nitrate, cellulose Polyethylene glycol derivatives such as e.g. polyethylene derivative selected from the group consisting of methylcellu 55 glycol di(2-ethyl hexoate), polyethylene glycols (200-600 lose, carboxymethylcellulose and salts thereof, cellulose daltons) or polyethylene oxides, e.g. with a molecular weight acetate phthalate, microcrystalline cellulose, ethylhydroxy of about 800-500,000 daltons, typically about 1,000-100,000 ethylcellulose, ethylmethylcellulose, hydroxyethylcellulose, daltons, more typically 1,000-50,000 daltons, especially hydroxyethylmethylcellulose, hydroxypropylcellulose, about 1,000-10,000 daltons, in particular about 1,500-5,000 hydroxypropylmethylcellulose, hydroxymethylcellulose and 60 daltons, and mixtures thereof. hydroxymethylpropylcellulose, cellulose acetate, polylactic Cellulose and cellulose derivative selected from the group acid or polyglycolic acid and copolymers thereof, methacry consisting of methylcellulose, carboxymethylcellulose and lates, a co-polymer of methacrylate-galactomannan etc., salts thereof, microcrystalline cellulose, ethylhydroxyethyl Polyvinyl alcohols, glycerinated gelatin, cocoa butter cellulose, ethylcellulose, cellulose acetate, cellulose propri Other suitable modifier may be selected from the group 65 onate, cellulose nitrate, cellulose acetate phthalate, ethylm consisting of inorganic acids, inorganic bases, inorganic salts, ethylcellulose, hydroxyethylcellulose, organic acids or bases and pharmaceutically acceptable salts hydroxyethylmethylcellulose, hydroxypropylcellulose, US 8,821,928 B2 37 38 hydroxypropylmethylcellulose, hydroxymethylcellulose and the active substance and the conversion from the crystalline hydroxymethylpropylcellulose. state to the amorphous state requires addition of energy (heat Preparation of a Composition of the Present Invention ing). A composition of the invention may be produced by vari Normally, when preparing a composition according to the ous methods which are either known per se in the pharma invention heating is employed for e.g. an injection moulding ceutical industry or which, for example, are used in the pro process. During heating it has been observed that PEO in duction of polymer-based materials, depending upon the various qualities forms free radicals that results in the forma desired embodiment and the materials employed in the com tion of interalia formaldehyde and formic acid. These prod position in question. One advantage of the composition ucts may often lead to further degradation e.g. of the active 10 Substance present in the composition and it is therefore nec according to the invention is that it may be produced by essary to take the necessary precautions in this respect. Oxi methods, which are relatively simple and inexpensive. dative free radicals degradation by hydroperoxides can be Suitable preparation methods for compositions according catalysed by certain transition metal ions, especially those of to the invention include extrusion, injection moulding, tablet copper, cobalt and manganese. Thus, employment of PEO ting, capsule filling, thermoforming, spray coating, micro 15 qualities devoid of or only containing a very small amount of encapsulation and other methods suitable for preparation of Such transition metal ions may improve stability. Another controlled release compositions. possibility is to use component in a quality that ensures that Compositions according to the invention may be prepared free radicals formed, if any, do not significantly increase the in numerous ways giving rise to different release mecha degradation of the active Substance in the composition. Such nisms. Particularly the composition may be prepared by 1, 2 a quality could e.g. be a quality containing an antioxidant that or multiple component injection mouldings, by conventional functions by preventing the formation of free radical during tablet compression, by tablet compression and afterward tem heating or by Scavenging any free radicals formed. Another perature curing, by micro encapsulation, by 1, 2 or multiple possibility is to add such antioxidant to the formulation component extrusions, by capsule filling or by thermoform before any heating takes place. ing. In cases were a preparation is needed in order to make the 25 A composition according to the invention may therefore controlled release properties before/after the above mentions further comprise one or more antioxidants that inhibits the preparation steps, the preparation may also comprise separate formation of peroxides and/or inactivates any peroxides steps as for example wet granulation, dry granulation, melt present. granulation, pelletizing, roller compaction, spray coating, Suitable antioxidants for use includes beta-carotein (a vita 30 minA precursor), ascorbic acid, ascorbyl palmitate, butylated electrostatic coating or other forms of controlled release hydroxyanisole, butylated hydroxytoluene, hypophospho preparation methods. rous acid, monothioglycerol, potassium metabisulfite, In a particular example the composition is prepared by Sodium metabisulfite, propyl gallate, sodium formaldehyde two/three component injection moulding of a matrix and a sulfoxylate, sodium thiosulfate, sulfur dioxide, tocopherol, coat partly covering the matrix and exposing two ends of the 35 tocopherolacetate, tocopherol hemisuccinate, TPGS or other composition for erosion governed release. tocopherol derivatives, sulfides, phosphine etc. Other suitable During the injection moulding process it is possible to antioxidants are described herein. place separately prepared components and include these in It is believed that the amorphous state of the active sub the final product by insert-moulding or similar methods. Fur stance is furthermore favoured by the processing procedures ther separately prepared components from injection mould 40 of the preparation of the product according to the present ing or other processes e.g. tablets, pellets etc. can be invention, which in a preferred embodiment involves injec assembled in a separate, automated assembly process. tion moulding of the pharmaceutical units. A composition may also be produced by, for example, For further details reference is made to the experimental injection moulding, co-extrusion of the coating with the section herein. matrix composition and the active Substance, extrusion and 45 Other Specific Embodiments of the Invention dip coating, injection moulding and dip coating, or by extru In the following is described various embodiments of the sion or injection moulding and solvent coating by spraying or present invention. These embodiments illustrate the flexibil dipping, electrostatic coating. Multiple component injection ity of the technology to obtain different release patterns and moulding, or a combination of these methods. the flexibility with respect to including two or more, the same The injection moulding technique have the advantage of 50 or different, active Substances in a composition of the inven simultaneous mixing and heating the components during tion in order to obtain a composition that releases the active increased pressure in a one step procedure without exposure Substance in a different manner dependent on in which layer to air and moisture because