US 2010O239667A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2010/0239667 A1 Hemmingsen et al. (43) Pub. Date: Sep. 23, 2010

(54) CONTROLLED RELEASE Publication Classification PHARMACEUTICAL COMPOSITIONS FOR (51) Int. Cl. PROLONGED EFFECT A69/46 (2006.01) A6IR 9/16 (2006.01) (75) Inventors: Pernille Hoyrup Hemmingsen, A6IPI/00 (2006.01) Bagsvaerd (DK); Anders Vagno A6IP 29/00 (2006.01) Pedersen, Virum (DK); Daniel A6IP35/00 (2006.01) Bar-Shalom, Kokkedal (DK) (52) U.S. Cl...... 424/466; 424/495;977/775 Correspondence Address: (57) ABSTRACT STOEL RIVES LLP - SLC Layered pharmaceutical composition Suitable for oral use in 201 SOUTH MAIN STREET, SUITE 1100, ONE the treatment of diseases where absorption takes place over a UTAH CENTER large part of the gastrointestinal tract. The composition com SALT LAKE CITY, UT 84111 (US) prising A) a solid inner layer comprising i) an active Sub stance, and ii) one or more disintegrants/exploding agents, (73) Assignee: EGALET A/S, Vaerlose (DK) one of more effervescent agents or a mixture thereof. the solid inner layer being sandwiched between two outer layers B1) (21) Appl. No.: 12/602.953 and B2), each outer layer comprisingiii) a Substantially water soluble and/or crystalline polymer or a mixture of substan (22) PCT Fled: Jun. 4, 2008 tially water soluble and/or crystalline polymers, the polymer being a polyglycol in the form of one of a) a homopolymer (86) PCT NO.: PCT/EP2008/056910 having a MW of at least about 100,000 daltons, and b) a copolymer having a MW of at least about 2,000 daltons, or a S371 (c)(1), mixture thereof, and iv) an active substance, which is the (2), (4) Date: Jun. 7, 2010 same as in said solid inner layer A), and layer Abeing differ ent from layer B, the layered composition being coated with Related U.S. Application Data a coating C) that has at least one opening exposing at least one surface of said outer layer, the coating being substantially (60) Provisional application No. 60/941,848, filed on Jun. insoluble in and impermeable to fluids and comprising a 4, 2007. polymer, and the composition having a cylindrical form optionally with one or more tapered ends, wherein the ratio (30) Foreign Application Priority Data between the surface area of one end surface of the cylinder and the length of the cylinder is in a range of from 0.02 to 45 Jun. 4, 2007 (DK) ...... PA 2007 OO816 . Active plug (B)

Active plug (A)

Shell (C) Patent Application Publication Sep. 23, 2010 Sheet 1 of 24 US 2010/0239667 A1

Second burst matrix (A) First burst matrix

Delay plug (B) Shell (C)

Fig. 1 Patent Application Publication Sep. 23, 2010 Sheet 2 of 24 US 2010/0239667 A1

Active plug (B)

Active plug (A)

Shell (C)

Fig. 2 Patent Application Publication Sep. 23, 2010 Sheet 3 of 24 US 2010/0239667 A1

& S S.

100 – S

80 N a-Ša Burst-Hydrocodone as a Controlled - Morphine (vst 60 9 SS S 40 - S sšS Ss S SS 20 ss Ss S

O 2 4. 8 10 12 Time (h)

Fig. 3 Patent Application Publication Sep. 23, 2010 Sheet 4 of 24 US 2010/0239667 A1

100 - sSSSSSSSSSS & S

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

6 O

4. O -

2 O -

Time (h)

Fig. 4 Patent Application Publication Sep. 23, 2010 Sheet 5 of 24 US 2010/0239667 A1

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

end plug (AVB)

Fig. 5 Patent Application Publication Sep. 23, 2010 Sheet 6 of 24 US 2010/0239667 A1

1OO -

8O 60

D s 40 -0-buffer 7.2 2O -H buffer 6.8 -o-0.1 NHC

O r r O 5O 1OO 15O 2OO 250 3OO Time (min)

Fig. 6 Patent Application Publication Sep. 23, 2010 Sheet 7 of 24 US 2010/0239667 A1

Shell (C)

End Plug(B)

Center plug (A)

Fig. 7 Patent Application Publication Sep. 23, 2010 Sheet 8 of 24 US 2010/0239667 A1

100,0

80,0

60,0 i * s - s g - 20,0 -

3 4 5 6 7 Time (h)

Fig. 8 Patent Application Publication Sep. 23, 2010 Sheet 9 of 24 US 2010/0239667 A1

1 OO -

8 O

6 O

4 O

2 O

Time (h)

Fig. 9 Patent Application Publication Sep. 23, 2010 Sheet 10 of 24 US 2010/0239667 A1

Shell (C)

End plug(B)

Pellets (A) Filler (A)

Fig. 10 Patent Application Publication Sep. 23, 2010 Sheet 11 of 24 US 2010/0239667 A1

100

8 O ... Phosphate-buffer && 40%. EtOH 6 O

4 O

10 15 20 Time (h)

Fig.11 Patent Application Publication Sep. 23, 2010 Sheet 12 of 24 US 2010/0239667 A1

100 - ser-Kršur-se&s&srêSsssssssssssss

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

0,5 15 2 Time (h)

Fig. 12 Patent Application Publication Sep. 23, 2010 Sheet 13 of 24 US 2010/0239667 A1

120 - 100 saw's 80

6 O

Fig. 13 Patent Application Publication Sep. 23, 2010 Sheet 14 of 24 US 2010/0239667 A1

120 ;

1OO -: &S saaSax\wax$\\\\\\\\SYSYS &

80 s

9. & 3 60 : $s' S. SS

S 40 S S

S8 S S

s : & O

Fig. 14 Patent Application Publication Sep. 23, 2010 Sheet 15 of 24 US 2010/0239667 A1

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

Burst: 1 - 100% in less than 1 h

Fig. 15 Patent Application Publication Sep. 23, 2010 Sheet 16 of 24 US 2010/0239667 A1

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

Fig. 16 Patent Application Publication Sep. 23, 2010 Sheet 17 of 24 US 2010/0239667 A1

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

Fig. 17 Patent Application Publication Sep. 23, 2010 Sheet 18 of 24 US 2010/0239667 A1

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

Fig. 18 Patent Application Publication Sep. 23, 2010 Sheet 19 of 24 US 2010/0239667 A1

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

Fig. 19 Patent Application Publication Sep. 23, 2010 Sheet 20 of 24 US 2010/0239667 A1

OControlled-controlled : Controlled: 0.1%/h - 30%/h (50%/h) in a duration of 1 to 10 SS h X OControlled: 0.1%/h - 30%/h 4- (50%/h) in a duration of 1 to 10 Time h

Fig. 20 Patent Application Publication Sep. 23, 2010 Sheet 21 of 24 US 2010/0239667 A1

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

Fig. 21 Patent Application Publication Sep. 23, 2010 Sheet 22 of 24 US 2010/0239667 A1

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

Fig. 22 Patent Application Publication Sep. 23, 2010 Sheet 23 of 24 US 2010/0239667 A1

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

Fig. 23 Patent Application Publication Sep. 23, 2010 Sheet 24 of 24 US 2010/0239667 A1

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

1 - 100% in less than 12h

Fig. 24 US 2010/0239667 A1 Sep. 23, 2010

CONTROLLED RELEASE pharmaceutical compositions useful for the above-mentioned PHARMACEUTICAL COMPOSITIONS FOR therapies (including chronotherapy) in a relatively simple PROLONGED EFFECT manner, preferably in a procedure involving relatively few steps and relatively simple equipment, and in an economical feasible manner. Moreover, it is desired to obtain a technol 0001. The present invention relates to a technology that is especially Suitable for designing oral pharmaceutical compo ogy that is Suitable for use for many different drug Substances, sitions that are useful in the treatment of diseases where i.e. a technology that is relatively flexible with respect to how absorption e.g. takes place over a large part of the gastrointes to obtain a desired release pattern of the active substance. tinal tract (e.g. in stomach, the Small intestine as well as in the Thus, a relatively simple technology is desired that enables colon). Accordingly, the present invention provides a compo combination of e.g. delayed release followed by controlled sition that enables a first release of the active Substance (e.g. (extended) release, delayed release followed by immediate a burst or a controlled release) followed by a second release of release, burst release followed by delayed release followed by the same active Substance (e.g. a burstora controlled release). either controlled or immediate release, burst release followed The design of the composition takes into account the fact that by controlled release, controlled release followed by con different conditions are present in different parts of the gas trolled release or immediate release. A further advantage trointestinal system. Thus, e.g. in the colon, the Surface area could be a technology that enables variation in the design in a of the mucosal Surface through which the active Substance relatively easy manner Such that the composition also must be absorbed is much smaller than in the small intestine includes e.g. a burst dose or controlled release dose (of dif and, moreover, the amount of body liquid present is also much ferent active Substance). Smaller. The compositions of the present invention may also 0006. The present invention provides such a technology. be suitable in the treatment of diseases in which circadian The technology is a further development of the Applicant's rhythm or biorhythm effects can influence the condition being proprietary technology described in WO 99/51208, WO treated or when an effective therapy is desired e.g. in the early 03/24426, WO 03/24429, WO 03/24430, WO 2004/41252, morning before awakening or when the active Substance have WO 2004/84869, WO 2005/107713, WO2006/128471 that is a narrow absorption window or the absorption is poor e.g. in based on matrix compositions comprising a substantially the colon or for local effect/treatment. Some physiologically water soluble and/or crystalline polymer. Moreover it is a active Substances are periodically produced in vivo at certain further development of the technology described in WO time intervals and it may accordingly be desirable to admin 2006/128471 that relates to a composition having an inner ister Such substances in a controlled release formulation part of a composition that liquefies at body temperature sand which periodically releases the active substance at predeter wiched between two matrix compositions. In this manner a mined time intervals to obtain certain fluctuation in the drug delay is obtained with respect to release of the active sub level which may be desirable in connection with the treatment stance contained in the inner part and once, the matrix com of various diseases. The present technology provides a means positions are eroded away, the liquefied inner part is designed for designing Such compositions and moreover, Such compo to flow out of the shell that surrounds the cylindrical part of a sitions may be combined with an initiated burst release and/or cylindrical shaped composition (i.e. the shell (or coating) Zero order controlled release of the active substance. covers the cylindrical surface, but not the end surfaces). In this manner the active substance in the inner part should be BACKGROUND OF THE INVENTION immediately released once the matrix parts are eroded. How 0002. In the past decades many controlled release tech ever, in some situations the present inventors have observed nologies have appeared. However, for drug Substances that that the outflow of the liquefied inner part is not that easy, e.g. can be absorbed through many segments of the gastrointesti in situations where the composition reaches the large intes nal (GI) tract, there is still a need for developing compositions tine or the colon. In these situations, a limited amount of water that enable sufficient absorption of the drug substance over is present and, accordingly, the flow is limited and moreover, broader range of segment of the gastrointestinal (GI) tract in in the colon lumps of feces may block the open ends of the order to enable a less frequent dosage of the drug and/or in shell leading to limited release of the active substance. order to avoid excretion of unabsorbed drug via the faces. Accordingly, the present inventors have developed composi 0003 Pharmacodynamics and pharmacokinetics chal tions that substantially overcome the above-mentioned prob lenges might enforce the need for special release patters (such lems. as paracetamol in which the first pass metabolism makes it 0007. The present invention provides an extended release difficult to make a constant release unit work). Furthermore, composition for prolonged effect and a way to ensure pro the passage of material through the gastrointestinal tract is longed effect e.g. once daily administration is to ensure opti carefully controlled by several mechanisms. This “house mal absorption of the active Substance though the gastrointes keeping” (intestinal peristalsis) might lead to anomalies in the tinal tract i.e. from the stomach to rectum. effect of solid oral dosage forms which might be compensated 0008. When absorption of the active substance is limited by the formulation. or do not proceed substantially good in the distal part of the 0004 Furthermore, the active substance may exert its small intestine and/or in colon a relatively fast release of the effect locally in the colon or other parts of the gastrointestinal active Substance is an advantage when the controlled release system, such as for treatment of cancer, inflammation, gas composition enter this part of the tract and especially in those trointestinal diseases and treatment with anthelmintic agents. cases where the active substance is poorly absorbed in the distal part of the Small intestine or in ascending and first part DETAILED DESCRIPTION OF THE INVENTION of the transverse colon. A release composition having con 0005. However, to the best of our knowledge there is still trolled release follow by immediate release behavior is desir a need to develop a technology that enables preparation of able for optimal absorption and effect. US 2010/0239667 A1 Sep. 23, 2010

0009. A composition having controlled release follow by applies for the release mechanism as well as the release rate immediate release of the active Substance is also an advantage and time for 80-100% w/w release, when the active substance is poorly soluble and therefore 0020 V) it is possible to e.g. obtain a Zero order release for requires a substantial amount of water/fluid to dissolve in the one or both of the active substance, Zero order release for one distal part of the small intestine before it enters colon for of the active substances and another order of release for the absorption. other active substance or the like, 0010. If absorption of the active substance is unchanged 0021 vi) it is possible to obtain e.g. a relatively slow through the gastrointestinal tract a better absorption of the release followed by a faster release of one of the active sub active substance in the colon can be achieved if a relatively stance without impact on the release of the other active sub fast release of controlled release multiple units is released stance, and/or from the controlled release composition in the distal part of 0022 vii) it is possible to use a formulation technique that the small intestine to prevent limited absorption of the active potentially may improve the bioavailability of at least one of substance due to block of the open ends of the shell in the the active substances and, preferably, of both of the active colon lumps of feces. A composition having controlled Substance (due to the fact that both active Substances gener release follow by controlled release behavior in the shape of ally have a low bioavailability). controlled release multiple units is desirable. 0023. In one aspect, the present invention relates to a lay 0011. The opposite is the case (i.e. a composition having ered pharmaceutical composition comprising burst release follow by delay and/or controlled release behav 0024 A) a solid inner layer comprising ior) if there is absorption problem in the first part of the 0025 i) an active substance, and gastrointestinal tract e.g. the stomach. It is also the case if fast 0026 ii) one or more disintegrants/exploding agents, one effect follow by maintenance of the effect is desirable. of more effervescent agents or a mixture thereof. 0012 Controlling the release of the active substance from 0027 the solid inner layer being sandwiched between two the composition and thereby the absorption of the active outer layers B1) and B2), each outer layer comprising substance, makes it possible to control the blood level of the 0028 iii) a substantially water soluble and/or crystalline active Substance and maintain the concentration within the polymer or a mixture of substantially water soluble and/or therapeutic range over an extended period of time without crystalline polymers, the polymer being a polyglycol in the high peak trough fluctuation which improve the therapeutic form of one of a) a homopolymer having a MW of at least effect and reduced incidence of side effects. about 100,000 daltons, and b) a copolymer having a MW of at 0013. It is an object of centian embodiments of the present least about 2,000 daltons, or a mixture thereof, and invention to provide bioavailable formulations suitable for 0029 iv) an active substance, which is the same as in said once daily administration which substantially improve effi solid inner layer A), and layer Abeing different from layer B. ciency and quality of the treatment. 0030 the layered composition being coated with a coating 0014. It is an object of centian embodiments of the present C) that has at least one opening exposing at least one Surface invention to provide oral controlled release composition Suit of said outer layer, the coating being Substantially insoluble in able for once daily administration which provide an early and impermeable to fluids and comprising a polymer, and the onset of therapeutic effect and which, after rising to a maxi composition having a cylindrical form optionally with one or mum concentration during the dosage interval, provide a more tapered ends, wherein the ratio between the surface area relatively flat plasma profile, meaning that the plasma level of of one end surface of the cylinder and the length of the the active substance provides a peak trough ratio of about 0.5 cylinder is in a range of from 0.02 to 45 mm. to about 1.0, and which provides effective treatment. 0031. In a specific embodiment of the present invention, 0015. Another advantage relating to the present invention layer A) comprises is the possibility of administering the two active Substances at 0032 v) a substantially water soluble and/or crystalline the same time and advantageous in the same pharmaceutical polymer or a mixture of substantially water soluble and/or composition. However, as such a combination treatment is crystalline polymers, the polymer being a polyglycol in the expected to have optimized effect with respect to each of the from of one of c) a homopolymer having a MW of at the most two Substances at different points in time it is important to about 16,000 daltons, and d) a copolymer having a MW of at incorporate the two active Substances in the composition in the most about 30,000 daltons. 0033. As mentioned above, the present invention is a fur Such a manner that ther development of the Applicant's proprietary technology, 0016 i) it is possible to incorporate a suitable amount of namely preparation of pharmaceutical compositions based on each active Substance (notably an amount corresponding to a a water soluble and/or crystalline polymer or mixture of such daily dose and should be present in a specific weight ratio that polymers involving a step of melting or softening the polymer is optimized with respect to therapeutic effect), by means of injection moulding, extrusion or the like. The 0017 ii) it is possible to avoid any negative interaction of injection moulding technique has the advantage of simulta the two active Substances in the composition, neous mixing and heating the components during increased 0018 iii) it is possible to avoid an excessive degree of pressure in a one step procedure without exposure to air and oxidation of the active substances (however, levels corre moisture because the injection moulding is performed in a sponding to normally accepted levels are acceptable), iii) it is single closed compartment from the time a blend of the com possible to obtain release patterns of both substances that are ponents has entered the machine to the final pharmaceutical optimized with respect to therapeutic effect (see iv)-vi) for units are ejected ready for packaging. More details regarding more specific details), the preparation method are given below and in the experimen 0019 iv) it is possible to control the release pattern of the tal section. two active substances from the composition in Such a manner 0034. As appears from the above, the invention concerns a that the release of S1 is independent of the release of S2; this layered pharmaceutical composition having an inner layer US 2010/0239667 A1 Sep. 23, 2010

