US 2015.0024048A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2015/0024048A1 Hemmingsen et al. (43) Pub. Date: Jan. 22, 2015

(54) CONTROLLED RELEASE (52) U.S. Cl. PHARMACEUTICAL COMPOSITIONS FOR CPC ...... A61K9/2086 (2013.01); A61 K9/2853 PROLONGED EFFECT (2013.01); A61 K3I/573 (2013.01); A61 K 3 1/167 (2013.01); A61 K31/485 (2013.01) (71) Applicant: Egalet Ltd., London (GB) USPC ...... 424/472: 514/179; 514/630; 514/282 (72) Inventors: Pernille Hoyrup Hemmingsen, (57) ABSTRACT Bagsvaerd (DK); Anders Vagno Pedersen, Virum (DK); Daniel Layered pharmaceutical composition Suitable for oral use in Bar-Shalom, Kokkedal (DK) the treatment of diseases where absorption takes place over a large part of the gastrointestinal tract. The composition com (21) Appl. No.: 14/446,234 prising A) a solid inner layer comprising i) an active substance, and (22) Filed: Jul. 29, 2014 ii) one or more disintegrants/exploding agents, one of more effervescent agents or a mixture thereof. Related U.S. Application Data the solid inner layer being sandwiched between two outer (63) Continuation of application No. 12/602.953, filed on layers B1) and B2), each outer layer comprising Jun. 7, 2010, now Pat. No. 8,821,928, filed as applica iii) a substantially water soluble and/or crystalline polymer or tion No. PCT/EP2008/056910 on Jun. 4, 2008. a mixture of substantially water soluble and/or crystalline polymers, the polymer being a polyglycol in the form of one (60) Provisional application No. 60/941,848, filed on Jun. ofa) a homopolymer having a MW of at least about 100,000 4, 2007. daltons, and b) a copolymer having a MW of at least about (30) Foreign Application Priority Data 2,000 daltons, or a mixture thereof, and iv) an active Substance, which is the same as in said solidinner Jun. 4, 2007 (DK) ...... PA 2007 OO816 layer A), and layer A being different from layer B. Publication Classification the layered composition being coated with a coating C) that has at least one opening exposing at least one Surface of said (51) Int. Cl. outer layer, the coating being Substantially insoluble in and A6 IK9/20 (2006.01) impermeable to fluids and comprising a polymer, and the A6 IK3I/485 (2006.01) composition having a cylindrical form optionally with one or A6 IK3I/67 (2006.01) more tapered ends, wherein the ratio between the surface area A6 IK 9/28 (2006.01) of one end surface of the cylinder and the length of the A 6LX3/573 (2006.01) cylinder is in a range of from 0.02 to 45 mm. Patent Application Publication Jan. 22, 2015 Sheet 1 of 24 US 2015/0024048A1

Second burst matrix (A) First burst matrix

Delay plug (B) Shell (C)

Fig. 1 Patent Application Publication Jan. 22, 2015 Sheet 2 of 24 US 2015/0024048A1

Active plug (B)

Active plug (A)

Shell (C)

Fig. 2 Patent Application Publication Jan. 22, 2015 Sheet 3 of 24 US 2015/0024048A1

1OO Š -- 80 --S. Burst-Hydrocodone 'Na' S i --&- Controlled - Morphine g 60 sŠS as s 3. Š SS 40 s

s is

O 2 4. 6 8 10 12 14 16 18 Time (h)

Fig. 3 Patent Application Publication Jan. 22, 2015 Sheet 4 of 24 US 2015/0024048A1

--&-Morphine 6 O or Sr. OxyCodone

40 - 20 p. o: O 5 10 15 20 Time (h)

Fig. 4 Patent Application Publication Jan. 22, 2015 Sheet 5 of 24 US 2015/0024048A1

A delay.plug - B / / ) \ Center plug Shell \ (A) / \ , ? Ys -l |- ^ N - -

end plug (AVB)

Fig. 5 Patent Application Publication Jan. 22, 2015 Sheet 6 of 24 US 2015/0024048A1

1OO –

8O

6O –

40 - --buffer 7.2 2O -H buffer 6.8 -o-0.1 NHCl

O r r O 50 1OO 15O 2OO 250 3OO Time (min)

Fig. 6 Patent Application Publication Jan. 22, 2015 Sheet 7 of 24 US 2015/0024048A1

Shell (C)

End Plug(B)

Center plug (A)

Fig. 7 Patent Application Publication Jan. 22, 2015 Sheet 8 of 24 US 2015/0024048A1

100,0 ... --o-o-o-o----- *** I i 80, O – i i 60,0- s s : ?: -o-' SS 40.0 - * - s - 20,0- - - - s s O,O (s O 1 2 3 4 5 6 7 8 9 10 Time (h)

Fig. 8 Patent Application Publication Jan. 22, 2015 Sheet 9 of 24 US 2015/0024048A1

.xerx-8* ...x-x-8**.-- ...x-8-8-"*** c 80 - - f 60 i

s 40 i 2O - | a x O s.--S$SS Nrs O 1 2 3 4 Time (h)

Fig. 9 Patent Application Publication Jan. 22, 2015 Sheet 10 of 24 US 2015/0024048A1

Shell (C)

End plug(B)

Pellets (A) Filler (A)

Fig. 10 Patent Application Publication Jan. 22, 2015 Sheet 11 of 24 US 2015/0024048A1

80 -

6O -

4 O

20

10 15 20 Time (h)

Fig.11 Patent Application Publication Jan. 22, 2015 Sheet 12 of 24 US 2015/0024048A1

100 - s a s O 80 - A A : N • & sixx &r & 40%O EtOH A -8. Phosphate-buffer is 60 - 4 f f &

S. f 40 – g

O O O,5 1 15 2 Time (h)

Fig. 12 Patent Application Publication Jan. 22, 2015 Sheet 13 of 24 US 2015/0024048A1

120 100 re

8 O

6 O

Fig. 13 Patent Application Publication Jan. 22, 2015 Sheet 14 of 24 US 2015/0024048A1

120 ;

1OO sa-Šasasasasa-Šarxvts

80 : W&

3. : S. 3 6o : s g & S. &

40

20 Patent Application Publication Jan. 22, 2015 Sheet 15 of 24 US 2015/0024048A1

Burst-lag-burst f Burst: 1 - 100% in less than 1h - Lag: less than 10% (5%) in a

s duration of 1 to 10h Burst: 1 - 100% in less than 1 h

Fig. 15 Patent Application Publication Jan. 22, 2015 Sheet 16 of 24 US 2015/0024048A1

ac Burst-controlled-burst $ Burst: 1 - 100% in eSS than 1 h Controlled: 0.1%/h - 30%/h (50 %/h) in a duration of 1 to 10h Burst: 1 - 100% in eSS than 1 h

Fig. 16 Patent Application Publication Jan. 22, 2015 Sheet 17 of 24 US 2015/0024048A1

Burst-controlled Burst: 1 - 99% in less than 1 h econtrolled: 0.1%/h -30%/h (50 %/h) in a duration of 1 to 10h

Fig. 17 Patent Application Publication Jan. 22, 2015 Sheet 18 of 24 US 2015/0024048A1

Controlled-burst Controlled: 0.1%/h - 30%/h (50%/h) in a duration of 1 to 10 h Burst: 1 - 100% in less than 1 h

Fig. 18 Patent Application Publication Jan. 22, 2015 Sheet 19 of 24 US 2015/0024048A1

Lag-burst Lag: less than 10% (5%) in a duration of 1 to 10h Burst: 1 - 100% in leSS than 1h Lag-burst-lag-burst etc

Fig. 19 Patent Application Publication Jan. 22, 2015 Sheet 20 of 24 US 2015/0024048A1

Controlled-controlled Controlled: 0.1%/h - 30%/h / (50%/h) in a duration of 1 to 10

a Controlled: 0.1%/h - 30%/h (50%/h) in a duration of 1 to 10 h

Fig. 20 Patent Application Publication Jan. 22, 2015 Sheet 21 of 24 US 2015/0024048A1

Controlled-controlled oControlled: 0.1%/h - 30%/h (50%/h) in a duration of 1 to 10 h oControlled: 0.1%/h - 30%/h L1 (50%/h) in a duration of 1 to 10 Time h

Fig. 21 Patent Application Publication Jan. 22, 2015 Sheet 22 of 24 US 2015/0024048A1

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

Time

Fig. 22 Patent Application Publication Jan. 22, 2015 Sheet 23 of 24 US 2015/0024048A1

1 Active A 1/ / 1 - 100% in less than 12h 2 Active B 0.1%/h - 30%/h (50%/h) in a duration of 1 to 12h 1 - 100% in less than 12h

Fig. 23 Patent Application Publication Jan. 22, 2015 Sheet 24 of 24 US 2015/0024048A1

-aaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaa 1 Active A 1 - 100% in less than 12h 2 Active B 2 eless than 10% (5%) in a duration of 1 to 12 h 1 - 100% in less than 12h

Fig. 24 US 2015/0024048 A1 Jan. 22, 2015

CONTROLLED RELEASE keeping” (intestinal peristalsis) might lead to anomalies in the PHARMACEUTICAL COMPOSITIONS FOR effect of solid oral dosage forms which might be compensated PROLONGED EFFECT by the formulation. 0005. Furthermore, the active substance may exert its CROSS-REFERENCE TO RELATED effect locally in the colon or other parts of the gastrointestinal APPLICATIONS system, Such as for treatment of cancer, inflammation, gas 0001. This application is a continuation of U.S. patent trointestinal diseases and treatment with anthelmintic agents. application Ser. No. 12/602.953, filed Jun. 7, 2010, which is a BRIEF DESCRIPTION OF THE DRAWINGS National Stage of International Application No. PCT/ EP2002/056910, filed Jun. 4, 2008, which claims the benefit 0006 FIG. 1, illustrate double burst unit, with a delay under 35 U.S.C. S 119(e) of U.S. Provisional Patent Applica between the two bursts. tion No. 60/941,848, filed Jun. 4, 2007, these applications are 0007 FIG. 2, illustrate simple combination formulation. incorporated herein by reference in their entireties. 0008 FIG.3, releases of Hydrocodone and Morphine with burst-controlled release behaviour see preparation 4. INTRODUCTION 0009 FIG. 4, releases of Oxycodone and Morphine with controlled-controlled release behaviour see preparation 5. 0002 The present invention relates to a technology that is (0010 FIG. 5, illustrate double burst unit, with a delay especially Suitable for designing oral pharmaceutical compo between the two bursts. sitions that are useful in the treatment of diseases where 0011 FIG. 6, release of Paracetamol with double burst absorption e.g. takes place over a large part of the gastrointes release behaviour see example 2. tinal tract (e.g. in stomach, the Small intestine as well as in the 0012 FIG. 7, illustrate unit exhibiting controlled-burst or colon). Accordingly, the present invention provides a compo burst-burst release behaviour. sition that enables a first release of the active Substance (e.g. (0013 FIG. 8, release of Morphine with controlled-burst a burst or a controlled release) followed by a second release of release behaviour see example 3. the same active Substance (e.g. a burstora controlled release). (0014 FIG. 9, release of Morphine with controlled-burst The design of the composition takes into account the fact that release behaviour see example 4. different conditions are present in different parts of the gas 0015 FIG. 10, illustrate unit exhibiting controlled-con trointestinal system. Thus, e.g. in the colon, the Surface area trolled or burst-controlled release behaviour. of the mucosal Surface through which the active Substance must be absorbed is much smaller than in the small intestine (0016 FIG. 11, release of Morphine with controlled-con and, moreover, the amount of body liquid present is also much trolled release behaviour see example 5. Smaller. The compositions of the present invention may also (0017 FIG. 12, release of Morphine pellets see example 5. be suitable in the treatment of diseases in which circadian (0018 FIG. 13, release of Morphine with controlled-con rhythm or biorhythm effects can influence the condition being trolled release behaviour see example 6. treated or when an effective therapy is desired e.g. in the early (0019 FIG. 14, release of Morphine with burst-controlled morning before awakening or when the active Substance have release behaviour see example 7. a narrow absorption window or the absorption is poor e.g. in 0020 FIG. 15, illustrate burst-lag-burst release character the colon or for local effect/treatment. Some physiologically istics. active Substances are periodically produced in vivo at certain 0021 FIG. 16, illustrate burst-controlled-burst release time intervals and it may accordingly be desirable to admin characteristics. ister Such substances in a controlled release formulation 0022 FIG. 17, illustrate burst-controlled release charac which periodically releases the active substance at predeter teristics. mined time intervals to obtain certain fluctuation in the drug 0023 FIG. 18, illustrate controlled-burst release charac level which may be desirable in connection with the treatment teristics. of various diseases. The present technology provides a means 0024 FIG. 19, illustrate lag-burst release characteristics. for designing Such compositions and moreover, Such compo 0025 FIG. 20, illustrate controlled-controlled release sitions may be combined with an initiated burst release and/or characteristic. Zero order controlled release of the active substance. 0026 FIG. 21, illustrate controlled-controlled release characteristic. BACKGROUND OF THE INVENTION 0027 FIG. 22, illustrate releases of two active substances 0003. In the past decades many controlled release tech with the same release characteristics. nologies have appeared. However, for drug Substances that 0028 FIG. 23, illustrate releases of two active substances can be absorbed through many segments of the gastrointesti with different release characteristics. nal (GI) tract, there is still a need for developing compositions 0029 FIG. 24, illustrate releases of two active substances that enable sufficient absorption of the drug substance over with sequential release characteristics. broader range of segment of the gastrointestinal (GI) tract in order to enable a less frequent dosage of the drug and/or in DETAILED DESCRIPTION OF THE INVENTION order to avoid excretion of unabsorbed drug via the faeces. 0030. However, to the best of our knowledge there is still 0004 Pharmacodynamics and pharmacokinetics chal a need to develop a technology that enables preparation of lenges might enforce the need for special release patters (such pharmaceutical compositions useful for the above-mentioned as paracetamol in which the first pass metabolism makes it therapies (including chronotherapy) in a relatively simple difficult to make a constant release unit work). Furthermore, manner, preferably in a procedure involving relatively few the passage of material through the gastrointestinal tract is steps and relatively simple equipment, and in an economical carefully controlled by several mechanisms. This “house feasible manner. Moreover, it is desired to obtain a technol US 2015/0024048 A1 Jan. 22, 2015

ogy that is suitable for use for many different drug Substances, 0035) If absorption of the active substance is unchanged i.e. a technology that is relatively flexible with respect to how through the gastrointestinal tract a better absorption of the to obtain a desired release pattern of the active substance. active substance in the colon can be achieved if a relatively Thus, a relatively simple technology is desired that enables fast release of controlled release multiple units is released combination of e.g. delayed release followed by controlled from the controlled release composition in the distal part of (extended) release, delayed release followed by immediate the small intestine to prevent limited absorption of the active release, burst release followed by delayed release followed by substance due to block of the open ends of the shell in the either controlled or immediate release, burst release followed colon lumps of faeces. A composition having controlled by controlled release, controlled release followed by con release follow by controlled release behavior in the shape of trolled release or immediate release. A further advantage controlled release multiple units is desirable. could be a technology that enables variation in the design in a 0036. The opposite is the case (i.e. a composition having relatively easy manner Such that the composition also burst release follow by delay and/or controlled release behav includes e.g. a burst dose or controlled release dose (of dif ior) if there is absorption problem in the first part of the ferent active Substance). gastrointestinal tract e.g. the stomach. It is also the case if fast 0031. The present invention provides such a technology. effect follow by maintenance of the effect is desirable. The technology is a further development of the Applicants 0037 Controlling the release of the active substance from proprietary technology described in WO 99/51208, WO the composition and thereby the absorption of the active 03/24426, WO 03/24429, WO 03/24430, WO 2004/41252, substance, makes it possible to control the blood level of the WO 2004/84869, WO 2005/107713, WO2006/128471 that is active Substance and maintain the concentration within the based on matrix compositions comprising a substantially therapeutic range over an extended period of time without water soluble and/or crystalline polymer. Moreover it is a high peak trough fluctuation which improve the therapeutic further development of the technology described in WO effect and reduced incidence of side effects. 2006/128471 that relates to a composition having an inner 0038. It is an object of certain embodiments of the present part of a composition that liquefies at body temperature sand invention to provide bioavailable formulations suitable for wiched between two matrix compositions. In this manner a once daily administration which substantially improve effi delay is obtained with respect to release of the active sub ciency and quality of the treatment. stance contained in the inner part and once, the matrix com 0039. It is an object of certain embodiments of the present positions are eroded away, the liquefied inner part is designed invention to provide oral controlled release composition Suit to flow out of the shell that surrounds the cylindrical part of a able for once daily administration which provide an early cylindrical shaped composition (i.e. the shell (or coating) onset of therapeutic effect and which, after rising to a maxi covers the cylindrical surface, but not the end surfaces). In mum concentration during the dosage interval, provide a this manner the active substance in the inner part should be relatively flat plasma profile, meaning that the plasma level pf immediately released once the matrix parts are eroded. How the active substance provides a peak trough ratio of about 0.5 ever, in some situations the present inventors have observed that the outflow of the liquefied inner part is not that easy, e.g. to about 1.0, and which provides effective treatment. in situations where the composition reaches the large intes 0040 Another advantage relating to the present invention tine or the colon. In these situations, a limited amount of water is the possibility of administering the two active Substances at is present and, accordingly, the flow is limited and moreover, the same time and advantageous in the same pharmaceutical in the colon lumps of faeces may block the open ends of the composition. However, as such a combination treatment is shell leading to limited release of the active substance. expected to have optimized effect with respect to each of the Accordingly, the present inventors have developed composi two Substances at different points in time it is important to tions that substantially overcome the above-mentioned prob incorporate the two active substances in the composition in lems. Such a manner that 0032. The present invention provides an extended release i) it is possible to incorporate a suitable amount of each active composition for prolonged effect and a way to ensure pro Substance (notably an amount corresponding to a daily dose longed effect e.g. once daily administration is to ensure opti and should be present in a specific weight ratio that is opti mal absorption of the active Substance though the gastrointes mized with respect to therapeutic effect), tinal tract i.e. from the stomach to rectum. ii) it is possible to avoid any negative interaction of the two 0033. When absorption of the active substance is limited active Substances in the composition, or do not proceed substantially good in the distal part of the iii) it is possible to avoid an excessive degree of oxidation of small intestine and/or in colon a relatively fast release of the the active Substances (however, levels corresponding to nor active Substance is an advantage when the controlled release mally accepted levels are acceptable), composition enter this part of the tract and especially in those iii) it is possible to obtain release patterns of both substances cases where the active substance is poorly absorbed in the that are optimized with respect to therapeutic effect (see distal part of the Small intestine or in ascending and first part iv)-vi) for more specific details), of the transverse colon. A release composition having con iv) it is possible to control the release pattern of the two active trolled release follow by immediate release behavior is desir Substances from the composition in Such a manner that the able for optimal absorption and effect. release of S1 is independent of the release of S2; this applies 0034. A composition having controlled release follow by for the release mechanism as well as the release rate and time immediate release of the active Substance is also an advantage for 80-100% w/w release, when the active substance is poorly soluble and therefore V) it is possible to e.g. obtain a Zero order release for one or requires a substantial amount of water/fluid to dissolve in the both of the active substance, Zero order release for one of the distal part of the small intestine before it enters colon for active substances and another order of release for the other absorption. active substance or the like, US 2015/0024048 A1 Jan. 22, 2015 vi) it is possible to obtain e.g. a relatively slow release fol drical shape and then the cylindrical Surface is coated leaving lowed by a faster release of one of the active substance with one or two of the end Surfaces without any coating (normally out impact on the release of the other active Substance, and/or both end Surfaces are without coating). In order to ensure a vii) it is possible to use a formulation technique that poten sufficient release of the active substance contained in layer A) tially may improve the bioavailability of at least one of the of the composition, the present inventor's have found that the active substances and, preferably, of both of the active sub following two properties are important, namely the geometry stance (due to the fact that both active Substances generally and dimensions of the composition and the present of a dis have a low bioavailability). integrant and/or an effervescent agent (or couple). The first 0041. In one aspect, the present invention relates to a lay parameter ensures that the distance to travel for the inner layer ered pharmaceutical composition comprising is not too big compared with the size of the opening (i.e. the A) a Solid inner layer comprising end Surface) and the other one ensures that a driving force i) an active substance, and activates the mobility of the active substance in layer A) when ii) one or more disintegrants/exploding agents, one of more it comes into contact with a body liquid. Moreover, as will be effervescent agents or a mixture thereof. explained below, a further parameter has also a positive influ the solid inner layer being sandwiched between two outer ence in order to enable a release of the active substance from layers B1) and B2), each outer layer comprising layer A), namely the incorporation of the active Substance in iii) a substantially water soluble and/or crystalline polymer or readily flowable multiple units. a mixture of substantially water soluble and/or crystalline polymers, the polymer being a polyglycol in the form of one Geometry ofa) a homopolymer having a MW of at least about 100,000 0045. The lag-time mechanisms (and the release mechan daltons, and b) a copolymer having a MW of at least about ics of any active Substance contained in the outer layers) 2,000 daltons, or a mixture thereof, and described above depends on the geometry of the composition. iv) an active Substance, which is the same as in said solidinner For example erosion based release from a matrix depends on layer A), the exposed area of the matrix. In this case the area may be and layer Abeing different from layer B. manipulated by employment of a coat that is not subject to the layered composition being coated with a coating C) that erosion and thus covering the areas of the matrix that hence has at least one opening exposing at least one surface of said will not be a releasing site. In particular, a cylindrical com outer layer, the coating being Substantially insoluble in and position with the two ends exposing the eroding matrix will impermeable to fluids and comprising a polymer, and the give rise to zero order release because the releasing area is composition having a cylindrical form optionally with one or COnStant. more tapered ends, wherein the ratio between the surface area 0046. The geometric form of the composition is very of one end surface of the cylinder and the length of the important for the obtainment of the above-mentioned con cylinder is in a range of from 0.02 to 45 mm. trolled release. Thus, in one embodiment of the invention, the 0042. In a specific embodiment of the present invention, pharmaceutical composition has a geometric shape, which layer A) comprises enables a Substantially constant Surface area to become v) a substantially water soluble and/or crystalline polymer or exposed during erosion of the matrix. As explained above, the a mixture of substantially water soluble and/or crystalline present inventors have found that the proportions between the polymers, the polymer being a polyglycol in the from of one surface area of the end surface and the length of the cylinder of c) a homopolymer having a MW of at the most about are important in order to ensure that the active Substance (or, 16,000 daltons, and d) a copolymer having a MW of at the if relevant, of the multiple unit formulation containing the most about 30,000 daltons. active substance) can be released from the inner part. Specific 0043. As mentioned above, the present invention is a fur examples appear from the examples herein. In general, the ther development of the Applicant's proprietary technology, following ratio between the surface area of one end surface namely preparation of pharmaceutical compositions based on and the length of the cylinder has been found to be suitable in a water soluble and/or crystalline polymer or mixture of such order to ensure a proper release: from about 0.02 to about 45 polymers involving a step of melting or softening the polymer mm Such as, e.g., from about 0.1 to about 10 mm or from by means of injection moulding, extrusion or the like. The about 0.5 to about 8 mm. In most cases, the composition of the injection moulding technique has the advantage of simulta invention has two end Surfaces, and, if the ratio is calculated neous mixing and heating the components during increased on the total surface area of the end surfaces, then the ratio is pressure in a one step procedure without exposure to air and from about 0.02 to about 85 mm such as, e.g., from about 0.1 moisture because the injection moulding is performed in a to about 10 mm or from about 1.3 to about 14 mm. single closed compartment from the time a blend of the com 0047. In a specific example, the compositions employed ponents has entered the machine to the final pharmaceutical are coated in Such a manner that the Surface has a Substantially units are ejected ready for packaging. More details regarding constant or controlled surface area during release or erosion. the preparation method are given below and in the experimen In the present context controlled Surface area relates to a tal section. predetermined surface area typically predicted from the 0044 As appears from the above, the invention concerns a shape of the coat of the unit dosage system. It may have a layered pharmaceutical composition having an inner layer simple uniform cylindrical shape or the cylindrical form can with the active substance sandwiched between two lag-time have one or more tapered ends in order to decrease (or providing layers, i.e. layers that enable a delay in the release increase) the initial release period. of the active substance contained in the inner layer. The 0048. As another example, in diffusion based systems the layered composition is coated in Such a manner that only a release will furthermore depend on the thickness of the dif Surface layer from the outer layer(s) is free of coating mate fusion layer and in this case the release will depend both on rial. In a preferred embodiment, the composition has a cylin the diffusion area and thickness of the diffusion system. US 2015/0024048 A1 Jan. 22, 2015