the injection moulding is per the active Substance is present. Accordingly, a composition of formed in a single closed compartment from the time the the present invention can be designed to have release proper blend has entered the machine to the final pharmaceutical 55 ties including burst release (very fast release of substantially units are ejected ready for packaging. the whole content in that part of the composition), controlled In a further aspect of the invention, the blending process release (typically prolonged or extended release), delayed may be followed by an extrusion step for obtaining pellets release (i.e. release only after a certain lag time) and imme Suitable for feeding of the injection moulding machines. The diate release (relatively fast release). Thus, the following extruding step may secure a more intimate blending and 60 types can be obtained: thereby higher reproducibility of the final pharmaceutical If only one active Substance is present in the composition: product. Delayed release immediate release It should also be mentioned that the present technology Delayed release—controlled release also can be applied when it is desired to have an amorphous Burst release—delayed release immediate release form of the active Substance in the composition, because the 65 Burst release—delayed release—controlled release most convenient process for the preparation of a composition Burst release immediate release of the invention involves heating of the polymer together with Burst release—controlled release US 8,821,928 B2 39 40 Controlled release Immediate release dosage regimen, e.g. requiring administration of a drug at set Controlled release—controlled release intervals up to several times a day, may be dispensed with. It If e.g. two different active substances (S1 and S2) are is possible to combine two or more active substances each present, the following can be designed: following and independent release pattern however the Delayed release for S1, but controlled release for S2 im release pattern of Such Substances may also be identical. mediate release for S1 The matrix of the outer layer of a pharmaceutical compo Delayed release for S1, but controlled release for S2 con sition of the invention may be designed to release an active trolled release for S1 Substance, if any, in a controlled manner Such as by a Zero Burst release for S1 and/or S2 delayed release for S1, but order release mechanism. Accordingly, the composition is controlled release for S2 immediate release S1 10 also suitable for controlled release of an active substance, i.e. Burst release for S1 and/or S2 delayed release for S1, but first a controlled release of an active substance (from the controlled release for S2-controlled release for S1. matrix, layer B) and then a relatively fast release of the same Burst release for S1 and/or S2 immediate release for S1 or different active substance (from the Layer A) or other and/or S2 suitable release combinations. In the present context the term Burst release for S1 and/or S2-controlled release for S1 15 “controlled release' is used to designate a release a desired and/or S2 from multiple units rate during a predetermined release period. Terms like “modi Controlled release for S1 and/or S2 Immediate release fied”, “delayed, “sustained”, “prolonged”, “extended” etc. for S1 and/or S2 release are in the present context synonyms to the term “con Controlled release for S1 and/or S2-controlled release for trolled release'. Normally, the term relates to compositions S1 and/or S2 from multiple units that have a slower release of the active ingredient than that of A person skilled in the art will know how to obtain other a plain tablet or a tablet designed for immediate release. A combinations in view of the guidelines given herein. person skilled in the art knows of these terms. In a specific embodiment, the present invention provides a In order to more detailed explain the invention; reference is composition for controlled delivery of at least one active made to (EP 0406315, EP 0493513, WO 2006/128471) substance. It is possible to include two or more different 25 herein although the invention is not limited to this type and active Substances in the composition of the invention, adapted shape of the composition. However, the general idea is to have to enable release at different concentrations, intervals and/or a layered composition, wherein the layers are separate layers. release rates. However, a person skilled in the art will understand that Apart from the content of an active Substance in the inner other forms may fulfil the same objective. The most simpli layer, the same and/or a different active Substance (second 30 fied versions of the pharmaceutical composition according to active Substance) can be substantially homogeneously dis the invention are either a sphere or an oval shaped first frac persed in the outer layer (the polymer matrix), in which case tion surrounded by a sphere oran oval shaped second fraction, a substantially zero order release of the second active sub reference is made to (EP 0406315, EP 0493513, WO 2006/ stance is obtained. Alternatively or in addition, a burst release 128471). of the same or a different active substance may be obtained in 35 In one embodiment of the invention a double burst unit is a composition of the invention which comprises alternating presented by having a layered composition placed inside an layers. In a composition comprising alternating layers, the immediate release tablet matrix in such a way that the outer alternating layers may comprise, respectively, none, one, two matrix is eroded or disintegrated, exposing the layered com or more different active substances. position, as shown in FIG. 1. As described in detail above, an inner layer comprises a 40 In one embodiment of the invention, the inner layer of a quick release function obtained by e.g. fast disintegration, composition according to the invention comprises an active exploding and/or effervescent effects. The first fraction com substance. The release of the active substance is delayed prises because the outer layer must erode before the first fraction is a) a disintegration agent, an exploding agent, an efferves exposed to the gastrointestinal fluids after oral administra cent agent or a mixture thereof 45 tion. b) optionally, an active Substance In one embodiment of the invention it is possible to obtain c) optionally, multiple units comprising an active Sub a substantially controlled burst release, optionally in combi stance and, nation with a constant rate of release over a specific period of d) optionally, one or more pharmaceutically acceptable time. It is possible to combine two or more active substances excipients 50 each following and independent release pattern however the The outer layers (matrix compositions) comprise release pattern of Such substances may also be identical. It a) a polymer or a mixture of polymers, may in certain cases be desirable to incorporate a mixture of b) optionally, an active Substance and, two active substances into the matrix in order to release both c) optionally, multiple units comprising an active Sub active Substances in the matrix with the same release rate. In stance and, 55 other cases it is