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 0039. 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. drical shape and then the cylindrical Surface is coated leaving 0040. As yet another example the release mechanism of one or two of the end Surfaces without any coating (normally dissolving/solubilization also depend on the releasing area both end Surfaces are without coating). In order to ensure a and the release rate may be controlled by covering parts of the sufficient release of the active substance contained in layer A) releasing matrix by a coat. Controlling the coverage of the of the composition, the present inventor's have found that the matrix by the coat hence refers to covering from 0 to 100% of following two properties are important, namely the geometry the matrix by a coat. 0041 Inner Layer A) and dimensions of the composition and the present of a dis 0042. The object of the present invention is to design a integrant and/or an effervescent agent (or couple). The first composition comprising an active Substance that is released parameter ensures that the distance to travel for the inner layer after a certain period of time (e.g. burst release followed by is not too big compared with the size of the opening (i.e. the controlled release, controlled release followed by burst end Surface) and the other one ensures that a driving force release, controlled release followed by controlled release, activates the mobility of the active substance in layer A) when burst release followed by burst release). However, as it comes into contact with a body liquid. Moreover, as will be explained above one of the problems the inventors were faced explained below, a further parameter has also a positive influ with was how to ensure that the inner layer exits the shell ence in order to enable a release of the active substance from (coating) once the outer layers have disappeared. As layer A), namely the incorporation of the active Substance in explained above, two parameters are of importance. Firstly, readily flowable multiple units. incorporation of a pharmaceutically acceptable excipient that 0035 Geometry aids in disintegrating the inner layer seems to be of relevance. 0036. The lag-time mechanisms (and the release mechan Accordingly, the inner layer may also contain one or more ics of any active Substance contained in the outer layers) disintegration/exploding agents, one of more effervescent described above depends on the geometry of the composition. agents or a mixture thereof. For example erosion based release from a matrix depends on 0043. It is important to note that once the inner layer is the exposed area of the matrix. In this case the area may be “released' from the shell and brought into direct contact with manipulated by employment of a coat that is not subject to an aqueous medium (e.g. the gastrointestinal fluids after oral erosion and thus covering the areas of the matrix that hence administration) then various types of release of the active will not be a releasing site. In particular, a cylindrical com Substance can be obtained ranging from immediate release position with the two ends exposing the eroding matrix will (e.g. the active Substance is readily available for release Such give rise to Zero order release because the releasing area is as e.g. present in dissolved form in a form that is easily COnStant. dissolvable) to controlled release (e.g. in the form of pellets 0037. The geometric form of the composition is very designed to controlled release or other well-known types of important for the obtainment of the above-mentioned con formulations including beads, flakes, mini-tablets, granules, trolled release. Thus, in one embodiment of the invention, the microspheres, nanoparticles, crystals or the like). pharmaceutical composition has a geometric shape, which 0044 As the shell (coating) has properties that ensure enables a Substantially constant Surface area to become exposure of a well-defined (normally constant or Substan exposed during erosion of the matrix. As explained above, the tially constant) Surface area of the composition to the Sur present inventors have found that the proportions between the rounding medium so that the outer layer(s) can be eroded with surface area of the end surface and the length of the cylinder a constant rate until the layer(s) are eroded away, it is impor are important in order to ensure that the active Substance (or, tant that the shell remains intact until the outer layer(s) have if relevant, of the multiple unit formulation containing the eroded. This normally means that the shell is left when the active substance) can be released from the inner part. Specific inner layer is the only layer left of the composition. Accord examples appear from the examples herein. In general, the ingly, the difficulty of the problem is to ensure a “release' of following ratio between the surface area of one end surface the inner layer from the shell or, in other words, a delivery of and the length of the cylinder has been found to be suitable in the inner layer material from the inside of the shell to the order to ensure a proper release: from about 0.02 to about 45 outside. mm Such as, e.g., from about 0.1 to about 10 mm or from 0045 Disintegrants, Swelling Agents, Exploding Agents, about 0.5 to about 8 mm. In most cases, the composition of the Effervescent Agents invention has two end Surfaces, and, if the ratio is calculated 0046. The inner layer may be formulated such that it dis on the total surface area of the end surfaces, then the ratio is integrates upon contact with water. The disintegration may be from about 0.02 to about 85 mm such as, e.g., from about 0.1 by a mechanism of exploding, by effervescence, by Swelling, to about 10 mm or from about 1.3 to about 14 mm. by rapid erosion or combinations thereof. The disintegration 0038. In a specific example, the compositions employed by exploding may be governed by rapid water influx into- and are coated in Sucha manner that the Surface has a Substantially Swelling of one or several of the matrix components leading constant or controlled surface area during release or erosion. to a collapse of the inner layer structure (normally a matrix In the present context controlled Surface area relates to a structure) Such that the active Substance may be released or predetermined surface area typically predicted from the Such that e.g. multiple units, crystals etc. containing the active shape of the coat of the unit dosage system. It may have a substance may be released. The multiple units may be simple uniform cylindrical shape or the cylindrical form can designed as quick release (/burst releasefimmediate release) US 2010/0239667 A1 Sep. 23, 2010

multiple units or controlled release multiple units for release e.g., from about 10% w/w to about 70% w/w, from about 15% of the active Substance in the Small intestine and/or colon. w/w to about 60% w/w or from about 20% w/w to about 50% 0047. The disintegration may be by means of swelling. wfw. The inner layer comprises an excipient (here a disintegrant), 0055 One or more pharmaceutically acceptable excipi which Swells rapidly upon contact with aqueous media makes ents or additives may also be present in inner layer A) (see the it possible to push the active Substance or active multiple units section “Pharmaceutically acceptable excipients”) 0056. The inner layer A) may also contain a polymer. The out of the shell. Preferably, the detachment of the active same applies to the outer layers B) and in the following is matrix should be in Smaller lumps with a large area-to-Vol given a general description of Suitable polymers for the two ume ratio. (three) layers A) and B). It is important to note that in those 0048. As mentioned above, the “release' of the inner layer cases where the active Substance in layer A) is present in the (or delivery of the inner layer material to the outside of the form of multiple units, then the multiple units may be in the shell) may be aided by incorporation of e.g. a disintegrant also form of e.g. pellets, beads or the like, and in Such cases one or called Swelling and/or exploding agent. A disintegrant typi more polymer may be employed in the preparation of the cally swells upon contact with water and enable disruption of multiple units. In such cases, the polymers mentioned in the the inner layer to agglomerates or particle. Examples of Suit following are Suitable and Such polymers may appropriately able disintegrants include Sodium starch glycolate, Povi be of the same nature as the polymers employed in the B) done, Sodium alginate, Alginic acid, Calcium alginate, Car layers. In contrast hereto, the layer A may also contain a boxymethylcellulose calcium, Carboxymethylcellulose polymeric Substance (as a dispersion medium for the active sodium, Powdered cellulose, Chitosan, Croscarmellose Substance), but in this case, it is important that the polymeric Sodium, Crospovidone, Hydroxypropyl Starch, Hydroxypro substance has different properties from that used in layer B). pyl cellulose low-substituted, Magnesium aluminium sili To differentiate between the individual polymers, the notation cate, Methylcellulose, Microcrystalline cellulose, pregelati “matrix polymer is used to indicate that the polymer is nized starch, Docusae sodium, Guar gum, Polacrilin suitable for use in layer B) and in multiple units, whereas the potassium. notation “layer A polymer is used to indicate that the poly meris Suitable for use as a dispersion medium or excipient in 0049. The disintegration may also be due to an efferves layer A. cent effect, whereby gas such as CO is released from the 0057 Suitable polymers for use according to the invention inner layer upon contact with water and a rapid dissolving typically comprises a polyglycol, e.g. in the form of a system is formed. The formation of gas bubbles will push the homopolymer and/or a copolymer. In a specific embodiment inner layer out in small lumps and thereby manifold increase the polymer is substantially water soluble, thermoplastic, the exposed area of the inner layer (e.g. containing active crystalline, semi-crystalline or amorphous or a mixture of Substance, active multiple units or the like) to the medium. Substantially water soluble, crystalline, semi-crystalline or For example sodium bicarbonate releases CO by reaction amorphous polymers. Suitable polymers for use in a compo with water in an acidic environment. It is possible to develop sition according to the invention are polyethylene glycols, a more pH-robust formulation by adding an acidic excipient including derivatives Such as mono and dimethoxypolyethyl to the formulation. The rate of which the gas formation occurs ene glycols (mPEGs) polyethylene oxides and/or block depends on the rate of hydration and diffusion of water into copolymers of ethylene oxide and propylene oxide. the matrix. 0.058 Polyethylene glycols (PEGs) are linear polydis NaHCO(s) Na" (aq)+HCOs (aq) (1) perse polymers composed of repeating units of ethylene gly col. Their chemical formula is HOCH2CHOCH2CH2OH HCOs (aq)+HO'(aq), H2CO(aq)+HO(l) (2) where m represents the average number of repeating units. HCO(aq) PCO(g)+HO(l) (3) Alternatively, the general formula HOCHCH-OH may be used to represent polyethylene glycol, where n is a number m 0050 “Release' of the inner layer may also take place by in the previous formula +1. See the structural presentations of means of gas formation using effervescent Substances or polyethylene glycol below. n is the average number of oxy effervescent couples. Examples of suitable effervescentagent ethylene groups. n equals m+1. include Effer-Soda, Citric acid, monohydrate, Dextrates, Fumaric acid, Potassium bicarbonate, Sodium bicarbonate, Sodium citrate dehydrate, Tartaric acid. 0051 Disintegration may also take place by rapid erosion, "S-N-N- 11 N-1so which can be obtained by employing for example short chained polymers in the matrix, Such that the matrix is readily wetted and dissolved exposing either the active multiple units 0059 Polyethylene oxides (PEOs) are linear polydisperse or the matrix component(s) containing the active Substance. nonionic polymers composed of repeating units of ethylene oxide. Their chemical formula is HOCH2CH2OH where n 0052 Furthermore, disintegration might be facilitated by represents the average number of oxyethylene groups. See the facilitating water transport through the matrix by for example structural presentation of polyethylene oxide below. n is the open pores. average number of oxyethylene groups. Depending on prepa 0053. In order to ensure suitable properties of the inner ration method high molecular weigh PEO may have one layer A, the inner layer A) without B) and C) disintegrates terminal methyl group. within at the most 60 min such as, e.g., at the most about 30 minor at the most about 15 min, when subjected to a disin tegration test according to Ph. Eur. 0054 Normally, the concentration of the one or more dis I-N-1s integrants, exploding agent and/or effervescent agent in the inner layer is from about 5% w/w to about 80% w/w such as, US 2010/0239667 A1 Sep. 23, 2010