0049. As yet another example the release mechanism of 0054 The disintegration may be by means of swelling. dissolving/solubilization also depend on the releasing area The inner layer comprises an excipient (here a disintegrant), and the release rate may be controlled by covering parts of the which Swells rapidly upon contact with aqueous media makes releasing matrix by a coat. Controlling the coverage of the it possible to push the active Substance or active multiple units matrix by the coat hence refers to covering from 0 to 100% of out of the shell. Preferably, the detachment of the active the matrix by a coat. matrix should be in Smaller lumps with a large area-to-Vol ume ratio. Inner Layer A) 0055 As mentioned above, the “release” of the inner layer (or delivery of the inner layer material to the outside of the 0050. The object of the present invention is to design a shell) may be aided by incorporation of e.g. a disintegrant also composition comprising an active Substance that is released called Swelling and/or exploding agent. A disintegrant typi after a certain period of time (e.g. burst release followed by cally swells upon contact with water and enable disruption of controlled release, controlled release followed by burst the inner layer to agglomerates or particle. Examples of Suit release, controlled release followed by controlled release, able disintegrants include Sodium starch glycolate, Povi burst release followed by burst release). However, as done, Sodium alginate, Alginic acid, Calcium alginate, Car explained above one of the problems the inventors were faced boxymethylcellulose calcium, Carboxymethylcellulose with was how to ensure that the inner layer exits the shell sodium, Powdered cellulose, Chitosan, Croscarmellose (coating) once the outer layers have disappeared. As Sodium, Crospovidone, Hydroxypropyl Starch, Hydroxypro explained above, two parameters are of importance. Firstly, pyl cellulose low-substituted, Magnesium aluminium sili incorporation of a pharmaceutically acceptable excipient that cate, Methylcellulose, Microcrystalline cellulose, pregelati aids in disintegrating the inner layer seems to be of relevance. nized starch, Docusae sodium, Guar gum, Polacrilin Accordingly, the inner layer may also contain one or more potassium. disintegration/exploding agents, one of more effervescent 0056. The disintegration may also be due to an efferves agents or a mixture thereof. cent effect, whereby gas such as CO is released from the 0051. It is important to note that once the inner layer is inner layer upon contact with water and a rapid dissolving “released from the shell and brought into direct contact with system is formed. The formation of gas bubbles will push the an aqueous medium (e.g. the gastrointestinal fluids after oral inner layer out in Small lumps and thereby manifold increase administration) then various types of release of the active the exposed area of the inner layer (e.g. containing active substance can be obtained ranging from immediate release Substance, active multiple units or the like) to the medium. (e.g. the active Substance is readily available for release Such For example sodium bicarbonate releases CO by reaction as e.g. present in dissolved form in a form that is easily with water in an acidic environment. It is possible to develop dissolvable) to controlled release (e.g. in the form of pellets a more pH-robust formulation by adding an acidic excipient designed to controlled release or other well-known types of to the formulation. The rate of which the gas formation occurs formulations including beads, flakes, mini-tablets, granules, depends on the rate of hydration and diffusion of water into microspheres, nanoparticles, crystals or the like). the matrix. 0052. As the shell (coating) has properties that ensure NaHCO(s) Na" (aq)+HCOs (aq) (1) exposure of a well-defined (normally constant or Substan HCOs (aq)+HO'(aq) HCO,(aq)+HO(l) (2) tially constant) Surface area of the composition to the Sur rounding medium so that the outer layer(s) can be eroded with HCOs (aq) CO(g)+HO(l) (3) a constant rate until the layer(s) are eroded away, it is impor 0057 "Release' of the inner layer may also take place by tant that the shell remains intact until the outer layer(s) have means of gas formation using effervescent Substances or eroded. This normally means that the shell is left when the effervescent couples. Examples of suitable effervescentagent inner layer is the only layer left of the composition. Accord include Effer-Soda, Citric acid, monohydrate, Dextrates, ingly, the difficulty of the problem is to ensure a “release' of Fumaric acid, Potassium bicarbonate, Sodium bicarbonate, the inner layer from the shell or, in other words, a delivery of Sodium citrate dehydrate, Tartaric acid. the inner layer material from the inside of the shell to the 0.058 Disintegration may also take place by rapid erosion, outside. which can be obtained by employing for example short chained polymers in the matrix, such that the matrix is readily Disintegrants, Swelling Agents, Exploding Agents, wetted and dissolved exposing either the active multiple units Effervescent Agents or the matrix component(s) containing the active Substance. 0059. Furthermore, disintegration might be facilitated by 0053. The inner layer may be formulated such that it dis facilitating water transport through the matrix by for example integrates upon contact with water. The disintegration may be open pores. by a mechanism of exploding, by effervescence, by Swelling, 0060. In order to ensure suitable properties of the inner by rapid erosion or combinations thereof. The disintegration layer A, the inner layer A) without B) and C) disintegrates by exploding may be governed by rapid water influx into- and within at the most 60 min such as, e.g., at the most about 30 Swelling of one or several of the matrix components leading minor at the most about 15 min, when subjected to a disin to a collapse of the inner layer structure (normally a matrix tegration test according to Ph. Eur. structure) Such that the active substance may be released or 0061 Normally, the concentration of the one or more dis Such that e.g. multiple units, crystals etc. containing the active integrants, exploding agent and/or effervescent agent in the substance may be released. The multiple units may be inner layer is from about 5% w/w to about 80% w/w such as, designed as quick release (/burst releasefimmediate release) e.g., from about 10% w/w to about 70% w/w, from about 15% multiple units or controlled release multiple units for release w/w to about 60% w/w or from about 20% w/w to about 50% of the active Substance in the Small intestine and/or colon. wfw. US 2015/0024048 A1 Jan. 22, 2015

0062 One or more pharmaceutically acceptable excipi 0067 Polyethylene glycols are mixtures of addition of ents or additives may also be present in inner layer A) (see the ethylene glycol. In general PEG refers to polymers chains section “Pharmaceutically acceptable excipients”) with molecular weights below 20,000, while PEO refers to 0063. The inner layer A) may also contain a polymer. The higher molecular weights polymers. However, because of the same applies to the outer layers B) and in the following is similarities between PEO and PEG, the terms are often used given a general description of Suitable polymers for the two interchangeably for the same compound. (three) layers A) and B). It is important to note that in those 0068 Poloxamers are copolymers or block copolymers cases where the active Substance in layer A) is present in the and are a range of non-ionic Surfactants of polyethylene gly form of multiple units, then the multiple units may be in the col (PEG) and polypropylene glycol (PPG). form of e.g. pellets, beads or the like, and in Such cases one or 0069. In chemical abstracts Diol EO/PO block copoly more polymer may be employed in the preparation of the mers are described under the scientific name—hydroxy-hy multiple units. In Such cases, the polymers mentioned in the droxypoly(oxyethylene)poly(oxypropylene)-poly(Oxyethyl following are Suitable and Such polymers may appropriately ene)-block copolymer in combination with the CAS register be of the same nature as the polymers employed in the B) number. layers. In contrast hereto, the layer A may also contain a 0070. In specific embodiments a suitable poloxamer for polymeric Substance (as a dispersion medium for the active use in a composition of the invention has a HLB value of at Substance), but in this case, it is important that the polymeric least about 18 Such as, e.g., at least about 20. The mean substance has different properties from that used in layer B). molecular weight of a Suitable poloxamer is typically at least To differentiate between the individual polymers, the notation about 2,000. “matrix polymer is used to indicate that the polymer is (0071 Mixtures of PEO with different average molecular suitable for use in layer B) and in multiple units, whereas the weights can be used in order to obtain a PEO with a desirable notation “layer A polymer is used to indicate that the poly average molecular weight. The same applies to PEG. meris Suitable for use as a dispersion medium or excipient in 0072 The polymer has a melting point higher than the layer A. body temperature of the human in which the composition is to be used. Thus, the polymer(s) employed in the matrix com 0064 Suitable polymers for use according to the invention position will suitably have a melting point of about 20-120° typically comprises a polyglycol, e.g. in the form of a C. such as, e.g. from about 30 to about 100° C. or from about homopolymer and/or a copolymer. In a specific embodiment 40 to about 80° C. the polymer is substantially water soluble, thermoplastic, (0073. In addition to a polymer of a polyglycol type as crystalline, semi-crystalline or amorphous or a mixture of described above other polymers may be suitable for use in a Substantially water soluble, crystalline, semi-crystalline or pharmaceutical composition provided that the solubility and/ amorphous polymers. Suitable polymers for use in a compo or release rate of the active Substance from the composition in sition according to the invention are polyethylene glycols, water is higher than or equal to the solubility of the matrix in including derivatives Such as mono and dimethoxypolyethyl 40% w/w ethanol in water. Thus, in other embodiments of the ene glycols (mPEGs) polyethylene oxides and/or block invention, the polymer oran additional polymer to the polyg copolymers of ethylene oxide and propylene oxide. lycol may be selected from one or more of the following 0065 Polyethylene glycols (PEGs) are linear polydis polymers: modified or unmodified water soluble natural poly perse polymers composed of repeating units of ethylene gly merS Such as glucomannan, galactan, glucan, polygalactur col. Their chemical formula is HOCH2CHOCH2CH2OH onic acid, polyxylane, polygalactomannans, rhamnogalactu where m represents the average number of repeating units. roman, polyxyloglycan, arabinogalactan, and starch, Alternatively, the general formula HOCH2CH2OH may be cellulose, chitosan, alginate, fibrin, collagen, gelatin, hyalu used to represent polyethylene glycol, where n is a numberm ronic acid, amylopectin, pectin including low methylated or in the previous formula--1. See the structural presentations of methoxylated pectins, dextran and fatty acids and alcohols; polyethylene glycol below. n is the average number of oxy synthetic polymers such as polyvinylpyrrolidone (PVP), ethylene groups. n equals m+1. PVA, PVB, Eudragit L methyl ester, Eudragit L., Eudragit RL, Eudragit E, Eudragit S, PHPV. PHA, PCL, PLGA and PLA; and hydrogels made from the polymers or combined poly mers mentioned above and or from polymers originated from: "N-no-N-" --N-No HEMA HEEMA, MEMA, MEEMA, EDGMA, NVP, VAc, AA, acrylamide, MAA, HPMA, PEGA, PEGMA, PEGDMA, PEGDA, and PEGDMA. 0066 Polyethylene oxides (PEOs) are linear polydisperse nonionic polymers composed of repeating units of ethylene Polymers in Layer A) oxide. Their chemical formula is HOCH2CH2O.H where n represents the average number of oxyethylene groups. See the 0074. In one embodiment of the invention, layer A) com structural presentation of polyethylene oxide below. n is the prises V) a substantially water soluble and/or crystalline poly average number of oxyethylene groups. Depending on prepa mer or a mixture of substantially water soluble and/or crys ration method high molecular weigh PEO may have one talline polymers, the polymer being a polyglycol in the from terminal methyl group. of one ofc) a homopolymer having a MW of at the most about 16,000 daltons, and d) a copolymer having a MW of at the most about 30,000 daltons. 0075. In specific embodiments, the polymer comprises a u-N-1st homopolymer having a MW of at least about 1,000 daltons Such as, e.g., a homopolymer having a MW in a range from about 1,000 to about 15,000 daltons, from about 1,000 to US 2015/0024048 A1 Jan. 22, 2015

about 12,000 daltons, from about 1,500 to about 10,000 dal Concentration of Polymers in Layer A and/or B tons, from about 1,500 to about 8,000 daltons. 0080. The polymer may also be a mixture of the above 0076. The polymer may also comprise a co-polymer hav mentioned polymers. Normally, the concentration of the ing a MW of at the most about 25,000 daltons such as, e.g., at polymer(s) in layer A) when applied is from about 1 to about the most about 20,000 daltons, at the most about 15,000 99.9% w/w dependent on the desired release properties relat daltons, at the most about 10,000 daltons, at the most about ing to the release of the active Substance from the inner layer. 5,000 daltons, at the most about 2,000 daltons. In those cases where a relative fast release of the active Substance (or multiple units e.g. a pellet composition or the Polymers in Layers B) or Used in Multiple Units Containing like containing the active Substance) is desired or there is a the Active Substance and Incorporated in Layer A) relatively high concentration of active Substance in layer A), a relative low concentration of the polymer may be of interest 0077 Polyethylene glycols and/or polyethylene oxides, Such as, e.g. from about 1 to about 30% w/w Such as, e.g., which are suitable for use in the matrix composition are those from about 5 to about 25% w/w, from about 5 to about 20% having a molecular weights of from about 20,000 daltons, wfw or from about 10 to about 20% w/w. In other cases, the such as, e.g., from about 20,000 to about 700,000 daltons, concentration of the polymer in layer A) may be such as from from about 20,000 to about 600,000 daltons, from about about 10 to about 95% w/w, from about 15% to about 90% 35,000 to about 500,000 daltons, from about 35,000 to about w/w, such as from 20 to 85%, such as from 30% to 85% from 400,000 daltons, from about 35,000 to about 300,000 daltons, about 30 to about 99% w/w such as, e.g., from about 35 to from about 50,000 to about 300,000 daltons, such as, e.g. about 95% w/w, from about 35 to about 90% w/w, from about about 35,000 daltons, about 50,000 daltons, about 75,000 35 to about 85% w/w, from about 35 to about 80% w/w, from daltons, about 100,000 daltons, about 150,000 daltons, about about 40 to about 75% w/w, from about 45 to about 70% w/w, 200,000 daltons, about 250,000 daltons, about 300,000 dal from about 45 to about 65% w/w. from about 55 to about 85% tons or about 400,000 daltons. w/w or from about 60 to about 85% w/w. 0078. In a specific embodiment the matrix polymer is a I0081. One or more polymers are typically present in a polyethylene oxide or a polyethylene glycol that has a composition of the invention in a concentration amount of molecular weight of about 20,000 daltons, about 35,000 dal from 5 to 99.9% w/w Such as from 10 to 95%. Such as from tons, about 50,000 daltons, about 100,000 daltons, about 15% to 90%, such as from 20 to 85%, such as from 30% to 200,000 daltons, about 300,000 daltons and about 400,000 85% calculated as w/w % of the composition. daltons. PEG is commercially available with average molecu I0082 In those cases, where mixture of polymers are lar weights up to 35 000. PEO is commercially available with present in the composition, the concentration of an individual average molecular weights up to 8,000,000. In specific polymer in the composition may typically be from about 0% embodiment, the polymer is a PEO having a molecular to about 95% w/w such as, e.g., from about 0.5% to about weight of at least about 100,000 such as, e.g., from about 90% w/w, from about 1% to about 90% w/w, from about 5% 100,000 to about 8,000,000, from about 100,000 to about to about 90% w/w, from about 10% to about 90% w/w, from 7,000,000, from about 100,000 to about 5,000,000, from about 10% to about 80% w/w, from about 10% to about 70% about 100,000 to about 4,000,000, from about 100,000 to w/w, from about 10% to about 60%, from about 10% to about about 2,000,000, from about 100,000 to about 1,000,000, 50%, from about 15% to about 50% w/w, from about 15% to form about 100,000 to about 900,000. When PEO is about 45% w/w, from about 15% to about 40% w/w, from employed with a molecular weight in the lower end, the PEO about 20% to about 40% w/w, from about 20% to about 35% typically has a molecular weight as mentioned in the preced w/w or from about 20% to about 30% w/w. In specific ing paragraph. Commercially available PEOs with a molecu embodiments, the concentration is even lower Such as from lar weight in the higher end have typically the following about 1% to about 15% w/w or from about 5% to about 15% molecular weights: about 900,000, about 1,000,000, about wfw. 2,000,000, about 4,000,000, about 5,000,000, about 7,000, I0083. The total concentration of the polymers (notably the 000, about 8,000,000. It should be noted that when PEO with Sum of homo- and copolymers of the polyglycol type) in the a molecular weight of up to about 700,000 is used, it is composition is typically from about 5 to about 99.9% w/w possible to obtain a matrix composition (prepared e.g. by such as from about 10 to about 95% w/w, from about 15% to injection molding) that releases the active Substance con about 90% w/w, such as from 20 to 85%, such as from 30% to tained in the matrix with a Zero order release (erosion of a 85% from about 30 to about 99% w/w such as, e.g., from constant Surface area). However, the applicanthas indications about 35 to about 95% w/w, from about 35 to about 90% w/w, that employment of PEO with a molecular weight of 1,000, from about 35 to about 85% w/w, from about 35 to about 80% 000 or higher leads to a slower release and a different release wfw, from about 40 to about 75% w/w, from about 45 to about pattern. However, Zero order release may not always be 70% w/w, from about 45 to about 65% w/w. from about 55 to required from the layer B), but a slow release may be impor about 85% w/w or from about 60 to about 85% w/w. In tant. In such cases, the high molecular weight PEOs are specific embodiments (e.g. for burst layer (may be layer A) Suitable for use in a composition of the invention. and/or layer B)), the concentration is even lower such as from 007.9 Typical block copolymers of ethylene oxide and about 5% to about 40% w/w or from about 5% to about 35% propylene oxide have a molecular weight of from about 2,000 wfw. daltons, typically about 3,000 to about 30,000 daltons such I0084. The concentration of the polyglycol homopolymer as, e.g. from about 4,000 to about 15,000 daltons. If the is typically from about 0.5 to about 99.9% w/w such as from copolymer is the Sole thermoplastic polymer present in the 5 to about 99.9% w/w, from about 0.5% to about 90% w/w, composition it must not bee too brittle in order to avoid abuse from about 1% to about 90% w/w, from about 5% to about by crushing of the composition, i.e. it must have an HLB value 90% w/w, from about 20 to about 90% w/w, from about to of about 18 to about 24. about 90% w/w, and, in those cases where the homopolymer US 2015/0024048 A1 Jan. 22, 2015

is the only thermoplastic polymer present in the composition, 800 um or from about 300 um to about 750 um. In a specific then the concentration is normally from about 50 to about embodiment of the invention the particle size of the multiple 95% w/w such as, e.g. from about 55 to about 90% w/w, from units is at the most about 500 um to about 1000 um, or from about 60 to about 90%, from about 65 to about 90%, from about 350 um to about 500 um. In some cases, the particle size about 70% to about 90% or from about 70 to about 85% w/w. of the multiple units may be even higher. Thus, in Some cases In specific embodiments, the concentration is even lower Such the particle size may be at the most about 2 mm. as from about 1% to about 15% w/w or from about 5% to 0092. The release of the active substance may take place about 15% w/w. by diffusion by which the rate of release depends on several 0085. The concentration of the polyglycol copolymer, if mechanisms, for example: the concentration difference present in combination with a polyglycol homopolymer, is between the matrix active Substance concentration and the typically from about 1 to about 60% w/w such as, e.g. from bulk concentration, the release surface area and the diffusion about 2.5 to about 50% w/w, from about 5 to about 45% w/w. constant of the drug Substance in the matrix. In special cases If the copolymer is the sole thermoplastic polymer in the diffusion controlled release may be zero order. composition the concentration may be from about 5 to about 0093. Once the inner layer is exposed to the gastrointesti 99.5% w/w such as those ranges described above and nal fluids (or another aqueous medium) the release of the described for the homopolymer. In specific embodiments, the active Substance may take place. In contrast to a release from concentration is even lower such as from about 1% to about a matrix that erodes (i.e. a matrix like the one of the outer 15% w/w or from about 5% to about 15% w/w. layer), the release of the active substance from the inner layer I0086. In embodiments where the outer layer matrix com may follow a kinetic that is different from a zero order release. position comprises a PEO and a poloxamer the weight ratio The present formulation principle is designed to delay the (PEO/poloxamer) is normally in a range from about 10:0.1 to release not necessarily to enable a Zero order release or other about 0.1:10 such as, e.g., from about 10:1 to about 1:10, from types of release kinetics that are relevant when designing about 5:1 to about 1:5 or from about 3:1 to about 1:3. controlled or modified release compositions. However, the 0087. The one or more, the same or different active sub basic formulation principle of the present invention may be stance in the inner layer may be designed to various types of combined with known formulation principles e.g. if an active release once the inner layer is “released from the shell. substance also is included in the matrix of the outer layer B), 0088. In one embodiment of the invention, the inner layer then this active substance can be released by Zero order kinet contains the active Substance incorporated into a multiple unit ics, i.e. in a controlled manner, and the active Substance formulation or it may be present in the form of relatively large contained in the first fraction is released once exposed to the crystals (i.e. 100 um or more). gastrointestinal fluids (or another aqueous medium) or in a controlled manner, but once the release of active Substance or Inner Layer Active Substance in Multiple Units active multiple units from the first fraction starts it may be 0089. As mentioned above, the active substance may be relatively fast. present in many forms in the inner layer. Thus, it may be present in dissolved form, e.g. dissolved in the ingredients of Outer Layers B1) and B2) the inner layer such as in the form of a solid dispersion or solid Solution. It may also be present in Solid form e.g. in the form 0094. The outer layers of a composition according to the of particles or crystals of the active substance. Moreover, the invention are typically based on the matrix principle dis active Substance may be incorporated into a formulation closed in WO99/51208, WO 03/24426, WO 03/24429, WO before it is incorporation into the inner layer. Such formula 03/24430, WO 2004/41252, WO 2004/84869, WO 2005/ tions are described in the following including multiple units. 107713, WO2006/128471 (to the same applicant). Such In Such a formulation, the active Substance may be present in matrices have unique properties in that they erode, i.e. it does solid or dissolved form as well. The multiple units for use not disintegrate into Smaller particles or conglomerates of according to the invention may be crystals of an active Sub particles upon exposure to the gastrointestinal fluid. Simpli stance, inert cores coated with active Substance—inert cores fied, erosion means that a layer is eroded from the composi like e.g. calcium alginate beads, cellulose spheres, charged tion into the Surrounding medium almost as if a slice of the resin spheres, glass beads, polystyrene spheres, sand silica matrix is cut off. Only the outer surface is exposed to erosion beads or units, sodium hydroxide beads. Sucrose spheres. and from this outer layer the active substance will be released Cores containing active Substance like e.g. beads, pellets, and/or dissolved provided that an active Substance is present flake, pieces, granules, granulates (also denoted agglomer in the matrix. This means that if it is possible to control the ates), spheres, tablets, especially minitablets etc. size of the Surface area by maintaining a constant size, it is 0090 The shape of the multiple units may be any suitable possible to control the size of the release rate and, further shape including a rounded or oval shape as well as a polygo more, a Zero order release rate can be obtained. nal or rod-like or flake-like shape. 0.095 The outer layers contain the same active substance 0091. The mean particle size of the multiple units is at the as the inner layer A) to ensure optimal absorption of the active most about 1400 um. In particular embodiments, the particle Substance though the gastrointestinal tract a way to prolong size of the multiple units is at the most about 1200 um such as, the effect of e.g. a once-daily dosage form. e.g., at the most about 1100 um, at the most about 1000 um, at 0096. As mentioned above, each of the outer layers B1) the most about 900 um, at the most about 800 um, at the most and B2) comprises iii) a substantially water soluble and/or about 750 um, at the most about 700 um, at the most about 650 crystalline polymer or a mixture of substantially water um, at the most about 600 um, at the most about 550 um or at soluble and/or crystalline polymers, the polymer being a the most about 500 um; such as, e.g., from about 150 um to polyglycol in the from of one of a) a homopolymer having a about 1200 um, from about 200 um to about 1200 um, from MW of at least about 100,000 daltons, and b) a copolymer about 200 um to about 1000 um, from about 250 um to about having a MW of at least about 2,000 daltons, US 2015/0024048 A1 Jan. 22, 2015