desirable to have different release rates of the d) optionally, one or more pharmaceutically acceptable two active substances. In Such cases the composition may be excipients. composed of two different matrixes, each with different A third component may also be present comprising release characteristics. In yet another case the release of the a) a polymer or a mixture of polymers, active Substances may be sequential. Such that during the b) optionally, one or more pharmaceutically acceptable 60 initial dissolution phase one active Substance S1 is released excipients. and then the other S2. In this case the second release is onset Due to the nature of the composition of the invention, it is after a lag defined by the first release. possible to obtain a substantially controlled pulsatile/burst More specifically, without limiting the invention thereto, release, optionally in combination with a constant rate of the invention is illustrated by the embodiments mentioned release of the active substance over a specific period of time. 65 below. Various different formulations of layers A) and B) are The amount of drug release corresponds to the dosage neces given and any combination of layers A) and B) is contem sary for the treatment in question, so that adherence to a strict plated (i.e. any of the layer B) of 1, 2, 5-9 may be combined US 8,821,928 B2 41 42 with any of layer A) 3, 4, 10-14, and the multiple unit formu 7. A controlled release layer B): lations 15 or 16 may be part of either layer A) or B), and the coat formulations 17 or 18 may be applied to any of the combined formulations): Ingredient % Wiw 1. A burst release layer B) or multiple units: 5 PEO SOOOOO 2O Poloxamer 407 50 Mannitol 2 Ingredient % Wiw Active substance 28 Homopolymer (e.g. 20,000-100,000 daltons 5-70 PEO) 10 8. A controlled release layer B): Co-polymer (e.g. 1,000-16,000 daltons 5-70 Poloxamer) Active Substance O. 1-80 Filler Up to 100% Ingredient % Wiw 15 PEO 700 OOO 2O Poloxamer 407 50 2. A controlled release layer B) or multiple units: Sorbitol 2 Active substance 28

Ingredient % Wiw 9. A controlled release layer B): Homopolymer (e.g. 100,000-700,000 daltons 5-70 2O PEO) Co-polymer (e.g. 1,000-30,000 daltons 5-70 Poloxamer) Ingredient % Wiw Active Substance O. 1-80 Filler Up to 100% PEO 100 OOO 52 25 Poloxamer188 10 Eudragit RL 10 3. A burst release inner layer A): Active substance 28

Ingredient % Wiw 10. A burst release inner layer A): 30 Homopolymer (e.g. 1,000-16,000 daltons 5-70 PEO) Co-polymer (e.g. 2,000-30,000 daltons 5-70 Ingredient % ww Poloxamer) Croscarmellose 2O Swelling agent S-80% Lactose 2O Active Substance O. 1-80 35 PEO 100 OOO 5 Filler Up to 100% Poloxamer 188 5 Active substance 50 4. A burst release inner layer A): 11. A burst release inner layer A): 40 Ingredient % Wiw Homopolymer (e.g. 1,000-16,000 daltons 5-70 Ingredient % Wiw PEO) Co-polymer (e.g. 2,000-30,000 daltons 5-70 Starch 2O Poloxamer) Lactose 2O Effervescent agent S-80% 45 PEG 1500 5 Active Substance O. 1-80 Poloxamer 188 5 Filler Up to 100% Active substance 50

5. A burst release layer B): 12. A burst release inner layer A): 50

Ingredient % Wiw Ingredient % Wiw

PEO 1 OOOOO 5 PEO 100 OOO 5 Poloxamer 188 5 Poloxamer 188 5 Maltitol 15 55 Citric Acid 10 Active Substance 75 NaHCO 10 Active substance 70 6. A controlled release layer B): 13. A burst release inner layer A): 60 Ingredient % Wiw Ingredient % Wiw PEO 200 OOO 25 Poloxamer 338 25 PEO 100 OOO 5 Xylitol 10 Poloxamer 188 5 Active Substance 40 65 Povidone 2 Citric Acid 10 US 8,821,928 B2 44 -continued ii) an active Substance, the solid inner core being sandwiched between two outer Ingredient % Wiw layers B1 and B2), each outer layer comprising iii) a substantially water soluble and/or crystalline polymer NaHCO, 10 Active Substance 68 or a mixture of substantially water soluble and/or crystalline polymers, the polymer being a polyglycol in the from of one of c) a homopolymer having a MW of at least about 100,000 14. A burst release inner layer A): daltons, and d) a copolymer having a MW of at least about 2,000 daltons, 10 and i) of layer Abeing different from iii) of layer B. Ingredient % Wiw the layered composition being coated with a coating C) that PEO 1 OOOOO 5 has at least one opening exposing at least one Surface of said Poloxamer 188 5 outer layer, the coating being Substantially insoluble in and Povidone 2 Citric Acid 10 impermeable to fluids and comprising a polymer. NaHCO 10 15 2. A composition according to item 1, wherein A) further Active Substance 68 comprises one or more disintegration/exploding agents, one of more effervescent agents or a mixture thereof. 3. A composition according to item 2, wherein the disinte 15. Burst release multiple units: grant/exploding is Sodium starch glycolate, Povidone, Sodium alginate, Alginic acid, Calcium alginate, Carboxym Ingredient % Wiw ethylcellulose calcium, Carboxymethylcellulose sodium, Powdered cellulose, Chitosan, Croscarmellose sodium, PEO 1 OOOOO 5 Crospovidone, Hydroxypropyl starch, Hydroxypropyl cellu Poloxamer 188 5 Povidone 2O lose low-substituted, Magnesium aluminium silicate, Meth Active Substance 70 25 ylcellulose, Microcrystalline cellulose, pregelatinized starch, Docusae sodium, Guar gum, Polacrilin potassium or the like. 4. A composition according to item 2, wherein the effer 16. Controlled release multiple units: Vescent agent is Effer-Soda, Citric acid, Citric acid, monohy drate, Dextrates, Fumaric acid, Potassium bicarbonate, 30 Sodium bicarbonate, Sodium citrate dehydrate, Tartaric acid Ingredient % Wiw or the like. PEO 100 OOO 5 5. A composition according to any of the preceding items, Poloxamer 407 15 Ethylcellulose 70 wherein the outer layer B1 and/or B2 when exposed to an Active Substance 10 aqueous medium erodes at a substantially constant rate. 35 6. A composition according to any of the preceding items, wherein the active substance in A) is subject to release after a 17. Controlled release multiple units coated with Eudragit lag time corresponding to the erosion time of the layer B1 RL 3ODFRS 3OD: and/or B2. 7. A composition according to any of the preceding items, 40 wherein the inner layer A) without B) and C) disintegrates Ingredient % Wiw within at the most 60 min such as, e.g., at the most about 30 PEO 1 OOOOO 5 minor at the most about 15 min, when subjected to a disin Poloxamer 188 5 tegration test according to Ph. Eur. Povidone 2O 8. A composition according to any of the preceding items Active Substance 70 45 having a cylindrical shape optionally with one or more tapered ends. 18. Coat with a solid content of 20% 9. A composition according to any of the preceding items, wherein the coating C) appears as a Substantially intact empty shell when the composition has been subjected to a dissolu Ingredient % Wiw 50 tion test according to Ph. Eur, by which the outer layer B) Eudragit RL30D 3.9 erodes and the inner layer A) disappears from the composi Eudragit RS 30D 35.3 tion optionally by means of one or more disintegration agents, Talc 5.9 explosion agents, effervescent agents or a mixture thereof. Triethyl citrate 2.33 10. A composition according to any of the preceding items, Water 52.5 55 wherein the polymers i) and iii), and the polymer contained in the coating C) are thermoplastic. In the appended FIGS. 15-24 are given release profiles Inner Layer obtainable by compositions of the present invention. 