0060 Polyethylene glycols are mixtures of addition of about 12,000 daltons, from about 1,500 to about 10,000 dal ethylene glycol. In general PEG refers to polymers chains tons, from about 1,500 to about 8,000 daltons. with molecular weights below 20,000, while PEO refers to 0070 The polymer may also comprise a co-polymer hav higher molecular weights polymers. However, because of the ing a MW of at the most about 25,000 daltons such as, e.g., at similarities between PEO and PEG, the terms are often used the most about 20,000 daltons, at the most about 15,000 interchangeably for the same compound. daltons, at the most about 10,000 daltons, at the most about 0061 Poloxamers are copolymers or block copolymers and are a range of non-ionic Surfactants of polyethylene gly 5,000 daltons, at the most about 2,000 daltons. col (PEG) and polypropylene glycol (PPG). (0071 Polymers in Layers B) or Used in Multiple Units 0062. In chemical abstracts Diol EO/PO block copoly Containing the Active Substance and Incorporated in Layer mers are described under the scientific name—hydroxy-hy A) droxypoly(oxyethylene)poly(oxypropylene)-poly(oxyethyl 0072 Polyethylene glycols and/or polyethylene oxides, ene) block copolymer in combination with the CAS register which are suitable for use in the matrix composition are those number. having a molecular weights of from about 20,000 daltons, 0063. In specific embodiments a suitable poloxamer for such as, e.g., from about 20,000 to about 700,000 daltons, use in a composition of the invention has a HLB value of at from about 20,000 to about 600,000 daltons, from about least about 18 Such as, e.g., at least about 20. The mean 35,000 to about 500,000 daltons, from about 35,000 to about molecular weight of a Suitable poloxamer is typically at least 400,000 daltons, from about 35,000 to about 300,000 daltons, about 2,000. from about 50,000 to about 300,000 daltons, such as, e.g. 0064. Mixtures of PEO with different average molecular about 35,000 daltons, about 50,000 daltons, about 75,000 weights can be used in order to obtain a PEO with a desirable daltons, about 100,000 daltons, about 150,000 daltons, about average molecular weight. The same applies to PEG. 200,000 daltons, about 250,000 daltons, about 300,000 dal 0065. The polymer has a melting point higher than the tons or about 400,000 daltons. body temperature of the human in which the composition is to 0073. In a specific embodiment the matrix polymer is a be used. Thus, the polymer(s) employed in the matrix com polyethylene oxide or a polyethylene glycol that has a position will suitably have a melting point of about 20-120° molecular weight of about 20,000 daltons, about 35,000 dal C. such as, e.g. from about 30 to about 100° C. or from about tons, about 50,000 daltons, about 100,000 daltons, about 40 to about 80° C. 200,000 daltons, about 300,000 daltons and about 400,000 daltons. PEG is commercially available with average molecu 0066. In addition to a polymer of a polyglycol type as lar weights up to 35 000. PEO is commercially available with described above other polymers may be suitable for use in a average molecular weights up to 8,000,000. In specific pharmaceutical composition provided that the solubility and/ embodiment, the polymer is a PEO having a molecular or release rate of the active Substance from the composition in weight of at least about 100,000 such as, e.g., from about water is higher than or equal to the solubility of the matrix in 100,000 to about 8,000,000, from about 100,000 to about 40% w/w ethanol in water. Thus, in other embodiments of the 7,000,000, from about 100,000 to about 5,000,000, from invention, the polymer oran additional polymer to the polyg about 100,000 to about 4,000,000, from about 100,000 to lycol may be selected from one or more of the following about 2,000,000, from about 100,000 to about 1,000,000, polymers: modified or unmodified water soluble natural poly form about 100,000 to about 900,000. When PEO is mers such as glucomannan, galactan, glucan, polygalactur employed with a molecular weight in the lower end, the PEO onic acid, polyxylane, polygalactomannans, rhanogalactur typically has a molecular weight as mentioned in the preced onan, polyxyloglycan, arabinogalactan, and starch, cellulose, ing paragraph. Commercially available PEOs with a molecu chitosan, alginate, fibrin, collagen, gelatin, hyaluronic acid, lar weight in the higher end have typically the following amylopectin, pectin including low methylated or methoxy molecular weights: about 900,000, about 1,000,000, about lated pectins, dextran and fatty acids and alcohols; synthetic 2,000,000, about 4,000,000, about 5,000,000, about 7,000, polymers such as polyvinylpyrrolidone (PVP), PVA, PVB, 000, about 8,000,000. It should be noted that when PEO with Eudragit L. methyl ester, Eudragit L., Eudragit RL, Eudragit E. a molecular weight of up to about 700,000 is used, it is Eudragit S, PHPV. PHA, PCL, PLGA and PLA; and hydro possible to obtain a matrix composition (prepared e.g. by gels made from the polymers or combined polymers men injection molding) that releases the active Substance con tioned above and or from polymers originated from: HEMA, tained in the matrix with a Zero order release (erosion of a HEEMA, MEMA, MEEMA, EDGMA, NVPVAc, AA, acry constant Surface area). However, the applicanthas indications lamide, MAA, HPMA, PEGA, PEGMA, PEGDMA, that employment of PEO with a molecular weight of 1,000, PEGDA, and PEGDMA. 000 or higher leads to a slower release and a different release 0067 Polymers in Layer A) pattern. However, Zero order release may not always be 0068. In one embodiment of the invention, layer A) com required from the layer B), but a slow release may be impor prises V) a substantially water soluble and/or crystalline poly tant. In such cases, the high molecular weight PEOs are mer or a mixture of substantially water soluble and/or crys Suitable for use in a composition of the invention. talline polymers, the polymer being a polyglycol in the from 0074 Typical block copolymers of ethylene oxide and of one ofc) a homopolymer having a MW of at the most about propylene oxide have a molecular weight of from about 2,000 16,000 daltons, and d) a copolymer having a MW of at the daltons, typically about 3,000 to about 30,000 daltons such most about 30,000 daltons. as, e.g. from about 4,000 to about 15,000 daltons. If the 0069. In specific embodiments, the polymer comprises a copolymer is the Sole thermoplastic polymer present in the homopolymer having a MW of at least about 1,000 daltons composition it must not bee too brittle in order to avoid abuse Such as, e.g., a homopolymer having a MW in a range from by crushing of the composition, i.e. it must have an HLB value about 1,000 to about 15,000 daltons, from about 1,000 to of about 18 to about 24. US 2010/0239667 A1 Sep. 23, 2010

0075 Concentration of Polymers in Layer A and/or B is the only thermoplastic polymer present in the composition, 0076. The polymer may also be a mixture of the above then the concentration is normally from about 50 to about mentioned polymers. Normally, the concentration of the 95% w/w such as, e.g. from about 55 to about 90% w/w, from polymer(s) in layer A) when applied is from about 1 to about about 60 to about 90%, from about 65 to about 90%, from 99.9% w/w dependent on the desired release properties relat about 70% to about 90% or from about 70 to about 85% w/w. ing to the release of the active Substance from the inner layer. In specific embodiments, the concentration is even lower Such In those cases where a relative fast release of the active as from about 1% to about 15% w/w or from about 5% to Substance (or multiple units e.g. a pellet composition or the about 15% w/w. like containing the active Substance) is desired or there is a I0081. The concentration of the polyglycol copolymer, if relatively high concentration of active Substance in layer A), present in combination with a polyglycol homopolymer, is a relative low concentration of the polymer may be of interest typically from about 1 to about 60% w/w such as, e.g. from Such as, e.g. from about 1 to about 30% w/w Such as, e.g., about 2.5 to about 50% w/w, from about 5 to about 45% w/w. from about 5 to about 25% w/w, from about 5 to about 20% If the copolymer is the sole thermoplastic polymer in the w/w or from about 10 to about 20% w/w. In other cases, the composition the concentration may be from about 5 to about concentration of the polymer in layer A) may be such as from 99.5% w/w such as those ranges described above and about 10 to about 95% w/w, from about 15% to about 90% described for the homopolymer. In specific embodiments, the w/w, such as from 20 to 85%, such as from 30% to 85% from concentration is even lower such as from about 1% to about about 30 to about 99% w/w such as, e.g., from about 35 to 15% w/w or from about 5% to about 15% w/w. about 95% w/w, from about 35 to about 90% w/w, from about I0082 In embodiments where the outer layer matrix com 35 to about 85% w/w, from about 35 to about 80% w/w, from position comprises a PEO and a poloxamer the weight ratio about 40 to about 75% w/w, from about 45 to about 70% w/w, (PEO/poloxamer) is normally in a range from about 10:0.1 to from about 45 to about 65% w/w. from about 55 to about 85% about 0.1:10 such as, e.g., from about 10:1 to about 1:10, from w/w or from about 60 to about 85% w/w. about 5:1 to about 1:5 or from about 3:1 to about 1:3. 0077 One or more polymers are typically present in a 0083. The one or more, the same or different active sub composition of the invention in a concentration amount of stance in the inner layer may be designed to various types of from 5 to 99.9% w/w Such as from 10 to 95%. Such as from release once the inner layer is “released from the shell. 15% to 90%, such as from 20 to 85%, such as from 30% to I0084. In one embodiment of the invention, the inner layer 85% calculated as w/w % of the composition. contains the active Substance incorporated into a multiple unit 0078. In those cases, where mixture of polymers are formulation or it may be present in the form of relatively large present in the composition, the concentration of an individual crystals (i.e. 100 um or more). polymer in the composition may typically be from about 0% I0085 Inner Layer Active Substance in Multiple Units to about 95% w/w such as, e.g., from about 0.5% to about I0086. As mentioned above, the active substance may be 90% w/w, from about 1% to about 90% w/w, from about 5% present in many forms in the inner layer. Thus, it may be to about 90% w/w, from about 10% to about 90% w/w, from present in dissolved form, e.g. dissolved in the ingredients of about 10% to about 80% w/w, from about 10% to about 70% the inner layer such as in the form of a solid dispersion or solid w/w, from about 10% to about 60%, from about 10% to about Solution. It may also be present in Solid form e.g. in the form 50%, from about 15% to about 50% w/w, from about 15% to of particles or crystals of the active substance. Moreover, the about 45% w/w, from about 15% to about 40% w/w, from active Substance may be incorporated into a formulation about 20% to about 40% w/w, from about 20% to about 35% before it is incorporation into the inner layer. Such formula w/w or from about 20% to about 30% w/w. In specific tions are described in the following including multiple units. embodiments, the concentration is even lower Such as from In Such a formulation, the active Substance may be present in about 1% to about 15% w/w or from about 5% to about 15% solid or dissolved form as well. The multiple units for use wfw. according to the invention may be crystals of an active Sub 007.9 The total concentration of the polymers (notably the stance, inert cores coated with active Substance—inert cores Sum of homo- and copolymers of the polyglycol type) in the like e.g. calcium alginate beads, cellulose spheres, charged composition is typically from about 5 to about 99.9% w/w resin spheres, glass beads, polystyrene spheres, sand silica such as from about 10 to about 95% w/w, from about 15% to beads or units, sodium hydroxide beads. Sucrose spheres. about 90% w/w, such as from 20 to 85%, such as from 30% to Cores containing active Substance like e.g. beads, pellets, 85% from about 30 to about 99% w/w such as, e.g., from flake, pieces, granules, granulates (also denoted agglomer about 35 to about 95% w/w, from about 35 to about 90% w/w, ates), spheres, tablets, especially minitablets etc. from about 35 to about 85% w/w, from about 35 to about 80% I0087. The shape of the multiple units may be any suitable wfw, from about 40 to about 75% w/w, from about 45 to about shape including a rounded or oval shape as well as a polygo 70% w/w, from about 45 to about 65% w/w. from about 55 to nal or rod-like or flake-like shape. about 85% w/w or from about 60 to about 85% w/w. In I0088. The mean particle size of the multiple units is at the specific embodiments (e.g. for burst layer (may be layer A) most about 1400 um. In particular embodiments, the particle and/or layer B)), the concentration is even lower such as from size of the multiple units is at the most about 1200 um such as, about 5% to about 40% w/w or from about 5% to about 35% e.g., at the most about 1100 um, at the most about 1000 um, at wfw. the most about 900 um, at the most about 800 um, at the most 0080. The concentration of the polyglycol homopolymer about 750 um, at the most about 700 um, at the most about 650 is typically from about 0.5 to about 99.9% w/w such as from um, at the most about 600 um, at the most about 550 um or at 5 to about 99.9% w/w, from about 0.5% to about 90% w/w, the most about 500 um; such as, e.g., from about 150 um to from about 1% to about 90% w/w, from about 5% to about about 1200 um, from about 200 um to about 1200 um, from 90% w/w, from about 20 to about 90% w/w, from about 30 to about 200 um to about 1000 um, from about 250 um to about about 90% w/w, and, in those cases where the homopolymer 800 um or from about 300 um to about 750 um. In a specific US 2010/0239667 A1 Sep. 23, 2010 embodiment of the invention the particle size of the multiple they may have the same or different size. In a preferred units is at the most about 500 um to about 1000 um, or from embodiment, the composition and size of the two B) layers about 350 um to about 500 um. In some cases, the particle size are the same. of the multiple units may be even higher. Thus, in Some cases 0096 Suitable polymers for use in the outer layers are the particle size may be at the most about 2 mm. described in detail in the section above. However, with 0089. The release of the active substance may take place respect to the outer layer, it is important to ensure a control of by diffusion by which the rate of release depends on several the rate with which the outer layer disappears from the com mechanisms, for example: the concentration difference position once it is exposed to an aqueous medium. As between the matrix active Substance concentration and the described above, the outer layers are composed in Such a bulk concentration, the release surface area and the diffusion manner that the outer layer leaves the composition with a constant of the drug Substance in the matrix. In special cases constant rate (corresponding to a Zero order release rate in the diffusion controlled release may be zero order. event that a drug Substance was present in the layer). Such a constant rate can be achieved by use of one or more polygly 0090. Once the inner layer is exposed to the gastrointesti cols, but in contrast to the polymers suitable for used in the nal fluids (or another aqueous medium) the release of the inner layer A), the homopolymer should preferably have a active Substance may take place. In contrast to a release from much higher molecular weight in order to ensure a constant a matrix that erodes (i.e. a matrix like the one of the outer erosion rate of the outer layer. Moreover, it is contemplated layer), the release of the active substance from the inner layer that when a co-polymer is employed preferably one or more may follow a kinetic that is different from a zero order release. The present formulation principle is designed to delay the of another polymer is included in the outer layer in order to release not necessarily to enable a Zero order release or other obtain a Suitable constant erosion rate. types of release kinetics that are relevant when designing (0097. As the function of the outer layers is different from controlled or modified release compositions. However, the the function of the inner layer, the polymer composition of the basic formulation principle of the present invention may be outer layer(s) B is different from the polymer composition of combined with known formulation principles e.g. if an active the inner layer A). substance also is included in the matrix of the outer layer B). 0098. One or more pharmaceutically acceptable excipi then this active substance can be released by Zero order kinet ents or additives may also be incorporated into the outer ics, i.e. in a controlled manner, and the active Substance layer(s), see the section herein. However, it is important that contained in the first fraction is released once exposed to the Such excipients or additives do not significantly change the gastrointestinal fluids (or another aqueous medium) or in a manner in which the outer layer disappears from the compo controlled manner, but once the release of active Substance or sition, i.e. it is important that this disappearance still is by a active multiple units from the first fraction starts it may be Substantially constant rate e.g. by erosion or diffusion; addi relatively fast. tion of such Substances may have impact on the rate (e.g. slow down or increase the rate), but it must not significantly change 0091 Outer Layers B1) and B2) the properties of the outer layer B) so that the function as a 0092. The outer layers of a composition according to the “controlled lag-time layer provider' is destroyed. invention are typically based on the matrix principle dis 0099. In some embodiments of the invention, the outer closed in WO99/51208, WO 03/24426, WO 03/24429, WO layer B) may also contain one or more second active Sub 03/24430, WO 2004/41252, WO 2004/84869, WO 2005/ stances. Normally, Such a second active Substance in layer B) 107713, WO2006/128471 (to the same applicant). Such will be a different substance from that contained in layer A) in matrices have unique properties in that they erode, i.e. it does order to achieve a suitable combination treatment with two of not disintegrate into Smaller particles or conglomerates of more different active substance, one of which with a desired particles upon exposure to the gastrointestinal fluid. Simpli controlled release following a Zero order release (the one fied, erosion means that a layer is eroded from the composi contained in the outer layer B)) and the other one contained in tion into the Surrounding medium almost as if a slice of the the inner layer and designed for immediate release (or, alter matrix is cut off. Only the outer surface is exposed to erosion natively, as detailed described under the section “Inner layer. and from this outer layer the active substance will be released as a controlled release composition e.g. with Zero or 1st order and/or dissolved provided that an active Substance is present release). in the matrix. This means that if it is possible to control the 0100. In the section “Other embodiments of the invention size of the Surface area by maintaining a constant size, it is examples of various combinations are described. possible to control the size of the release rate and, further 0101 Coating more, a Zero order release rate can be obtained. 0102. As described above, the layered composition is pro 0093. The outer layers contain the same active substance vided with a coating C) that has at least one opening exposing as the inner layer A) to ensure optimal absorption of the active at least one surface of said outer layer (layer B), the coating Substance though the gastrointestinal tract a way to prolong being substantially insoluble in and impermeable to fluids the effect of e.g. a once-daily dosage form. and comprising a polymer. 0094. As mentioned above, each of the outer layers B1) 0103) A composition according to the invention may be and B2) comprises iii) a substantially water soluble and/or provided with a coating that can be applied in Such a manner crystalline polymer or a mixture of substantially water that it leaves a well-defined surface area free of coating while soluble and/or crystalline polymers, the polymer being a the remaining Surface is covered and at the same time ensur polyglycol in the from of one of a) a homopolymer having a ing that the coating fulfils the requirement that no transport of MW of at least about 100,000 daltons, and b) a copolymer water into the matrix (or other parts of the composition) takes having a MW of at least about 2,000 daltons, place through the coating (or, if any water should enter, then 0095. The layers B1) and B2) may have the same or dif it does not result in a transport of dissolved active Substance ferent composition and in a cylindrical shaped composition out through the coating). In other words, it has been the object US 2010/0239667 A1 Sep. 23, 2010