0097. The layers B1) and B2) may have the same or dif place through the coating (or, if any water should enter, then ferent composition and in a cylindrical shaped composition it does not result in a transport of dissolved active Substance they may have the same or different size. In a preferred out through the coating). In other words, it has been the object embodiment, the composition and size of the two B) layers to develop a coating that does not leave an uncontrollable are the same. Surface area of the matrix exposed to the aqueous environ 0098 Suitable polymers for use in the outer layers are ment and that has suitable properties compared to the matrix, described in detail in the section above. However, with i.e. if the coating dissolves or otherwise disappears then it respect to the outer layer, it is important to ensure a control of should only take place after the matrix has eroded or dis the rate with which the outer layer disappears from the com Solved away (during the release period, the coating may of position once it is exposed to an aqueous medium. As course also partly dissolve or disappear provided that the part described above, the outer layers are composed in Such a it concerns covered a part of the matrix that has already been manner that the outer layer leaves the composition with a Subject to erosion or diffusion, thus, leaving the remaining constant rate (corresponding to a Zero order release rate in the composition “intact with a matrix that is surrounded by the event that a drug Substance was present in the layer). Such a coating apart from the open end from which erosion or dif constant rate can be achieved by use of one or more polygly fusion of the matrix takes place). cols, but in contrast to the polymers suitable for used in the 0105. The composition may be partly or fully covered by inner layer A), the homopolymer should preferably have a a coat with specific properties in Such a way that the exposed much higher molecular weight in order to ensure a constant area of the matrix may be controlled by the use of a coat. In a erosion rate of the outer layer. Moreover, it is contemplated specific example the coat is substantially insoluble, non-erod that when a co-polymer is employed preferably one or more ible and non-permeable to water leaving only the exposed of another polymer is included in the outer layer in order to areas of the composition for release. Such a coat may be obtain a suitable constant erosion rate. composed of a polymer that has thermoplastic properties. 0099. As the function of the outer layers is different from Examples of Such materials are mentioned below including the function of the inner layer, the polymer composition of the cellulose derivative which has thermoplastic properties, plas outer layer(s) B is different from the polymer composition of ticizer or plasticizers and/other functional excipients. the inner layer A). 0106 The coating may also be a coating, which is substan 0100. One or more pharmaceutically acceptable excipi tially soluble in and permeable to fluids such as body fluids ents or additives may also be incorporated into the outer during the intended release period provided that the coating layer(s), see the section herein. However, it is important that dissolves so much slower than the matrix composition that the Such excipients or additives do not significantly change the coating remains intact until the matrix has eroded and/or manner in which the outer layer disappears from the compo released the inner layer containing an active Substance. sition, i.e. it is important that this disappearance still is by a Examples of Suitable polymers include polyglycols as Substantially constant rate e.g. by erosion or diffusion; addi described herein. tion of such Substances may have impact on the rate (e.g. slow 0107 The coating may further comprise any of the men down or increase the rate), but it must not significantly change tioned matrix materials (i.e. polymeric material suitable for the properties of the outer layer B) so that the function as a use in the outer layers B) in a form, which erodes at a sub “controlled lag-time layer provider' is destroyed. stantially slower rate than the rest of the matrix. The coating 0101. In some embodiments of the invention, the outer may thus comprise a matrix of one or more Substantially layer B) may also contain one or more second active Sub water Soluble crystalline polymers and, optionally, a non stances. Normally, Such a second active Substance in layer B) ionic emulsifier, the coating being one which is eroded in the will be a different substance from that contained in layer A) in aqueous phase at a Substantially slower rate than the outer order to achieve a suitable combination treatment with two of layer B, whereby a substantially controlled area of the outer more different active substance, one of which with a desired layer B matrix composition (in some cases also comprising a controlled release following a Zero order release (the one second active Substance) is exposed during erosion of the contained in the outer layer B)) and the other one contained in matrix composition and/or during release of the active Sub the inner layer and designed for immediate release (or, alter stance, and whereby the coating is Substantially eroded upon natively, as detailed described under the section “Inner layer. erosion of the matrix composition and/or during release of the as a controlled release composition e.g. with Zero or 1st order active Substance. Such a coating will be designed so that its release). longitudinal erosion rate is substantially the same as the lon 0102. In the section “Other embodiments of the invention” gitudinal erosion rate of the matrix, whereby the matrix and examples of various combinations are described. the coating will erode longitudinally towards the centre of the composition at Substantially the same rate. Thus, when the Coating outer layer matrix composition has been completely eroded 0103) As described above, the layered composition is pro and/or dissolved by the aqueous medium and the inner layer vided with a coating C) that has at least one opening exposing has been released from the shell (i.e. the coating), the coating at least one surface of said outer layer (layer B), the coating will also be substantially completely eroded. A matrix com being substantially insoluble in and impermeable to fluids position having Such a coating has the obvious advantage of and comprising a polymer. being completely biodegraded upon release of the active Sub 0104. A composition according to the invention may be Stance. provided with a coating that can be applied in Such a manner 0108. The coating may impart delayed properties for that it leaves a well-defined surface area free of coating while releasing the active Substance or it may be a film-coating or a the remaining Surface is covered and at the same time ensur coating containing the active Substance for immediate release ing that the coating fulfils the requirement that no transport of prior to the controlled release or other kinds of coatings that water into the matrix (or other parts of the composition) takes does not delay the release but e.g. make it easier to Swallow US 2015/0024048 A1 Jan. 22, 2015

the composition or it may e.g. mask a bad taste. Materials and at least one of: Suitable for Such coatings are well-known for a person skilled 0114 (b) a second cellulose derivative which is soluble in the art and information can be found e.g. in the latest or dispersible in water, e.g. a cellulose derivative editions of handbooks like Handbook of Pharmaceutical Selected from the group consisting of methylcellulose, Excipients or in Remington’s Pharmaceutical Sciences. carboxymethylcellulose and salts thereof, cellulose acetate phthalate, microcrystalline cellulose, ethylhy 0109. In an embodiment of the invention, the coating is droxyethylcellulose, ethylmethylcellulose, hydroxyeth one, which biodegrades, disintegrates crumbles or dissolves ylcellulose, hydroxyethylmethylcellulose, hydroxypro after erosion of the matrix and/or during the release of the pylcellulose, hydroxypropylmethylcellulose, active Substance. A coating applied for an erosion matrix will hydroxymethylcellulose and hydroxymethylpropylcel remain intact as long as it is supported by the matrix contain lulose; ing the active Substance, but it lacks the ability to remain 0115 (c) a plasticizer, e.g. selected from the group con intact after erosion of the matrix, because it then biodegrades, sisting of phosphate esters; phthalate esters; amides; disintegrates or crumbles, so that it will not remain in e.g. a mineral oils; fatty acids and esters thereof; polyethylene human for any significant amount of time after the complete glycol, glycerin or Sugars; fatty alcohols and ethers erosion of the outer matrix layer Band the release of the inner thereof, vegetable oils; or a non-ionic Surfactant; and layer A. 0116 (d) a filler, e.g. selected from conventional tablet 0110 In an interesting embodiment, the composition of or capsule excipients such as diluents, binders, lubri the invention further comprises a coating having at least one cants and disintegrants. opening exposing at least one Surface of the matrix, the coat 0117 The first cellulose derivative (a) such as, e.g., ethyl ing being one which crumbles and/or erodes upon exposure to cellulose is typically contained in the coating in a concentra the aqueous medium at a rate which is equal to or slower than tion of from about 10 to about 99% w/w such as, e.g., from the rate at which the matrix erodes in the aqueous medium, about 20 to about 95% w/w, from about 30 to about 90% w/w, allowing exposure of said Surface of the matrix to the aqueous from about 40 to about 90% w/w, from about 45 to about 90% medium to be controlled. w/w, from about 50 to about 85% w/w or from about 50 to about 80% w/w. 0111 Polymers useful as coatings are such as e.g. cellu 0118. In general, the concentration of the polymer in the lose derivative e.g. ethylcellulose, cellulose acetate, cellulose coating is from about 60% w/w to about 100% w/w. 0-40% propionate, cellulose nitrate, cellulose derivative selected W/w of one or more of a plasticizer, a colouring agent, a from the group consisting of methylcellulose, carboxymeth stabilizer, a glidants or the like may also be present in the ylcellulose and salts thereof, cellulose acetate phthalate, coating. microcrystalline cellulose, ethylhydroxyethylcellulose, eth 0119 Moreover, in some embodiments of the invention a ylmethylcellulose, hydroxyethylcellulose, hydroxyethylm further active Substance may be incorporated in the coating or ethylcellulose, hydroxypropylcellulose, hydroxypropylm the composition may be provided with a second coating com ethylcellulose, hydroxymethylcellulose and prising the further active Substance. Such a coating may be hydroxymethylpropylcellulose, cellulose acetate, Eudragit L designed to release the active Substance from the coating methyl ester, Eudragit RL, Eudragit E. polyamide, polyeth immediately after oral administration or a composition of the ylene, polyethylene terephthalate, polypropylene polyure invention may be subject to enteric coating Such that release thane, polyvinyl acetate, polyvinyl chloride, silicone rubber, will be pH dependent. latex, polyhydroxybutyrate, polyhydroxyvalerate, teflon, 0120 Such compositions wherein a coating contains an polylactic acid or polyglycolic acid and copolymers thereof, active Substance may be of interest in those situations where copolymers such as ethylene vinyl acetate (EVA), styrene a fast onset of action is desired, i.e. a fast release of an active butadienestyrene (SBS) and styrene-isoprene-styrene (SIS). Substance is desired in order to quickly obtain a therapeuti The coating may also be copolymers of polylactic acid and cally effective plasma concentration of the active Substance. polyglycolic acid. The coating may also be an enteric coating Such an active substance may be the same or different from employing methacrylates Eudragit L., Eudragit S, Eudragit that contained in layer B and/or the inner layer A dependent FS, a co-polymer of methacrylate-galactomannan etc. on the particular disease or condition to be treated. 0112. In one embodiment, the controlled release compo 0121. In Such cases where a second coating is provided on sition of the invention further comprises a coating having at the composition Sucha coating is generally a film-coating and least one opening exposing at least one Surface of the matrix, it is normally applied in a separate manufacturing step (e.g. the coating being one which crumbles and/or erodes upon not by injection moulding, but using processes generally exposure to the aqueous medium at a rate which is equal to or applicable for film-coating of tablets Such as, e.g., pan coat slower than the rate at which the matrix erodes in the aqueous ing, fluid bed coating, spray coating, dip coating etc.). medium, allowing exposure of said Surface of the matrix to the aqueous medium to be controlled. Coatings of this type Dose Dumping are described in WO95/22962, to which reference is made I0122. In one aspect, the invention is based on controlled and which is incorporated herein by reference. These coatings release compositions comprising polymer or a mixture of comprise: polymers, more specifically a polyglycol, an active Substance 0113 (a) a first cellulose derivative which has thermo and optionally one or more pharmaceutically acceptable plastic properties and which is substantially insoluble in excipients in layer B. Polymers and pharmaceutically accept the aqueous medium in which the composition is to be able excipients suitable for use in Such a composition as well used, e.g. an ethylcellulose Such as ethylcellulosehaving as relevant active Substances are described herein. Such com an ethoxyl content in the range of 44.5-52.5%, or cellu positions have proved to mitigate the risk of alcohol induced lose acetate, cellulose propionate or cellulose nitrate; dose dumping. "Dose dumping is unintended, rapid drug US 2015/0024048 A1 Jan. 22, 2015

release in a short period of time of the entire amount or a rectally, vaginally, or administered to a body cavity (e.g. the significant fraction of the active substance retained in a con urinary bladder, kidney pelvis, the gallbladder, the uterus, a trolled release dosage. central nervous system cavity, infectious/malignant/post-op 0123. In a specific embodiment of the invention the release erative cavities, etc.). mechanism is primarily erosion or diffusion from layer B composed of a polymer matrix, an active Substance and if 0.133 Examples of specific active substances suitable for necessary one or more excipients. The mechanism of erosion use in a composition of the invention are: Stomatological enables the composition to release with a rate depending on active substances; Epinephrine, BenZydamine, Acetylsali the exposed area. Inner layer A of the invention contains cylic acid, Adrenalone, Amlexanox, Sodium fluoride, active Substance or active multiple units (e.g. pellets or mini Sodium monofluorophosphate, Olaflur, Stannous fluoride, tablets) in such a form that the active substance or individual Sodium fluoride, Hydrogen peroxide, Chlorhexidine, active units will be made available upon disintegration of the Amphotericin B, Polynoxylin, Domiphen, Oxyquinoline, composition in the stomach, Small intestine and/or colon after Neomycin, Miconazole, Natamycin, Hexetidine, Tetracy erosion of layer B. The individual units are of a size, which cline, BenZOxonium chloride, TibeZonium iodide, Mepartri allows them to be incorporated into Such a composition. cin, Metronidazole, Clotrimazole, Sodium perborate, Chlo 0.124. The matrix composition of layer B and active mul rtetracycline, Doxycycline, Minocycline, Triamcinolone, tiple units according to the invention has (in total) a lower (or Dexamethasone, Hydrocortisone, Prednisolone. Active sub equal) solubility and/or release rate in alcohol containing stances for acid related disorders; Magnesium carbonate, media (e.g. ethanol) than in aqueous media (e.g. water, Magnesium oxide, Magnesium peroxide, Magnesium buffer). hydroxide, Magnesium silicate, Aluminium hydroxide, 0125. The active substance in the above mention matrix Algeldrate, Aluminium phosphate, Dihydroxialumini composition optionally comprising chosen polymers and Sodium carbonate, Aluminium acetoacetate, Aloglutamol. excipients in a suitable ratio attains an unchanged or lower Aluminium glycinate, Calcium carbonate, Calcium silicate, dissolution rate when tested in alcohol containing media as Ordinary salt combinations, Magaldrate, Almagate, Hydro compared to aqueous media. talcite, Almasilate, Magaldrate, Cimetidine, Ranitidine, 0126. In principle, the use of a composition to avoid alco Famotidine, Nizatidine, Niperotidine, Roxatidine, Ranitidine hol dose dumping can be of relevance for any active Sub bismuth citrate, Lafutidine, Cimetidine, Famotidine, Miso Stance. prostol, Enprostil, Omeprazole, Pantoprazole, Lansoprazole, 0127. An easy manner to investigate whether a composi Rabeprazole, Esomeprazole, Carbenoxolone. Sucralfate, tion potentially will be subject to alcohol induced dose dump Pirenzepine, Methiosulfonium chloride, Bismuth subcitrate, ing is to Subject the composition to an dissolution test using a Proglumide, Gefarnate, Sulglicotide, Acetoxolone, Zolimi dissolution medium with and without alcohol and investigate dine, Troxipide, Bismuth submitrate, Alginic acid. Active sub whether there are any differences in the release pattern under stances for functional gastrointestinal disorders; Oxyphen the two different conditions. The harshest conditions are in a cyclimine, Camylofin, Mebeverine, Trimebutine, Rociverine, dissolution medium containing 40% (v/v) ethanol. If the dis Dicycloverine, Dihexyverine. Difemerine, Piperidolate, solution rate of the composition is substantially unaffected or Metoclopramide, Cisapride, Domperidone, Bromopride, slower, then it is likely to assume that no alcohol induced dose Alizapride, Clebopride. Antiemetic and antinauseant active dumping will take place in vivo. Substances; Serotonin (5HT3) antagonists, Ondansetron, Granisetron, Tropisetron, Dolasetron, Palonosetron, Scopo Active Substances for Use in a Composition of the Invention lamine, Cerium oxalate, Chlorobutanol, Metopimazine, Dronabinol, Nabilone, Aprepitant. Active substances for bile 0128. A composition according to the invention comprises and liver therapy; Bile acid preparations, Chenodeoxycholic one or more active Substances. At least one active Substance is acid, Ursodeoxycholic acid, Nicotinyl methylamide, Pipro included in the inner layer and outer layer(s) of the composi Zolin, Hymecromone, Cyclobutyrol, Arginine glutamate, tion, which are the same, but the outer layer(s) may also Silymarin, Citiolone, Epomediol, Ornithine oxoglurate, Tidi contain one or more active Substances that is different from acic arginine. Laxative active Substances; Softeners, Emol the active Substance contained in the inner layer. lients, Liquid paraffin, Docusate Sodium, Liquid paraffin, 0129. Typically, the amount of each active substance in the Contact laxatives, Oxyphenisatine, Bisacodyl, Dantron, Phe composition if the same active Substance is present in the nolphthalein, Castor oil, Senna glycosides, Cascara, Sodium inner layer and/or outer layer and/or in the coating) corre picosulfate, Bisoxatin, Belladonna alkaloids, Bisacodyl, sponds to a daily or part of a daily therapeutic dose. Dantron, Senna glycosides, Cascara, Sodium picosulfate, 0130. A pharmaceutical composition according to the Ispaghula (psylla seeds), Ethulose, Sterculia, Linseed, Meth invention is suitable for use for both water soluble as well as ylcellulose, Triticum (wheat fibre), Polycarbophil calcium, slightly soluble or insoluble active substances. Magnesium carbonate, Magnesium oxide, Magnesium per 0131 Thus, a pharmaceutical composition according to oxide, Magnesium Sulfate, Lactulose, Lactitol, Sodium Sul the invention may comprise one or more active Substances, fate, Pentaerithrityl, Macrogol, Mannitol, Sodium phosphate, i.e. Substances, which are therapeutically, prophylactically, Sorbitol, Magnesium citrate, Sodium tartrate, Enemas, diagnostically and/or biologically active Substance. The term Sodium phosphate, Bisacodyl, Glycerol, Oil, Laurilsulfate, “active substance' as used herein broadly includes any com Carbon dioxide producing drugs. Antidiarrheal, intestinal, pound, or mixture thereof, that can be delivered from the anti-inflammatory/antiinfective active Substances; Antibiot composition to produce a beneficial result. ics, Neomycin, Nystatin, Natamycin, Streptomycin, Poly 0132. The active substance or substances included in a myxin B, Paromomycin, Amphotericin B, Kanamycin, Van pharmaceutical composition of the invention may be selected comycin, Colistin, Rifaximin, Sulfonamides, from many therapeutic categories, in particular from Sub Phthalylsulfathiazole, Sulfaguanidine, Succinylsulfathiaz stances which may advantageously be administered orally, ole, Imidazole derivatives, Miconazole, Broxyquinoline, US 2015/0024048 A1 Jan. 22, 2015

Acetarsol, Nifuroxazide, Nifurzide, Medicinal charcoal, Bis ronic acid hydroxymethylester, Adrenalone, Thrombin, Col muth, Pectin, Kaolin, Crospovidone, Attapulgite, Diosmec lagen, Calcium alginate, Epinephrine, Blood coagulation fac tite, Diphenoxylate, Opium, Loperamide, Difenoxin, Lopera tors, Coagulation factor IX, II, VII and X in combination, mide oxide, Morphine, Prednisolone, Hydrocortisone, Coagulation factor VIII, Factor VIII inhibitor bypassing Prednisone, Betamethasone, Tixocortol, Budesonide, activity, Coagulation factor IX, Coagulation factor VII, Von BeclometaSone, Antiallergic agents, excl. corticosteroids, Willebrand factor and coagulation factor VIII in combination, Cromoglicic acid, Aminosalicylic acid and similar agents, Coagulation factor XIII, Eptacog alfa (activated). Nonacog Sulfasalazine, Mesalazine, Olsalazine, Balsalazide, Antidiar alfa, Thrombin, Etamsylate, Carbazochrome, Batroxobin. rheal microorganisms, Lactic acid producing organisms, Sac Antianemic active Substances; Ferrous glycine Sulfate, Fer charomyces boulardii, Lactic acid producing organisms, rous fumarate, Ferrous gluconate, Ferrous carbonate, Ferrous Albumin tannate, Ceratonia, Calcium compounds, Raceca chloride, Ferrous succinate, Ferrous sulfate, Ferrous tartrate, dotril. Antiobesity active substances; Phentermine, Fenflu Ferrous aspartate, Ferrous ascorbate, Ferrous iodine, Ferric ramine, Amfepramone, Dexfenfluramine, Mazindol, Etilam sodium citrate, Saccharated iron oxide, Sodium feredetate, fetamine, Cathine, Clobenzorex, Mefenorex, Sibutramine, Ferric hydroxide, Dextriferron, Ferric citrate, Chondroitin Ephedrine, Orlistat, Rimonabant. Digestiveactive sub sulfate-iron complex, Ferric acetyl transferrin, Ferric prote stances; Enzyme preparations, Diastase, Multienzymes (li insuccinylate, Dextriferron, Vitamin B12 (cyanocobalamin pase, protease etc.), Pepsin, Tilactase, Acid preparations, and analogues), Cyanocobalamin, Cyanocobalamin tannin Glutamic acid hydrochloride, Betaine hydrochloride, Hydro complex, Hydroxocobalamin, Cobamamide, Mecobalamin, chloric acid, Citric acid. Diabetes active substances; Insulins Folic acid and derivatives, Erythropoietin, Darbepoetin alfa, and analogues, Biguanides, Phenformin, Metformin, Methoxy polyethylene glycol-epoetin beta. Hematological Buformin, Sulfonamides, urea derivatives, Glibenclamide, active Subtances; Fibrinolysin and desoxyribonuclease, Chlorpropamide, Tolbutamide, Glibornuride, Tolazamide, Hyaluronidase, Chymotrypsin, Trypsin, Desoxyribonu Carbutamide, Glipizide, Gliquidone, Gliclazide, Metahexa clease, Bromelains, Streptokinase, combinations, Hematin. mide, Glisoxepide, Glimepiride, Acetohexamide, Sulfona mides (heterocyclic), Glymidine, Combinations of oral blood 0.135 Cardiac stimulantactive substances; Cardiac glyco glucose lowering drugs, Alpha glucosidase inhibitors, Acar sides, Digitalis glycosides, Acetyldigitoxin, Acetyldigoxin, bose, Miglitol, Voglibose. Thiazolidinediones, Troglitazone, Digitalis leaves, Digitoxin, Digoxin, Lanatoside C. Deslano Rosiglitazone, Pioglitazone, Dipeptidyl peptidase 4 (DPP-4) side, Metildigoxin, Gitoformate, Scilla glycosides, Proscil inhibitors, Sitagliptin, Vildagliptin, Guar gum, Repaglinide, laridin, Strophantus glycosides, G-strophanthin, Cymarin, Nateglinide, Exenatide, Aldose reductase inhibitors, Tolr Peruvoside, Adrenergic and dopaminergic agents, Etilefrine, estat. Anabolic active Substances; Androstan derivatives, Isoprenaline, Norepinephrine, Dopamine, Norfenefrine, Phe Androstanolone, Stanozolol, Metandienone, Metenolone, nylephrine, Dobutamine, Oxedrine, Metaraminol, Methox Oxymetholone, Quinbolone, Prasterone, Oxandrolone, amine, Mephentermine, Dimetofrine, Prenalterol, Dopexam Norethandrolone, Estren derivatives, Nandrolone, Ethyl ine, Gepefrine, Ibopamine, Midodrine, Octopamine, estrenol, Oxabolone cipionate. Metabolism active sub Fenoldopam, Cafedrine, Arbutamine. Theodrenaline, Epi stances; Amino acids and derivatives, Levocarnitine, Ademe nephrine, Phosphodiesterase inhibitors, Amrinone, Mil tionine, Glutamine, Mercaptamine, Carglumic acid, Betaine, rinone, Enoximone, Bucladesine. Other cardiac stimulants, Enzymes, Alglucerase, Imiglucerase, Agallsidase alfa, Agal Angiotensinamide, Xamoterol, Levosimendan. Antiarrhyth mics active Subtances; class Ia, Quinidine, Procainamide, sidase beta, Laronidase, Sacrosidase, Alglucosidase alfa, Disopyramide, Sparteine, Ajmaline, Prajmaline, Lorajmine, Galsulfase, Idursulfase, Tioctic acid, Anethole trithione, Sodium phenylbutyrate, Nitisinone, Zinc acetate, Miglustat, Antiarrhythmics, class Ib, Lidocaine, Mexiletine, Tocainide, Sapropterin. Aprindine, Antiarrhythmics, class Ic, Propafenone, Flecain ide, Lorcainide, Encainide, Antiarrhythmics, class III, Amio 0134. Antithrombotic active substances; Vitamin K darone, Bretylium tosilate, Bunaftine, Dofetilide, Ibutilide, antagonists, Dicoumarol, Phenindione, Warfarin, Phenproc Other class I antiarrhythmics, Moracizine, Cibenzoline. oumon, Acenocoumarol, Ethyl biscoumacetate, Clorindione, Active Substances for vasodilation; Organic nitrates, Glyceryl Diphenadione, Tioclomarol, Heparin, Antithrombin III, trinitrate, Methylpropylpropanediol dinitrate, Pentaerithrityl Dalteparin, Enoxaparin, Nadroparin, Parnaparin, Reviparin, tetranitrate, Propatylnitrate, Isosorbide dinitrate, Trolnitrate, Danaparoid, Tinzaparin, Sulodexide, Bemiparin, Platelet Eritrity1 tetranitrate, Isosorbide mononitrate, Tenitramine, aggregation inhibitors excl. heparin, Ditazole, Cloricromen, Floseduinan, Itramin tosilate, Prenylamine, Oxyfedrine, Picotamide, Clopidogrel, Ticlopidine, Acetylsalicylic acid, Benziodarone, Carbocromen, Hexobendine, Etafenone, Hep Dipyridamole, Carbasalate calcium, Epoprostenol, taminol, Imolamine, Dilazep, Trapidil, Molsidomine, Eflox Indobufen, Iloprost, Abciximab, Aloxiprin, Eptifibatide, ate, Cinepazet, Cloridarol, Nicorandil, Linsidomine, Nesir Tirofiban, Triflusal, Beraprost, Treprostinil, Enzymes, Strep itide. Cardiac active Substances; Prostaglandins, Alprostadil, tokinase, Alteplase, Anistreplase, Urokinase, Fibrinolysin, Other cardiac preparations, Camphora, Indometacin, Cratae Brinase, Reteplase, Saruplase, Ancrod, Drotrecogin alfa (ac gus glycosides, Creatinolfosfate, Fosfocreatine, Fructose 1.6- tivated), Tenecteplase, Protein C, Direct thrombin inhibitors, diphosphate, Ubidecarenone, Adenosine, Tiracizine, Tedis Desirudin, Lepirudin, Argatroban, Melagatran, Ximelagat amil, Acadesine, Trimetazidine, Ibuprofen, Ivabradine, ran, Bivalirudin, Dabigatran etexilate, Defibrotide, Dermatan Ranolazine. Antihypertensive active Substances; Rauwolfia Sulfate, Fondaparinux. Antihemorrhagics active Substances; alkaloids, Rescinnamine, Reserpine, Deserpidine, Methoser Amino acids, Aminocaproic acid, Tranexamic acid, Ami pidine, Bietaserpine, Methyldopa, Imidazoline receptor ago nomethylbenzoic acid, Proteinase inhibitors, Aprotinin, nists, Clonidine, Guanfacine, Tolonidine, Moxonidine, Ril Alfal antitrypsin, C1-inhibitor, Camostat, Vitamin K. Phy menidine, Sulfonium derivatives, Trimetaphan, Secondary tomenadione, Menadione, Fibrinogen, Local hemostatics, and tertiary amines, Mecamylamine, Bisquaternary ammo Absorbable gelatin sponge, Oxidized cellulose, Tetragalactu nium compounds, Alpha-adrenoreceptor antagonists, Pra US 2015/0024048 A1 Jan. 22, 2015