11. A composition according to any of the preceding items, Other specific embodiments are listed in the following: wherein polymeri) comprises a homopolymer having a MW 1. A layered pharmaceutical composition comprising 60 of at least about 1,000 daltons such as, e.g., a homopolymer A) a solid inner layer comprising having a MW in a range from about 1,000 to about 15,000 i) a substantially water soluble and/or crystalline polymer daltons, from about 1,000 to about 12,000 daltons, from about or a mixture of substantially water soluble and/or crystalline 1,500 to about 10,000 daltons, from about 1,500 to about polymers, the polymer being a polyglycol in the from of one 8,000 daltons. of a) a homopolymer having a MW of at the most about 65 12. A composition according to any of the preceding items, 16,000 daltons, and b) a copolymer having a MW of at the wherein polymeri) comprises a copolymer having a MW of at most about 30,000 daltons, and the most about 25,000 daltons such as, e.g., at the most about US 8,821,928 B2 45 46 20,000 daltons, at the most about 15,000 daltons, at the most 26. A composition according to any of the preceding items, about 10,000 daltons, at the most about 5,000 daltons, at the wherein the coating does not completely crumble or erode most about 2,000 daltons. before the layer B) has completely eroded and the layer A) is 13. A composition according to any of the preceding items, released. wherein the active Substance in A) is present at least partly in 5 The invention is further illustrated in the following non solid or dissolved form. limiting examples. 14. A composition according to any of the preceding items, wherein the active substance in A) is present in form of DESCRIPTION OF THE FIGURES pellets, beads, flakes, mini-tablets, granules, microspheres, nanoparticle, crystals or the like. 10 FIG. 1, illustrate double burst unit, with a delay between 15. A composition according to claim 14, wherein the the two bursts active Substance containing pellets, beads, flakes, mini-tab lets, granules, microspheres, nanoparticles, crystal or the like FIG. 2, illustrate simple combination formulation are dispersed in the polymeri). FIG.3, releases of Hydrocodone and Morphine with burst 16. A composition according to any of the preceding items, 15 controlled release behaviour see preparation 4 wherein the concentration of the polymeri) in inner layer A) FIG. 4, releases of Oxycodone and Morphine with con is from about 5% w/w to about 100% w/w. trolled-controlled release behaviour see preparation 5 17. A composition according to any of the preceding items FIG. 5, illustrate double burst unit, with a delay between 2-16, wherein the concentration of the one or more disinte the two bursts gration/exploding agent, if present, is from about 5% w/w to FIG. 6, release of Paracetamol with double burst release about 80% w/w such as, e.g., from about 10% w/w to about behaviour see example 2 70% w/w, from about 15% w/w to about 60% w/w or from FIG. 7, illustrate unit exhibiting controlled-burst or burst about 20% w/w to about 50% w/w. burst release behaviour 18. A composition according to any of the preceding items, FIG. 8, release of Morphine with controlled-burst release wherein the concentration of the one or more effervescent 25 behaviour see example 3 agent, if present, is from about 5% w/w to about 80% w/w FIG. 9, release of Morphine with controlled-burst release such as, e.g., from about 10% w/w to about 70% w/w, from behaviour see example 4 about 15% w/w to about 60% w/w or from about 20% w/w to FIG. 10, illustrate unit exhibiting controlled-controlled or about 50% w/w. burst-controlled release behaviour Outer Layer 30 FIG. 11, release of Morphine with controlled-controlled 19. A composition according to any of the preceding items, release behaviour see example wherein polymeriii) comprises one or more of a polyethylene FIG. 12, release of Morphine pellets see example 5 glycol, a polyethylene oxide and/or a copolymer of ethylene FIG. 13, release of Morphine with controlled-controlled oxide and propylene oxide including poly(ethylene-glycol-b- release behaviour see example 6 (DL-lactic acid-co-glycolic acid)-b-ethylene glycol (PEG 35 PLGA PEG), poly((DL-lactic acid-co-glycolic acid)-g-ethyl FIG. 14, release of Morphine with burst-controlled release ene glycol) (PLGA-g-PEG), and polyethylene oxide behaviour see example 7 polypropylene oxide (PEO-PPO). FIG. 15, illustrate burst-lag-burst release characteristics 20. A composition according to item 19, wherein the poly FIG. 16 illustrate burst-controlled-burst release character ethylene glycol or a polyethylene oxide has a molecular 40 istics weight from about 100,000 to about 700,000. FIG. 17 illustrate burst-controlled release characteristics 21. A composition according to item 19, wherein the FIG. 18 illustrate controlled-burst release characteristics copolymer of ethylene oxide and propylene oxide comprises FIG. 19 illustrate lag-burst release characteristics up to about 30% w/w of the propylene oxide based block, and FIG. 20 illustrate controlled-controlled release character has a molecular weight of from about 5,000 to about 15,000 45 istic daltons. FIG. 21 illustrate controlled-controlled release character 22. A composition according to any of the preceding items, istic wherein the concentration of polymer iii) in layer B) is from FIG.22 illustrate releases of two active substances with the about 5% w/w to about 100% w/w. same release characteristics 23. A composition according to any of the preceding items, 50 FIG. 23 illustrate releases of two active substances with wherein layer B1) and/or B2) contain a second active sub different release characteristics Stance. FIG. 24 illustrate releases of two active substances with 24. A composition according to item 23, wherein the sequential release characteristics release of the second active substance follows a Zero order release pattern at least up to 80% w/w release of the total 55 EXAMPLES content of second active Substance in layer B). Coating Dissolution Method for Testing Dosage Units 25. A composition according to any of the preceding items, According to the Invention wherein the polymer comprised in the coating is selected from the group consisting of ethylcellulose, cellulose acetate, 60 Dissolution testing is performed according to USP 30, NF cellulose propionate, cellulose nitrate, polyamide, polyethyl 25 (711), and apparatus 2 (paddle method). The dissolution ene, polyethylene terephtalate, polypropylene, polyurethane, medium may consist of 0.1M HCl or phosphate buffer e.g. polyvinyl acetate, polyvinyl chloride, silicone rubber, latex, pH 6.8, pH 6.8 & 40% ethanol or pH 7.2. The volume of polyhydroxybutyrate, polyhydroxyvalerate, teflon, polylac dissolution medium is typically 900 ml or 1000 ml and the tic acid or polyglycolic acid and copolymers thereof, copoly 65 paddle speed is 50 rpm. Samples are withdrawn at suitable mers including ethylene vinyl acetate, styrene-butadiensty time points and analysed for content of active Substance by rene and styrene-isoprene-styrene. means of on-line UV detection or HPLC with UV detection. US 8,821,928 