to develop a coating that does not leave an uncontrollable editions of handbooks like Handbook of Pharmaceutical Surface area of the matrix exposed to the aqueous environ Excipients or in Remington's Pharmaceutical Sciences. ment and that has suitable properties compared to the matrix, 0108. In an embodiment of the invention, the coating is i.e. if the coating dissolves or otherwise disappears then it one, which biodegrades, disintegrates crumbles or dissolves should only take place after the matrix has eroded or dis after erosion of the matrix and/or during the release of the Solved away (during the release period, the coating may of active Substance. A coating applied for an erosion matrix will course also partly dissolve or disappear provided that the part remain intact as long as it is supported by the matrix contain it concerns covered a part of the matrix that has already been ing the active Substance, but it lacks the ability to remain Subject to erosion or diffusion, thus, leaving the remaining intact after erosion of the matrix, because it then biodegrades, composition “intact with a matrix that is surrounded by the disintegrates or crumbles, so that it will not remain in e.g. a coating apart from the open end from which erosion or dif human for any significant amount of time after the complete fusion of the matrix takes place). erosion of the outer matrix layer Band the release of the inner 0104. The composition may be partly or fully covered by layer A. a coat with specific properties in Such away that the exposed 0109. In an interesting embodiment, the composition of area of the matrix may be controlled by the use of a coat. In a the invention further comprises a coating having at least one specific example the coat is substantially insoluble, non-erod opening exposing at least one surface of the matrix, the coat able and non-permeable to water leaving only the exposed ing being one which crumbles and/or erodes upon exposure to areas of the composition for release. Such a coat may be the aqueous medium at a rate which is equal to or slower than composed of a polymer that has thermoplastic properties. the rate at which the matrix erodes in the aqueous medium, Examples of Such materials are mentioned below including allowing exposure of said Surface of the matrix to the aqueous cellulose derivative which has thermoplastic properties, plas medium to be controlled. ticizer or plasticizers and/other functional excipients. 0110 Polymers useful as coatings are such as e.g. cellu 0105. The coating may also be a coating, which is substan lose derivative e.g. ethylcellulose, cellulose acetate, cellulose tially soluble in and permeable to fluids such as body fluids propionate, cellulose nitrate, cellulose derivative selected during the intended release period provided that the coating from the group consisting of methylcellulose, carboxymeth dissolves so much slower than the matrix composition that the ylcellulose and salts thereof, cellulose acetate phthalate, coating remains intact until the matrix has eroded and/or microcrystalline cellulose, ethylhydroxyethylcellulose, eth released the inner layer containing an active Substance. ylmethylcellulose, hydroxyethylcellulose, hydroxyethylm Examples of suitable polymers include polyglycols as ethylcellulose, hydroxypropylcellulose, hydroxypropylm described herein. ethylcellulose, hydroxymethylcellulose and 0106 The coating may further comprise any of the men hydroxymethylpropylcellulose, cellulose acetate, Eudragit L tioned matrix materials (i.e. polymeric material suitable for methyl ester, Eudragit RL, Eudragit E. polyamide, polyeth use in the outer layers B) in a form, which erodes at a sub ylene, polyethylene terephthalate, polypropylenem polyure stantially slower rate than the rest of the matrix. The coating thane, polyvinyl acetate, polyvinyl chloride, silicone rubber, may thus comprise a matrix of one or more substantially latex, polyhydroxybutyrate, polyhydroxyvalerate, teflon, water Soluble crystalline polymers and, optionally, a non polylactic acid or polyglycolic acid and copolymers thereof, ionic emulsifier, the coating being one which is eroded in the copolymers such as ethylene vinyl acetate (EVA), styrene aqueous phase at a Substantially slower rate than the outer butadienestyrene (SBS) and styrene-isoprene-styrene (SIS). layer B, whereby a substantially controlled area of the outer The coating may also be copolymers of polylactic acid and layer B matrix composition (in Some cases also comprising a polyglycolic acid. The coating may also be an enteric coating second active Substance) is exposed during erosion of the employing methacrylates Eudragit L., Eudragit S, Eudragit matrix composition and/or during release of the active Sub FS, a co-polymer of methacrylate-galactomannan etc. stance, and whereby the coating is Substantially eroded upon 0111. In one embodiment, the controlled release compo erosion of the matrix composition and/or during release of the sition of the invention further comprises a coating having at active Substance. Such a coating will be designed so that its least one opening exposing at least one Surface of the matrix, longitudinal erosion rate is substantially the same as the lon the coating being one which crumbles and/or erodes upon gitudinal erosion rate of the matrix, whereby the matrix and exposure to the aqueous medium at a rate which is equal to or the coating will erode longitudinally towards the centre of the slower than the rate at which the matrix erodes in the aqueous composition at Substantially the same rate. Thus, when the medium, allowing exposure of said Surface of the matrix to outer layer matrix composition has been completely eroded the aqueous medium to be controlled. Coatings of this type and/or dissolved by the aqueous medium and the inner layer are described in WO95/22962, to which reference is made has been released from the shell (i.e. the coating), the coating and which is incorporated herein by reference. These coatings will also be substantially completely eroded. A matrix com comprise: position having Such a coating has the obvious advantage of 0112 (a) a first cellulose derivative which has thermo being completely biodegraded upon release of the active Sub plastic properties and which is substantially insoluble in Stance. the aqueous medium in which the composition is to be 0107 The coating may impart delayed properties for used, e.g. an ethylcellulose Such as ethylcellulosehaving releasing the active substance or it may be a film-coating or a an ethoxyl content in the range of 44.5-52.5%, or cellu coating containing the active Substance for immediate release lose acetate, cellulose propionate or cellulose nitrate; prior to the controlled release or other kinds of coatings that and at least one of: does not delay the release but e.g. make it easier to Swallow 0113 (b) a second cellulose derivative which is soluble the composition or it may e.g. mask a bad taste. Materials or dispersible in water, e.g. a cellulose derivative Suitable for Such coatings are well-known for a person skilled Selected from the group consisting of methylcellulose, in the art and information can be found e.g. in the latest carboxymethylcellulose and salts thereof, cellulose US 2010/0239667 A1 Sep. 23, 2010

acetate phthalate, microcrystalline cellulose, ethylhy necessary one or more excipients. The mechanism of erosion droxyethylcellulose, ethylmethylcellulose, hydroxyeth enables the composition to release with a rate depending on ylcellulose, hydroxyethylmethylcellulose, hydroxypro the exposed area. Inner layer A of the invention contains pylcellulose, hydroxypropylmethylcellulose, active Substance or active multiple units (e.g. pellets or mini hydroxymethylcellulose and hydroxymethylpropylcel tablets) in such a form that the active substance or individual lulose; active units will be made available upon disintegration of the 0114 (c) a plasticizer, e.g. selected from the group con composition in the stomach, Small intestine and/or colon after sisting of phosphate esters; phthalate esters; amides; erosion of layer B. The individual units are of a size, which mineral oils; fatty acids and esters thereof; polyethylene allows them to be incorporated into such a composition. glycol, glycerin or Sugars; fatty alcohols and ethers thereof, vegetable oils; or a non-ionic Surfactant; and 0.124. The matrix composition of layer B and active mul 0115 (d) a filler, e.g. selected from conventional tablet tiple units according to the invention has (in total) a lower (or or capsule excipients such as diluents, binders, lubri equal) solubility and/or release rate in alcohol containing cants and disintegrants. media (e.g. ethanol) than in aqueous media (e.g. water, 0116. The first cellulose derivative (a) such as, e.g., ethyl buffer). cellulose is typically contained in the coating in a concentra 0.125. The active substance in the above mention matrix tion of from about 10 to about 99% w/w such as, e.g., from composition optionally comprising chosen polymers and about 20 to about 95% w/w, from about 30 to about 90% w/w, excipients in a suitable ratio attains an unchanged or lower from about 40 to about 90% w/w, from about 45 to about 90% dissolution rate when tested in alcohol containing media as w/w, from about 50 to about 85% w/w or from about 50 to compared to aqueous media. about 80% w/w. I0126. In principle, the use of a composition to avoid alco 0117. In general, the concentration of the polymer in the hol dose dumping can be of relevance for any active Sub coating is from about 60% w/w to about 100% w/w. 0-40% Stance. W/w of one or more of a plasticizer, a colouring agent, a I0127. An easy manner to investigate whether a composi stabilizer, a glidants or the like may also be present in the tion potentially will be subject to alcohol induced dose dump coating. ing is to Subject the composition to an dissolution test using a 0118 Moreover, in some embodiments of the invention a dissolution medium with and without alcohol and investigate further active Substance may be incorporated in the coating or whether there are any differences in the release pattern under the composition may be provided with a second coating com the two different conditions. The harshest conditions are in a prising the further active Substance. Such a coating may be dissolution medium containing 40% (v/v) ethanol. If the dis designed to release the active Substance from the coating solution rate of the composition is substantially unaffected or immediately after oral administration or a composition of the slower, then it is likely to assume that no alcohol induced dose invention may be subject to enteric coating Such that release dumping will take place in vivo. will be pH dependent. I0128 Active Substances for Use in a Composition of the 0119 Such compositions wherein a coating contains an Invention active Substance may be of interest in those situations where a fast onset of action is desired, i.e. a fast release of an active I0129. A composition according to the invention comprises Substance is desired in order to quickly obtain a therapeuti one or more active Substances. At least one active Substance is cally effective plasma concentration of the active Substance. included in the inner layer and outer layer(s) of the composi Such an active substance may be the same or different from tion, which are the same, but the outer layer(s) may also that contained in layer Band/or the inner layer A dependent contain one or more active Substances that is different from on the particular disease or condition to be treated. the active Substance contained in the inner layer. 0120 In such cases where a second coating is provided on 0.130 Typically, the amount of each active substance in the the composition Such a coating is generally a film-coating and composition if the same active Substance is present in the it is normally applied in a separate manufacturing step (e.g. inner layer and/or outer layer and/or in the coating) corre not by injection moulding, but using processes generally sponds to a daily or part of a daily therapeutic dose. applicable for film-coating of tablets such as, e.g., pan coat 0131 A pharmaceutical composition according to the ing, fluid bed coating, spray coating, dip coating etc.). invention is suitable for use for both water soluble as well as 0121 Dose Dumping slightly soluble or insoluble active substances. 0122. In one aspect, the invention is based on controlled 0.132. Thus, a pharmaceutical composition according to release compositions comprising polymer or a mixture of the invention may comprise one or more active Substances, polymers, more specifically a polyglycol, an active Substance i.e. Substances, which are therapeutically, prophylactically, and optionally one or more pharmaceutically acceptable diagnostically and/or biologically active Substance. The term excipients in layer B. Polymers and pharmaceutically accept “active substance' as used herein broadly includes any com able excipients Suitable for use in Such a composition as well pound, or mixture thereof, that can be delivered from the as relevantactive Substances are described herein. Such com composition to produce a beneficial result. positions have proved to mitigate the risk of alcohol induced 0133. The active substance or substances included in a dose dumping. "Dose dumping is unintended, rapid drug pharmaceutical composition of the invention may be selected release in a short period of time of the entire amount or a from many therapeutic categories, in particular from Sub significant fraction of the active substance retained in a con stances which may advantageously be administered orally, trolled release dosage. rectally, vaginally, or administered to a body cavity (e.g. the 0123. In a specific embodiment of the invention the release urinary bladder, kidney pelvis, the gallbladder, the uterus, a mechanism is primarily erosion or diffusion from layer B central nervous system cavity, infectious/malignant/post-op composed of a polymer matrix, an active Substance and if erative cavities, etc.). US 2010/0239667 A1 Sep. 23, 2010