Zosin, Indoramin, TrimaZosin, Doxazosin, Urapidil, Guani Atorvastatin, Cerivastatin, Rosuvastatin, Pitavastatin, dine derivatives, Betanidine, Guanethidine, Guanoxan, Fibrates, Clofibrate, Bezafibrate, Aluminium clofibrate, Debrisoquine, Guanoclor, GuanaZodine, GuanoxabenZ, Thi Gemfibrozil, Fenofibrate, Simfibrate, Ronifibrate, Ciprofi azide derivatives, Diazoxide, Hydrazinophthalazine deriva brate, Etofibrate, Clofibride, Bile acid sequestrants, Col tives, Dihydralazine, Hydralazine, Endralazine, Cadralazine, estyramine, Colestipol, Colextran, Colesevelam, Nicotinic Pyrimidine derivatives, Minoxidil, Nitroferricyanide deriva acid and derivatives, Niceritrol, Nicofuranose, Aluminium tives, Nitroprusside, Guanidine derivatives, Pinacidil, Ver nicotinate, Nicotinyl alcohol (pyridylcarbinol), Acipimox, atrum, Tyrosine hydroxylase inhibitors, Metirosine, MAO Other lipid modifying agents, Dextrothyroxine, Probucol, inhibitors, Pargyline, Serotonin antagonists, Ketanserin, Tiadenol, Benfluorex, Meglutol, Omega-3-triglycerides, http://www.who.cc.no/atcddd/indexdatabase/index. Magnesium pyridoxal 5-phosphate glutamate, Policosanol, php?query=CO2KX Bosentan, Ambrisentan, Sitaxentan. EZetimibe Diuretic active substances; Thiazides, Bendroflumethiazide, 0.136) Dermatological active substances for system use: Hydroflumethiazide, Hydrochlorothiazide, Chlorothiazide, Antifungals, Griseofulvin, Terbinafine, Protectives against Polythiazide, Trichlormethiazide, Cyclopenthiazide, Methy UV-radiation for systemic use, Betacarotene, Antipsoriatics, clothiazide, Cyclothiazide, Mebutizide, Sulfonamides, Psoralens, Trioxysalen, Methoxsalen, Bergapten, Retinoids, Quinethazone, Clopamide, Chlortalidone, Mefruside, Clofe Etretinate, Acitretin, Anti-acne, Isotretinoin, Ichtasol. Anti namide, MetolaZone, Meticrane, Xipamide, Indapamide, infective and antiseptic active Substances; Antibiotics, Nys Clorexolone, Fenguizone, Mercurial diuretics, Mersalyl, tatin, Natamycin, Amphotericin B, Candicidin, Chloram Xanthine derivatives, Theobromine, Cicletanine, Furo phenicol, AZidamfenicol, Hachimycin, Oxytetracycline, semide, Bumetanide, Piretanide, Torasemide, Aryloxyacetic Carfecillin, Mepartricin, Clindamycin, Pentamycin, Arsenic acid derivatives, Etacrynic acid, Tienilic acid, Pyrazolone compounds, Acetarsol, Quinoline derivatives, Diiodohydrox derivatives, Muzolimine, EtoZolin, Aldosterone antagonists, ycuinoline, Clioquinol, Chlorquinaldol, Dequalinium, BroX Spironolactone, Potassium canrenoate, Canrenone, ycuinoline, Oxyquinoline, Organic acids, Lactic acid, Acetic Eplerenone, Amiloride, Triamterene. Active substances for acid, Ascorbic acid, Sulfonamides, Sulfatolamide, Combina peripheral vasodilation: 2-amino-1-phenylethanol deriva tions of sulfonamides, Imidazole derivatives, Metronidazole, tives, ISOXSuprine, Buphenine, Bamethan, Imidazoline Clotrimazole, Miconazole, Econazole, Ornidazole, Isocona derivatives, Phentolamine, Tolazoline, Nicotinic acid, Nicoti Zole, Tioconazole, Ketoconazole, Fenticonazole, AZanida nyl alcohol (pyridylcarbinol), Inositol nicotinate, Cicloni Zole, Propenidazole, Butoconazole, Omoconazole, Oxicona cate, Purine derivatives, Pentifylline, Xantinol nicotinate, Zole, Flutrimazole, Triazole derivatives, Terconazole, Pentoxifylline, Etofylline nicotinate, Ergot alkaloids, Ergol Clodantoin, Inosine, Policresulen, Nifuratel, Furazolidone, oid mesylates, Nicergoline, Dihydroergocristine, Kallidino Methylrosaniline, Povidone-iodine, Ciclopirox, Protiofate, genase, Cyclandelate, Phenoxybenzamine, Vincamine, Lactobacillus fermentum, Copper usinate, Octenidine Moxisylyte, Bencyclane, Vinburnine, Suloctidil, Buflomedil, 0.137 Gynecological active substances; Ergot alkaloids, Naftidrofuryl, Butalamine, Visnadine, Cetiedil, Cinepazide, Methylergometrine, Ergot alkaloids, Ergometrine, Oxytocin, Ifenprodil, AZapetine, Fasudil. Vasoprotective active sub Prostaglandins, Dinoprost, Dinoprostone, Gemeprost, Car stances; Heparinoid, Sodium apolate, Heparin, Pentosan boprost, Sulprostone, Misoprostol, Ritodrine, Buphenine, polysulfate sodium, Monoethanolamine oleate, Polidocanol, Fenoterol, Prolactine inhibitors, Bromocriptine, Lisuride, Invert sugar, Sodium tetradecyl sulfate, Phenol, Glucose, Cal Cabergoline, Quinagolide, Metergoline. Hormones; Norg cium dobesilate, Bioflavonoids, Rutoside, Monoxerutin, estrel, Gestodene, Norgestimate, Drospirenone, Norel Diosmin, Troxerutin, Hidrosmin, Tribenoside. Beta blocking gestromin, Progestogens, Norethisterone, Lynestrenol, active Substances; Beta blocking agents, non-selective, Levonorgestrel, Quingestanol, Megestrol, Medroxyprogest Alprenolol, Oxprenolol, Pindolol, Propranolol, Timolol. erone, Norgestrienone, Etonogestrel, Desogestrel, 3-oxoan Sotalol, Nadolol, Mepindolol, Carteolol, Tertatolol, Bopin drosten (4) derivatives, Fluoxymesterone, Methyltestoster dolol, Bupranolol, Penbutolol, Cloranolol, Beta blocking one, Testosterone, 5-androstanon (3) derivatives, agents, selective, Practolol, Metoprolol, Atenolol, Acebu Mesterolone, Androstanolone, Ethinylestradiol, Estradiol, tolol, Betaxolol, Bevantolol, Bisoprolol, Celiprolol, Esmolol. Estriol, Chlorotrianisene, Estrone, Promestriene, Conjugated Epanolol, S-atenolol, Nebivolol, Talinolol, Alpha and beta estrogens, Dienestrol, Diethylstilbestrol, Methallenestril, blocking agents, Labetalol, Carvedilol. Calium channel Moxestrol, Dienestrol, Methallenestril, Estrone, Diethylstil blockers; Dihydropyridine derivatives, Amlodipine, Felo bestrol, Pregnen (4) derivatives, Gestonorone, Medrox dipine, Isradipine, Nicardipine, Nifedipine, Nimodipine, yprogesterone, Hydroxyprogesterone, Progesterone, Pregna Nisoldipine, Nitrendipine, Lacidipine, Nilvadipine, Manid dien derivatives, Dydrogesterone, Megestrol, Medrogestone, ipine, Barnidipine, Lercanidipine, Cilnidipine, Benidipine, Nomegestrol, Demegestone, Chlormadinone, Promegestone, Mibefradil, Phenylalkylamine derivatives, Verapamil, Gallo Estren derivatives, Allylestrenol, Norethisterone, Lynestre pamil, Benzothiazepine derivatives, Diltiazem, Phenylalky nol, Ethisterone, Tibolone. Etynodiol, Methylestrenolone, lamine derivatives, Fendiline, Bepridil, Lidoflazine, Perhex Methyltestosterone, Methylnortestosterone, Noretynodrel, iline. Active substances acting on the renin-angiotensin Dienogest, Trimegeston, Gonadotropins, Urofollitropin, Fol system; ACE inhibitors, Captopril, Enalapril, Lisinopril, Per litropin alfa, Follitropin beta, Lutropin alfa, Choriogonadot indopril, Ramipril, Quinapril, Benazepril, Cilazapril, Fosino ropin alfa, Cyclofenil, Clomifene, Epimestrol, Cyproterone, pril, Trandolapril, Spirapril, Delapril, Moexipril, Temocapril, Danazol, Gestrinone, Antiprogestogens, Mifepristone, Ral Zofenopril, Imidapril. Other, Renin-inhibitors, Remikiren, oxifene, Corticotropin, Tetracosactide, Thyrotropin, Thy Aliskiren, Angiotensin II antagonists, Losartan, Eprosartan, rotropin, Somatropin and Somatropin agonists, Somatropin, Valsartan, Irbesartan, Candesartan, Telmisartan, Olmesartan. Somatrem, Mecasermin, Sermorelin, Mecasermin rinfabate, Lipid modifying active substances; HMG CoA reductase Pegvisomant, Vasopressin and analogues, Vasopressin, Des inhibitors, Simvastatin, Lovastatin, Pravastatin, Fluvastatin, mopressin, Lypressin, Terlipressin, Ornipressin, Argipressin, US 2015/0024048 A1 Jan. 22, 2015

Oxytocin and analogues, Demoxytocin, Oxytocin, Carbeto Sulfametoxydiazine, Sulfamethoxypyridazine, Sulfaperin, cin, Gonadotropin-releasing hormones, Gonadorelin, Sulfamerazine, Sulfaphenazole, Sulfamazone, Macrollides, Nafarelin, Histrelin, Antigrowth hormone, Somatostatin, Erythromycin, Spiramycin, Midecamycin, Oleandomycin, Octreotide, Lanreotide, Vapreotide, Anti-gonadotropin-re Roxithromycin, Josamycin, Troleandomycin, Clarithromy leasing hormones, Ganirelix, Cetrorelix, Glycogenolytic hor cin, Azithromycin, Miocamycin, Rokitamycin, Dirithromy mones, Glucagon, Parathyroid hormones and analogues, cin, Flurithromycin, Telithromycin, Lincosamides, Clinda Teriparatide, Parathyroid hormone, Calcitonin, http://www. mycin, Lincomycin, Streptogramins, Pristinamycin, whocc.no/atcddd/indexdatabase/index. 0.139 Quinupristin/dalfopristin, Streptomycins, Strepto php?query=H05BA01 Elcatonin, Cinacalcet. Urological mycin, Streptoduocin, Other aminoglycosides, Tobramycin, active Substances; Acidifiers, Ammonium chloride, Calcium Gentamicin, Kanamycin, Azithromycin, Neomycin, Amika chloride, Urinary concrement solvents, Urinary antispas cin, Retapamulin, Netilmicin, Sisomicin, Dibekacin, Ribos modics, Emepronium, Flavoxate, Meladrazine, Oxybutynin, tamycin, Isepamicin, Fluoroquinolones, Ofloxacin, Ciprof Terodiline, Propiverine, Tolterodine, Solifenacin, Trospium, loxacin, Pefloxacin, Enoxacin, Temafloxacin, Norfloxacin, Darifenacin, Fesoterodine, Drugs used in erectile dysfunc Lomefloxacin, Fleroxacin, Sparfloxacin, Rufloxacin, Grepa tion, Alprostadil, Papaverine, Sildenafil. Yohimbin, Phento floxacin, Levofloxacin, Trovafloxacin, Moxifloxacin, Gemi lamine, Moxisylyte, Apomorphine, Tadalafil. Vardenafil. floxacin, Gatifloxacin, Prulifloxacin, PaZufloxacin, Combinations, Papaverine, combinations, Magnesium Garenoxacin, Other quinolones, Rosoxacin, Nalidixic acid, hydroxide, Acetohydroxamic acid, Phenazopyridine. Succin Piromidic acid, Pipemidic acid, Oxolinic acid, Cinoxacin, imide, Collagen, Phenyl salicylate, Dimethyl sulfoxide, Flumequine, Glycopeptide antibacterials, Vancomycin, Alpha-adrenoreceptor antagonists, AlfuZosin, Tamsulosin, Teicoplanin, Telavancin, Polymyxins, Colistin, Polymyxin Terazosin, Testosterone-5-alpha reductase inhibitors, Finas B, Steroid antibacterials, Fusidic acid, Imidazole derivatives, teride, Dutasteride, Pygeum africanum, Serenoa repens, Metronidazole, Tinidazole, Ornidazole, Nitrofuran deriva Mepartricin. Corticosteroids; Mineralocorticoids, Aldoster tives, Nitrofurantoin, Nifurtoinol, Fosfomycin, Xibornol, one, Fludrocortisone, Desoxycortone, Glucocorticoids, Clofoctol, Spectinomycin, Methenamine, Mandelic acid, Betamethasone, Dexamethasone, Fluocortolone, Methyl Nitroxoline, Linezolid, Daptomycin. Antimycotic active sub prednisolone, Paramethasone, Prednisolone, Prednisone, Tri stances; Antibiotics, Amphotericin B. Hachimycin, Imida amcinolone, Hydrocortisone, Cortisone, Prednylidene, Zole derivatives, Miconazole, Ketoconazole, Triazole deriva Rimexolone, Deflazacort, Cloprednol, Meprednisone, Corti tives, Fluconazole, Itraconazole, Voriconazole, vazol, Anticorticosteroids, Trilostane. Thyroid and antithy Posaconazole, Flucytosine, Caspofungin, Micafungin, roid active substances; Thyroid hormones, Levothyroxine Anidulafungin. Antimycobacterial active Substances; Ami sodium, Liothyronine sodium, Tiratricol. Thiouracils, Meth nosalicylic acid and derivatives, Sodium aminosalicylate, ylthiouracil, Propylthiouracil, Benzylthiouracil, Sulfur-con Calcium aminosalicylate, Antibiotics, Cycloserine, Rifampi taining imidazole derivatives, Carbimazole. Thiamazole, Per cin, Rifamycin, Rifabutin, Rifapentine, Capreomycin, chlorates, Potassium perchlorate, Diiodotyrosine, Hydrazides, Isoniazid, Isoniazid. Thiocarbamide derivatives, Dibromotyrosine, Iodine. Protionamide, Tiocarlide, Ethionamide, Pyrazinamide, 0138 Antiinfective active substances: Demeclocycline, Ethambutol, Terizidone, Morinamide, Clofazimine, Dap Doxycycline, Chlortetracycline, Lymecycline, Metacycline, Sone, Aldesulfone sodium. Antiviral active Substances. Thi Oxytetracycline, Tetracycline, Minocycline, Rolitetracy osemicarbazones, MetisaZone, Nucleosides and nucleotides, cline, Penimepicycline, Clomocycline, Tigecycline, Aciclovir, Idoxuridine, Vidarabine, Ribavirin, Ganciclovir, Amphenicols, Chloramphenicol. Thiamphenicol, Ampicil Famciclovir, Valaciclovir, Cidofovir, Penciclovir, Valganci lin, Pivampicillin, Carbenicillin, Amoxicillin, Carindacillin, clovir, Brivudine, Cyclic amines, Rimantadine, Tromanta Bacampicillin, Epicillin, Pivmecillinam, AZlocillin, dine, Phosphonic acid derivatives, Foscarnet, Fosfonet, Pro Mezlocillin, Mecillinam, Piperacillin, Ticarcillin, Metampi tease inhibitors, Saquinavir, Indinavir, Ritonavir, Nelfinavir, cillin, Talampicillin, Sulbenicillin, Temocillin, Hetacillin, Amprenavir, Lopinavir, Fosamprenavir, Atazanavir, Benzylpenicillin, Phenoxymethylpenicillin, Propicillin, Azi Tipranavir, Darunavir, Zidovudine, Didanosine, Zalcitabine, docillin, Pheneticillin, Penamecillin, Clometocillin, Benza Stavudine, Lamivudine, Abacavir, Tenofovir disoproxil, Ade thine, benzylpenicillin, Procaine benzylpenicillin, Benza fovir dipivoxil, Emtricitabine, Entecavir, Telbivudine, Nevi thine phenoxymethylpenicillin, Dicloxacillin, Cloxacillin, rapine, Delavirdine, Efavirenz, Zanamivir, Oseltamivir, Meticillin, Oxacillin, Flucloxacillin, Sulbactam, Tazobac Moroxydine, Lysozyme, Inosine pranobex, Pleconaril, Enfu tam, Sultamicillin, Cefalexin, Cefaloridine, Cefalotin, Cefa Virtide, Raltegravir, Maraviroc. Immune Sera and immuno Zolin, Cefadroxil, Cefazedone, Cefatrizine, Cefapirin, Cefra globulin; Diphtheria antitoxin, Tetanus antitoxin, Snake dine, Cefacetrile, Cefroxadine, Ceftezole, Cefoxitin, Venom antiserum, Botulinum antitoxin, Gas-gangrene Sera, Cefuroxime, Cefamandole, Cefaclor, Cefotetan, Cefonicide, Rabies serum, Immunoglobulins from human, Anti-D (rh) Cefotiam, Loracarbef, Cefnmetazole, Cefprozil, Ceforanide, immunoglobulin, Tetanus immunoglobulin, Varicella/Zoster Cefotaxime, Ceftazidime, Cefsulodin, Ceftriaxone, Cef immunoglobulin, Hepatitis B immunoglobulin, Rabies menoxime, Latamoxef, Ceftizoxime, Cefixime, Cefodizime, immunoglobulin, Rubella immunoglobulin, Vaccinia immu Cefetamet, Ce?piramide, Cefoperazone, Cefpodoxime, Cef noglobulin, Staphylococcus immunoglobulin, Cytomega tibuten, Cefdinir, Cefditoren, Ceftriaxone, Cefepime, Cef lovirus immunoglobulin, Diphtheria immunoglobulin, Hepa pirome, Monobactams, Aztreonam, Carbapenems, Mero titis A immunoglobulin, Encephalitis, tick borne penem, Ertapenem, Imipenem, Trimethoprim, Brodimoprim, immunoglobulin, Pertussis immunoglobulin, Measles immu Sulfaisodimidine, Sulfamethizole, Sulfadimidine, Sulfapyri noglobulin, Mumps immunoglobulin, Palivizumab, dine, Sulfafurazole, Sulfanilamide, Sulfathiazole, Sulfathio Nebacumab. Vaccines; Bacterial vaccines, Anthrax vaccines, urea, Sulfamethoxazole, Sulfadiazine, Sulfamoxole, Sul Anthrax antigen, Brucellosis vaccines, Brucella antigen, fadimethoxine, Sulfalene, Sulfametomidine, Cholera vaccines, Diphtheria vaccines, Diphtheria toxoid, US 2015/0024048 A1 Jan. 22, 2015

Hemophilus influenzae B vaccines, Meningococcal vaccines, Aldesleukin, Oprelvekin, Lentinan, Roquinimex, BCG vac Meningococcus A, Meningococcus B. Meningococcus C. cine, Pegademase, Pidotimod, Poly I:C, Poly ICLC, Thymo Pertussis vaccines, Plague vaccines, Pneumococcal vaccines, pentin, Immunocyanin, Tasonermin, Melanoma vaccine, Pneumococcus, Tetanus vaccines, Tuberculosis vaccines, Glatirameracetate. Histamine dihydrochloride, Mifamurtide. Typhoid vaccines, Typhus (exanthematicus) vaccines. Other Immunosuppressive active Substances: Ciclosporin, bacterial vaccines, viral vaccines, Encephalitis vaccines, Muromonab-CD3, Antilymphocyte immunoglobulin, Anti Influenza vaccines, Hepatitis vaccines, Measles vaccines, thymocyte immunoglobulin, Tacrolimus, Mycophenolic Mumps vaccines, Poliomyelitis vaccines, Rabies vaccines, acid, Daclizumab, Basiliximab, Sirolimus, Etanercept, Rota virus Vaccines, Rubella Vaccines, Varicella Zoster vac Infliximab, Leflunomide, Anakinra, Alefacept, Afelimomab, cines, Yellow fever vaccines, Papillomavirus vaccines. Other Adalimumab, Everolimus, Gusperimus, Efalizumab, Abeti viral vaccines. mus, Natalizumab, Abatacept, Eculizumab, Certolizumab 0140 Antineoplastic and immunomodulating active Sub pegol, Other immunosuppressive agents, AZathioprine, Tha stances; Nitrogen mustard analogues, Cyclophosphamide, lidomide, Methotrexate, Lenalidomide. Chlorambucil, Melphalan, Chlormethine, Ifosfamide, Tro 0141 Antiinflammatory and antirheumatic active sub fosfamide, Prednimustine, Alkyl sulfonates, Busulfan, Treo stances; Butylpyrazolidines, Phenylbutazone, Mofebuta sulfan, Mannosulfan, Ethylene imines. Thiotepa, Triazi Zone, OxyphenbutaZone, ClofeZone, KebuZone, Acetic acid quone, Carboquone, Nitrosoureas, Carmustine, Lomustine, derivatives and related Substances, Indometacin, Sulindac, Semustine, Streptozocin, Fotemustine, Nimustine, Ranimus Tolimetin, Zomepirac, Diclofenac, Alclofenac, Bumadizone, tine, Epoxides, Etoglucid, Other alkylating agents, Mito Etodolac, Lonazolac, Fentiazac, Acemetacin, Difempiramide, bronitol, Pipobroman, Temozolomide, Dacarbazine. Antime Oxametacin, Proglumetacin, Ketorolac, Aceclofenac, Bufex tabolite active substances; Folic acid analogues, amac. Oxicams, PiroXicam, Tenoxicam, Droxicam, Lornoxi Methotrexate, Raltitrexed, Pemetrexed, Purine analogues, cam, Meloxicam, Propionic acid derivatives, Ibuprofen, Mercaptopurine, Tioguanine, Cladribine, Fludarabine, Clo Naproxen, Ketoprofen, Fenoprofen, Fenbufen, Benoxapro farabine, Nelarabine, Pyrimidine analogues, Cytarabine, fen, Suprofen, Pirprofen, Flurbiprofen, Indoprofen, Tiapro Fluorouracil, Tegafur, Carmofur, Gemcitabine, Capecitabine, fenic acid, Oxaprozin, Ibuproxam, Dexibuprofen, Flunox Vinca alkaloids and analogues, Vinblastine, Vincristine, Vin aprofen, Alminoprofen, Dexketoprofen, Fenamates, desine, Vinorelbine, Podophyllotoxin derivatives, Etoposide, Mefenamic acid, Tolfenamic acid, Flufenamic acid, Meclofe Teniposide, Colchicine derivatives, Demecolcine, Taxanes, namic acid, Coxibs, Celecoxib, Rofecoxib, Valdecoxib, Pare Paclitaxel, Docetaxel. Other plant alkaloids and natural prod coxib, Etoricoxib, Lumiracoxib, Nabumetone, Niflumic acid, ucts, Trabectedin. Cytotoxic antibiotic and related active sub AZapropaZone, Glucosamine, BenZydamine, Glucosami stances; Actinomycines, Dactinomycin, Anthracyclines and noglycan polysulfate, ProquaZone, Orgotein, NimeSulide, related substances, Doxorubicin, Daunorubicin, Epirubicin, Feprazone, Diacerein, Morniflumate, Tenidap, Oxaceprol, Aclarubicin, Zorubicin, Idarubicin, Mitoxantrone, Pirarubi Chondroitin sulfate, Feprazone, Dipyrocetyl, Acetylsalicylic cin, Valrubicin, Other cytotoxic antibiotics, Bleomycin, Pli acid, Quinolines, Oxycinchophen, Gold preparations, camycin, Mitomycin, Ixabepilone. Antineoplastic active Sub Sodium aurothiomalate, Sodium aurotiosulfate, Auranofin, stances; Platinum compounds, Cisplatin, Carboplatin, Aurothioglucose, Aurotioprol, Penicillamine and similar Oxaliplatin, Methylhydrazines, Procarbazine, Monoclonal agents, Bucillamine. Muscle relaxant active Substances; antibodies, Edrecolomab, Rituximab, Trastuzumab, Alemtu Peripherally acting agents, Curare alkaloids, Alcuronium, Zumab, Gemtuzumab, Cetuximab, Bevacizumab, Panitu Tubocurarine, Dimethyltubocurarine, Choline derivatives, mumab, Sensitizers used in photodynamic/radiation therapy, Suxamethonium, Other quaternary ammonium compounds, Porfimer sodium, Methyl aminolevulinate, Aminolevulinic Pancuronium, Gallamine, Vecuronium, Atracurium, acid, Temoporfin, Efaproxiral, Protein kinase inhibitors, Ima Hexafluronium, Pipecuronium bromide, Doxacurium chlo tinib, Gefitinib, Erlotinib, Sunitinib, Sorafenib, Dasatinib, ride, Fazadinium bromide, Rocuronium bromide, Mivacu Lapatinib, Nilotinib. Otherantineoplastic agents, Amsacrine, rium chloride, Cisatracurium, Botulinum toxin, Centrally Asparaginase, Altretamine, Hydroxycarbamide, acting agents, Carbamic acid esters, Phenprobamate, Cariso Lonidamine, Pentostatin, Miltefosine, Masoprocol, Estra prodol, Methocarbamol, Styramate, Febarbamate, Oxazol, mustine, Tretinoin, MitoguaZone, Topotecan, Tiazofurine, thiazine, and triazine derivatives, ChlormeZanone, ChlorZOX Irinotecan, Alitretinoin, Mitotane, Pegaspargase, Bexaro aZone, Ethers, chemically close to antihistamines, tene, Arsenic trioxide, Denileukin diftitox, Bortezomib, Orphenadrine (citrate). Other centrally acting agents, Celecoxib, Anagrelide, Oblimersen, Sitimagene ceraden Baclofen, Tizanidine, Pridinol, Tolperisone. Thiocolchico ovec, Combinations of antineoplastic agents. Endocrine side, Mephenesin, Tetrazepam, Cyclobenzaprine, Fenyrami active substances; Estrogens, Diethylstilbestrol, Polyestra dol, Directly acting agents, Dantrolene and derivatives. Anti diol phosphate, Ethinylestradiol, Fosfestrol. Progestogens, gout active Substances; Preparations inhibiting uric acid Megestrol, Medroxyprogesterone, Medroxyprogesterone, production, Allopurinol, Tisopurine, FebuXostat, Prepara Gestonorone, Gonadotropin releasing hormone analogues, tions increasing uric acid excretion, Probenecid, Sulfinpyra Buserelin, Leuprorelin, Goserelin, Triptorelin, hormones Zone, Benzbromarone, Isobromindione, Preparations with no antagonists, Anti-estrogens, Tamoxifen, Toremifene, Fulves effect on uric acid metabolism, Colchicine, Cinchophen, trant, Anti-androgens, Flutamide, Nilutamide, Bicalutamide, Other antigout preparations, Urate oxidase. Active Sub Enzyme inhibitors, Aminogluthetimide, Formestane, Anas stances affecting bone struture and mineralization; Bisphos trozole, Letrozole, Vorozole, Exemestane, Abarelix. Immu phonates, Etidronic acid, Clodronic acid, Pamidronic acid, nostimulant active Substances; Cytokines and immunomodu Alendronic acid, Tiludronic acid, Ibandronic acid, Risedronic lators, Colony stimulating factors, Filgrastim, acid, Zoledronic acid, Bone morphogenetic proteins, Dibo MolgramoStim, SargramoStim, Lenograstim, Ancestim, Peg termin alfa, Eptotermin alfa, Other drugs affecting bone filgrastim, Interferons, Peginterferons, Interleukins, structure and mineralization, Ipriflavone, Aluminium chloro US 2015/0024048 A1 Jan. 22, 2015