B2 47 48 Methods Pellets (batch 108-009-05-001C) comprising Hydrocorti A general method for preparation dosage unit is described sone (55% w/w), PEG 8000 (40% w/w) and PVP C15 (5% below. w/w) was prepared by hot melt extrusion followed by grind Preparation of a Matrix Composition ing. The pellets were sieved to reach a final size of 1000 An accurate amount of the polymer is loaded into a MTI um-1200 um. 35-37 mg pellets were mixed with 206-230 mg mixer followed by an accurate amount of the active Substance filler material comprising Lactose (StarLacR). The material and of the pharmaceutically acceptable excipients(s), if any. was placed in an IR-tablet preparing device and compressed The mixing is performed at 900-2000 rpm and at a time period at a pressure of 5 metric tons. up to 20 min. At the start of the mixing the temperature is 10 Dissolution shows that the tablet is completely disinte about 19-21 C. and the final temperature of the mixture is grated after 18 minutes leaving the pellets for slower disso about 30-50° C. The mixture is then allowed to cool to room lution. Upon testing with an USP 2 apparatus using 900 ml temperature and is ready to be fed into an injection moulding phosphate buffered media, pH 6.8 and 50 RPM the following machine. release profile was obtained. Preparation of the Coating Composition The coating composition is prepared by first adding the 15 Ethylcellulose then Cetostearyl alcohol, and finally the Tita Time (min) Release (%) nium dioxide to an MTI-Mixer at a temperature about 19-21 50 min 50 C. Mixing rate is 1000 rpm. The mixer is stopped when the 245 min 8O temperature reaches 40-50° C. and the adhered material is 490 min 90 manually incorporated into the mixture. The mixture is left to cool for about 10 minutes. The mixing is then finalized with a short high-speed mix in order to minimize lumps formation. Preparation 3 The mixture is then allowed to cool to room temperature, after An inner layer A for a dosage unit according to the inven which it has a suitable consistency for being fed into an 25 tion prepared by direct compression (PHH-0120-062-4) injection moulding machine. Pellets (batch 108-009-05-001 C) comprising Hydrocorti Example of a coat composition; son (55% w/w), PEG 8000 (40% w/w) and PVP C15 (5% w/w) was prepared by hot melt extrusion followed by grind ing. The pellets were sieved to reach a final size of 1000 Batch: 58–014-01-013 Batch: 08-0017-058 30 um-1200 um. 35-37 mg pellets were mixed with 165-336 mg Material %(wfw) %(wfw) filler material comprising Lactose (StarLacR):NaHCO:Cit Ethylcellulose 79 86.5 ric Acid (1497:333:272% w/w). The material was placed in Cetostearyl alcohol 2O 12.5 an IR-tablet preparing device and compressed at a pressure of Titanium dioxide 1 1 5 metric tons. 35 Dissolution shows that the tablet disintegrates immediately Small Scale Preparation leaving the pellets for slower dissolution. Upon testing with A mixture may be prepared by simple Volumetric mixing of an USP2 apparatus using 900 ml phosphate buffered media, the components. 3 g of the mixture is then feeded into a table pH 6.8 and 50 RPM the following release profile was top injection molding machine (Haake MiniJet II, Thermo 40 obtained. Electron, Karlsruhe, Germany) and molded directly into a pre-molden shell and/or matrix. Typical settings in the Mini Jet are: Temperature 90-120° C. and pressure 600-800 bar. Time (min) Release (%) Preparation of Dosage Unit 40 min 50 The final dosage units may be prepared according to two 45 185 min 8O different methods. In one method, the coat and the matrix are 435 min 90 moulded individually followed by a manually incorporation of the moulded matrix plug into the moulded coat. The injec Preparation 4 tion moulding machine used is an Arburg Allrounder 220S 250/60. In the second method, the coat and matrix are moul 50 A dosage unit exhibiting Burst-controlled behaviour ded in one process where the coat is moulded in a first step and (MQV batch 1047-041, 1047-042 & 1047-044), see FIG. 2. the matrix is moulded directly into the coat in a second step As both Morphine and Hydrocodone absorb at the same wave (co-moulding or 2-component moulding). The injection length, it has been necessary to conduct two parallel experi moulding machine used is Arburg Allrounder 420 V 800-60/ ments—each experiment applying a dosage unit with active 35. 55 Substance combined with placebo. The dosage units consisted Preparation 1 of two plugs, one containing the active Substance, one being Pellets for the inner layer A of a dosage unit according to a placebo-formulation. Finally the results from the two the invention (PHH 0120-063) experiments were pooled, thereby simulating one dosage unit Pellets were prepared by mixing Poloxamer 188 (48% consisting of the two active Substances, one plug which w/w), Eudragit RL (24% w/w) and Hydrocortisone (28% 60 exhibits burst release of Hydrocodone and the other con w/w) in a beaker on a heat stage set at 150°C. The melt was trolled release of Morphine. applied to a punched plate (hole size 1 mm) and pellets of The shell was produced by injection moulding. The plugs diameter 1 mm was formed. The pellets disintegrated in cold were injection moulded using the mini-jet at applying a tem MQ water in less than 1 h. perature 110°C., a pressure of 800 bar and a cycle time of 20 Preparation 2 65 S. The thickness and the diameter of the plug was 4.5 mm An inner layer A for a dosage unit according to the inven diameter. The exposed area of the matrix (i.e. two ends) is tion prepared by direct compression (PHH-0120-061-2) 35.04 mm and the length of the dosage unit is 9 mm. US 8,821,928 B2 49 50 Preparation of a Controlled Release Plug: perature 110°C., a pressure of 800 bar and a cycle time of 20 The active plug comprised: PoloXamer 188, PEO 300 000, S. The thickness and the diameter of the plug was 4.5 mm Morphine Sulphate pentahydrate and Mannitol, which were diameter. The exposed area of the matrix (i.e. two ends) is mixed. Afterwards the powder mixture fed to the injection 35.04 mm and the length of the dosage unit is 9 mm. moulding machine. 5 Preparation of Plug (for Controlled Release of Morphine): The inactive (placebo) plug comprised: PoloXamer 407, The active plug comprised: PoloXamer 188, PEO 300 000, PEO 300 000, which were mixed. Then the powder mixture Morphine Sulphate pentahydrate and Mannitol, which were was fed to the injection moulding machine. mixed. Afterwards the powder mixture fed to the injection Preparation of a Burst Release Plug: moulding machine. The active plug comprised: Hydrocodone bitartarte, PEG 10 Preparation of Plug (for Controlled Release of Oxyc 3350S, Sodium hydrogen carbonate and Citric acid, which odone): were mixed. Afterwards the powder mixture fed to the injec The active plug comprised: Oxycodone hydrochloride, tion moulding machine. PEO 200 000, Mannitol, PoloXamer 407, which were mixed. The inactive (placebo) plug comprised: PEG 3350S, Afterwards the powder mixture fed to the injection moulding Sodium hydrogen carbonate and Citric acid, which were 15 mixed. Then the powder mixture was fed to the injection machine. moulding machine. In both cases the inactive (placebo) plug comprised: The Controlled Release Plug has the Composition: PoloXamer 