0134 Examples of specific active substances suitable for Prednisone, Betamethasone, Tixocortol, Budesonide, use in a composition of the invention are: Beclometasone, Antiallergic agents, excl. corticosteroids, 0135 Stomatological active substances; Epinephrine, Cromoglicic acid, Aminosalicylic acid and similar agents, BenZydamine, Acetylsalicylic acid, Adrenalone, Amlexanox, Sulfasalazine, Mesalazine, Olsalazine, Balsalazide, Antidiar Sodium fluoride, Sodium monofluorophosphate, Olaflur, rheal microorganisms, Lactic acid producing organisms, Sac Stannous fluoride, Sodium fluoride, Hydrogen peroxide, charomyces boulardii, Lactic acid producing organisms, Chlorhexidine, Amphotericin B, Polynoxylin, Domiphen, Albumin tannate, Ceratonia, Calcium compounds, Raceca Oxyquinoline, Neomycin, Miconazole, Natamycin, Hexeti dotril. Antiobesity active substances; Phentermine, Fenflu dine, Tetracycline, Benzoxonium chloride, TibeZonium ramine, Amfepramone, Dexfenfluramine, Mazindol, Etilam iodide, Mepartricin, Metronidazole, Clotrimazole, Sodium fetamine, Cathine, Clobenzorex, Mefenorex, Sibutramine, perborate, Chlortetracycline, Doxycycline, Minocycline, Tri Ephedrine, Orlistat, Rimonabant. Digestiveactive sub amcinolone, Dexamethasone, Hydrocortisone, Prednisolone. stances: Enzyme preparations, Diastase, Multienzymes (li Active Substances for acid related disorders; Magnesium car pase, protease etc.), Pepsin, Tilactase, Acid preparations, bonate, Magnesium oxide, Magnesium peroxide, Magne Glutamic acid hydrochloride, Betaine hydrochloride, Hydro sium hydroxide, Magnesium silicate, Aluminium hydroxide, chloric acid, Citric acid. Diabete active substances; Insulins Algeldrate, Aluminium phosphate, Dihydroxialumini and analogues, Biguanides, Phenformin, Metformin, Sodium carbonate, Aluminium acetoacetate, Aloglutamol. Buformin, Sulfonamides, urea derivatives, Glibenclamide, Aluminium glycinate, Calcium carbonate, Calcium silicate, Chlorpropamide, Tolbutamide, Glibornuride, Tolazamide, Ordinary salt combinations, Magaldrate, Almagate, Hydro Carbutamide, Glipizide, Gliquidone, Gliclazide, Metahexa talcite, Almasilate, Magaldrate, Cimetidine, Ranitidine, mide, Glisoxepide, Glimepiride, Acetohexamide, Sulfona Famotidine, Nizatidine, Niperotidine, Roxatidine, Ranitidine mides (heterocyclic), Glymidine, Combinations of oral blood bismuth citrate, Lafutidine, Cimetidine, Famotidine, Miso glucose lowering drugs, Alpha glucosidase inhibitors, Acar prostol, Enprostil, Omeprazole, Pantoprazole, Lansoprazole, bose, Miglitol, Voglibose. Thiazolidinediones, Troglitazone, Rabeprazole, Esomeprazole, Carbenoxolone. Sucralfate, Rosiglitazone, Pioglitazone, Dipeptidyl peptidase 4 (DPP-4) Pirenzepine, Methiosulfonium chloride, Bismuth subcitrate, inhibitors, Sitagliptin, Vildagliptin, Guar gum, Repaglinide, Proglumide, Gefarnate, Sulglicotide, Acetoxolone, Zolimi Nateglinide, Exenatide, Aldose reductase inhibitors, Tolr dine, Troxipide, Bismuth submitrate, Alginic acid. Active sub estat. Anabolic active Substances; Androstan derivatives, stances for functional gastrointestinal disorders; Oxyphen Androstanolone, Stanozolol, Metandienone, Metenolone, cyclimine, Camylofin, Mebeverine, Trimebutine, Rociverine, Oxymetholone, Quinbolone, Prasterone, Oxandrolone, Dicycloverine, Dihexyverine. Difemerine, Piperidolate, Norethandrolone, Estren derivatives, Nandrolone, Ethyl Metoclopramide, Cisapride, Domperidone, Bromopride, estrenol, Oxabolone cipionate. Metabolism active sub Alizapride, Clebopride. Antiemetic and antinauseant active stances; Amino acids and derivatives, Levocarnitine, Ademe Substances; Serotonin (5HT3) antagonists, Ondansetron, tionine, Glutamine, Mercaptamine, Carglumic acid, Betaine, Granisetron, Tropisetron, Dolasetron, Palonosetron, Scopo Enzymes, Alglucerase, Imiglucerase, Agallsidase alfa, Agal lamine, Cerium oxalate, Chlorobutanol, Metopimazine, sidase beta, Laronidase, Sacrosidase, Alglucosidase alfa, Dronabinol, Nabilone, Aprepitant. Active substances for bile Galsulfase, Idursulfase, Tioctic acid, Anethole trithione, and liver therapy; Bile acid preparations, Chenodeoxycholic Sodium phenylbutyrate, Nitisinone, Zinc acetate, Miglustat, acid, Ursodeoxycholic acid, Nicotinyl methylamide, Pipro Sapropterin. Zolin, Hymecromone, Cyclobutyrol, Arginine glutamate, 0.136 Antithrombotic active substances; Vitamin K Silymarin, Citiolone, Epomediol, Ornithine oxoglurate, Tidi antagonists, Dicoumarol, Phenindione, Warfarin, Phenproc acic arginine. Laxative active Substances; Softeners, Emol oumon, Acenocoumarol, Ethyl biscoumacetate, Clorindione, lients, Liquid paraffin, Docusate Sodium, Liquid paraffin, Diphenadione, Tioclomarol, Heparin, Antithrombin III, Contact laxatives, Oxyphenisatine, Bisacodyl, Dantron, Phe Dalteparin, Enoxaparin, Nadroparin, Parnaparin, Reviparin, nolphthalein, Castor oil, Senna glycosides, Cascara, Sodium Danaparoid, Tinzaparin, Sulodexide, Bemiparin, Platelet picosulfate, Bisoxatin, Belladonna alkaloids, Bisacodyl, aggregation inhibitors excl. heparin, Ditazole, Cloricromen, Dantron, Senna glycosides, Cascara, Sodium picosulfate, Picotamide, Clopidogrel, Ticlopidine, Acetylsalicylic acid, Ispaghula (psylla seeds), Ethulose, Sterculia, Linseed, Meth Dipyridamole, Carbasalate calcium, Epoprostenol, ylcellulose, Triticum (wheat fibre), Polycarbophil calcium, Indobufen, Iloprost, Abciximab, Aloxiprin, Eptifibatide, Magnesium carbonate, Magnesium oxide, Magnesium per Tirofiban, Triflusal, Beraprost, Treprostinil, Enzymes, Strep oxide, Magnesium Sulfate, Lactulose, Lactitol, Sodium Sul tokinase, Alteplase, Anistreplase, Urokinase, Fibrinolysin, fate, Pentaerithrityl, Macrogol, Mannitol, Sodium phosphate, Brinase, Reteplase, Saruplase, Ancrod, Drotrecogin alfa (ac Sorbitol, Magnesium citrate, Sodium tartrate, Enemas, tivated), Tenecteplase, Protein C, Direct thrombin inhibitors, Sodium phosphate, Bisacodyl, Glycerol, Oil, Laurilsulfate, Desirudin, Lepirudin, Argatroban, Melagatran, Ximelagat Carbon dioxide producing drugs. Antidiarrheal, intestinal, ran, Bivalirudin, Dabigatran etexilate, Defibrotide, Dermatan anti-inflammatory/antiinfective active Substances; Antibiot Sulfate, Fondaparinux. Antihemorrhagics active Substances; ics, Neomycin, Nystatin, Natamycin, Streptomycin, Poly Amino acids, Aminocaproic acid, Tranexamic acid, Ami myxin B, Paromomycin, Amphotericin B, Kanamycin, Van nomethylbenzoic acid, Proteinase inhibitors, Aprotinin, comycin, Colistin, Rifaximin, Sulfonamides, Alfa1 antitrypsin, C1-inhibitor, Camostat, Vitamin K. Phy Phthalylsulfathiazole, Sulfaguanidine. Succinylsulfathiaz tomenadione, Menadione, Fibrinogen, Local hemostatics, ole, Imidazole derivatives, Miconazole, Broxyquinoline, Absorbable gelatin sponge, Oxidized cellulose, Tetragalactu 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 US 2010/0239667 A1 Sep. 23, 2010 activity, Coagulation factor IX, Coagulation factor VII, Von tives, Dihydralazine, Hydralazine, Endralazine, Cadralazine, Willebrand factor and coagulation factor VIII in combination, Pyrimidine derivatives, Minoxidil, Nitroferricyanide deriva Coagulation factor XIII, Eptacog alfa (activated). Nonacog tives, Nitroprusside, Guanidine derivatives, Pinacidil, Ver alfa, Thrombin, Etamsylate, Carbazochrome, Batroxobin. atrum, Tyrosine hydroxylase inhibitors, Metirosine, MAO Antianemic active Substances; Ferrous glycine Sulfate, Fer inhibitors, Pargyline, Serotonin antagonists, Ketanserin, rous fumarate, Ferrous gluconate, Ferrous carbonate, Ferrous Bosentan, Ambrisentan, Sitaxentan. Diuretic active sub chloride, Ferrous succinate, Ferrous sulfate, Ferrous tartrate, stances: Thiazides, Bendroflumethiazide, Hydroflumethiaz Ferrous aspartate, Ferrous ascorbate, Ferrous iodine, Ferric ide, Hydrochlorothiazide, Chlorothiazide, Polythiazide, sodium citrate, Saccharated iron oxide, Sodium feredetate, Trichlormethiazide, Cyclopenthiazide, Methyclothiazide, Ferric hydroxide, Dextriferron, Ferric citrate, Chondroitin Cyclothiazide, Mebutizide, Sulfonamides, Quinethazone, sulfate-iron complex, Ferric acetyl transferrin, Ferric prote Clopamide, Chlortalidone, Mefruside, Clofenamide, Metola insuccinylate, Dextriferron, Vitamin B12 (cyanocobalamin Zone, Meticrane, Xipamide, Indapamide, Clorexolone, Fen and analogues), Cyanocobalamin, Cyanocobalamin tannin quizone, Mercurial diuretics, Mersalyl, Xanthine derivatives, complex, Hydroxocobalamin, Cobamamide, Mecobalamin, Theobromine, Cicletanine, Furosemide, Bumetanide, Piret Folic acid and derivatives, Erythropoietin, Darbepoetin alfa, anide, Torasemide, Aryloxyacetic acid derivatives, Etacrynic Methoxy polyethylene glycol-epoetin beta. Hematological acid, Tienilic acid, Pyrazolone derivatives, Muzolimine, Eto active Substances; Fibrinolysin and desoxyribonuclease, Zolin, Aldosterone antagonists, Spironolactone, Potassium Hyaluronidase, Chymotrypsin, Trypsin, Desoxyribonu canrenoate, Canrenone, Eplerenone, Amiloride, Triamterene. clease, Bromelains, Streptokinase, combinations, Hematin. Active Substances for peripheral vasodilation: 2-amino-1- 0.137 Cardiac stimulantactive substances; Cardiac glyco phenylethanol derivatives, ISOXSuprine, Buphenine, Bam sides, Digitalis glycosides, Acetyldigitoxin, Acetyldigoxin, ethan, Imidazoline derivatives, Phentolamine, Tolazoline, Digitalis leaves, Digitoxin, Digoxin, Lanatoside C. Deslano Nicotinic acid, Nicotinyl alcohol (pyridylcarbinol), Inositol side, Metildigoxin, Gitoformate, Scilla glycosides, Proscil nicotinate, Ciclonicate, Purine derivatives, Pentifylline, Xan laridin, Strophantus glycosides, G-strophanthin, Cymarin, tinol nicotinate, Pentoxifylline, Etofylline nicotinate, Ergot Peruvoside, Adrenergic and dopaminergic agents, Etilefrine, alkaloids, Ergoloid mesylates, Nicergoline, Dihydroergocris Isoprenaline, Norepinephrine, Dopamine, Norfenefrine, Phe tine, Kallidinogenase, Cyclandelate, Phenoxybenzamine, nylephrine, Dobutamine, Oxedrine, Metaraminol, Methox Vincamine, Moxisylyte, Bencyclane, Vinburnine, Suloctidil, amine, Mephentermine, Dimetofrine, Prenalterol, Dopexam Buflomedil, Naftidrofuryl, Butalamine, Visnadine, Cetiedil, ine, Gepefrine, Ibopamine, Midodrine, Octopamine, Cinepazide, Ifenprodil, Azapetine, Fasudil. Vasoprotective Fenoldopam, Cafedrine, Arbutamine. Theodrenaline, Epi active Substances; Heparinoid, Sodium apolate, Heparin, nephrine, Phosphodiesterase inhibitors, Amrinone, Mil Pentosan polysulfate Sodium, Monoethanolamine oleate, rinone, Enoximone, Bucladesine. Other cardiac stimulants, Polidocanol, Invert sugar, Sodium tetradecyl sulfate, Phenol, Angiotensinamide, Xamoterol, Levosimendan. Antiarrhyth Glucose, Calcium dobesilate, Bioflavonoids, Rutoside, Mon mics active Subtances; class la, Quinidine, Procainamide, oxerutin, Diosmin, Troxerutin, Hidrosmin, Tribenoside. Beta Disopyramide, Sparteine, Ajmaline, Prajmaline, Lorajmine, blocking active Substances; Beta blocking agents, non-selec Antiarrhythmics, class Ib, Lidocaine, Mexiletine, Tocainide, tive, Alprenolol, Oxprenolol, Pindolol, Propranolol, Timolol, Aprindine, Antiarrhythmics, class Ic, Propafenone, Flecain Sotalol, Nadolol, Mepindolol, Carteolol, Tertatolol, Bopin ide, Lorcainide, Encainide, Antiarrhythmics, class III, Amio dolol, Bupranolol, Penbutolol, Cloranolol, Beta blocking darone, Bretylium tosilate, Bunaftine, Dofetilide, Ibutilide, agents, selective, Practolol, Metoprolol, Atenolol, Acebu Other class I antiarrhythmics, Moracizine, Cibenzoline. tolol, Betaxolol, Bevantolol, Bisoprolol, Celiprolol, Esmolol, Active substances for vasodilation; Organic nitrates, Glyceryl Epanolol, S-atenolol, Nebivolol, Talinolol, Alpha and beta trinitrate, Methylpropylpropanediol dinitrate, Pentaerithrityl blocking agents, Labetalol, Carvedilol. Calium channel tetranitrate, Propatylnitrate, Isosorbide dinitrate, Trolnitrate, blockers; Dihydropyridine derivatives, Amlodipine, Felo Eritrity1 tetranitrate, Isosorbide mononitrate, Tenitramine, dipine, Isradipine, Nicardipine, Nifedipine, Nimodipine, Floseduinan, Itramin tosilate, Prenylamine, Oxyfedrine, Nisoldipine, Nitrendipine, Lacidipine, Nilvadipine, Manid Benziodarone, Carbocromen, Hexobendine, Etafenone, Hep ipine, Barnidipine, Lercanidipine, Cilnidipine, Benidipine, taminol, Imolamine, Dilazep, Trapidil, Molsidomine, Eflox Mibefradil, Phenylalkylamine derivatives, Verapamil, Gallo ate, Cinepazet, Cloridarol, Nicorandil, Linsidomine, Nesir pamil, Benzothiazepine derivatives, Diltiazem, Phenylalky itide. Cardiac active Substances; Prostaglandins, Alprostadil, lamine derivatives, Fendiline, Bepridil, Lidoflazine, Perhexy Other cardiac preparations, Camphora, Indometacin, Cratae line. Active Substances acting on the renin-angiotensin gus glycosides, Creatinolfosfate, Fosfocreatine, Fructose 1.6- system; ACE inhibitors, Captopril, Enalapril, Lisinopril, Per diphosphate, Ubidecarenone, Adenosine, Tiracizine, Tedis indopril, Ramipril, Quinapril, Benazepril, Cilazapril, Fosino amil, Acadesine, Trimetazidine, Ibuprofen, Ivabradine, pril, Trandolapril, Spirapril, Delapril, Moexipril, Temocapril, Ranolazine. Antihypertensive active Substances; Rauwolfia Zofenopril, Imidapril. Other, Renin-inhibitors, Remikiren, alkaloids, Rescinnamine, Reserpine, Deserpidine, Methoser Aliskiren, Angiotensin II antagonists, Losartan, Eprosartan, pidine, Bietaserpine, Methyldopa, Imidazoline receptor ago Valsartan, Irbesartan, Candesartan, Telmisartan, Olmesartan. nists, Clonidine, Guanfacine, Tolonidine, Moxonidine, Ril Lipid modifying active substances; HMG CoA reductase menidine, Sulfonium derivatives, Trimetaphan, Secondary inhibitors, Simvastatin, Lovastatin, Pravastatin, Fluvastatin, and tertiary amines, Mecamylamine, Bisquaternary ammo Atorvastatin, Cerivastatin, Rosuvastatin, Pitavastatin, nium compounds, Alpha-adrenoreceptor antagonists, Pra Fibrates, Clofibrate, Bezafibrate, Aluminium clofibrate, Zosin, Indoramin, TrimaZosin, Doxazosin, Urapidil, Guani Gemfibrozil, Fenofibrate, Simfibrate, Ronifibrate, Ciprofi dine derivatives, Betanidine, Guanethidine, Guanoxan, brate, Etofibrate, Clofibride, Bile acid sequestrants, Col Debrisoquine, Guanoclor, GuanaZodine, GuanoxabenZ, Thi estyramine, Colestipol, Colextran, Colesevelam, Nicotinic azide derivatives, Diazoxide, Hydrazinophthalazine deriva acid and derivatives, Niceritrol, Nicofuranose, Aluminium US 2010/0239667 A1 Sep. 23, 2010 12 nicotinate, Nicotinyl alcohol (pyridylcarbinol), Acipimox, Teriparatide, Parathyroid hormone, Calcitonin, Elcatonin, Other lipid modifying agents, Dextrothyroxine, Probucol, Cinacalcet. Urological active substances; Acidifiers, Ammo Tiadenol, Benfluorex, Meglutol, Omega-3-triglycerides, nium chloride, Calcium chloride, Urinary concrement sol Magnesium pyridoxal 5-phosphate glutamate, Policosanol, vents, Urinary antispasmodics, Emepronium, Flavoxate, EZetimibe Meladrazine, Oxybutynin, Terodiline, Propiverine, Tolterod 0138 Dermatological active substances for system use: ine, Solifenacin, Trospium, Darifenacin, Fesoterodine, Drugs Antifungals, Griseofulvin, Terbinafine, Protectives against used in erectile dysfunction, Alprostadil, Papaverine, UV-radiation for systemic use, Betacarotene, Antipsoriatics, Sildenafil. Yohimbin, Phentolamine, Moxisylyte, Apomor Psoralens, Trioxysalen, Methoxsalen, Bergapten, Retinoids, phine, Tadalafil. Vardenafil. Combinations, Papaverine, com Etretinate, Acitretin, Anti-acne, Isotretinoin, Ichtasol. Anti binations, Magnesium hydroxide, Acetohydroxamic acid, infective and antiseptic active Substances; Antibiotics, Nys Phenazopyridine. Succinimide, Collagen, Phenyl salicylate, tatin, Natamycin, Amphotericin B, Candicidin, Chloram Dimethylsulfoxide, Alpha-adrenoreceptor antagonists, Alfu phenicol, AZidamfenicol, Hachimycin, Oxytetracycline, Zosin, Tamsulosin, Terazosin, Testosterone-5-alpha reduc Carfecillin, Mepartricin, Clindamycin, Pentamycin, Arsenic tase inhibitors, Finasteride, Dutasteride, Pygeum africanum, compounds, AcetarSol, Quinoline derivatives, Diiodohydrox Serenoa repens, Mepartricin. Corticosteroids; Mineralocorti yduinoline, Clioquinol, Chlorquinaldol, Dequalinium, BroX coids, Aldosterone, Fludrocortisone, Desoxycortone, Gluco yduinoline, Oxyquinoline, Organic acids, Lactic acid, Acetic corticoids, Betamethasone, Dexamethasone, Fluocortolone, acid, Ascorbic acid, Sulfonamides, Sulfatolamide, Combina Methylprednisolone, Paramethasone, Prednisolone, Pred tions of sulfonamides, Imidazole derivatives, Metronidazole, nisone, Triamcinolone, Hydrocortisone, Cortisone, Pred Clotrimazole, Miconazole, Econazole, Ornidazole, Isocona nylidene, Rimexolone, Deflazacort, Cloprednol, Mepred Zole, Tioconazole, Ketoconazole, Fenticonazole, AZanida nisone, Cortivazol, Anticorticosteroids, Trilostane. Thyroid Zole, Propenidazole, Butoconazole, Omoconazole, Oxicona and antithyroid active Substances; Thyroid hormones, Zole, Flutrimazole, Triazole derivatives, Terconazole, Levothyroxine Sodium, Liothyronine Sodium, Tiratricol, Clodantoin, Inosine, Policresulen, Nifuratel, Furazolidone, Thiouracils, Methylthiouracil, Propylthiouracil, Benzylth Methylrosaniline, Povidone-iodine, Ciclopirox, Protiofate, iouracil, Sulfur-containing imidazole derivatives, Carbima Lactobacillus fermentum, Copper usinate, Octenidine Zole. Thiamazole, Perchlorates, Potassium perchlorate, 0139 Gynecological active substances; Ergot alkaloids, Diiodotyrosine, Dibromotyrosine, Iodine. Methylergometrine, Ergot alkaloids, Ergometrine, Oxytocin, 0140 Antiinfective active substances: Demeclocycline, Prostaglandins, Dinoprost, Dinoprostone, Gemeprost, Car Doxycycline, Chlortetracycline, Lymecycline, Metacycline, boprost, Sulprostone, Misoprostol, Ritodrine, Buphenine, Oxytetracycline, Tetracycline, Minocycline, Rolitetracy Fenoterol, Prolactine inhibitors, Bromocriptine, Lisuride, cline, Penimepicycline, Clomocycline, Tigecycline, Cabergoline, Quinagolide, Metergoline. Hormones; Norg Amphenicols, Chloramphenicol. Thiamphenicol, Ampicil estrel, Gestodene, Norgestimate, Drospirenone, Norel lin, Pivampicillin, Carbenicillin, Amoxicillin, Carindacillin, gestromin, Progestogens, Norethisterone, Lynestrenol, Bacampicillin, Epicillin, Pivmecillinam, AZlocillin, Levonorgestrel, Quingestanol, Megestrol, Medroxyprogest Mezlocillin, Mecillinam, Piperacillin, Ticarcillin, Metampi erone, Norgestrienone, Etonogestrel, Desogestrel, 3-oxoan cillin, Talampicillin, Sulbenicillin, Temocillin, Hetacillin, drosten (4) derivatives, Fluoxymesterone, Methyltestoster Benzylpenicillin, Phenoxymethylpenicillin, Propicillin, Azi one, Testosterone, 5-androstanon (3) derivatives, docillin, Pheneticillin, Penamecillin, Clometocillin, Benza Mesterolone, Androstanolone, Ethinylestradiol, Estradiol, thine, benzylpenicillin, Procaine benzylpenicillin, Benza Estriol, Chlorotrianisene, Estrone, Promestriene, Conjugated thine phenoxymethylpenicillin, Dicloxacillin, Cloxacillin, estrogens, Dienestrol, Diethylstilbestrol, Methallenestril, Meticillin, Oxacillin, Flucloxacillin, Sulbactam, Tazobac Moxestrol, Dienestrol, Methallenestril, Estrone, Diethylstil tam, Sultamicillin, Cefalexin, Cefaloridine, Cefalotin, Cefa bestrol, Pregnen (4) derivatives, Gestonorone, Medrox Zolin, Cefadroxil, Cefazedone, Cefatrizine, Cefapirin, Cefra yprogesterone, Hydroxyprogesterone, Progesterone, Pregna dine, Cefacetrile, Cefroxadine, Ceftezole, Cefoxitin, dien derivatives, Dydrogesterone, Megestrol, Medrogestone, Cefuroxime, Cefamandole, Cefaclor, Cefotetan, Cefonicide, Nomegestrol, Demegestone, Chlormadinone, Promegestone, Cefotiam, Loracarbef, Cefinetazole, Cefprozil, Ceforanide, Estren derivatives, Allylestrenol, Norethisterone, Lynestre Cefotaxime, Ceftazidime, Cefsulodin, Ceftriaxone, nol, Ethisterone, Tibolone. Etynodiol, Methylestrenolone, Cefinenoxime, Latamoxef, Ceftizoxime, Cefixime, Cefodiz Methyltestosterone, Methylnortestosterone, Noretynodrel, ime, Cefetamet, Ce?piramide, CefoperaZone, Cefpodoxime, Dienogest, Trimegeston, Gonadotropins, Urofollitropin, Fol Ceftibuten, Cefdinir, Cefditoren, Ceftriaxone, Cefepime, litropin alfa, Follitropin beta, Lutropin alfa, Choriogonadot Ce?pirome, Monobactams, Aztreonam, Carbapenems, Mero ropin alfa, Cyclofenil, Clomifene, Epimestrol, Cyproterone, penem, Ertapenem, Imipenem, Trimethoprim, Brodimoprim, Danazol, Gestrinone, Antiprogestogens, Mifepristone, Ral Sulfaisodimidine, Sulfamethizole, Sulfadimidine, Sulfapyri oxifene, Corticotropin, Tetracosactide, Thyrotropin, Thy dine, Sulfafurazole, Sulfanilamide, Sulfathiazole, Sulfathio rotropin, Somatropin and Somatropin agonists, Somatropin, urea, Sulfamethoxazole, Sulfadiazine, Sulfamoxole, Sul Somatrem, Mecasermin, Sermorelin, Mecasermin rinfabate, fadimethoxine, Sulfalene, Sulfametomidine, Pegvisomant, Vasopressin and analogues, Vasopressin, Des Sulfametoxydiazine, Sulfamethoxypyridazine, Sulfaperin, mopressin, Lypressin, Terlipressin, Ornipressin, Argipressin, Sulfamerazine, Sulfaphenazole, Sulfamazone, Macrollides, Oxytocin and analogues, Demoxytocin, Oxytocin, Carbeto Erythromycin, Spiramycin, Midecamycin, Oleandomycin, cin, Gonadotropin-releasing hormones, Gonadorelin, Roxithromycin, Josamycin, Troleandomycin, Clarithromy Nafarelin, Histrelin, Antigrowth hormone, Somatostatin, cin, Azithromycin, Miocamycin, Rokitamycin, Dirithromy Octreotide, Lanreotide, Vapreotide, Anti-gonadotropin-re cin, Flurithromycin, Telithromycin, Lincosamides, Clinda leasing hormones, Ganirelix, Cetrorelix, Glycogenolytic hor mycin, Lincomycin, Streptogramins, Pristinamycin, mones, Glucagon, Parathyroid hormones and analogues, Quinupristin/dalfopristin, Streptomycins, Streptomycin, US 2010/0239667 A1 Sep. 23, 2010