hydrate, Strontium ranelate, Quinine and derivatives, Hydro Melevodopa, Etilevodopa, Adamantane derivatives, Amanta quinine, Enzymes, Chymopapain, Trypsin, Hyaluronic acid. dine, Dopamine agonists, Bromocriptine, Pergolide, Dihy Colecalciferol. droergocryptine mesylate, Ropinirole, Pramipexole, Caber 0142 Analgesics; Opioids, Natural opium alkaloids, Mor goline, Apomorphine, Piribedil, Rotigotine, Monoamine, phine, Opium, Hydromorphone, Nicomorphine, Oxycodone, oxidase B inhibitors, Selegiline, Rasagiline. Other dopamin Dihydrocodeine, Diamorphine, Papaveretum, Codeine, Phe ergic agents, Tolcapone, Entacapone, Budipine. Antipsy nylpiperidine derivatives, Ketobemidone, Pethidine, Fenta chotic active substances; Phenothiazines with aliphatic side nyl, Diphenylpropylamine derivatives, Dextromoramide, Pir chain, Chlorpromazine, Levomepromazine, Promazine, itramide, Dextropropoxyphene, Bezitramide, Methadone, Acepromazine, Triflupromazine, Cyamemazine, Chlorproet Benzomorphan derivatives, Pentazocine, Phenazocine, Ori hazine, Phenothiazines with piperazine structure, Dixyra pavine derivatives, Buprenorphine, Morphinan derivatives, zine, Fluphenazine, Perphenazine, Prochlorperazine. Thio Butorphanol, Nalbuphine, Tilidine, Tramadol, Dezocine, propaZate, Trifluoperazine, Acetophenazine, Salicylic acid and derivatives, Acetylsalicylic acid, Aloxiprin, Thioproperazine. Butaperazine, Perazine, Phenothiazines Choline salicylate, Sodium salicylate, Salicylamide, Sal with piperidine structure, Periciazine. Thioridazine, salate, Ethenzamide, Morpholine salicylate, Dipyrocetyl, Mesoridazine, Pipotiazine, Butyrophenone derivatives, Benorilate. Diflunisal, Potassium salicylate, Guacetisal, Car Haloperidol, Trifluperidol, Melperone, Moperone, Pipam basalate calcium, Imidazole Salicylate, Pyrazolones, perone, Bromperidol, Benperidol, Droperidol, Fluanisone, PhenaZone, Metamizole sodium, AminophenaZone, Propy Indole derivatives, Oxypertine, Molindone, Sertindole, phenaZone, NifenaZone, Anilides, Paracetamol, Phenacetin, Ziprasidone. Thioxanthene derivatives, Flupentixol, Clo Bucetin, Propacetamol. Other analgesics and antipyretics, penthixol, Chlorprothixene, Tiotixene, Zuclopenthixol, Rimazolium, Glafenine, Floctafenine, Viminol, Nefopam, Diphenylbutylpiperidine derivatives, Fluspirilene, Pimozide, Flupirtine, Ziconotide. Anesthetics: Ethers, Diethyl ether, Penfluridol, Diazepines, oxazepines and thiazepines, Loxap Vinyl ether, Halogenated hydrocarbons, Halothane, Chloro ine, Clozapine, Olanzapine, Quetiapine, Neuroleptics, in tar form, Methoxyflurane, Enflurane, Trichloroethylene, Isoflu dive dyskinesia, Tetrabenazine, Benzamides, Sulpiride, Sul rane, Desflurane, Sevoflurane, Barbiturates, Methohexital, topride, Tiapride, Remoxipride, Amisulpride, Veralipride, Hexobarbital. Thiopental, Narcobarbital, Opioid anesthetics, Levosulpiride, Lithium, Other antipsychotics, Prothipendyl, Fentanyl, Alfentanil, Sufentanil, Phenoperidine, Anileridine, Risperidone, Clotiapine, Mosapramine, Zotepine, Aripipra Remifentanil. Other general anesthetics, Droperidol, Ket Zole, Paliperidone. Anxiolytic active substances; Benzodiaz amine, Propanidid, Alfaxalone, Etomidate, Propofol, epine derivatives, Diazepam, Chlordiazepoxide, Hydroxybutyric acid, Nitrous oxide, Esketamine, Xenon, Medazepam, Oxazepam, Potassium cloraZepate, Lorazepam, Esters of aminobenzoic acid, Metabutethamine, Procaine, Adinazolam, Bromazepam, Clobazam, Ketazolam, Tetracaine, Chloroprocaine, Benzocaine, Amides, Bupiv Prazepam, Alprazolam, Halazepam, Pinazepam, acaine, Lidocaine, Mepivacaine, Prilocaine. Butanilicaine, Camazepam, Nordazepam, Fludiazepam, Ethyl loflazepate, Cinchocaine, Etidocaine, Articaine, Ropivacaine, Levobupi Etizolam, Clotiazepam, Cloxazolam, Tofisopam, Diphenyl vacaine, Esters of benzoic acid, Cocaine. Other local anes methane derivatives, Hydroxyzine, Captodiame, Carbam thetics, Ethyl chloride, Dyclonine, Phenol, Capsaicin. Anti ates, Meprobamate, Emylcamate, Mebutamate, Dibenzo-bi migraine active Substances; Ergot alkaloids, cyclo-octadiene derivatives, BenZoctamine, Dihydroergotamine, Ergotamine, Methysergide, Lisuride, AZaspirodecanedione derivatives, Buspirone. Other anxiolyt Corticosteroid derivatives, Flumedroxone, Selective seroto ics, Mephenoxalone, Gedocarnil, Etifoxine. Hypnotic and nin (5HT1) agonists, Sumatriptan, Naratriptan, Zolmitriptan, sedative active substances; Barbiturates, Pentobarbital, Rizatriptan, Almotriptan, Eletriptan, Frovatriptan, Otheranti Amobarbital, Butobarbital, Barbital, Aprobarbital, Secobar migraine preparations, Pizotifen, Clonidine, Iprazochrome, bital, Talbutal, Vinylbital, Vinbarbital, Cyclobarbital, Hept Dimetotiazine, Oxetorone. Antiepileptic active Substances; abarbital, Reposal, Methohexital, Hexobarbital. Thiopental, Barbiturates and derivatives, Methylphenobarbital, Phe Etallobarbital, Allobarbital, Proxibarbal, Aldehydes and nobarbital, Primidone, Barbexaclone, Metharbital, Hydan derivatives, Chloral hydrate, Chloralodol, Acetylglycinamide toin derivatives, Ethotoin, Phenytoin, chloral hydrate, Dichloralphenazone, Paraldehyde, Benzodi 0143 Amino(diphenylhydantoin) valeric acid, Mepheny azepineemepronium derivatives, Flurazepam, Nitrazepam, toin, Fosphenytoin, Oxazolidine derivatives, Paramethadi Flunitrazepam, Estazolam, Triazolam, Lorimetazepam, one, Trimethadione, Ethadione, Succinimide derivatives, Temazepam, Midazolam, Brotizolam, Quazepam, Lopra Ethosuximide, Phensuximide, Mesuximide, Benzodiazepine Zolam, Doxefazepam, Cinolazepam, Piperidinedione deriva derivatives, Clonazepam, Carboxamide derivatives, Carbam tives, Glutethimide, Methyprylon, Pyrithyldione, Benzodiaz azepine, Oxcarbazepine, Rufinamide, Fatty acid derivatives, epine related drugs, Zopiclone, Zolpidem, Zaleplon, Valproic acid, Valpromide, Aminobutyric acid, Vigabatrin, Ramelteon, Other hypnotics and sedatives, Methaqualone, Progabide, Tiagabine. Other antiepileptics, Sultiame, Phena Clomethiazole, Bromisoval, Carbromal, Scopolamine, Pro cemide, Lamotrigine, Felbamate, Topiramate, Gabapentin, piomazine, Triclofos, Ethchlorvynol, Valerian, Hexapropy Pheneturide, Levetiracetam, Zonisamide, Pregabalin, Stirip mate, Bromides, Apronal, Valnoctamide, Methylpentynol, entol, Lacosamide, Beclamide. Anticholinergic active Sub Niaprazine, Melatonin, Dexmedetomidine, Dipiperonylami stances; Tertiary amines, Trihexyphenidyl, Biperiden, Metix noethanol. Antidepressant active Substances; Non-selective ene, Procyclidine, Profenamine, Dexetimide, monoamine reuptake inhibitors, Desipramine, Imipramine, Phenglutarimide, Mazaticol, Bornaprine, Tropatepine, Imipramine oxide, Clomipramine, Opipramol, Trimi Ethers chemically close to antihistamines, Etanautine, pramine, Lofepramine, Dibenzepin, Amitriptyline, Nortrip Orphenadrine (chloride), Ethers of tropine or tropine deriva tyline, Protriptyline, Doxepin, Iprindole, Melitracen, Butrip tives, BenZatropine, Etybenzatropine. Dopaminergic ative tyline, DoSulepin, Amoxapine, Dimetacrine, Amineptine, Substances; Dopa and dopa derivatives, Levodopa, Maprotiline, Quinupramine, Selective serotonin reuptake US 2015/0024048 A1 Jan. 22, 2015

inhibitors, Zimeldine, Fluoxetine, Citalopram, Paroxetine, pyrimidine derivatives, Pyrantel, Oxantel, Imidazothiazole Sertraline, Alaproclate, Fluvoxamine, Etoperidone, Escitalo derivatives, Levamisole, Avermectines, Ivermectin, Pyrv pram, Monoamine oxidase inhibitors, non-selective, Isocar inium, Bephenium, anticestodal active Substance: Salicylic boxazid, Nialamide, Phenelzine, Tranylcypromine, Iproniaz acid derivatives, Niclosamide, Desaspidin, Dichlorophen. ide, Iproclozide, Monoamine oxidase A inhibitors, Ectoparasiticide active Substances; Sulfur containing prod Moclobemide, Toloxatone. Other antidepressants, Oxitrip ucts, Dixanthogen, Potassium polysulfide, Mesulfen, Disul tan, Tryptophan, Mianserin, Nomifensine, Trazodone, Nefa firam, Thiram, Chlorine containing products, Clofenotane, Zodone, Minaprine, Bifemelane, Viloxazine, Oxaflozane, Lindane, Pyrethrines, incl. synthetic compounds, Pyrethrum, Mirtazapine, Medifoxamine, Tianeptine, Pivagabine, Ven Bioallethrin, Phenothrin, Permethrin, Benzylbenzoate, Cop lafaxine, Milnacipran, Reboxetine, Gepirone, Duloxetine, per oleinate, Malathion, Quassia. Insecticide and repellent Agomelatine, Desvenlafaxine, Centrally acting sympathomi active substances; Pyrethrines, Cyfluthrin, Cypermethrin, metics, Amfetamine, Dexamfetamine, Metamfetamine, Decamethrin, Tetramethrin, Diethyltoluaide, Dimeth Methylphenidate, Pemoline, Fencamfamin, Modafinil, Feno ylphthalate, Dibutylphthalate, Dibutylsuccinate, Dimethyl Zolone, Atomoxetine, Fenetyline, Xanthine derivatives, Caf carbate, Etohexadiol. feine, Propentofylline. Other psychostimulants and nootro pics, Meclofenoxate, Pyritinol, Piracetam, Deanol, Fipexide, 0145 Decongestant active substances; Sympathomimet Citicoline, Oxiracetam, Pirisudanol, Linopirdine, ics, Cyclopentamine, Ephedrine, Phenylephrine, Oxymeta Nizofenone, Aniracetam, Acetylcarnitine, Idebenone, Prolin Zoline, Tetry Zoline, Xylometazoline, Naphazoline, Tramazo tane, Pipradrol, Pramiracetam, Adrafinil, Vinpocetine. Anti line, Metizoline, Tuaminoheptane, Fenoxazoline, dementia active Subtances; Anticholinesterases, Tacrine, Tymazoline, Epinephrine, Cromoglicic acid, Levocabastine, Donepezil, Rivastigmine, Galantamine. Other anti-dementia AZelastine, Antazoline, Spaglumic acid, Thonzylamine, drugs, Memantine, Ginkgo biloba. Other nervous system Nedocromil, Olopatadine, Corticosteroids, Beclometasone, active Substances; Parasympathomimetics, Anticholinest Prednisolone, Dexamethasone, Flunisolide, Budesonide, erases, Neostigmine, Pyridostigmine, Distigmine, Betamethasone, Tixocortol, Fluticasone, Mometasone, Tri Ambenonium, Choline esters, Carbachol, Bethanechol, amcinolone, FluticaSone furoate, Hydrocortisone, Calcium Other parasympathomimetics, Pilocarpine, Choline alfoscer hexamine thiocyanate, Retinol, Ipratropium bromide, Riti ate. Active substances used in addictive disorders; Drugs used ometan, Mupirocin, Hexamidine, Framycetin, Phenylpro in nicotine dependence, Nicotine, Bupropion, Varenicline, panolamine, Pseudoephedrine, Phenylephrine. Throat active Drugs used in alcohol dependence, Disulfiram, Calcium car Substances; Antiseptics, AmbaZone, Dequalinium, Dichlo bimide, Acamprosate, Naltrexone, Drugs used in opioid robenzyl alcohol, Chlorhexidine, Cetylpyridinium, Benze dependence, Buprenorphine, Methadone, Levacetylmeth thonium, Myristyl-benzalkonium, Chlorquinaldol, Hexylre adol, Lofexidine. Antivertigo active Subtances; Betahistine, sorcinol, Acriflavinium chloride, Oxyquinoline, Povidone Cinnarizine, Flunarizine, Acetylleucine, other nervous sys iodine, Benzalkonium, Cetrimonium, Hexamidine, Phenol, tem drugs, Gangliosides and ganglioside derivatives, Tir Antibiotics, Neomycin, Tyrothricin, Fusafungine, Bacitracin, ilazad, Riluzole, Xaliproden, Hydroxybutyric acid, Amifam Gramicidin, Benzocaine, Lidocaine, Cocaine, Dyclonine. pridine. Active substances for obstructive airway diseases; Orciprena line, Salbutamol, Terbutaline, Fenoterol, Rimiterol, Hexopre 0144 Active Substances against amoebiasis and other pro naline, Isoetarine, Pirbuterol, Tretoquinol, Carbuterol, toZoal diseases; Hydroxyquinoline derivatives, Broxyquino Tulobuterol, Salmeterol, Formoterol, Clenbuterol, Reprot line, Clioquinol, Chlorquinaldol, Tilbroquinol, Nitroimida erol, Procaterol, Bitolterol, Glucocorticoids, Beclometasone, Zole derivatives, Metronidazole, Tinidazole, Ornidazole, Budesonide, Flunisolide, Betamethasone, Fluticasone, Tri Azanidazole, Propenidazole, Nimorazole, Secnidazole, amcinolone, MometaSone, Ciclesonide, pratropium bro Dichloroacetamide derivatives, Diloxanide, Clefamide, Eto mide, OXitropium bromide, Stramoni preparations, Tiotro famide, Teclozan, Arsenic compounds, Arsthinol, Dilfetar pium bromide, Cromoglicic acid, Nedocromil, Fenspiride, Sone, Glycobiarsol, Chiniofon, Emetine, Phanquinone, Methoxyphenamine, Bambuterol, Xanthines, Diprophylline, Mepacrine, Atovaquone, Trimetrexate, Tenonitrozole, Dihy Choline theophyllinate, Proxyphylline. Theophylline, Ami droemetine, Fumagillin, NitaZoxanide. Antimalarial active nophylline, Etamiphylline. Theobromine, Bamifylline, Ace Substances; Aminoquinolines, Chloroquine, Hydroxychloro fylline piperazine, Bufylline, Doxofylline, Zafirlukast, Pran quine, Primaquine. Amodiaquine, Biguanides, Proguanil, lukast, Montelukast, Ibudilast, Amlexanox, EproZinol, Cycloguanil embonate, Methanolduinolines, Quinine, Fenspiride, Omalizumab, Seratrodast, Roflumilast. Cough Mefloquine, Diaminopyrimidines, Pyrimethamine, Artemisi and cold active Substances; Expectorants, Tyloxapol, Potas nin and derivatives, Artemether, Artesunate, Artemotil, sium iodide, Guaifenesin, Ipecacuanha, Althea root, Senega, Artenimol, Halofantrine. Active Substances against leishma Antimony pentasulfide, Creosote, Guaiacolsulfonate, Levo niasis and trypanosomiasis; Nitroimidazole derivatives, Ben verbenone. Mucolytics, Acetylcysteine, Bromhexine, Car Znidazole, Antimony compounds, Meglumine antimonate, bocisteine, Eprazinone, Mesna, Ambroxol, Sobrerol, Domi Sodium stibogluconate, Nitrofuran derivatives, Nifurtimox, odol, Letosteine, Stepronin, Tiopronin, Dornase alfa Nitrofural, Arsenic compounds, Melarsoprol, Acetarsol, Pen (desoxyribonuclease), Neltenexine, Erdosteine, Opium alka tamidine isethionate, Suramin sodium, Eflornithine. Anti loids and derivatives, Ethylmorphine, Hydrocodone, trematodal active Substances; Quinoline derivatives and Codeine, Opium alkaloids with morphine, Normethadone, related Substances, Praziquantel, Oxamniquine, Organophos Noscapine, Pholcodine, Dextromethorphan, Thebacon, phorous compounds, Metrifonate, Bithionol, Niridazole, Sti Dimemorfan, Acetyldihydrocodeine, Benzonatate, Benpro bophen, Triclabendazole. Antinematodal active Substances; perine, Clobutinol, Isoaminile, Pentoxyverine, Oxolamine, Benzimidazole derivatives, Mebendazole, Tiabendazole, Oxeladin, Clo?edanol, Pipazetate, Bibenzonium bromide, Albendazole, Ciclobendazole, Flubendazole, Fenbendazole, Butamirate, Fedrilate, Zipeprol, Dibunate, Droxypropine, Piperazine and derivatives, Diethylcarbamazine, Tetrahydro Prenoxdiazine, Dropropizine, Cloperastine, Meprotixol, Pip US 2015/0024048 A1 Jan. 22, 2015 eridione, Tipepidine, Morclofone, Nepinalone, Levodro Suppressants, decongestants, antitussives, antihistamines, propizine, Dimethoxanate. Antihistamine active Substances; antiemetics, antidiarrheals, and drugs used to treat narcolepsy Aminoalkyl ethers, Bromazine, Diphenhydramine, Clemas and attention deficit hyperactivity disorder. tine, Chlorphenoxamine, Diphenylpyraline, Carbinoxamine, 0153. In specific embodiments, the active substance is Doxylamine, Substituted alkylamines, Brompheniramine, associated with abuse syndromes include opioids, CNS Dexchlorpheniramine, Dimetindene, Chlorphenamine, Phe depressants, CNS stimulants, cannabinoids, nicotine-like niramine, Dexbrompheniramine, Talastine, Substituted eth compounds, glutamate antagonists and N-methyl-D-aspar ylene diamines, Mepyramine. Histapyrrodine, Chloropy tate (NMDA) antagonists. ramine, Tripelennamine, Methapyrilene, Thonzylamine, 0154) In specific embodiments, the active substance is Phenothiazine derivatives, Alimemazine, Promethazine. Thi buprenorphine, codeine, dextromoramide, dihydrocodeine, ethylperazine, Methdilazine, Hydroxyethylpromethazine, fentanyl, hydrocodone, hydromorphone, morphine, pentaZo Thiazinam, Mequitazine, Oxomemazine, Isothipendyl, Pip cine, oxycodeine, oxycodone, oxymorphone and tramadol. erazine derivatives, Buclizine, Cyclizine, Chlorcyclizine, 0.155 The active substance can be in various forms, such Meclozine, Oxatomide, Cetirizine, Levocetirizine, Bami as uncharged or charged molecules, molecular complexes, pine, Cyproheptadine. Thenalidine, Phenindamine, AntaZo crystalline forms, amorphous form, polyamorphous form, line, Triprolidine, Pyrrobutamine, AZatadine, Astemizole, polymorphous form, complexes, Solvates, anhydrates, if rel Terfenadine, Loratadine, Mebhydrolin, Deptropine, Keto evant isomers, enantiomers, racemic mixtures and pharma tifen, Acrivastine, AZelastine, Tritoqualine, Ebastine, Pime cologically acceptable salts such as e.g. hydrochloride, thixene, Epinastine, Mizolastine, Fexofenadine, Deslorata hydrobromide, Sulfate, laurylate, palmitate, phosphate, dine, Rupatadine. Other respiratory system active Substances; nitrite, nitrate, citrate, borate, acetate, maleate, tartrate, ole Lung Surfactants, Colfosceril palmitate, Natural phospholip ate, and salicylate. For acidic active Substance, salts of metals ids. Respiratory stimulants, Doxapram, Nikethamide, Pentet e.g. alkali metal salts such as, e.g., sodium or potassium salts, razol, Etamivan, Bemegride, Prethcamide, Almitrine, Dime alkaline earth metal salts such as, e.g., calcium and magne fline, Mepixanox, Nitric oxide. sium salts, amines amino acids or organic cations, quaternary 0146. Other active substances: Antidotes, Ipecacuanha, ammoniums, can be used. Derivatives of active substances Nalorphine, Edetates, Pralidoxime, Prednisolone and Such as esters, ethers and amides which have solubility char promethazine. Thiosulfate, Sodium nitrite, Dimercaprol, acteristics suitable for use herein can be used alone or mixed Obidoxime, Protamine, Naloxone, Methylthioninium chlo with other drugs. After release of the derivative from the drug ride, Potassium permanganate, Physostigmine, Copper Sul delivery system it may be converted by enzymes, hydrolysed fate, Potassium iodide, Amyl nitrite, Acetylcysteine, Digitalis by body pH or other metabolic processes to the parent drug or antitoxin, Flumazenil, Methionine, 4-dimethylaminophenol, to another biologically active form. Cholinesterase, Prussian blue, Glutathione, Hydroxocobal 0156 A pharmaceutical composition of the invention may amin, Fomepizole, Iron chelating agents, Deferoxamine, in addition be suitable for the delivery of peptides, polypep Deferiprone, Deferasirox, Polystyrene sulfonate, Sevelamer, tides or proteins, for example hormones, enzymes Such as Lanthanum carbonate, Mesna, DexraZoxane, Calcium foli lipases, proteases, carbohydrates, amylases, lactoferrin, lac nate, Calcium levofolinate, Amifostine, Sodium folinate, toperoxidases, lysozymes, nanoparticles, etc., and antibod Rasburicase, Palifermin, Glucarpidase, Sodium cellulose ies. The composition may also be employed for the delivery phosphate, Diazoxide. of microorganisms, either living, attenuated or dead, for 0147 In specific embodiments, the active substance is for example bacteria, e.g. gastrointestinal bacteria Such as Strep cardiac therapy including e.g. cardiac glycosides, antiar tococci, e.g. S. faecium, Bacillus spp. Such as B. subtilis and rhythmics, cardiac stimulants, vasodilators, antihyperten B. licheniformis, lactobacteria, Aspergillus spp., bifidogenic sives, diuretics, vasoprotectives, beta blockers, calcium chan factors, or viruses such as indigenous vira, enterovira, bacte nel blockers, agents acting on the rennin-angiotensin System, riophages, e.g. as vaccines, and fungi such as baker's yeast, lipid modifying agents. Saccharomyces cerevisiae and fungi imperfecti. 0148. In specific embodiments, the active substance is 0157. In an embodiment of the invention, the active sub from the therapeutic classes including antiemetics, antinau stance is a pharmaceutically active powder. The powder typi seants, antiobesity and anabolic agents. cally has a particle size of from about 0.1 um to about 500 um, 0149. In specific embodiments, the active substance is typically from about 0.5 um to about 300 um, more typically from the therapeutic classes including antiinflammatory and from about 1 um to about 200 um, especially from about 5um antiinfective agents, corticosteroids, non-steroids anti-in to about 100 um. flammatory and antirheumatic agents. 0158. In an embodiment of the invention, the active sub 0150. In specific embodiments, the active substance is stance is a pharmaceutically active crystal. The crystal typi from the therapeutic classes including decongestants, adren cally has a particle size of from about 0.1 um to about 1000 ergics, expectorants, cough Suppressant and antihistamines. um Such as, e.g., about 0.1 um to about 750Lim, about 0.1 um 0151. In specific embodiments, the active substance is to about 500 um, typically from about 0.5 um to about 500 from the therapeutic classes including anesthetics, analge um, more typically from about 1 um to about 500 um, espe sics, opioids, antipyretics, antimigraine agents, antiepilep cially from about 5 um to about 500 Lum. tics, anti-parkinson agents, dopaminergic agents, antipsy 0159. In another embodiment of the invention, a compo chotics, anxiolytics, sedatives, antidepressants, sition comprises active Substance that at least partially is psychostimulants agents used for ADHD and nootropics, present in amorphous form with a mean particle size of at agents used in addictive disorders. least about 0.01 um Such as, e.g., from about 0.01 um to about 0152. In specific embodiments, the active substance is 500 um, from about 0.05um to about 500 um, from about 0.1 from the therapeutic classes including anaesthetics, centrally um to about 500 um, from about 0.5 um to about 500 um, acting analgesics, sedative-hypnotics, anxiolytics; appetite about 1 um to about 500 um, typically from about 0.5um to US 2015/0024048 A1 Jan. 22, 2015