407, PEO 300 000, which were mixed. Then the powder mixture was fed to the injection moulding machine. The dosage form (controlled release) consists of an active Content % (w.fw) plug and a placebo plug, the composition is given below: Active plug Morphine sulphate pentahydrate 53 Content % (w.fw) Mannitol 3 25 Active plug PEO 3OOOOO 35 Poloxamer 188 9 Morphine sulphate pentahydrate 53 Inactive (placebo) plug Mannitol 3 PEO 3OOOOO 35 PEO 3OOOOO 85 Poloxamer 188 9 Poloxamer 407 15 30 Oxycodone hydrochloride 53 Mannitol 5 PEO 200 000 17 The Burst Release Plug has the Composition: Poloxamer 407 25 Placebo plug Content % (w.fw) 35 PEO 3OOOOO 85 Poloxamer 407 15 Active plug Shell Hydrocodone bitartrate 53 Ethylcellulose 86.5 PEG 335OS 41 Cetostearyl alcohol 12.5 Sodium hydrogen carbonate 3 40 Titanium dioxide 1.O Citric acid 3 Inactive (placebo) plug The dissolution behaviour as tested by USP 2 apparatus, PEG 335OS 94 (pH 6.8, 900 ml phosphate buffered media, 50 RPM), see Sodium hydrogen carbonate 3 FIG. 4. Citric acid 3 45 Shell Example 1 Ethylcellulose 86.5 Cetostearyl alcohol 12.5 Dissolution of non-compressed inner layer A for a dosage Titanium dioxide 1.O unit according to the invention (PHH-0120-067). 50 Units were prepared by the following procedure: Pellets The dissolution behaviour as tested by USP2 apparatus, comprising Hydrocortison (55% w/w), PEG 8000 (40% w/w) (pH 6.8, 900 ml phosphate buffered media, 50 RPM), see and PVP C15 (5% w/w) was prepared by hot melt extrusion FIG. 3. followed by grinding. The pellets were sieved to reach a Preparation 5 uniform size. 36-38 mg pellets were mixed with 170-175 mg A dosage unit exhibiting Controlled-controlled behaviour 55 filler material comprising lactose (StarLacR), NaHCO and (MQV batch 1047-041), see FIG. 2. As both active substances Citric Acid (18500:825:675% w/w). Shell comprising Ethyl Morphine and Oxycodone absorb at the same wave length, it cellulose (89% w/w), Cetostearyl alcohol (10% w/w) and has been necessary to conduct two parallel experiments— Titanium dioxide (1% w/w) (batch 06-0010-058) was pre each experiment applying a dosage unit with active Substance pared by injection moulding. The dosage unit was hand combined with placebo. The dosage units consisted of two 60 assembled first with a 2 mm thick delay plug comprising PEO plugs, one containing the active substances, one being a pla 200 000, the pellet/filler blend was added and then another 2 cebo-formulation. Finally the results from the two experi mm thick delay plug comprising PEO 200 000. The exposed ments were pooled, thereby simulating one dosage unit con area of the matrix is 77 mm and the length of the shell is 22.7 sisting of Morphine and Oxycodone, both exhibiting . controlled release behavior. 65 Dissolution analysis using USP2 apparatus, pH 6.8, 900 The shell was produced by injection moulding. The plugs ml phosphate buffered media at 50 RPM showed a delay for were injection moulded using the mini-jet at applying a tem more than 4 hours followed by the immediate release of the US 8,821,928 B2 51 52 un-dissolved pellets from the unit into the dissolution media. The shell was produced by injection moulding. The injec From the pellets 50% release of Hydrocortison was reached tion moulding machine used is a Haake Minijet II. End plugs within 4h from time of onset (end of delay). and centre plug were prepared by hand and hand assembled. Each plug had a thickness of 3 mm. Example 2 Preparation of End Plugs (for Controlled Release): PoloXamer 338, PEO 200 000, Morphine Sulphate pen Dosage unit according to the invention exhibiting double tahydrate and Mannitol were mixed. Afterwards the powder burst behaviours (batch 05-0126-110/05-0134-110), see FIG. mixture was heated to approximately 110° C. The melt was 5. moulded into a 3 mm thick, and a 4.5 mm diameter, hole metal Shell, end plugs (layer B), delay plugs and centre plug 10 filter to attain the plugs. (inner layer A) were prepared by injection moulding and hand Preparation of Centre Plug (for Burst Release): assembled. The procedure was as follows: Explotab, Sodium Starch Glycolate & Sodium Carboxym 1 Locate the shell with injection side upward ethyl Starch, Maize starch and Morphine Sulphate pentahy 2 Place the first delay plug with the injection side down drate were mixed. Then the powder mixture was compressed word at the top of the shell 15 to a plug (tablet) by direct compression. Centre plugs of 3 mm 3 Gently push the delay plug a few mm into the shell thickness and a diameter of 4.5 mm were prepared. 4 Place the inner plug at the delay plug and push it into the The procedure was as follows: shell also moving the delay plug 1 Locate the shell with injection side upward 2 Place the first end plug with the injection side down word 5 Place the second delay plug with the injection side at the top of the shell upward at the inner plug and push it into the shell 3 Gently push the centre plug into the shell 6 One end plug is placed at each end of the shell 4 The last end plug is placed at the end of the shell The Dosage Form has the Composition: The Dosage Form has the Composition:

25 Content % (w.fw) Content % (w.fw) End plug End plug Paracetamol 8O Morphine sulphate pentahydrate 16 Peg 8000 10 30 Mannitol 10 Hard fat 4 PEO 200 OOO 34 Sodium bicarbonate 3.3 Citric acid, monohydrate 2.7 PoloXamer 338 40 Delay plug Centre plug Morphine sulphate pentahydrate 32 PEO 200 OOO 99.5 Explotab 50 BHT O.S 35 Maize starch 18 Centre plug Shell Paracetamol 75.2 Ethylcellulose 86.5 Peg 8000 9.4 Hard fat 3.8 Cetostearyl alcohol 12.5 Titanium dioxide 1.O Sodium bicarbonate 9.1 40 Citric acid, monohydrate 2.5 Shell The exposed area of the matrix is 34.72 mm (i.e. two ends) Ethylcellulose 79 and the length of the dosage unit is 9 mm. Cetostearoyl 2O The dissolution behaviour as tested by USP 2 apparatus, Titanium dioxide 1 45 (pH 6.8, 900 ml phosphate buffered media, 50 RPM), see FIG 8. The exposed area of the matrix is 77 mm (i.e. sum of surface area of the two ends) and the length of the shell is 22.7 Example 4 . The dissolution behaviour as tested by USP2 apparatus, 50 A dosage unit according to the invention exhibiting Con trolled-burst behaviour (MQV batch 1047-045), see FIG. 7. (pH 6.8, 1000 ml phosphate buffered media, 50 RPM) was as The shell was produced by injection moulding. The injec follows (see FIG. 6): tion moulding machine used is a Haake Minijet II. End plugs and centre plug were prepared by hand and hand assembled. Time (min) Release (%) 55 Each plug had a thickness of 3 mm. Preparation of End Plugs (for Controlled Release): 15 49 155 50 PoloXamer 338, PEO 200 000, Morphine Sulphate pen 211 70 tahydrate and Mannitol were mixed. Afterwards the powder 218 75 mixture was heated to approximately 110° C. The melt was 241 92 60 moulded into a 3 mm thick, and a 4.5 mm diameter, hole metal 250 94 filter to attain the plugs. Preparation of Centre Plug (for Burst Release): Sodium hydrogen carbonate, Citric acid and Morphine Example 3 Sulphate pentahydrate were mixed. Then the powder mixture 65 was compressed to a plug (tablet) by direct compression. A dosage unit according to the invention exhibiting Con Centre plugs of 3 mm thickness and a diameter of 4.5 mm trolled-burst behaviour (MQV batch 1047-040), see