Streptoduocin, Other aminoglycosides, Tobramycin, Gen vaccines, Varicella Zoster vaccines, Yellow fever vaccines, tamicin, Kanamycin, Azithromycin, Neomycin, Amikacin, Papillomavirus vaccines. Other viral vaccines. Retapamulin, Netilmicin, Sisomicin, Dibekacin, Ribostamy 0141 Antineoplastic and immunomodulating active Sub cin, Isepamicin, Fluoroquinolones, Ofloxacin, Ciprofloxacin, stances; Nitrogen mustard analogues, Cyclophosphamide, Pefloxacin, Enoxacin, Temafloxacin, Norfloxacin, Lom Chlorambucil, Melphalan, Chlormethine, Ifosfamide, Tro efloxacin, Fleroxacin, Sparfloxacin, Rufloxacin, Grepafloxa fosfamide, Prednimustine, Alkylsulfonates, Busulfan, Treo cin, Levofloxacin, Trovafloxacin, Moxifloxacin, Gemifloxa sulfan, Mannosulfan, Ethylene imines. Thiotepa, Triazi cin, Gatifloxacin, Prulifloxacin, PaZufloxacin, Garenoxacin, quone, Carboquone, Nitrosoureas, Carmustine, Lomustine, Other quinolones, Rosoxacin, Nalidixic acid, Piromidic acid, Semustine, Streptozocin, Fotemustine, Nimustine, Ranimus Pipemidic acid, OXolinic acid, Cinoxacin, Flumequine, Gly tine, Epoxides, Etoglucid, Other alkylating agents, Mito copeptide antibacterials, Vancomycin, Teicoplanin, Telavan bronitol, Pipobroman, Temozolomide, Dacarbazine. Antime cin, Polymyxins, Colistin, Polymyxin B, Steroid antibacteri tabolite active substances; Folic acid analogues, als, Fusidic acid, Imidazole derivatives, Metronidazole, Methotrexate, Raltitrexed, Pemetrexed, Purine analogues, Timidazole, Ornidazole, Nitrofuran derivatives, Nitrofuran Mercaptopurine, Tioguanine, Cladribine, Fludarabine, Clo toin, Nifurtoinol, Fosfomycin, Xibornol, Clofoctol, Specti farabine, Nelarabine, Pyrimidine analogues, Cytarabine, nomycin, Methenamine, Mandelic acid, Nitroxoline, Lin Fluorouracil, Tegafur, Carmofur, Gemcitabine, Capecitabine, eZolid, Daptomycin. Antimycotic active Substances; Vinca alkaloids and analogues, Vinblastine, Vincristine, Vin Antibiotics, Amphotericin B. Hachimycin, Imidazole deriva desine, Vinorelbine, Podophyllotoxin derivatives, Etoposide, tives, Miconazole, Ketoconazole, Triazole derivatives, Flu Teniposide, Colchicine derivatives, Demecolcine, Taxanes, conazole, Itraconazole, Voriconazole, Posaconazole, Flucy Paclitaxel, Docetaxel, Other plant alkaloids and natural prod tosine, Caspofungin, Micafungin, Anidulafungin. ucts, Trabectedin. Cytotoxic antibiotic and related active sub Antimycobacterial active substances; Aminosalicylic acid stances; Actinomycines, Dactinomycin, Anthracyclines and and derivatives, Sodium aminosalicylate, Calcium aminosali related substances, Doxorubicin, Daunorubicin, Epirubicin, cylate, Antibiotics, Cycloserine, Rifampicin, Rifamycin, Aclarubicin, Zorubicin, Idarubicin, Mitoxantrone, Pirarubi Rifabutin, Rifapentine, Capreomycin, Hydrazides, Isoniazid, cin, Valrubicin, Other cytotoxic antibiotics, Bleomycin, Pli Isoniazid, Thiocarbamide derivatives, Protionamide, Tiocar camycin, Mitomycin, Ixabepilone. Antineoplastic active Sub lide, Ethionamide, Pyrazinamide, Ethambutol, Terizidone, stances; Platinum compounds, Cisplatin, Carboplatin, Morinamide, Clofazimine, Dapsone, Aldesulfone sodium. Oxaliplatin, Methylhydrazines, Procarbazine, Monoclonal Antiviral active substances: Thiosemicarbazones, Metisa antibodies, Edrecolomab, Rituximab, Trastuzumab, Alemtu Zone, Nucleosides and nucleotides, Aciclovir, Idoxuridine, Zumab, Gemtuzumab, Cetuximab, Bevacizumab, Panitu Vidarabine, Ribavirin, Ganciclovir, Famciclovir, Valaciclo mumab, Sensitizers used in photodynamic/radiation therapy, vir, Cidofovir, Penciclovir, Valganciclovir, Brivudine, Cyclic Porfimer sodium, Methyl aminolevulinate, Aminolevulinic amines, Rimantadine, Tromantadine, Phosphonic acid acid, Temoporfin, Efaproxiral, Protein kinase inhibitors, Ima derivatives, Foscarnet, Fosfonet, Protease inhibitors, tinib, Gefitinib, Erlotinib, Sunitinib, Sorafenib, Dasatinib, Saquinavir, Indinavir, Ritonavir, Nelfinavir, Amprenavir, Lapatinib, Nilotinib. Other antineoplastic agents, Amsacrine, Lopinavir, Fosamprenavir, Atazanavir, Tipranavir, Asparaginase, Altretamine, Hydroxycarbamide, Darunavir, Zidovudine, Didanosine, Zalcitabine, Stavudine, Lonidamine, Pentostatin, Miltefosine, Masoprocol, Estra Lamivudine, Abacavir, Tenofovir disoproxil, Adefovir dipiv mustine, Tretinoin, MitoguaZone, Topotecan, Tiazofurine, oxil, Emtricitabine, Entecavir, Telbivudine, Nevirapine, Irinotecan, Alitretinoin, Mitotane, Pegaspargase, Bexaro Delavirdine, Efavirenz, Zanamivir, Oseltamivir, Moroxy tene, Arsenic trioxide, Denileukin diftitox, Bortezomib, dine, Lysozyme, Inosine pranobex, Pleconaril, Enfluvirtide, Celecoxib, Anagrelide, Oblimersen, Sitimagene ceraden Raltegravir, Maraviroc. Immune Sera and immunoglobulin; ovec, Combinations of antineoplastic agents. Endocrine Diphtheria antitoxin, Tetanus antitoxin, Snake Venom antise active substances; Estrogens, Diethylstilbestrol, Polyestra rum, Botulinum antitoxin, Gas-gangrene Sera, Rabies serum, diol phosphate, Ethinylestradiol, Fosfestrol. Progestogens, Immunoglobulins from human, Anti-D (rh) immunoglobulin, Megestrol, Medroxyprogesterone, Medroxyprogesterone, Tetanus immunoglobulin, Varicella/Zoster immunoglobulin, Gestonorone, Gonadotropin releasing hormone analogues, Hepatitis B immunoglobulin, Rabies immunoglobulin, Buserelin, Leuprorelin, Goserelin, Triptorelin, hormones Rubella immunoglobulin, Vaccinia immunoglobulin, Sta antagonists, Anti-estrogens, Tamoxifen, Toremifene, Fulves phylococcus immunoglobulin, Cytomegalovirus immuno trant, Anti-androgens, Flutamide, Nilutamide, Bicalutamide, globulin, Diphtheria immunoglobulin, Hepatitis A immuno Enzyme inhibitors, Aminogluthetimide, Formestane, Anas globulin, Encephalitis, tick borne immunoglobulin, Pertussis trozole, Letrozole, Vorozole, Exemestane, Abarelix. Immu immunoglobulin, Measles immunoglobulin, Mumps immu nostimulant active Substances; Cytokines and immunomodu noglobulin, Palivizumab, Nebacumab. Vaccines: Bacterial lators, Colony stimulating factors, Filgrastim, vaccines, Anthrax vaccines, Anthrax antigen, Brucellosis Molgramostim, SargramoStim, Lenograstim, Ancestim, Peg vaccines, Brucella antigen, Cholera vaccines, Diphtheria vac filgrastim, Interferons, Peginterferons, Interleukins, cines, Diphtheria toxoid, Hemophilus influenzae B vaccines, Aldesleukin, Oprelvekin, Lentinan, Roquinimex, BCG vac Meningococcal vaccines, Meningococcus A. Meningococ cine, Pegademase, Pidotimod, Poly I:C, Poly ICLC, Thymo cus B. Meningococcus C. Pertussis vaccines, Plague vac pentin, Immunocyanin, Tasonermin, Melanoma vaccine, cines, Pneumococcal vaccines, Pneumococcus, Tetanus vac Glatirameracetate. Histamine dihydrochloride, Mifamurtide. cines, Tuberculosis vaccines, Typhoid vaccines, Typhus Immunosuppressive active Substances: Ciclosporin, (exanthematicus) vaccines. Other bacterial vaccines, viral Muromonab-CD3, Antilymphocyte immunoglobulin, Anti vaccines, Encephalitis vaccines, Influenza vaccines, Hepati thymocyte immunoglobulin, Tacrolimus, Mycophenolic tis vaccines, Measles vaccines, Mumps vaccines, Poliomy acid, Daclizumab, Basiliximab, Sirolimus, Etanercept, elitis vaccines, Rabies vaccines, Rota virus vaccines, Rubella Infliximab, Leflunomide, Anakinra, Alefacept, Afelimomab, US 2010/0239667 A1 Sep. 23, 2010