about 300 um, more typically from about 1 um to about 200 The amorphous state and/or the solid dispersion is stabilized um, especially from about 1 um to about 100 um. either by a very careful choice of the concentration of the 0160 The at least one therapeutically, prophylactically active Substance in the composition and/or by addition of and/or diagnostically and/or biologically active Substance Suitable stabilizing agents acting by stabilizing one or more of will suitably be present in an amount of up to about 80%, the conditions mentioned above under items 1) to 5). typically up to about 70%, up to about 60% or up to about 0170 In regards to condition 4) the stability may be 50%, such as, e.g., from 0.1% to 80%, such as from 0.25% to retrieved by several mechanisms of which the most important 75%, such as from 0.5% to 60%, such as from 0.75% to 50%, a such as from 1% to 40%, such as from 1.5% to 35%, such as 0171 a) Physical stabilization by decreasing the from 1.75% to 30% by weight of the composition or layer. molecular mobility of the components, i.e. Suitable With respect to situations where one or more active sub excipients and the active Substance of the formulation stances are contained in one of the layers or coat, a content of 0172 b) Chemical stabilization by increasing the appar about 60-80% w/w is contemplated to be the maximum con ent solubility of the active substance in the matrix for tent, which still allows for a sufficient content of the polymer mulation. and, when relevant, a pharmaceutically acceptable excipient 0173 Thus a stabilizing agent may serve more than one in the composition. The active Substance may, on the other purpose, it may stabilize the amorphous state of the active hand, be present in the composition in much smalleramounts, Substance in the composition in order to avoid, reduce or depending on the nature and potency of the active Substance delay any recrystallization, it may stabilize the active Sub in question. stance or other ingredients towards proteolytic or oxidative 0161. A composition according to the invention contain degradation or it may have an anti-plasticizing effect. ing a drug Substance is typically for oral administration. Due 0.174. A stabilizing agent may also contribute to an to the possibility of controlling the release rate of the active improved solubility of the active substance. Without being Substance the composition may be adapted for oral adminis bound to any theory it may be assumed that the stabilizing tration 1-6 times a day, normally 1-4 times daily Such as 1-3 agent together with the polyethylene glycol and/or polyeth times, 1-2 times or 1 times daily. The technology may also ylene oxide represent the dispersion medium wherein the provide compositions for administration only once or twice solubility of the active substance may be higher than in the daily. In the present context the term “once daily' is intended polyethylene glycol and/or polyethylene oxide alone. The to mean that it is only necessary to administer the pharma same may apply with respect to the stability of the amorphous ceutical composition once a day in order to obtain a suitable form of the active substance. therapeutic and/or prophylactic response; however, any administration may comprise co-administration of more than Pharmaceutically Acceptable Excipients one dosage unit, such as, e.g. 2-4 dosage units if the amount 0.175. The composition may also contain other excipients of active Substance required may not be formulated in only as well, e.g. in order to improve the technical properties of the one composition or if a composition of a smaller size is composition so that it may be easier to produce or in order to preferred. improve the properties of the composition Such as release rate 0162 The dosage of the active substance depends on the of the active substance, stability of the active substance or of particular substance, the age, weight condition etc. of the the composition itself etc. human oranimal that will be treated with the composition etc. 0176 A suitable pharmaceutically acceptable excipient All such factors are well known to a person skilled in the art. for use in a composition of the invention may be selected from the group consisting of fillers, diluents, disintegrants, Stability glidants, pH-adjusting agents, Viscosity adjusting agents, 0163 With respect to the fixed-dosed combination formu solubility increasing or decreasing agents, osmotically active lation stability is employed to encompass one or more of the agents and solvents. following: 0177 Suitable excipients include conventional tablet or 0164. 1) Stability with respect to the physical stability capsule excipients. These excipients may be, for example, of the composition (appearance, color, strength, etc.) diluents such as dicalcium phosphate, calcium Sulfate, lactose 0.165. 2) Stability with respect to in vitro dissolution or Sucrose or other disaccharides, cellulose, cellulose deriva behavior of the active substance from the composition tives, kaolin, mannitol, dry starch, glucose or other monosac charides, dextrin or other polysaccharides, Sorbitol, inositol Stability of the Individual Components; or mixtures thereof binders such as alginic acid, calcium alginate, Sodium alginate, starch, gelatin, Saccharides (in 0166 3) Stability with respect to the chemical stability cluding glucose, Sucrose, dextrose and lactose), molasses, of the active substance (degradation of the active sub panwar gum, ghatti gum, mucilage ofisapolhusk, carboxym stance to other—normally—unwanted products) ethylcellulose, methylcellulose, Veegum, larch arabolactan, (0167 4) Stability with respect to the form the active polyethylene glycols, ethylcellulose, water, alcohols, waxes, Substance has in the composition; if the active Substance polyvinylpyrrolidone such as, e.g., PVP K90 or mixtures is dissolved (molecularly dispersed) in the polymeras a thereof: lubricants such as talc, silicium dioxide, magnesium Solid dispersion. In such cases precipitation or otherwise Stearate, calcium Stearate, Stearic acid, hydrogenated veg formation of crystals of the active Substance in the com etable oils, sodium benzoate, Sodium chloride, leucine, car position is an indication of a stability problem. bowax 4000, magnesium lauryl sulfate, Sodium laurilsulfate, 0168 5) Physical and chemical stability of the pharma Stearyl alcohol, Polysorbate 20, Polysorbate 60, Polysorbate ceutically acceptable polymer and excipients employed 80, Macrogol stearate, Macrogol lauryl ether, Stearoyl mac 0169. In particular, the active substance or substances rogolglycerides, Sorbitan Stearate, Sorbitan laurate, Mac maybe stabilized in the dosage form in its amorphous form. rogol glycerol hydroxyStearat, colloidal silicon dioxide and US 2015/0024048 A1 Jan. 22, 2015 mixtures thereof, disintegrants such as starches, clays, cellu Zoate, butoxyethyl Stearate, butyl and glycol esters of fatty lose derivatives including microcrystalline cellulose, methy acids, butyl diglycol carbonate, butyl ricinoleate, butyl cellulose, carboxymethycellulose calcium, carboxymethyl phthalyl butyl glycolate, camphor, dibutyl sebacate, dibutyl cellulose sodium, cellulose, crosscarmellose sodium, gums, tartrate, diphenyl oxide, glycerine, HB-40, hydrogenated aligns, various combinations of hydrogencarbonates with methyl ester of rosin, methoxyethyl oleate, monoamylphtha weak acids (e.g. sodium hydrogencarbonate/tartaric acid or late, Nevillac 10, Paracril 26, technical hydroabietyl alcohol, citric acid) crosprovidone, sodium starch glycolate, agar, alg triethylene glycol dipelargonate, Solid aliphatic alcohols, inic acid, calcium alginate, sodium alginate, chitosan, colloi nitrobenzene, carbon disulfide, B-naphtyl salicylate, phthalyl dal silicon dioxide, docusate Sodium, guar gum, low-substi glycolate, dioctyl phthalate. and mixtures thereof. Other suit tuted hydroxypropyl cellulose, hydroxypropyl Starch, able plasticizers appear from EP-B-0 746 310 to which ref magnesium aluminium silicate, polacrilin potassium, povi erence is made. done, Sodium starch glycolate, pregelatinized Starch, cation 0180. The use of a plasticizer will often be desirable in exchange resins, citrus pulp, Veegum, glycolate, natural order to improve the processibility of the coating. The plas sponge, bentonite. Sucralfate, calcium hydroxyl-apatite or ticizer may also be a non-ionic Surfactant, e.g. a non-ionic mixtures thereof, effervescent agents (carbonate release) Surfactant as the one mentioned above. Such as citric acid, anhydrous, citric acid, monohydrate, dex 0181 Preferred stabilizers (chemical) include TPG e.g. in trates, fumaric acid, potassium bicarbonate, sodium bicar the form of TPGS due to surfactant properties, BHA, BHT, bonate, Sodium citrate, dehydrate, tartaric acid or mixtures t-butyl hydroquinone, calcium ascorbate, gallic acid, hydro thereof. quinone, maltol, octyl gallate, Sodium bisulfite, Sodium met 0178. Furthermore, the composition may comprise one or abisulfite, tocopherol and derivates thereof, citric acid, tar more agents selected from the group consisting of Sweetening taric acid, and ascorbic acid. Other stabilisers include agents, flavouring agents and colouring agents, in order to trivalent phosphorous like e.g. phosphite, phenolic antioxi provide an elegant and palatable preparation. Examples are dants, hydroxylamines, lactones such as Substituted benzo maltol, citric acid, water soluble FD&C dyes and mixtures furanones. Hindered phenols, thiosynergists and/or hindered thereof with corresponding lakes and direct compression Sug amines, acids (ascorbic acid, erythorbic acid, etidronic acid, ars such as Di-Pac from Amstar. In addition, coloured dye hypophosphorous acid, nordihydroguaiaretic acid, propionic migration inhibitors such as tragacanth, acacia or attapulgite acid etc.), phenols, dodecyl gallate, octyl gallate, 1,3,5-trihy talc may be added. Specific examples include Calcium car droxybenzene, organic and inorganic salts (calcium ascor bonate, 1,3,5-trihydroxybenzene, Chromium-cobalt-alu bate, sodium ascorbate, sodium bisulphite, sodium met minium oxide, ferric ferrocyanide, Ferric oxide, Iron ammo abisulfite, Sodium Sulfite, potassium bisulphite, potassium nium citrate, Iron (III) oxide hydrated, Iron oxides, Carmine metabisulphite), esters (calcium ascorbate, dilauryl thio red, Magnesium carbonate and Titanium dioxide. dipropionate, dimyristyl thiodipropionate, distearyl thio 0179 Plasticizer may be incorporated in the composition. dipropionate), pyranon (maltol), and vitamin E (tocopherol, A Suitable plasticizer is selected from Such as e.g. mono- and D-O-tocopherol, DL-C.-tocopherol, tocopheryl acetate, d-C.- di-acetylated monoglycerides, diacetylated monoglycerides, tocopheryl acetate, dl-C-tocopheryl acetate. However, other acetylated hydrogenated cottonseed glyceride, glyceryl anti-oxidative agents known in the art may be used according cocoate, Polyethylene glycols or polyethylene oxides (e.g. to the present invention. Other suitable stabilizer is selected with a molecular weight of about 1,000-500,000 daltons), from Such as e.g. Sorbitol glyceryl tricitrate. Sucrose octaac dipropylene glycol salicylate glycerin, fatty acids and esters, etate. phthalate esters, phosphate esters, amides, diocyl phthalate, 0182 Modifier may be incorporated in the composition. A phthalylglycolate, mineral oils, hydrogenated vegetable oils, Suitable modifier is selected from Such as e.g. fatty acids and Vegetable oils, acetylated hydrogenated Soybean oil glycer esters, fatty alcohols, cetyl alcohol, Stearyl alcohol, mineral ides, Castor oil, acetyl tributyl citrate, acetyl triethyl citrate, oils, hydrogenated vegetable oils, vegetable oils, acetylated methyl abietate, nitrobenzene, carbon disulfide, B-naphtyl hydrogenated soybean oil glycerides, Castor oil, phosphate salicylate, sorbitol, sorbitol glyceryl tricitrate, fatty alcohols, esters, amides, phthalate esters, glyceryl cocoate oleyl alco cetostearyl alcohol, cetyl alcohol, Stearyl alcohol, oleyl alco hol, myristyl alcohol. Sucrose octaacetate, diacetylated hol, myristyl alcohol. Sucrose octaacetate, alfa-tocopheryl monoglycerides, diethylene glycol monostearate, ethylene polyethylene glycol succinate (TPGS), tocopheryl derivative, glycol monostearate, glyceryl monooleate, glyceryl diacetylated monoglycerides, diethylene glycol monostear monostearate, propylene glycol monostearate, macrogol ate, ethylene glycol monostearate, glyceryl monooleate, esters, macrogol Stearate 400, macrogol Stearate 2000, poly glyceryl monostearate, propylene glycol monostearate, mac oxyethylene 50 Stearate, macrogol ethers, cetomacrogol rogol esters, macrogol Stearate 400, macrogol Stearate 2000, 1000, lauromacrogols, poloxamers, polyvinyl alcohols, Sor polyoxyethylene 50 Stearate, macrogol ethers, cetomacrogol bitan monolaurate, Sorbitan monooleate, Sorbitan mono 1000, lauromacrogols, nonoxinols, octocinols, tyloxapol, palmitate, Sorbitan monostearate, Sorbitan sesquioleate, Sor poloxamers, polyvinyl alcohols, polysorbate 20, polysorbate bitan trioleate, sorbitan tristearate, ethylcellulose, cellulose 40, polysorbate 60, polysorbate 65, polysorbate 80, polysor acetate, cellulose propionate, cellulose nitrate, cellulose bate 85, sorbitan monolaurate, sorbitan monooleate, sorbitan derivative selected from the group consisting of methylcellu monopalmitate, Sorbitan monostearate, Sorbitan sesqui lose, carboxymethylcellulose and salts thereof, cellulose oleate, Sorbitan trioleate, Sorbitan tristearate and Sucrose acetate phthalate, microcrystalline cellulose, ethylhydroxy esters, amyl oleate, butyl oleate, butyl stearate, diethylene ethylcellulose, ethylmethylcellulose, hydroxyethylcellulose, glycol monolaurate, glycerol tributyrate, Cumar W-1, Cumar hydroxyethylmethylcellulose, hydroxypropylcellulose, MH-1, Cumar V-1, Flexol B-400, monomeric polyethylene hydroxypropylmethylcellulose, hydroxymethylcellulose and ester, Piccolastic A-5, Piccalastic A-25, Beckolin, Clorafin hydroxymethylpropylcellulose, cellulose acetate, polylactic 40, acetyl tributyl citrate, acetyl triethylcitrate, benzyl ben acid or polyglycolic acid and copolymers thereof, methacry US 2015/0024048 A1 Jan. 22, 2015 20 lates, a co-polymer of methacrylate-galactomannan etc., especially about 1,000-10,000 daltons, in particular about Polyvinyl alcohols, glycerinated gelatin, cocoa butter 1,500-5,000 daltons, and mixtures thereof. 0183. Other suitable modifier may be selected from the 0194 Cellulose and cellulose derivative selected from the group consisting of inorganic acids, inorganic bases, inor group consisting of methylcellulose, carboxymethylcellulose ganic salts, organic acids or bases and pharmaceutically and salts thereof, microcrystalline cellulose, ethylhydroxy acceptable salts thereof, saccharides, oligosaccharides, ethylcellulose, ethylcellulose, cellulose acetate, cellulose polysaccharides, polyethylene glycol derivatives and cellu proprionate, cellulose nitrate, cellulose acetate phthalate, eth lose and cellulose derivatives. ylmethylcellulose, hydroxyethylcellulose, hydroxyethylm 0184 Alternatively or additionally, a suitable pharmaceu ethylcellulose, hydroxypropylcellulose, hydroxypropylm tically acceptable excipient is a mono-, di-, oligo, polycar ethylcellulose, hydroxymethylcellulose and boxylic acid or amino acids such as, e.g. acetic acid, Succinic hydroxymethylpropylcellulose. acid, citric acid, tartaric acid, acrylic acid, benzoic acid, malic acid, maleic acid, Sorbic acid etc., aspartic acid, glutamic acid Preparation of a Composition of the Present Invention etc. 0.195 A composition of the invention may be produced by 0185. Examples of suitable organic acids include acetic various methods which are either known perse in the phar acid/ethanoic acid, adipic acid, angelic acid, ascorbic acid/ maceutical industry or which, for example, are used in the Vitamin C, carbamic acid, cinnamic acid, citramalic acid, production of polymer-based materials, depending upon the formic acid, fumaric acid, gallic acid, gentisic acid, gluta desired embodiment and the materials employed in the com conic acid, glutaric acid, glyceric acid, glycolic acid, glyoxy position in question. One advantage of the composition lic acid, lactic acid, leVulinic acid, malonic acid, mandelic according to the invention is that it may be produced by acid, oxalic acid, oxamic acid, pimelic acid, and pyruvic acid. methods, which are relatively simple and inexpensive. 0186 Examples of suitable inorganic acids include pyro 0.196 Suitable preparation methods for compositions phosphoric, glycerophosphoric, phosphoric Such as ortho and according to the invention include extrusion, injection moul metaphosphoric, boric acid, hydrochloric acid, and Sulfuric ding, tabletting, capsule filling, thermoforming, spray coat acid. ing, micro encapsulation and other methods Suitable for 0187. Examples of suitable inorganic compounds include preparation of controlled release compositions. Composi aluminium. tions according to the invention may be prepared in numerous 0188 Examples of organic bases are p-nitrophenol, suc ways giving rise to different release mechanisms. Particularly cinimide, benzenesulfonamide, 2-hydroxy-2cyclohexenone, the composition may be prepared by 1, 2 or multiple compo imidazole, pyrrole, diethanolamine, ethyleneamine, tris(hy nent injection mouldings, by conventional tablet compres droxymethyl)aminomethane, hydroxylamine and derivates Sion, by tablet compression and afterward temperature cur of amines, sodium citrate, aniline, hydrazine. ing, by micro encapsulation, by 1, 2 or multiple component 0189 Examples of inorganic bases include aluminium extrusions, by capsule filling or by thermoforming. In cases oxide Such as, e.g., aluminium oxide trihydrate, alumina, were a preparation is needed in order to make the controlled Sodium hydroxide, potassium hydroxide, calcium carbonate, release properties before/after the above mentions prepara ammonium carbonate, ammonium hydroxide, KOH and the tion steps, the preparation may also comprise separate steps like. as for example wet granulation, dry granulation, melt granu 0190. Suitable pharmaceutically acceptable salts of an lation, pelletizing, roller compaction, spray coating, electro organic acid is e.g. an alkali metal salt or an alkaline earth static coating or otherforms of controlled release preparation metal salt Such as, e.g. sodium phosphate, sodium dihydro methods. genphosphate, disodium hydrogenphosphate etc., potassium 0.197 In a particular example the composition is prepared phosphate, potassium dihydrogenphosphate, potassium by two/three component injection moulding of a matrix and a hydrogenphosphate etc., calcium phosphate, dicalcium phos coat partly covering the matrix and exposing two ends of the phate etc., sodium sulfate, potassium Sulfate, calcium Sulfate, composition for erosion governed release. Sodium carbonate, Sodium hydrogencarbonate, potassium 0198 During the injection moulding process it is possible carbonate, potassium hydrogencarbonate, calcium carbonate, to place separately prepared components and include these in magnesium carbonate etc., sodium acetate, potassium the final product by insert-moulding or similar methods. Fur acetate, calcium acetate, Sodium Succinate, potassium Succi ther separately prepared components from injection mould nate, calcium Succinate, Sodium citrate, potassium citrate, ing or other processes e.g. tablets, pellets etc. can be calcium citrate, sodium tartrate, potassium tartrate, calcium assembled in a separate, automated assembly process. tartrate etc. 0199. A composition may also be produced by, for 0191) A suitable inorganic salt for use in a matrix compo example, injection moulding, co-extrusion of the coating sition of the invention is sodium chloride, potassium chloride, with the matrix composition and the active Substance, extru calcium chloride, magnesium chloride etc. sion and dip coating, injection moulding and dip coating, or 0.192 Saccharides such as glucose, ribose, arabinose, by extrusion or injection moulding and solvent coating by Xylose, lyxose, Xylol, allose, altrose, inosito, glucose, Sorbi spraying or dipping, electrostatic coating. Multiple compo tol, mannose, gulose, Glycerol, idose, galactose, talose, man nent injection moulding, or a combination of these methods. nitol, erythritol, ribitol, xylitol, maltitol, isomalt, lactitol, 0200. The injection moulding technique have the advan Sucrose, fructose, lactose, dextrin, dextran, amylose, Xylan. tage of simultaneous mixing and heating the components 0193 Polyethylene glycol derivatives such as e.g. poly during increased pressure in a one step procedure without ethylene glycol di(2-ethyl hexoate), polyethylene glycols exposure to air and moisture because the injection moulding (200-600 daltons) or polyethylene oxides, e.g. with a molecu is performed in a single closed compartment from the time the lar weight of about 800-500,000 daltons, typically about blend has entered the machine to the final pharmaceutical 1,000-100,000 daltons, more typically 1,000-50,000 daltons, units are ejected ready for packaging. US 2015/0024048 A1 Jan. 22, 2015