FIG. 7. were prepared. US 8,821,928 B2 53 The Procedure was as Follows: -continued 1 Locate the shell with injection side upward 2 Place the first end plug with the injection side down word Content % (w.fw) at the top of the shell PEO3OOOOO 35 3 Gently push the centre plug into the shell Poloxamer 188 9 4 The last end plug is placed at the end of the shell Pellets The dosage form has the composition: Morphine sulphate pentahydrate 53 Mannitol 3 PEO3OOOOO 35 Content % (w.fw) 10 Poloxamer 188 9 Centre plug End plug Pellets and 25% CrossPovidone were added Morphine sulphate pentahydrate 16 Mannitol 10 PEO 200 OOO 34 15 Shell Poloxamer 338 40 Ethylcellulose 86.5 Centre plug Cetostearyl alcohol 12.5 Titanium dioxide 1.O Morphine sulphate pentahydrate 32 Citric acid 34 Sodium hydrogen carbonate 34 The exposed area of the matrix (i.e. two ends) is 34.72mm Shell and the length of the dosage unit is 9 mm. Ethylcellulose 86.5 The dissolution behaviours as tested by USP2 apparatus, Cetostearyl alcohol 12.5 (pH 6.8 and pH 6.8/40% ethanol, 900 ml phosphate buffered Titanium dioxide 1.O media, 50 RPM), see FIG.11. Furthermore, it is demonstrated 25 that these pellets are abuse resistant as the dissolution rate is The exposed area of the matrix (i.e. two ends) is 34.72mm significantly lower in alcohol-containing media, see FIG. 12. and the length of the dosage unit is 9 mm. Example 6 The dissolution behaviour as tested by USP2 apparatus, (pH 6.8, 900 ml phosphate buffered media, 50 RPM), see A dosage unit according to the invention exhibiting Con FIG. 9. 30 trolled-controlled behaviour (MQV batch 1047-047, see FIG. 10. Example 5 The shell was produced by injection moulding. End plugs and centre plug, comprising pellets, were prepared by hand A dosage unit according to the invention exhibiting Con and hand assembled. Each plug had a thickness of 3 mm. trolled-controlled behaviour (MQV batch 1047-043), see 35 Preparation of End Plods (for Controlled Release): FIG 10. Morphine, PEO and PoloXamer 407 were mixed thor The shell was produced by injection moulding. End plugs oughly and melted to approximately 110° C., and the melt and centre plug, comprising pellets, were prepared by hand was moulded into a 2 mm thick, and a 4.5 mm diameter, hole and hand assembled. Each plug had a thickness of 3 mm. metal filter to attain the plugs. Preparation of End Plugs (for Controlled Release): 40 Preparation of Centre Plod (for Controlled Release): PoloXamer 188, PEO 300 000, Mannitol and Morphine PoloXamer 188, PEO 300 000, Mannitol and Morphine sulphate pentahydrate were mixed. The material was melted Sulphate pentahydrate were mixed and processed on a melt to approximately 110°C., and the melt was moulded into a 3 extruder. The extruded strings were cooled and cut into pel mm thick, and a 4.5 mm diameter, hole metal filter to attain lets. The pellets were sieved to reach a uniform size. Pellets the plugs. 45 were mixed with CrosPovidone to attain a centre plug of Preparation of Centre Plug (for Controlled Release): approximately 3 mm thickness and a 4.5 mm diameter. PoloXamer 188, PEO 300 000, Mannitol and Morphine The Procedure was as Follows: Sulphate pentahydrate were mixed and processed on a melt 1 Locate the shell with injection side upward extruder. The extruded strings were cooled and cut into pel 2 Place the first end plug with the injection side down word lets. The pellets were sieved to reach a uniform size. Pellets 50 at the top of the shell were mixed with CrosPovidone to attain a centre plug of 3 Pellets and CrosPovidone were added into the shell approximately 3 mm thickness and a 4.5 mm diameter. 4 The last end plug is placed at the end of the shell The Procedure was as Follows: The Dosage Form has the Composition: 1 Locate the shell with injection side upward 2 Place the first end plug with the injection side down word 55 at the top of the shell Content % (w.fw) 3 Pellets and CrosPovidone were added into the shell 4 The last end plug is placed at the end of the shell End plug The Dosage Form has the Composition: Morphine sulphate pentahydrate 2O 60 PEO 45 Poloxamer 407 35 Content% (w.fw) Pellets End plug Morphine sulphate pentahydrate 53 Mannitol 3 Morphine sulphate pentahydrate 65 PEO3OOOOO 35 Mannitol 3 Poloxamer 188 9 US 8,821,928 B2 55 56 -continued The exposed area of the matrix (i.e. two ends) is 34.72mm and the length of the dosage unit is 9 mm. Content% (w.fw) The dissolution behaviour as tested by USP 2 apparatus, (pH 6.8,900 ml phosphate buffered media, 50 RPM) see FIG. Centre plug 5 14. Pellets and 25% CrossPovidone were added Shell The invention claimed is: Ethylcellulose 86.5 1. A layered pharmaceutical composition formulated and Cetostearyl alcohol 12.5 configured to provide controlled release of an active sub Titanium dioxide 1.O 10 stance, the pharmaceutical composition comprising: a solid inner layer (A) comprising the active Substance and an effervescent agent selected to aid release of the active The exposed area of thematrix (i.e. two ends) is 34.72mm substance from the solid inner layer (A): and the length of the dosage unit is 9 mm. two outer layers (B1) and (B2) that are free of the efferves The dissolution behaviour as tested by USP2 apparatus, 15 cent agent, each of the two outer layers (B1) and (B2) (pH 6.8,900 ml phosphate buffered media, 50 RPM, see FIG. comprising the active Substance and a polymer selected 13. from a Substantially water Soluble or crystalline polyg lycol having a molecular weight (MW) of about 100,000 Example 7 daltons or greater, or a Substantially water Soluble or 2O crystalline polyglycol copolymer having a MW of about A dosage unit according to the invention exhibiting Burst 2,000 daltons or greater, and; controlled behaviour (MQV batch 1047-046), see FIG. 10. a coating (C) that is impermeable to gastrointestinal fluids, The shell was produced by injection moulding. End plugs the coating (C) comprising a polymer, wherein the coat and centre plug, comprising pellets, were prepared by hand ing (C) forms a shell around the Solid inner layer (A) and and hand assembled. Each plug had a thickness of 3 mm. 25 the two outer layers (B1) and (B2), the solid inner layer Preparation of End Plugs (for Burst Release): (A) is positioned between the two outer layers (B1) and Morphine sulphate pentahydrate, PEG 3350S, Sodium (B2) within the coating (C), and the shell formed by the hydrogen carbonate and Citric acid were mixed and melted to coating comprises a length extending between two open approximately 110° C., and the melt was moulded into a 3 ends with each of the two open ends exposing a surface mm thick, and a 4.5 mm diameter, hole metal filter to attain 30 area of each of the two outer layers (B1) and (B2); the plugs. wherein the solid inner layer (A), without the outer layers Preparation of Centre Plug (for Controlled Release): (B1) and (B2) and the coating (C), is formulated such that it disintegrates within 60 minutes when subjected to PoloXamer 188, PEO 300 000, Mannitol and Morphine the disintegration test according to Ph. Eur; Sulphate pentahydrate were mixed and processed on a melt 35 wherein the release of the active substance contained in the extruder. The extruded strings were cooled and cut into pel outer layers (B1) and (B2) follows a zero order release lets. The pellets were sieved to reach a uniform size. Pellets pattern for at least 80% w/w release of the total content were mixed with CrosPovidone to attain a centre plug of of the active substance in the outer layers (B1) and (B2); approximately 3 mm thickness and a 4.5 mm diameter. wherein the coating (C) appears as a Substantially intact The Procedure was as Follows: 40 empty shell after the composition has been subjected to 1 Locate the shell with injection side upward the dissolution test according to Ph. Eur. 2 Place the first end plug with the injection side down word 2. The composition according to claim 1, wherein the at the top of the shell active Substance in the Solid inner layer (A) is present in the 3 Pellets and CrosPovidone were added into the shell form of a multiple unit formulation. 