Adalimumab, Everolimus, Gusperimus, Efalizumab, Abeti Benzomorphan derivatives, Pentazocine, Phenazocine. Ori mus, Natalizumab, Abatacept, Eculizumab, Certolizumab pavine derivatives, Buprenorphine, Morphinan derivatives, pegol, Other immunosuppressive agents, Azathioprine, Tha Butorphanol, Nalbuphine, Tilidine, Tramadol, Dezocine, lidomide, Methotrexate, Lenalidomide. Salicylic acid and derivatives, Acetylsalicylic acid, Aloxiprin, 0142 Antiinflammatory and antirheumatic active sub Choline salicylate, Sodium salicylate, Salicylamide, Sal stances; Butylpyrazolidines, Phenylbutazone, Mofebuta salate, Ethenzamide, Morpholine salicylate, Dipyrocetyl, Zone, OxyphenbutaZone, ClofeZone, KebuZone, Acetic acid Benorilate. Diflunisal, Potassium salicylate, Guacetisal, Car derivatives and related Substances, Indometacin, Sulindac, basalate calcium, Imidazole salicylate, Pyrazolones, Tolimetin, Zomepirac, Diclofenac, Alclofenac, Bumadizone, PhenaZone, Metamizole sodium, AminophenaZone, Propy Etodolac, Lonazolac, Fentiazac, Acemetacin, Difempiramide, phenaZone, NifenaZone, Anilides, Paracetamol, Phenacetin, Oxametacin, Proglumetacin, Ketorolac, Aceclofenac, Bufex Bucetin, Propacetamol. Other analgesics and antipyretics, amac. Oxicams, Piroxicam, Tenoxicam, Droxicam, Lornoxi Rimazolium, Glafenine, Floctafenine, Viminol, Nefopam, cam, Meloxicam, Propionic acid derivatives, Ibuprofen, Flupirtine, Ziconotide. Anesthetics: Ethers, Diethyl ether, Naproxen, Ketoprofen, Fenoprofen, Fenbufen, Benoxapro Vinyl ether, Halogenated hydrocarbons, Halothane, Chloro fen, Suprofen, Pirprofen, Flurbiprofen, Indoprofen, Tiapro form, Methoxyflurane, Enflurane, Trichloroethylene, Isoflu fenic acid, Oxaprozin, Ibuproxam, Dexibuprofen, Flunox rane, Desflurane, Sevoflurane, Barbiturates, Methohexital, aprofen, Alminoprofen, Dexketoprofen, Fenamates, Hexobarbital. Thiopental, Narcobarbital, Opioid anesthetics, Mefenamic acid, Tolfenamic acid, Flufenamic acid, Meclofe Fentanyl, Alfentanil, Sufentanil, Phenoperidine, Anileridine, namic acid, Coxibs, Celecoxib, Rofecoxib, Valdecoxib, Pare Remifentanil. Other general anesthetics, Droperidol, Ket coxib, Etoricoxib, Lumiracoxib, Nabumetone, Niflumic acid, amine, Propanidid, Alfaxalone, Etomidate, Propofol, AZapropaZone, Glucosamine, BenZydamine, Glucosami Hydroxybutyric acid, Nitrous oxide, Esketamine, Xenon, noglycan polysulfate, ProquaZone, Orgotein, NimeSulide, Esters of aminobenzoic acid, Metabutethamine, Procaine, Feprazone, Diacerein, Morniflumate, Tenidap, Oxaceprol, Tetracaine, Chloroprocaine, Benzocaine, Amides, Bupiv Chondroitin sulfate, Feprazone, Dipyrocetyl, Acetylsalicylic acaine, Lidocaine, Mepivacaine, Prilocalne. Butanilicaine, acid, Quinolines, Oxycinchophen, Gold preparations, Cinchocaine, Etidocaine, Articaine, Ropivacaine, Levobupi Sodium aurothiomalate, Sodium aurotiosulfate, Auranofin, vacaine, Esters of benzoic acid, Cocaine. Other local anes Aurothioglucose, Aurotioprol, Penicillamine and similar thetics, Ethyl chloride, Dyclonine, Phenol, Capsaicin. Anti agents, Bucillamine. Muscle relaxant active Substances; migraine active Substances; Ergot alkaloids, Peripherally acting agents, Curare alkaloids, Alcuronium, Dihydroergotamine, Ergotamine, Methysergide, Lisuride, Tubocurarine, Dimethyltubocurarine, Choline derivatives, Corticosteroid derivatives, Flumedroxone, Selective seroto Suxamethonium, Other quaternary ammonium compounds, nin (5HT1) agonists, Sumatriptan, Naratriptan, Zolmitriptan, Pancuronium, Gallamine, Vecuronium, Atracurium, Rizatriptan, Almotriptan, Eletriptan, Frovatriptan, Other anti Hexafluoronium, Pipecuronium bromide, Doxacurium chlo migraine preparations, Pizotifen, Clonidine, Iprazochrome, ride, Fazadinium bromide, Rocuronium bromide, Mivacu Dimetotiazine, Oxetorone. Antiepileptic active Substances; rium chloride, Cisatracurium, Botulinum toxin, Centrally Barbiturates and derivatives, Methylphenobarbital, Phe acting agents, Carbamic acid esters, Phenprobamate, Cariso nobarbital, Primidone, Barbexaclone, Metharbital, Hydan prodol, Methocarbamol, Styramate, Febarbamate, Oxazol, toin derivatives, Ethotoin, Phenyloin, Amino(diphenylhydan thiazine, and triazine derivatives, ChlormeZanone, ChlorZOX toin) valeric acid, Mephenyloin, Fosphenyloin, Oxazolidine aZone, Ethers, chemically close to antihistamines, derivatives, Paramethadione, Trimethadione, Ethadione, Orphenadrine (citrate). Other centrally acting agents, Succinimide derivatives, Ethosuximide, Phensuximide, Baclofen, Tizanidine, Pridinol, Tolperisone. Thiocolchico Mesuximide, Benzodiazepine derivatives, Clonazepam, Car side, Mephenesin, Tetrazepam, Cyclobenzaprine, Fenyrami boxamide derivatives, Carbamazepine, Oxcarbazepine, Rufi dol, Directly acting agents, Dantrolene and derivatives. Anti namide, Fatty acid derivatives, Valproic acid, Valpromide, gout active Substances; Preparations inhibiting uric acid Aminobutyric acid, Vigabatrin, Progabide, Tiagabine. Other production, Allopurinol, Tisopurine, FebuXostat, Prepara antiepileptics, Sultiame, Phenacemide, Lamotrigine, Fel tions increasing uric acid excretion, Probenecid, Sulfinpyra bamate, Topiramate, Gabapentin, Pheneturide, Levetirac Zone, Benzbromarone, Isobromindione, Preparations with no etam, Zonisamide, Pregabalin, Stiripentol, Lacosamide, Bec effect on uric acid metabolism, Colchicine, Cinchophen, lamide. Anticholinergic active Substances; Tertiary amines, Other antigout preparations, Urate oxidase. Active Sub Trihexyphenidyl, Biperiden, Metixene, Procyclidine, Profe stances affecting bone struture and mineralization; Bisphos namine, Dexetimide, Phenglutarimide, Mazaticol, Bor phonates, Etidronic acid, Clodronic acid, Pamidronic acid, naprine, Tropatepine, Ethers chemically close to antihista Alendronic acid, Tiludronic acid, Ibandronic acid, Risedronic mines, Etanautine, Orphenadrine (chloride), Ethers of tropine acid, Zoledronic acid, Bone morphogenetic proteins, Dibo or tropine derivatives, Benzatropine. Etybenzatropine. termin alfa, Eptotermin alfa, Other drugs affecting bone Dopaminergic active Substances; Dopa and dopa derivatives, structure and mineralization, Ipriflavone, Aluminium chloro Levodopa, Melevodopa, Etilevodopa, Adamantane deriva hydrate, Strontium ranelate, Quinine and derivatives, Hydro tives, Amantadine, Dopamine agonists, Bromocriptine, Per quinine, Enzymes, Chymopapain, Trypsin, Hyaluronic acid. golide, Dihydroergocryptine mesylate, Ropinirole, Prami Colecalciferol. pexole, Cabergoline, Apomorphine, Piribedil, Rotigotine, 0143 Analgesics; Opioids, Natural opium alkaloids, Mor Monoamine, oxidase B inhibitors, Selegiline, Rasagiline, phine, Opium, Hydromorphone, Nicomorphine, Oxycodone, Other dopaminergic agents, Tolcapone, Entacapone, Dihydrocodeine, Diamorphine, Papavereturn, Codeine, Phe Budipine. Antipsychotic active substances; Phenothiazines nylpiperidine derivatives, Ketobemidone, Pethidine, Fenta with aliphatic side-chain, Chlorpromazine, Levomepro nyl, Diphenylpropylamine derivatives, Dextromoramide, Pir mazine, Promazine, Acepromazine, Triflupromazine, itramide, Dextropropoxyphene, Bezitramide, Methadone, Cyamemazine, Chlorproethazine, Phenothiazines with pip US 2010/0239667 A1 Sep. 23, 2010 erazine structure, Dixyrazine, Fluphenazine, Perphenazine, Agomelatine, Desvenlafaxine, Centrally acting sympathomi Prochlorperazine, Thiopropazate, Trifluoperazine, metics, Amfetamine, Dexamfetamine, Metamfetamine, Acetophenazine. Thioproperazine, Butaperazine, Perazine, Methylphenidate, Pemoline, Fencamfamin, Modafinil, Feno Phenothiazines with piperidine structure, Periciazine. Thior Zolone, Atomoxetine, Fenetyline, Xanthine derivatives, Caf idazine, Mesoridazine, Pipotiazine, Butyrophenone deriva feine, Propentofylline. Other psychostimulants and nootro tives, Haloperidol, Trifluperidol, Melperone, Moperone, pics, Meclofenoxate, Pyritinol, Piracetam, Deanol, Fipexide, Pipamperone, Bromperidol, Benperidol, Droperidol, Flu Citicoline, Oxiracetam, Pirisudanol, Linopirdine, anisone, Indole derivatives, Oxypertine, Molindone, Sertin Nizofenone, Aniracetam, Acetylcarnitine, Idebenone, Prolin dole, Ziprasidone. Thioxanthene derivatives, Flupentixol, tane, Pipradrol, Pramiracetam, Adrafinil, Vinpocetine. Anti Clopenthixol, Chlorprothixene, Tiotixene, Zuclopenthixol, dementia active Subtances; Anticholinesterases, Tacrine, Diphenylbutylpiperidine derivatives, Fluspirilene, Pimozide, Donepezil, Rivastigmine, Galantamine. Other anti-dementia Penfluridol, Diazepines, oxazepines and thiazepines, Loxap drugs, Memantine, Ginkgo biloba. Other nervous system ine, Clozapine, Olanzapine, Quetiapine, Neuroleptics, in tar active Substances; Parasympathomimetics, Anticholinest dive dyskinesia, Tetrabenazine, Benzamides, Sulpiride, Sul erases, Neostigmine, Pyridostigmine, Distigmine, topride, Tiapride, Remoxipride, Amisulpride, Veralipride, Ambenonium, Choline esters, Carbachol, Bethanechol, Levosulpiride, Lithium. Other antipsychotics, Prothipendyl, Other parasympathomimetics, Pilocarpine, Choline alfoscer Risperidone, Clotiapine, Mosapramine, Zotepine, Aripipra ate. Active substances used in addictive disorders; Drugs used Zole, Paliperidone. Anxiolytic active substances; Benzodiaz in nicotine dependence, Nicotine, Bupropion, Varenicline, epine derivatives, Diazepam, Chlordiazepoxide, Drugs used in alcohol dependence, Disulfuram, Calcium car Medazepam, Oxazepam, Potassium cloraZepate, Lorazepam, bimide, Acamprosate, Naltrexone, Drugs used in opioid Adinazolam, Bromazepam, Clobazam, Ketazolam, dependence, Buprenorphine, Methadone, Levacetylmeth Prazepam, Alprazolam, Halazepam, Pinazepam, adol, Lofexidine. Antivertigo active subtances; Betahistine, Camazepam, Nordazepam, Fludiazepam, Ethyl loflazepate, Cinnarizine, Flunarizine, Acetylleucine, other nervous sys Etizolam, Clotiazepam, Cloxazolam, Tofisopam, Diphenyl tem drugs, Gangliosides and ganglioside derivatives, Tir methane derivatives, Hydroxyzine, Captodiame, Carbam ilazad, Riluzole, Xaliproden, Hydroxybutyric acid, Amifam ates, Meprobamate, Emylcamate, Mebutamate, Dibenzo-bi pridine. cyclo-octadiene derivatives, BenZoctamine, 0144 Active Substances against amoebiasis and other pro AZaspirodecanedione derivatives, Buspirone. Other anxiolyt toZoal diseases; Hydroxyquinoline derivatives, Broxyquino ics, Mephenoxalone, Gedocarnil, Etifoxine. Hypnotic and line, Clioquinol, Chlorquinaldol, Tilbroquinol, Nitroimida sedative active substances; Barbiturates, Pentobarbital, Zole derivatives, Metronidazole, Tinidazole, Ornidazole, Amobarbital, Butobarbital, Barbital, Aprobarbital, Secobar Azanidazole, Propenidazole, Nimorazole, Secnidazole, bital, Talbutal, Vinylbital, Vinbarbital, Cyclobarbital, Hept Dichloroacetamide derivatives, Diloxanide, Clefamide, Eto abarbital, Reposal, Methohexital, Hexobarbital. Thiopental, famide, Teclozan, Arsenic compounds, Arsthinol, Dilfetar Etallobarbital, Allobarbital, Proxibarbal, Aldehydes and Sone, Glycobiarsol, Chiniofon, Emetine, Phanquinone, derivatives, Chloral hydrate, Chloralodol, Acetylglycinamide Mepacrine, Atovaquone, Trimetrexate, TenonitroZole, Dihy chloral hydrate, Dichloralphenazone, Paraldehyde, Benzodi droemetine, Fumagillin, NitaZoxanide. Antimalarial active azepineemepronium derivatives, Flurazepam, Nitrazepam, Substances; Aminoquinolines, Chloroquine, Hydroxychloro Flunitrazepam, Estazolam, Triazolam, Lorimetazepam, quine, Primaquine, Amodiaquine, Biguanides, Proguanil, Temazepam, Midazolam, Brotizolam, Quazepam, Lopra Cycloguanil embonate, Methanolduinolines, Quinine, Zolam, Doxefazepam, Cinolazepam, Piperidinedione deriva Mefloquine, Diaminopyrimidines, Pyrimethamine, Artemisi tives, Glutethimide, Methyprylon, Pyrithyldione, Benzodiaz nin and derivatives, Artemether, Artesunate, Artemotil, epine related drugs, Zopiclone, Zolpidem, Zaleplon, Artenimol, Halofantrine. Active Substances against leishma Ramelteon, Other hypnotics and sedatives, Methaqualone, niasis and trypanosomiasis; Nitroimidazole derivatives, Ben Clomethiazole, Bromisoval, Carbromal, Scopolamine, Pro Znidazole, Antimony compounds, Meglumine antimonate, piomazine, Triclofos, Ethchlorvynol, Valerian, Hexapropy Sodium stibogluconate, Nitrofuran derivatives, Nifurtimox, mate, Bromides, Apronal, Valnoctamide, Methylpentynol, Nitrofural, Arsenic compounds, Melarsoprol, Acetarsol, Pen Niaprazine, Melatonin, Dexmedetomidine, Dipiperonylami tamidine isethionate, Suramin sodium, Eflornithine. Anti noethanol. Antidepressant active substances; Non-selective trematodal active Substances; Quinoline derivatives and monoamine reuptake inhibitors, Desipramine, Imipramine, related Substances, Praziquantel, Oxamniquine, Organophos Imipramine oxide, Clomipramine, Opipramol, Trimi phorous compounds, Metrifonate, Bithionol, Niridazole, Sti pramine, Lofepramine, Dibenzepin, Amitriptyline, Nortrip bophen, Triclabendazole. Antinematodal active Substances; tyline, Protriptyline, Doxepin, Iprindole, Melitracen, Butrip Benzimidazole derivatives, Mebendazole, Tiabendazole, tyline, DoSulepin, Amoxapine, Dimetacrine, Amineptine, Albendazole, Ciclobendazole, Flubendazole, Fenbendazole, Maprotiline, Quinupramine, Selective serotonin reuptake piperazine and derivatives, Diethylcarbamazine, Tetrahydro 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 furam, 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 US 2010/0239667 A1 Sep. 23, 2010 active substances; Pyrethrines, Cyfluthrin, Cypermethrin, ethylperazine, Methdilazine, Hydroxyethylpromethazine, Decamethrin, Tetramethrin, Diethyltoluaide, Dimeth Thiazinam, Mequitazine, Oxomemazine, Isothipendyl, pip ylphthalate, Dibutylphthalate, Dibutylsuccinate, Dimethyl erazine derivatives, Buclizine, Cyclizine, Chlorcyclizine, carbate, Etohexadiol. Meclozine, Oxatomide, Cetirizine, Levocetirizine, Bami 0145 Decongestant active substances; Sympathomimet pine, Cyproheptadine. Thenalidine, Phenindamine, AntaZo ics, Cyclopentamine, Ephedrine, Phenylephrine, Oxymeta line, Triprolidine, Pyrrobutamine, AZatadine, Astemizole, Terfenadine, Loratadine, Mebhydrolin, Deptropine, Keto Zoline, Tetry Zoline, Xylometazoline, Naphazoline, Tramazo tifen, Acrivastine, AZelastine, Tritoqualine, Ebastine, Pime line, Metizoline, Tuaminoheptane, Fenoxazoline, thixene, Epinastine, Mizolastine, Fexofenadine, Deslorata Tymazoline, Epinephrine, Cromoglicic acid, Levocabastine, dine, Rupatadine. Other respiratory system active Substances; AZelastine, Antazoline, Spaglumic acid, Thonzylamine, Lung Surfactants, Colfosceril palmitate, Natural phospholip Nedocromil, Olopatadine, Corticosteroids, Beclometasone, ids. Respiratory stimulants, Doxapram, Nikethamide, Pentet Prednisolone, Dexamethasone, Flunisolide, Budesonide, razol, Etamivan, Bemegride, Prethcamide, Almitrine, Dime Betamethasone, Tixocortol, Fluticasone, Mometasone, Tri fline, Mepixanox, Nitric oxide. amcinolone, FluticaSone furoate, Hydrocortisone, Calcium 0146. Other active substances; Antidotes, Ipecacuanha, hexamine thiocyanate, Retinol, Ipratropium bromide, Riti Nalorphine, Edetates, Pralidoxime, Prednisolone and ometan, Mupirocin, Hexamidine, Framycetin, Phenylpro promethazine. Thiosulfate, Sodium nitrite, Dimercaprol, panolamine, Pseudoephedrine, Phenylephrine. Throat active Obidoxime, Protamine, Naloxone, Methylthioninium chlo Substances; Antiseptics, AmbaZone, Dequalinium, Dichlo ride, Potassium permanganate, Physostigmine, Copper Sul robenzyl alcohol, Chlorhexidine, Cetylpyridinium, Benze fate, Potassium iodide, Amyl nitrite, Acetylcysteine, Digitalis thonium, Myristyl-benzalkonium, Chlorquinaldol, Hexylre antitoxin, Flumazenil, Methionine, 4-dimethylaminophenol, sorcinol, Acriflavinium chloride, Oxyquinoline, Povidone Cholinesterase, Prussian blue, Glutathione, Hydroxocobal iodine, Benzalkonium, Cetrimonium, Hexamidine, Phenol, amin, Fomepizole, Iron chelating agents, Deferoxamine, Antibiotics, Neomycin, Tyrothricin, Fusafungine, Bacitracin, Deferiprone, Deferasirox, Polystyrene sulfonate, Sevelamer, Gramicidin, Benzocaine, Lidocaine, Cocaine, Dyclonine. Lanthanum carbonate, Mesna, DexraZOxane, Calcium foli Active substances for obstructive airway diseases; Orciprena nate, Calcium levofolinate, Amifostine, Sodium folinate, line, Salbutamol, Terbutaline, Fenoterol, Rimiterol, Hexopre Rasburicase, Palifermin, Glucarpidase, Sodium cellulose naline, Isoetarine, Pirbuterol, Tretoquinol, Carbuterol, phosphate, DiaZoxide. Tulobuterol, Salmeterol, Formoterol, Clenbuterol, Reprot erol, Procaterol, Bitolterol, Glucocorticoids, Beclometasone, 0147 In specific embodiments, the active substance is for Budesonide, Flunisolide, Betamethasone, Fluticasone, Tri cardiac therapy including e.g. cardiac glycosides, antiar amcinolone, MometaSone, Ciclesonide, Ipratropium bro rhythmics, cardiac stimulants, vasodilators, antihyperten mide, OXitropium bromide, Stramoni preparations, Tiotro sives, diuretics, vasoprotectives, beta blockers, calcium chan pium bromide, Cromoglicic acid, Nedocromil, Fenspiride, nel blockers, agents acting on the rennin-angiotensin System, Methoxyphenamine, Bambuterol, Xanthines, Diprophylline, lipid modifying agents. Choline theophyllinate, Proxyphylline. Theophylline, Ami 0.148. In specific embodiments, the active substance is nophylline, Etamiphylline. Theobromine, Bamifylline, Ace from the therapeutic classes including antiemetics, antinau fylline piperazine, Bufylline, Doxofylline, Zafirlukast, Pran seants, antiobesity and anabolic agents. lukast, Montelukast, Ibudilast, Amlexanox, EproZinol, 0149. In specific embodiments, the active substance is Fenspiride, Omalizumab, Seratrodast, Roflumilast. Cough from the therapeutic classes including antiinflammatory and and cold active Substances; Expectorants, Tyloxapol, Potas antiinfective agents, corticosteroids, non-steroids anti-in sium iodide, Guaifenesin, Ipecacuanha, Althea root, Senega, flammatory and antirheumatic agents. Antimony pentasulfide, Creosote, Guaiacolsulfonate, Levo 0150. In specific embodiments, the active substance is verbenone. Mucolytics, Acetylcysteine, Bromhexine, Car from the therapeutic classes including decongestants, adren bocisteine, Eprazinone, Mesna, Ambroxol, Sobrerol, Domi ergics, expectorants, cough suppressant and antihistamines. odol, Letosteine, Stepronin, Tiopronin, Dornase alfa 0151. In specific embodiments, the active substance is (desoxyribonuclease), Neltenexine, Erdosteine, Opium alka from the therapeutic classes including anesthetics, analge loids and derivatives, Ethylmorphine, Hydrocodone, sics, opioids, antipyretics, antimigraine agents, antiepilep Codeine, Opium alkaloids with morphine, Normethadone, tics, anti-parkinson agents, dopaminergic agents, antipsy Noscapine, Pholcodine, Dextromethorphan, Thebacon, chotics, anxiolytics, sedatives, antidepressants, Dimemorfan, Acetyldihydrocodeine, Benzonatate, Benpro psychostimulants agents used for ADHD and nootropics, perine, Clobutinol, Isoaminile, Pentoxyverine, Oxolamine, agents used in addictive disorders. Oxeladin, Clo?edanol, Pipazetate, Bibenzonium bromide, 0152. In specific embodiments, the active substance is Butamirate, Fedrilate, Zipeprol, Dibunate, Droxypropine, from the therapeutic classes including anaesthetics, centrally Prenoxdiazine, propropizine, Cloperastine, Meprotixol, Pip acting analgesics, sedative-hypnotics, anxiolytics; appetite 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, US 2010/0239667 A1 Sep. 23, 2010