0201 In a further aspect of the invention, the blending layer the active Substance is present. Accordingly, a compo process may be followed by an extrusion step for obtaining sition of the present invention can be designed to have release pellets suitable for feeding of the injection moulding properties including burst release (very fast release of Sub machines. The extruding step may secure a more intimate stantially the whole content in that part of the composition), blending and thereby higher reproducibility of the final phar controlled release (typically prolonged or extended release), maceutical product. delayed release (i.e. release only after a certain lag time) and 0202. It should also be mentioned that the present technol immediate release (relatively fast release). Thus, the follow ogy also can be applied when it is desired to have an amor ing types can be obtained: phous form of the active Substance in the composition, 0209 If only one active substance is present in the com because the most convenient process for the preparation of a position: composition of the invention involves heating of the polymer Delayed release immediate release together with the active substance and the conversion from Delayed release—controlled release the crystalline state to the amorphous state requires addition Burst release—delayed release immediate release of energy (heating). Burst release—delayed release—controlled release 0203 Normally, when preparing a composition according Burst release immediate release to the invention heating is employed for e.g. an injection Burst release—controlled release moulding process. During heating it has been observed that Controlled release Immediate release PEO in various qualities forms free radicals that results in the Controlled release—controlled release formation of interalia formaldehyde and formic acid. These 0210. If e.g. two different active substances (S1 and S2) products may often lead to further degradation e.g. of the are present, the following can be designed: active Substance present in the composition and it is therefore Delayed release for S1, but controlled release for S2 imme necessary to take the necessary precautions in this respect. diate release for S1 Oxidative free radicals degradation by hydroperoxides can be Delayed release for S1, but controlled release for S2 con catalysed by certain transition metal ions, especially those of trolled release for S1 copper, cobalt and manganese. Thus, employment of PEO Burst release for S1 and/or S2 delayed release for S1, but qualities devoid of or only containing a very small amount of controlled release for S2 immediate release S1 Such transition metal ions may improve stability. Another Burst release for S1 and/or S2 delayed release for S1, but possibility is to use component in a quality that ensures that controlled release for S2-controlled release for S1. free radicals formed, if any, do not significantly increase the Burst release for S1 and/or S2 immediate release for S1 degradation of the active Substance in the composition. Such and/or S2 a quality could e.g. be a quality containing an antioxidant that Burst release for S1 and/or S2-controlled release for S1 functions by preventing the formation of free radical during and/or S2 from multiple units heating or by Scavenging any free radicals formed. Another Controlled release for S1 and/or S2 Immediate release for possibility is to add such antioxidant to the formulation S1 and/or S2 before any heating takes place. Controlled release for S1 and/or S2-controlled release for 0204 A composition according to the invention may S1 and/or S2 from multiple units therefore further comprise one or more antioxidants that 0211 A person skilled in the art will know how to obtain inhibits the formation of peroxides and/or inactivates any other combinations in view of the guidelines given herein. peroxides present. 0212. In a specific embodiment, the present invention pro 0205 Suitable antioxidants for use includes beta-caroten vides a composition for controlled delivery of at least one (a vitamin A precursor), ascorbic acid, ascorbyl palmitate, active substance. It is possible to include two or more differ butylated hydroxyanisole, butylated hydroxytoluene, hypo ent active Substances in the composition of the invention, phosphorous acid, monothioglycerol, potassium met adapted to enable release at different concentrations, intervals abisulfite, Sodium metabisulfite, propyl gallate, Sodium form and/or release rates. aldehylde sulfoxylate, sodium thiosulfate, sulfur dioxide, 0213 Apart from the content of an active substance in the tocopherol, tocopherol acetate, tocopherol hemisuccinate, inner layer, the same and/or a different active substance (sec TPGS or other tocopherol derivatives, sulfides, phosphine ond active Substance) can be substantially homogeneously etc. Other suitable antioxidants are described herein. dispersed in the outer layer (the polymer matrix), in which 0206. It is believed that the amorphous state of the active case a Substantially Zero order release of the second active Substance is furthermore favoured by the processing proce substance is obtained. Alternatively or in addition, a burst dures of the preparation of the product according to the release of the same or a different active substance may be present invention, which in a preferred embodiment involves obtained in a composition of the invention which comprises injection moulding of the pharmaceutical units. alternating layers. In a composition comprising alternating 0207 For further details reference is made to the experi layers, the alternating layers may comprise, respectively, mental section herein. none, one, two or more different active Substances. 0214. As described in detail above, an inner layer com Other Specific Embodiments of the Invention prises a quick release function obtained by e.g. fast disinte 0208. In the following is described various embodiments gration, exploding and/or effervescent effects. of the present invention. These embodiments illustrate the 0215. The first fraction comprises flexibility of the technology to obtain different release pat 0216 a) a disintegration agent, an exploding agent, an terns and the flexibility with respect to including two or more, effervescent agent or a mixture thereof the same or different, active Substances in a composition of 0217 b) optionally, an active substance the invention in order to obtain a composition that releases the 0218 c) optionally, multiple units comprising an active active Substance in a different manner dependent on in which Substance and, US 2015/0024048 A1 Jan. 22, 2015 22

0219 d) optionally, one or more pharmaceutically 0234. In one embodiment of the invention it is possible to acceptable excipients obtain a substantially controlled burst release, optionally in 0220. The outer layers (matrix compositions) comprise combination with a constant rate of release over a specific 0221) a) a polymer or a mixture of polymers, period of time. It is possible to combine two or more active 0222 b) optionally, an active substance and, Substances each following and independent release pattern 0223 c) optionally, multiple units comprising an active however the release pattern of Such substances may also be Substance and, identical. It may in certain cases be desirable to incorporate a 0224 d) optionally, one or more pharmaceutically mixture of two active substances into the matrix in order to acceptable excipients. release both active substances in the matrix with the same 0225. A third component may also be present comprising release rate. In other cases it is desirable to have different 0226 a) a polymer or a mixture of polymers, release rates of the two active Substances. In such cases the 0227 b) optionally, one or more pharmaceutically composition may be composed of two different matrixes, acceptable excipients. each with different release characteristics. In yet another case 0228. Due to the nature of the composition of the inven the release of the active Substances may be sequential. Such tion, it is possible to obtain a Substantially controlled pulsa that during the initial dissolution phase one active Substance tile?burst release, optionally in combination with a constant S1 is released and then the other S2. In this case the second rate of release of the active substance over a specific period of release is onset after a lag defined by the first release. time. The amount of drug release corresponds to the dosage 0235 More specifically, without limiting the invention necessary for the treatment in question, so that adherence to a thereto, the invention is illustrated by the embodiments men strict dosage regimen, e.g. requiring administration of a drug tioned below. Various different formulations of layers A) and at set intervals up to several times a day, may be dispensed B) are given and any combination of layers A) and B) is with. It is possible to combine two or more active substances contemplated (i.e. any of the layer B) of 1, 2, 5-9 may be each following and independent release pattern however the combined with any of layer A) 3, 4, 10-14, and the multiple release pattern of Such substances may also be identical. unit formulations 15 or 16 may be part of either layer A) or B), 0229. The matrix of the outer layer of a pharmaceutical and the coat formulations 17 or 18 may be applied to any of composition of the invention may be designed to release an the combined formulations): active Substance, if any, in a controlled manner Such as by a Zero order release mechanism. Accordingly, the composition 1. A Burst Release Layer B) or Multiple Units: is also suitable for controlled release of an active substance, i.e. first a controlled release of an active substance (from the 0236 matrix, layer B) and then a relatively fast release of the same or different active substance (from the Layer A) or other suitable release combinations. In the present context the term Ingredient % ww “controlled release' is used to designate a release a desired Homopolymer (e.g. 20,000-100,000 daltons 5-70 rate during a predetermined release period. Terms like “modi PEO) fied”, “delayed”, “sustained”, “prolonged”, “extended” etc. Co-polymer (e.g. 1,000-16,000 daltons 5-70 Poloxamer) release are in the present context synonyms to the term “con Active Substance O. 1-80 trolled release'. Normally, the term relates to compositions Filler Up to 100% that have a slower release of the active ingredient than that of a plain tablet or a tablet designed for immediate release. A person skilled in the art knows of these terms. 0230. In order to more detailed explain the invention; ref 2. A Controlled Release Layer B) or Multiple Units: erence is made to (EP 0406315, EP 0493513, WO 2006/ 128471) herein although the invention is not limited to this 0237) type and shape of the composition. However, the general idea is to have a layered composition, wherein the layers are sepa rate layers. Ingredient % ww 0231. However, a person skilled in the art will understand Homopolymer (e.g. 100,000-700,000 daltons 5-70 PEO) that other forms may fulfil the same objective. The most Co-polymer (e.g. 1,000-30,000 daltons 5-70 simplified versions of the pharmaceutical composition Poloxamer) according to the invention are either a sphere or an oval Active Substance O. 1-80 shaped first fraction Surrounded by a sphere oran oval shaped Filler Up to 100% second fraction, reference is made to (EP 0406315, EP 0493513, WO 2006/128471). 0232. In one embodiment of the invention a double burst 3. A Burst Release Inner Layer A): unit is presented by having a layered composition placed inside an immediate release tablet matrix in Such a way that 0238 the outer matrix is eroded or disintegrated, exposing the lay ered composition, as shown in FIG. 1. Ingredient % Wiw 0233. In one embodiment of the invention, the inner layer of a composition according to the invention comprises an Homopolymer (e.g. 1,000-16,000 daltons 5-70 PEO) active substance. The release of the active substance is Co-polymer (e.g. 2,000-30,000 daltons 5-70 delayed because the outer layer must erode before the first Poloxamer) fraction is exposed to the gastrointestinal fluids after oral Swelling agent S-80% administration. US 2015/0024048 A1 Jan. 22, 2015

-continued -continued

Ingredient % Wiw Ingredient % Wiw Active Substance O. 1-80 Sorbitol Filler Up to 100% Active substance

4. A Burst Release Inner Layer A): 9. A Controlled Release Layer B). 0239) 0244

Ingredient % Wiw Ingredient % Wiw Homopolymer (e.g. 1,000-16,000 daltons 5-70 PEO 100 OOO 52 PEO) Poloxamer188 10 Co-polymer (e.g. 2,000-30,000 daltons 5-70 Eudragit RL 10 Poloxamer) Active substance 28 Effervescent agent S-80% Active Substance O. 1-80 Up to 100% Filler p 0. 10. A Burst Release Inner Layer A): 0245 5. A Burst Release Layer B): 0240 Ingredient % Wiw Croscarmellose 0. Lactose Ingredient % ww PEO 100 OOO 5 Poloxamer 188 PEO 1 OOOOO 50 Poloxamer 188 5 Active substance Maltitol 15 Active substance 75 11. A Burst Release Inner Layer A): 6. A Controlled Release Layer B): 0246 0241 Ingredient % Wiw

0. Starch Ingredient % ww Lactose PEO 200 OOO 25 PEG 1500 Poloxamer 338 25 Poloxamer 188 Active substance 50 Xylitol 10 Active substance 40 12. A Burst Release Inner Layer A): 7. A Controlled Release Layer B): 0247 0242 Ingredient % Wiw Ingredient % Wiw PEO 100 OOO PEO SOOOOO 2O Poloxamer 188 Poloxamer 407 50 Citric Acid 10 10 Mannitol 2 NaHCO 70 Active substance 28 Active substance

8. A Controlled Release Layer B): 13. A Burst Release Inner Layer A): 0243 0248

Ingredient % Wiw Ingredient % Wiw PEO 700 OOO 2O PEO 100 OOO Poloxamer 407 50 Poloxamer 188 US 2015/0024048 A1 Jan. 22, 2015 24

-continued -continued

Ingredient % Wiw Ingredient % Wiw Povidone 2 Triethylcitrate 2.33 Citric Acid 10 Water 52.5 NaHCO 10 Active substance 68 0252. In the appended FIGS. 15-24 are given release pro files obtainable by compositions of the present invention. 0253 Other specific embodiments are listed in the follow 14. A Burst Release Inner Layer A): ing: 0249 1. A layered pharmaceutical composition comprising A) a Solid inner layer comprising i) a substantially water soluble and/or crystalline polymer or Ingredient % Wiw a mixture of substantially water soluble and/or crystalline PEO 1 OOOOO 5 polymers, the polymer being a polyglycol in the from of one Poloxamer 188 5 of a) a homopolymer having a MW of at the most about Povidone 2 Citric Acid 10 16,000 daltons, and b) a copolymer having a MW of at the NaHCO 10 most about 30,000 daltons, and Active substance 68 ii) an active Substance, the solid inner core being sandwiched between two outer layers B1 and B2), each outer layer comprising 15. Burst Release Multiple Units: iii) a substantially water soluble and/or crystalline polymer or a mixture of substantially water soluble and/or crystalline 0250 polymers, the polymer being a polyglycol in the from of one of c) a homopolymer having a MW of at least about 100,000 daltons, and d) a copolymer having a MW of at least about Ingredient % Wiw 2,000 daltons, PEO 1 OOOOO 5 and i) of layer A being different from iii) of layer B. Poloxamer 188 5 Povidone 2O the layered composition being coated with a coating C) that Active substance 70 has at least one opening exposing at least one Surface of said outer layer, the coating being Substantially insoluble in and impermeable to fluids and comprising a polymer. 0254 2. A composition according to item 1, wherein A) 16. Controlled Release Multiple Units: further comprises one or more disintegration/exploding 0251 agents, one of more effervescent agents or a mixture thereof 0255 3. A composition according to item 2, wherein the disintegrant/exploding is Sodium starch glycolate, Povidone, Ingredient % Wiw Sodium alginate, Alginic acid, Calcium alginate, Carboxym PEO 1 OOOOO 5 ethylcellulose calcium, Carboxymethylcellulose sodium, Poloxamer 407 15 Powdered cellulose, Chitosan, Croscarmellose sodium, Ethylcellulose 70 Crospovidone, Hydroxypropyl starch, Hydroxypropyl cellu Active substance 10 lose low-substituted, Magnesium aluminium silicate, Meth ylcellulose, Microcrystalline cellulose, pregelatinized starch, 17. Controlled Release Multiple Units Coated with Eudragit Docusae sodium, Guar gum, Polacrilin potassium or the like. RL 3ODFRS 3OD: 0256 4. A composition according to item 2, wherein the effervescent agent is Effer-Soda, Citric acid, Citric acid, monohydrate, Dextrates, Fumaric acid, Potassium bicarbon Ingredient % Wiw ate, Sodium bicarbonate, Sodium citrate dehydrate, Tartaric acid or the like. PEO 1 OOOOO 5 Poloxamer 188 5 0257 5. A composition according to any of the preceding Povidone 2O items, wherein the outer layer B1 and/or B2 when exposed to Active substance 70 an aqueous medium erodes at a Substantially constant rate. 0258 6. A composition according to any of the preceding 18. Coat with a Solid Content of 20% items, wherein the active Substance in A) is Subject to release after a lag time corresponding to the erosion time of the layer B1 and/or B2. Ingredient % Wiw 0259 7. A composition according to any of the preceding Eudragit RL30D 3.9 items, wherein the inner layer A) without B) and C) disinte Eudragit RS 30D 35.3 grates within at the most 60 min Such as, e.g., at the most Talc 5.9 about 30 minor at the most about 15 min, when subjected to a disintegration test according to Ph. Eur. US 2015/0024048 A1 Jan. 22, 2015

0260 8. A composition according to any of the preceding g-ethylene glycol) (PLGA-g-PEG), and polyethylene oxide items having a cylindrical shape optionally with one or more polypropylene oxide (PEO-PPO). tapered ends. 0272. 20. A composition according to item 19, wherein the 0261 9. A composition according to any of the preceding polyethylene glycol or a polyethylene oxide has a molecular items, wherein the coating C) appears as a Substantially intact weight from about 100,000 to about 700,000. empty shell when the composition has been Subjected to a 0273 21. A composition according to item 19, wherein the dissolution test according to Ph. Eur, by which the outer layer copolymer of ethylene oxide and propylene oxide comprises B) erodes and the inner layer A) disappears from the compo up to about 30% w/w of the propylene oxide based block, and sition optionally by means of one or more disintegration has a molecular weight of from about 5,000 to about 15,000 agents, explosion agents, effervescent agents or a mixture daltons. thereof. 0274 22. A composition according to any of the preceding 0262 10. A composition according to any of the preceding items, wherein the concentration of polymer iii) in layer B) is items, wherein the polymers i) and iii), and the polymer from about 5% w/w to about 100% w/w. contained in the coating C) are thermoplastic. 0275 23. A composition according to any of the preceding items, wherein layer B1) and/or B2) contain a second active Inner Layer Substance. 0276 24. A composition according to item 23, wherein the 0263. 11. A composition according to any of the preceding release of the second active substance follows a Zero order items, wherein polymeri) comprises a homopolymer having release pattern at least up to 80% w/w release of the total a MW of at least about 1,000 daltons such as, e.g., a homopolymer having a MW in a range from about 1,000 to content of second active Substance in layer B). about 15,000 daltons, from about 1,000 to about 12,000 dal Coating tons, from about 1,500 to about 10,000 daltons, from about 1,500 to about 8,000 daltons. 0277 25. A composition according to any of the preceding 0264. 12. A composition according to any of the preceding items, wherein the polymer comprised in the coating is items, wherein polymer i) comprises a copolymer having a selected from the group consisting of ethylcellulose, cellu MW of at the most about 25,000 daltons such as, e.g., at the lose acetate, cellulose propionate, cellulose nitrate, polya most about 20,000 daltons, at the most about 15,000 daltons, mide, polyethylene, polyethylene terephtalate, polypropy at the most about 10,000 daltons, at the most about 5,000 lene, polyurethane, polyvinyl acetate, polyvinyl chloride, daltons, at the most about 2,000 daltons. silicone rubber, latex, polyhydroxybutyrate, polyhydroxyval 0265 13. A composition according to any of the preceding erate, teflon, polylactic acid or polyglycolic acid and copoly items, wherein the active Substance in A) is present at least mers thereof, copolymers including ethylene vinyl acetate, partly in solid or dissolved form. styrene-butadienstyrene and styrene-isoprene-styrene. 0266 14. A composition according to any of the preceding 0278. 26. A composition according to any of the preceding items, wherein the active Substance in A) is present inform of items, wherein the coating does not completely crumble or pellets, beads, flakes, mini-tablets, granules, microspheres, erode before the layer B) has completely eroded and the layer nanoparticle, crystals or the like. A) is released. 0267, 15. A composition according to claim 14, wherein 0279. The invention is further illustrated in the following the active substance containing pellets, beads, flakes, mini non-limiting examples. tablets, granules, microspheres, nanoparticles, crystal or the like are dispersed in the polymeri). EXAMPLES 0268 16. A composition according to any of the preceding Dissolution Method for Testing Dosage Units items, wherein the concentration of the polymer i) in inner According to the Invention layer A) is from about 5% w/w to about 100% w/w. 0269. 17. A composition according to any of the preceding 0280 Dissolution testing is performed according to USP items 2-16, wherein the concentration of the one or more 30, NF 25 (711), and apparatus 2 (paddle method). The dis disintegration/exploding agent, if present, is from about 5% solution medium may consist of 0.1 M HCl or phosphate w/w to about 80% w/w such as, e.g., from about 10% w/w to buffer e.g. pH 6.8, pH 6.8 & 40% ethanol or pH 7.2. The about 70% w/w, from about 15% w/w to about 60% w/w or volume of dissolution medium is typically 900 ml or 1000 ml from about 20% w/w to about 50% w/w. and the paddle speed is 50 rpm. Samples are withdrawn at 0270 18. A composition according to any of the preceding Suitable time points and analysed for content of active Sub items, wherein the concentration of the one or more efferves stance by means of on-line UV detection or HPLC with UV cent agent, if present, is from about 5% w/w to about 80% detection. w/w such as, e.g., from about 10% w/w to about 70% w/w, from about 15% w/w to about 60% w/w or from about 20% Methods w/w to about 50% w/w. 0281. A general method for preparation dosage unit is described below. Outer Layer 0271. 19. A composition according to any of the preceding Preparation of a Matrix Composition items, wherein polymer iii) comprises one or more of a poly 0282 An accurate amount of the polymer is loaded into a ethylene glycol, a polyethylene oxide and/or a copolymer of MTI mixer followed by an accurate amount of the active ethylene oxide and propylene oxide including poly(ethylene Substance and of the pharmaceutically acceptable excipients glycol-b-(DL-lactic acid-co-glycolic acid)-b-ethylene glycol (s), if any. The mixing is performed at 900-2000 rpm and at a (PEG-PLGA PEG), poly((DL-lactic acid-co-glycolic acid)- time period up to 20 min. At the start of the mixing the US 2015/0024048 A1 Jan. 22, 2015 26 temperature is about 19-21 C. and the final temperature of Preparation 2 the mixture is about 30-50° C. The mixture is then allowed to cool to room temperature and is ready to be fed into an An Inner Layer a for a Dosage Unit According to the injection moulding machine. Invention Prepared by Direct Compression (PHH-0120-061-2) Preparation of the Coating Composition (0289 Pellets (batch 108-009-05-001C) comprising 0283. The coating composition is prepared by first adding Hydrocortison (55% w/w), PEG 8000 (40% w/w) and PVP the Ethylcellulose then Cetostearyl alcohol, and finally the C15 (5% w/w) was prepared by hot melt extrusion followed Titanium dioxide to an MTI-Mixer at a temperature about by grinding. The pellets were sieved to reach a final size of 19-21° C. Mixing rate is 1000 rpm. The mixer is stopped 1000 um-1200 Lum. 35-37 mg pellets were mixed with 206 when the temperature reaches 40-50° C. and the adhered 230 mg filler material comprising Lactose (StarLacR). The material is manually incorporated into the mixture. The mix material was placed in an IR-tablet preparing device and ture is left to cool for about 10 minutes. The mixing is then compressed at a pressure of 5 metric tons. finalized with a short high-speed mix in order to minimize 0290 Dissolution shows that the tablet is completely dis lumps formation. The mixture is then allowed to cool to room integrated after 18 minutes leaving the pellets for slower temperature, after which it has a suitable consistency for dissolution. Upon testing with an USP2 apparatus using 900 being fed into an injection moulding machine. ml phosphate buffered media, pH 6.8 and 50 RPM the fol lowing release profile was obtained. Example of a Coat Composition; 0284 Time (min) Release (%) 50 min 50 245 min 8O Batch: 58–014-01-013 Batch: 08-0017-058 490 min 90 Material %(wfw) %(wfw) Ethylcellulose 79 86.5 Cetostearyl alcohol 2O 12.5 Preparation 3 Titanium dioxide 1 1 An Inner Layer A for a Dosage Unit According to the Invention Prepared by Direct Compression Small Scale Preparation (PHH-0120-062-4) 0285. A mixture may be prepared by simple volumetric 0291 Pellets (batch 108-009-05-001C) comprising mixing of the components. 3 g of the mixture is then feeded Hydrocortison (55% w/w), PEG 8000 (40% w/w) and PVP into a table top injection molding machine (Haake MiniJet II, C15 (5% w/w) was prepared by hot melt extrusion followed Thermo Electron, Karlsruhe, Germany) and molded directly by grinding. The pellets were sieved to reach a final size of into a pre-molden shell and/or matrix. Typical settings in the 1000 um-1200 Lum. 35-37 mg pellets were mixed with 165 MiniJet are: Temperature 90-120° C. and pressure 600-800 336 mg filler material comprising Lactose (StarLacR): bar. NaHCO:Citric Acid (1497.333:27.2% w/w). The material was placed in an IR-tablet preparing device and compressed Preparation of Dosage Unit at a pressure of 5 metric tons. 0292 Dissolution shows that the tablet disintegrates 0286 The final dosage units may be prepared according to immediately leaving the pellets for slower dissolution. Upon two different methods. In one method, the coat and the matrix testing with an USP 2 apparatus using 900 ml phosphate are moulded individually followed by a manually incorpora buffered media, pH 6.8 and 50 RPM the following release tion of the moulded matrix plug into the moulded coat. The profile was obtained. injection moulding machine used is an Arburg Allrounder 220 S 250/60. In the second method, the coat and matrix are moulded in one process where the coat is moulded in a first Time (min) Release (%) step and the matrix is moulded directly into the coat in a 40 min 50 second step (co-moulding or 2-component moulding). The 185 min 8O injection moulding machine used is Arburg Allrounder 420 V 435 min 90 800-60/35.