4 The last end plug is placed at the end of the shell 45 3. The composition according to claim 2, wherein the mul The Dosage Form has the Composition: tiple unit formulation is a controlled release multiple unit formulation. 4. The composition according to claim 1, wherein the ratio Content% (w.fw) between the Surface area exposed at one of the open ends and End plugs 50 the length of the shell is selected from about 0.02 to about 45 . Morphine sulphate pentahydrate 25 PEG 335OS 65 5. The composition according to claim 1, wherein the solid Sodium hydrogen carbonate 5 inner layer (A) further comprises a disintegrant. Citric acid 5 6. The composition according to claim 1, wherein the effer Pellets 55 vescent agent is selected from a stable surface-modified Morphine sulphate pentahydrate 53 Sodium bicarbonate powder, citric acid, citric acid monohy Mannitol 3 drate, dextrates, fumaric acid, potassium bicarbonate, sodium PEO3OOOOO 35 bicarbonate, Sodium citrate dehydrate, tartaric acid, or com Poloxamer 188 9 binations thereof. Centre plug 60 7. The composition according to claim 2, wherein the mul Pellets and 25% CrossPovidone were added tiple unit formulation comprises a polymer, wherein the poly Shell mer in the multiple unit formulation is selected from a sub stantially water soluble or crystalline polyglycol Ethylcellulose 86.5 Cetostearyl alcohol 12.5 homopolymer having a MW of about 100,000 daltons or Titanium dioxide 1.O 65 greater, or a substantially water Soluble or crystalline polyg lycol copolymer having a MW of about 2,000 daltons or greater. US 8,821,928 B2 57 58 8. The composition according to claim 1, wherein the solid 19. The composition according to claim 1, wherein at least inner layer (A) further comprises a filler. one of the outer layers (B1) and (B2) further contains a second 9. The composition according to claim 1, wherein the solid active substance different from the active substance of the inner layer (A) further comprises a polymer, wherein the solid inner layer (A). 20. The composition according to claim 19, wherein the polymer in the solid inner layer (A) is selected from a sub release of the second active substance follows a Zero order stantially water Soluble or crystalline polyglycol homopoly release pattern for at least 80% w/w release of the total con mer having a MW of about 16,000 daltons or fewer, or a tent of the second active substance in the at least one of the Substantially water soluble or crystalline polyglycol copoly outer layers (B1) and (B2). mer having a MW of about 30,000 daltons or fewer. 21. The composition according to claim 1, wherein the 10. The composition according to claim 9, wherein the 10 polymer in the coating (C) is selected from ethylcellulose, polymer in the solid inner layer (A) is a substantially water cellulose acetate, cellulose propionate, cellulose nitrate, soluble or crystalline polyglycol homopolymer having a MW polyamide, polyethylene, polyethylene terephtalate, polypro pylene, polyurethane, polyvinyl acetate, polyvinyl chloride, of between about 1,000 daltons and about 16,000 daltons. silicone rubber, latex, polyhydroxybutyrate, polyhydroxyval 11. The composition according to claim 9, wherein the 15 erate, polytetrafluoroethylene, polylactic acid or polyglycolic polymer in the solid inner layer (A) is a substantially water acid and copolymers thereof, copolymers including ethylene soluble or crystalline polyglycol copolymer having a MW of vinyl acetate, styrene-butadienstyrene, styrene-isoprene-sty about 25,000 daltons or fewer. rene, or combinations thereof. 12. The composition according to claim 1, wherein the 22. The composition according to claim 1, wherein the active Substance in the solid inner layer (A) is present in a coating (C) does not completely crumble or erode before at form selected from pellets, beads, flakes, mini-tablets, gran least one of the outer layers (B1) and (B2) has completely ules, microspheres, nanoparticles, crystals, and combinations eroded and the solid inner layer (A) is released. thereof. 23. The composition according to claim 1, wherein at least 13. The composition according to claim 5, wherein the one of the outer layers (B1) and (B2) erodes at a substantially 25 constant rate, when exposed to an aqueous medium. concentration of the disintegrant in the Solid inner layer (A) is 24. The composition according to claim 1, wherein the about 5% w/w to about 80% w/w. active Substance in the Solid inner layer (A) is Subject to 14. The composition according to claim 1, wherein the release after a lag time corresponding to the erosion time of at concentration of the effervescent agent in the solidinner layer least one of the outer layers (B1) and (B2). (A) is about 5% w/w to about 80% w/w. 25. The composition according to claim 1, wherein the 15. The composition according to claim 1, wherein the 30 polymer in each of the two outer layers (B1) and (B2), and the polymer in each of the two outer layers (B1) and (B2) is polymer in the coating (C) are thermoplastic. selected from a polyethylene glycol (PEG), mono- and 26. The composition according to claim 5, wherein the dimethoxypolyethylene glycols (mPEGs), a copolymer of disintegrant is selected from Sodium starch glycolate, povi ethylene oxide and propylene oxide, or a copolymer of PEG done, sodium alginate, alginic acid, calcium alginate, car and polypropylene glycol (PPG). 35 boxymethylcellulose calcium, carboxymethylcellulose Sodium, powdered cellulose, chitosan, croScarmellose 16. The composition according to claim 15, wherein the Sodium, crospovidone, hydroxypropyl Starch, hydroxypropyl PEG or the PEO has a MW selected from a range of about cellulose low-substituted, magnesium aluminium silicate, 100,000 daltons to about 700,000 daltons. methylcellulose, microcrystalline cellulose, pregelatinized 17. The composition according to claim 15, wherein the 40 copolymer of PEG and PPG has a MW selected from a range starch, docusae sodium, guar gum, polacrilin potassium, or of about 4,000 daltons to about 15,000 daltons. combinations thereof. 18. The composition according to claim 1, wherein the 27. The composition according to claim 1, wherein the concentration of the polymer in each of the two outer layers combined amount of the active substance and the effervescent (B1) and (B2) is selected from a range of about 5% w/w to agent in the solid inner layer (A) is about 70% w/w or greater. about 100% w/w. k k k k k