Preparation 1 Preparation 4 (0287 Pellets for the Inner Layer A of a Dosage Unit 0293. A dosage unit exhibiting Burst-controlled behav According to the Invention (PHH 0120-063) iour (MQV batch 1047-041, 1047-042 & 1047-044), see FIG. 0288 Pellets were prepared by mixing Poloxamer 188 2. As both Morphine and Hydrocodone absorb at the same (48% w/w), Eudragit RL (24% w/w) and Hydrocortisone wave length, it has been necessary to conduct two parallel (28% w/w) in a beaker on a heat stage set at 150°C. The melt experiments—each experiment applying a dosage unit with was applied to a punched plate (hole size 1 mm) and pellets of active Substance combined with placebo. The dosage units diameter 1 mm was formed. The pellets disintegrated in cold consisted of two plugs, one containing the active Substance, MQ water in less than 1 h. one being a placebo-formulation. Finally the results from the US 2015/0024048 A1 Jan. 22, 2015 27 two experiments were pooled, thereby simulating one dosage 0301 The dissolution behaviour as tested by USP2 appa unit consisting of the two active Substances, one plug which ratus, (pH 6.8, 900 ml phosphate buffered media, 50 RPM), exhibits burst release of Hydrocodone and the other con See FIG. 3. trolled release of Morphine. 0294 The shell was produced by injection moulding. The Preparation 5 plugs were injection moulded using the minijet at applying a temperature 110°C., a pressure of 800 bar and a cycle time of 0302) A dosage unit exhibiting Controlled-controlled 20s. The thickness and the diameter of the plug was 4.5 mm behaviour (MQV batch 1047-041), see FIG. 2. As both active diameter. The exposed area of the matrix (i.e. two ends) is substances Morphine and Oxycodone absorb at the same 35.04 mm and the length of the dosage unit is 9 mm. wave length, it has been necessary to conduct two parallel experiments—each experiment applying a dosage unit with Preparation of a Controlled Release Plug: active Substance combined with placebo. The dosage units 0295) The active plug comprised: PoloXamer 188, PEO consisted of two plugs, one containing the active Substances, 300 000, Morphine Sulphate pentahydrate and Mannitol, one being a placebo-formulation. Finally the results from the which were mixed. Afterwards the powder mixture fed to the two experiments were pooled, thereby simulating one dosage injection moulding machine. unit consisting of Morphine and Oxycodone, both exhibiting 0296. The inactive (placebo) plug comprised: PoloXamer controlled release beheveour. 407, PEO 300 000, which were mixed. Then the powder 0303. The shell was produced by injection moulding. The mixture was fed to the injection moulding machine. plugs were injection moulded using the minijet at applying a temperature 110°C., a pressure of 800 bar and a cycle time of Preparation of a Burst Release Plug: 20s. The thickness and the diameter of the plug was 4.5 mm 0297. The active plug comprised: Hydrocodone bitartarte, diameter. The exposed area of the matrix (i.e. two ends) is PEG 3350S, Sodium hydrogen carbonate and Citric acid, 35.04 mm and the length of the dosage unit is 9 mm. which were mixed. Afterwards the powder mixture fed to the injection moulding machine. Preparation of Plug (for Controlled Release of Morphine): 0298. The inactive (placebo) plug comprised: PEG 3350S, (0304) The active plug comprised: PoloXamer 188, PEO Sodium hydrogen carbonate and Citric acid, which were 300 000, Morphine Sulphate pentahydrate and Mannitol, mixed. Then the powder mixture was fed to the injection which were mixed. Afterwards the powder mixture fed to the moulding machine. injection moulding machine. The Controlled Release Plug has the Composition: Preparation of Plug (for Controlled Release of Oxycodone): 0299 0305 The active plug comprised: Oxycodone hydrochlo ride, PEO 200 000, Mannitol, PoloXamer 407, which were Content % (w.fw) mixed. Afterwards the powder mixture fed to the injection moulding machine. Active plug 0306 In both cases the inactive (placebo) plug comprised: Morphine sulphate pentahydrate 53 PoloXamer 407, PEO 300 000, which were mixed. Then the Mannitol 3 powder mixture was fed to the injection moulding machine. PEO 3OOOOO 35 Poloxamer 188 9 0307 The dosage form (controlled release) consists of an Inactive (placebo) plug active plug and a placebo plug, the composition is given below: PEO 3OOOOO 85 Poloxamer 407 15 Content % (w.fw) 0300. The Burst Release Plug has the Composition: Active plug Morphine sulphate pentahydrate 53 Content% (w.fw) Mannitol 3 PEO 3OOOOO 35 Active plug Poloxamer 188 9 Active plug Hydrocodone bitartrate 53 PEG 335OS 41 Oxycodone hydrochloride 53 Sodium hydrogen carbonate 3 Mannitol 5 Citric acid 3 PEO 200 OOO 17 Inactive (placebo) plug Poloxamer 407 25 Placebo plug PEG 335OS 94 Sodium hydrogen carbonate 3 PEO 3OOOOO 85 Citric acid 3 Poloxamer 407 15 Shell Shell Ethylcellulose 86.5 Ethylcellulose 86.5 Cetostearyl alcohol 12.5 Cetostearyl alcohol 12.5 Titanium dioxide 1.O Titanium dioxide 1.O US 2015/0024048 A1 Jan. 22, 2015 28

0308 The dissolution behaviour as tested by USP2 appa -continued ratus, (pH 6.8, 900 ml phosphate buffered media, 50 RPM), See FIG. 4. Content % (w.fw) Example 1 Delay plug PEO 200 OOO 99.5 Dissolution of Non-Compressed Inner Layer a for a BHT O.S Dosage Unit According to the Invention Centre plug (PHH-0120-067) Paracetamol 75.2 Peg 8000 9.4 0309 Units were prepared by the following procedure: Hard fat 3.8 Pellets comprising Hydrocortison (55% w/w), PEG 8000 Sodium bicarbonate 9.1 (40% w/w) and PVP C15 (5% w/w) was prepared by hot melt Citric acid, monohydrate 2.5 extrusion followed by grinding. The pellets were sieved to Shell reach a uniform size. 36-38 mg pellets were mixed with Ethylcellulose 79 170-175 mg filler material comprising lactose (StarLacR), Cetostearoyl 2O NaHCO, and Citric Acid (18500:825:675% w/w). Shellcom Titanium dioxide 1 prising Ethyl cellulose (89% w/w), Cetostearyl alcohol (10% w/w) and Titanium dioxide (1% w/w) (batch 06-0010-058) 0313. The exposed area of the matrix is 77 mm (i.e. sum was prepared by injection moulding. The dosage unit was of surface area of the two ends) and the length of the shell is hand assembled first with a 2 mm thick delay plug comprising 22.7 mm. PEO 200 000, the pellet/filler blend was added and then another 2 mm thick delay plug comprising PEO 200 000. The 0314. The dissolution behaviour as tested by USP2 appa exposed area of the matrix is 77 mm and the length of the ratus, (pH 6.8, 1000 ml phosphate buffered media, 50 RPM) shell is 22.7 mm. was as follows (see FIG. 6): 0310 Dissolution analysis using USP2 apparatus, pH 6.8, 900 ml phosphate buffered media at 50 RPM showed a delay Time (min) Release (%) for more than 4 hours followed by the immediate release of 15 49 the un-dissolved pellets from the unit into the dissolution 155 50 media. From the pellets 50% release of Hydrocortison was 211 70 reached within 4h from time of onset (end of delay). 218 75 241 92 Example 2 250 94 Dosage Unit According to the Invention Exhibiting Double Burst Behaviours (Batch Example 3 05-0126-110/05-0134-110), See FIG. 5. 0311. Shell, end plugs (layer B), delay plugs and centre A Dosage Unit According to the Invention plug (inner layer A) were prepared by injection moulding and Exhibiting Controlled-Burst Behaviour (MQV Batch hand assembled. The procedure was as follows: 1047-040), See FIG. 7. 1 Locate the shell with injection side upward 0315. The shell was produced by injection moulding. The 2 Place the first delay plug with the injection side down word injection moulding machine used is a Haake Minijet II. End at the top of the shell plugs and centre plug were prepared by hand and hand 3 Gently push the delay plug a few mm into the shell assembled. Each plug had a thickness of 3 mm. 4 Place the inner plug at the delay plug and push it into the shell also moving the delay plug Preparation of End Plugs (for Controlled Release): 5 Place the second delay plug with the injection side upward 0316 PoloXamer 338, PEO 200 000, Morphine Sulphate at the inner plug and push it into the shell pentahydrate and Mannitol were mixed. Afterwards the pow 6 One end plug is placed at each end of the shell der mixture was heated to approximately 110°C. The melt was moulded into a 3 mm thick, and a 4.5 mm diameter, hole The Dosage Form has the Composition: metal filter to attain the plugs. 0312 Preparation of Centre Plug (for Burst Release): 0317 Explotab, Sodium Starch Glycolate & Sodium Car Content % (w.fw) boxymethyl Starch, Maize starch and Morphine Sulphate pentahydrate were mixed. Then the powder mixture was com End plug pressed to a plug (tablet) by direct compression. Centre plugs Paracetamol 8O of 3 mm thickness and a diameter of 4.5 mm were prepared. Peg 8000 10 The procedure was as follows: Hard fat 4 Sodium bicarbonate 3.3 1 Locate the shell with injection side upward Citric acid, monohydrate 2.7 2 Place the first end plug with the injection side down word at the top of the shell US 2015/0024048 A1 Jan. 22, 2015 29

3 Gently push the centre plug into the shell The Dosage Form has the Composition: 4 The last end plug is placed at the end of the shell 0324 The Dosage Form has the Composition: 0318 Content % (w.fw) End plug Morphine sulphate pentahydrate 16 Content % (w.fw) Mannitol 10 End plug PEO 200 OOO 34 Poloxamer 338 40 Morphine sulphate pentahydrate 16 Centre plug Mannitol 10 PEO 200 OOO 34 Morphine sulphate pentahydrate 32 Poloxamer 338 40 Citric acid 34 Centre plug Sodium hydrogen carbonate 34 Shell Morphine sulphate pentahydrate 32 Explotab 50 Ethylcellulose 86.5 Maize starch 18 Cetostearyl alcohol 12.5 Shell Titanium dioxide 1.O Ethylcellulose 86.5 Cetostearyl alcohol 12.5 0325 The exposed area of the matrix (i.e. two ends) is Titanium dioxide 1.O 34.72 mm and the length of the dosage unit is 9 mm. 0326. The dissolution behaviour as tested by USP2 appa 0319. The exposed area of the matrix is 34.72 mm (i.e. ratus, (pH 6.8, 900 ml phosphate buffered media, 50 RPM), two ends) and the length of the dosage unit is 9 mm. See FIG. 9. 0320. The dissolution behaviour as tested by USP2 appa ratus, (pH 6.8, 900 ml phosphate buffered media, 50 RPM), Example 5 See FIG. 8. A Dosage Unit According to the Invention Example 4 Exhibiting Controlled-Controlled Behaviour (MQV Batch 1047-043), See FIG. 10. A Dosage Unit According to the Invention Exhibiting Controlled-Burst Behaviour (MQV Batch 0327. The shell was produced by injection moulding. End 1047-045), See FIG. 7. plugs and centre plug, comprising pellets, were prepared by 0321. The shell was produced by injection moulding. The hand and hand assembled. Each plug had a thickness of 3 mm. injection moulding machine used is a Haake Minijet II. End plugs and centre plug were prepared by hand and hand Preparation of End Plugs (for Controlled Release): assembled. Each plug had a thickness of 3 mm. 0328 PoloXamer 188, PEO 300 000, Mannitol and Mor Preparation of End Plugs (for Controlled Release): phine Sulphate pentahydrate were mixed. The material was melted to approximately 110°C., and the melt was moulded 0322 PoloXamer 338, PEO 200 000, Morphine Sulphate into a 3 mm thick, and a 4.5 mm diameter, hole metal filter to pentahydrate and Mannitol were mixed. Afterwards the pow attain the plugs. der mixture was heated to approximately 110°C. The melt was moulded into a 3 mm thick, and a 4.5 mm diameter, hole Preparation of Centre Plug (for Controlled Release): metal filter to attain the plugs. 0329 PoloXamer 188, PEO 300 000, Mannitol and Mor Preparation of Centre Plug (for Burst Release): phine Sulphate pentahydrate were mixed and processed on a melt extruder. The extruded strings were cooled and cut into 0323 Sodium hydrogen carbonate, Citric acid and Mor pellets. The pellets were sieved to reach a uniform size. Pel phine Sulphate pentahydrate were mixed. Then the powder lets were mixed with CrosPovidone to attain a centre plug of mixture was compressed to a plug (tablet) by direct compres approximately 3 mm thickness and a 4.5 mm diameter. Sion. Centre plugs of 3 mm thickness and a diameter of 4.5 mm were prepared. The procedure was as follows: The procedure was as follows: 0330 1 Locate the shell with injection side upward 1 Locate the shell with injection side upward 0331 2 Place the first end plug with the injection side 2 Place the first end plug with the injection side down word at down word at the top of the shell the top of the shell 0332 3 Pellets and CrosPovidone were added into the 3 Gently push the centre plug into the shell shell 4 The last end plug is placed at the end of the shell 0333 4. The last end plug is placed at the end of the shell US 2015/0024048 A1 Jan. 22, 2015 30

0334. The dosage form has the composition: The dosage form has the composition:

Content % (w.fw) Content % (w.fw) End plug End plug Morphine sulphate pentahydrate 53 Morphine sulphate pentahydrate 2O Mannitol 3 PEO 45 PEO 3OOOOO 35 Poloxamer 407 35 Poloxamer 188 9 Pellets Pellets Morphine sulphate pentahydrate 53 Morphine sulphate pentahydrate 53 Mannitol 3 Mannitol 3 PEO 3OOOOO 35 PEO 3OOOOO 35 Poloxamer 188 9 Poloxamer 188 9 Centre plug Centre plug Pellets and 25% CrossPovidone were added Pellets and 25% CrossPovidone were added Shell Shell Ethylcellulose 86.5 Ethylcellulose 86.5 Cetostearyl alcohol 12.5 Cetostearyl alcohol 12.5 Titanium dioxide 1.O Titanium dioxide 1.O 0344) The exposed area of the matrix (i.e. two ends) is 0335 The exposed area of the matrix (i.e. two ends) is 34.72 mm and the length of the dosage unit is 9 mm. 34.72 mm and the length of the dosage unit is 9 mm. 0345 The dissolution behaviour as tested by USP2 appa 0336. The dissolution behaviours as tested by USP2 appa ratus, (pH 6.8, 900 ml phosphate buffered media, 50 RPM, ratus, (pH 6.8 and pH 6.8/40% ethanol, 900 ml phosphate See FIG. 13. buffered media, 50 RPM), see FIG. 11. Furthermore, it is Example 7 demonstrated that these pellets are abuse resistant as the dissolution rate is significantly lower in alcohol-containing A Dosage Unit According to the Invention media, see FIG. 12. Exhibiting Burst-Controlled Behaviour (MQV Batch 1047-046), See FIG. 10. Example 6 0346. The shell was produced by injection moulding. End plugs and centre plug, comprising pellets, were prepared by A Dosage Unit According to the Invention hand and hand assembled. Each plug had a thickness of 3 mm. Exhibiting Controlled-Controlled Behaviour (MQV Batch 1047-047, See FIG. 10. Preparation of End Plugs (for Burst Release): (0347 Morphine sulphate pentahydrate, PEG 3350S, 0337 The shell was produced by injection moulding. End Sodium hydrogen carbonate and Citric acid were mixed and plugs and centre plug, comprising pellets, were prepared by melted to approximately 110°C., and the melt was moulded hand and hand assembled. Each plug had a thickness of 3 mm. into a 3 mm thick, and a 4.5 mm diameter, hole metal filter to attain the plugs. Preparation of End Plugs (for Controlled Release): Preparation of Centre Plug (for Controlled Release): 0338 Morphine, PEO and PoloXamer 407 were mixed 0348 PoloXamer 188, PEO 300 000, Mannitol and Mor thoroughly and melted to approximately 110°C., and the melt phine Sulphate pentahydrate were mixed and processed on a was moulded into a 2 mm thick, and a 4.5 mm diameter, hole melt extruder. The extruded strings were cooled and cut into metal filter to attain the plugs. pellets. The pellets were sieved to reach a uniform size. Pel lets 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. The procedure was as follows: 0339 PoloXamer 188, PEO 300 000, Mannitol and Mor 1 Locate the shell with injection side upward phine Sulphate pentahydrate were mixed and processed on a 2 Place the first end plug with the injection side down word at melt extruder. The extruded strings were cooled and cut into the top of the shell pellets. The pellets were sieved to reach a uniform size. Pel 3 Pellets and CrosPovidone were added into the shell lets were mixed with CrosPovidone to attain a centre plug of 4 The last end plug is placed at the end of the shell approximately 3 mm thickness and a 4.5 mm diameter. The dosage form has the composition: The procedure was as follows: 0340 1 Locate the shell with injection side upward 0341 2 Place the first end plug with the injection side Content % (w.fw) down word at the top of the shell End plugs 0342. 3 Pellets and CrosPovidone were added into the Morphine sulphate pentahydrate 25 shell PEG 335OS 65 0343 4. The last end plug is placed at the end of the shell US 2015/0024048 A1 Jan. 22, 2015 31

-continued homopolymers having a MW of about 100,000 daltons or greater and (ii) substantially water soluble or crystalline Content % (w.fw) polyglycol copolymers having a MW of about 2,000 daltons or greater. Sodium hydrogen carbonate 5 Citric acid 5 34. The pharmaceutical composition of claim 29, wherein Pellets solid inner layer (A) further comprises a filler. 35. The pharmaceutical composition of claim 29, wherein Morphine sulphate pentahydrate 53 Mannitol 3 Solid inner layer (A) further comprises a polymer selected PEO 3OOOOO 35 from the group consisting of (i) Substantially water Soluble or Poloxamer 188 9 crystalline polyglycol homopolymers having a MW of about Centre plug 16,000 daltons or less and (ii) substantially water soluble or Pellets and 25% CrossPovidone were added crystalline polyglycol copolymers having a MW of about Shell 30,000 daltons or less. 36. The pharmaceutical composition of claim 35, wherein Ethylcellulose 86.5 the polymer of solid inner layer (A) is a substantially water Cetostearyl alcohol 12.5 soluble or crystalline polyglycol homopolymer having a MW Titanium dioxide 1.O of between about 1,000 daltons and about 16,000 daltons. 37. The pharmaceutical composition of claim 35, wherein 0349 The exposed area of the matrix (i.e. two ends) is the polymer of the solid inner layer (A) is a substantially 34.72 mm and the length of the dosage unit is 9 mm. water soluble or crystalline polyglycol copolymer having a 0350. The dissolution behaviour as tested by USP2 appa MW of about 25,000 daltons or less. ratus, (pH 6.8, 900 ml phosphate buffered media, 50 RPM) 38. The pharmaceutical composition of claim 29, wherein See FIG. 14. the concentration of the disintegrant in the Solid inner layer 1-28. (canceled) (A) is from about 5% w/w to about 80% w/w. 29. A layered pharmaceutical composition for controlled 39. The pharmaceutical composition of claim 29, wherein release of an active Substance, comprising: the polymer of each of the two outer layers (B1) and (B2) is a solid inner layer (A) comprising the active Substance and selected from the group consisting of polyethylene glycols a disintegrant, the solid inner layer (A) being positioned (PEG), mono- and dimethoxypolyethylene glycols (mPEGs), between two outer layers (B1) and (B2), polyethylene oxides (PEOs), copolymers of ethylene oxide each outer layer (B1) and (B2) comprising a polymer and propylene oxide, copolymers of PEG and polypropylene Selected from the group consisting of (i) Substantially glycol (PPG), and derivatives thereof. water Soluble or crystalline polyglycol homopolymers 40. The pharmaceutical composition of claim 39, wherein having a molecular weight (MW) of about 100,000 dal the PEG or PEO has a MW of from about 100,000 daltons to tons or greater and (ii) Substantially water Soluble or about 700,000 daltons. crystalline polyglycol copolymers having a MW of 41. The pharmaceutical composition of claim 39, wherein about 2,000 daltons or greater, and mixtures thereof, the copolymer of PEG and PPG has a MW of from about wherein each outer layer is free of the disintegrant and 4,000 daltons to about 15,000 daltons. optionally further comprises a second active Substance, 42. The pharmaceutical composition of claim 29, wherein and the concentration of the polymer in each of the two outer a coating (C) forming a shell covering the Solid inner layer layers (B1) and (B2) is from about 5% w/w to about 100% (A) and partially covering outer layers (B1) and (B2) wfw. with two openings exposing a surface of each outer layer 43. The pharmaceutical composition of claim 29, wherein (B1) and (B2), wherein the coating (C) comprises a at least one of outer layers (B1) and (B2) comprises the polymer and is Substantially insoluble in and imperme second active Substance. able to gastrointestinal fluids; 44. The pharmaceutical composition of claim 43, wherein wherein the solid inner layer (A), without the outer layers the second active Substance is the same as the active Substance (B1) and (B2) and the coating (C), disintegrates within in the solid inner layer (A). 60 minutes when Subjected to disintegrating test accord 45. The pharmaceutical composition of claim 43, wherein ing to the Eur, Ph. the second active substance is different from the active sub 30. The pharmaceutical composition of claim 29, wherein stance of Solid inner layer (A). the active Substance in the Solid inner layer (A) is present in 46. The pharmaceutical composition of claim 43, wherein the form of a multiple unit formulation. the composition exhibits zero order release of the second 31. The pharmaceutical composition of claim 30, wherein active substance present in outer layer(s) (B1) and/or (B2). the multiple unit formulation is a controlled release multiple 47. The pharmaceutical composition of claim 43, wherein unit formulation. the composition exhibits zero order release of at least 80% 32. The pharmaceutical composition of claim 30, wherein W/w of the second active Substance present in outer layer(s) the active Substance of the Solid inner layer (A) is present in a (B1) and/or (B2). form selected from pellets, beads, flakes, mini-tablets, gran 48. The pharmaceutical formulation of claim 29, wherein ules, microspheres, nanoparticles, crystals, and combinations the polymer of the coating (C) is selected from the group thereof. consisting of ethylcellulose, cellulose acetate, cellulose pro 33. The pharmaceutical composition of claim 29, wherein pionate, cellulose nitrate, polyamide, polyethylene, polyeth the multiple unit formulation of solid inner layer (A) com ylene terephtalate, polypropylene, polyurethane, polyvinyl prises a polymer selected from the group consisting of (i) acetate, polyvinyl chloride, silicone rubber, latex, polyhy substantially water soluble or crystalline polyglycol droxybutyrate, polyhydroxyvalerate, teflon, polylactic acid US 2015/0024048 A1 Jan. 22, 2015 32 or polyglycolic acid and copolymers thereof, copolymers composition has been subjected to dissolution testing accord including ethylene vinyl acetate, styrene-butadienstyrene and ing to USP 30, NF 25 (711), apparatus 2 (paddle method), in styrene-isoprene-styrene, and combinations thereof. dissolution medium consisting of 0.1 M HCl or phosphate 49. The pharmaceutical formulation of claim 48, wherein buffer (pH 6.8, pH 6.8 and 40% ethanol, or pH 7.2) in a the polymer of the coating (C) is polylactic acid. dissolution medium volume of 900 ml or 1000 ml at a paddle 50. The pharmaceutical formulation of claim 29, wherein, speed of 50 rpm. when the formulation is exposed to an aqueous medium, the 54. The pharmaceutical formulation of claim 29, wherein coating (C) does not completely crumble or erode before at the polymer of each of the two outer layers (B1) and (B2), and least one of the outer layers (B1) and (B2) has completely the polymer of the coating (C) are thermoplastic. eroded and the Solid inner layer (A) is exposed. 51. The pharmaceutical formulation of claim 29, wherein, 55. The pharmaceutical composition of claim 29, wherein when the formulation is exposed to an aqueous medium, at the disintegrant is selected from the group consisting of least one of the outer layers (B1) and (B2) erodes at a sub Sodium starch glycolate, povidone, Sodium alginate, alginic stantially constant rate. acid, calcium alginate, carboxymethylcellulose calcium, car 52. The pharmaceutical formulation of claim 29, wherein, boxymethylcellulose Sodium, powdered cellulose, chitosan, when the formulation is exposed to an aqueous medium, croScarmellose sodium, crospovidone, hydroxypropyl Starch, release of the active substance from the solid inner layer (A) hydroxypropyl cellulose low-substituted, magnesium alu is subject a lag time corresponding to the erosion time of at minium silicate, methylcellulose, microcrystalline cellulose, least one of the outer layers (B1) and (B2). pregelatinized Starch, docusae sodium, guar gum, polacrilin 53. The pharmaceutical formulation of claim 29, wherein potassium, and combinations thereof. the coating (C) is a Substantially intact empty shell after the k k k k k