fentanyl, hydrocodone, hydromorphone, morphine, pentaZo With respect to situations where one or more active sub cine, oxycodeine, oxycodone, oxymorphone and tramadol. stances are contained in one of the layers or coat, a content of O155 The active substance can be in various forms, such about 60-80% w/w is contemplated to be the maximum con as uncharged or charged molecules, molecular complexes, tent, which still allows for a sufficient content of the polymer crystalline forms, amorphous form, polyamorphous form, and, when relevant, a pharmaceutically acceptable excipient polymorphous form, complexes, Solvates, anhydrates, if rel in the composition. The active Substance may, on the other evant isomers, enantiomers, racemic mixtures and pharma hand, be present in the composition in much smalleramounts, cologically acceptable salts such as e.g. hydrochloride, depending on the nature and potency of the active Substance hydrobromide, Sulfate, laurylate, palmitate, phosphate, in question. nitrite, nitrate, citrate, borate, acetate, maleate, tartrate, ole 0.161. A composition according to the invention contain ate, and salicylate. For acidic active Substance, salts of metals ing a drug Substance is typically for oral administration. Due e.g. alkali metal salts such as, e.g., sodium or potassium salts, to the possibility of controlling the release rate of the active alkaline earth metal salts such as, e.g., calcium and magne Substance the composition may be adapted for oral adminis sium salts, amines amino acids or organic cations, quaternary tration 1-6 times a day, normally 1-4 times daily Such as 1-3 ammoniums, can be used. Derivatives of active substances times, 1-2 times or 1 times daily. The technology may also Such as esters, ethers and amides which have solubility char provide compositions for administration only once or twice acteristics suitable for use herein can be used alone or mixed daily. In the present context the term “once daily' is intended with other drugs. After release of the derivative from the drug to mean that it is only necessary to administer the pharma delivery system it may be converted by enzymes, hydrolysed ceutical composition once a day in order to obtain a Suitable by body pH or other metabolic processes to the parent drug or therapeutic and/or prophylactic response; however, any to another biologically active form. administration may comprise co-administration of more than 0156 A pharmaceutical composition of the invention may one dosage unit, such as, e.g. 2-4 dosage units if the amount in addition be suitable for the delivery of peptides, polypep of active Substance required may not be formulated in only tides or proteins, for example hormones, enzymes Such as one composition or if a composition of a smaller size is lipases, proteases, carbohydrates, amylases, lactoferrin, lac preferred. toperoxidases, lysozymes, nanoparticles, etc., and antibod 0162 The dosage of the active substance depends on the ies. The composition may also be employed for the delivery particular substance, the age, weight condition etc. of the of microorganisms, either living, attenuated or dead, for human oranimal that will be treated with the composition etc. example bacteria, e.g. gastrointestinal bacteria such as strep All such factors are well known to a person skilled in the art. tococci, e.g. S. faecium, Bacillus spp. Such as B. subtilis and (0163 Stability B. lichenifonnis, lactobacteria, Aspergillus spp., bifidogenic factors, or viruses such as indigenous vira, enterovira, bacte 0164. With respect to the fixed-dosed combination formu riophages, e.g. as vaccines, and fungi such as baker's yeast, lation stability is employed to encompass one or more of the Saccharomyces cerevisiae and fungi imperfecti. following: O157. In an embodiment of the invention, the active sub 0.165. 1) Stability with respect to the physical stability stance is a pharmaceutically active powder. The powder typi of the composition (appearance, color, strength, etc.) cally has a particle size of from about 0.1 um to about 500 um, 0166 2) Stability with respect to in vitro dissolution typically from about 0.5 um to about 300 um, more typically behavior of the active substance from the composition from about 1 um to about 200 um, especially from about 5um (0167 Stability of the individual components: to about 100 Lum. 0168 3) Stability with respect to the chemical stability 0158. In an embodiment of the invention, the active sub of the active substance (degradation of the active sub stance is a pharmaceutically active crystal. The crystal typi stance to other—normally—unwanted products) cally has a particle size of from about 0.1 um to about 1000 (0169. 4) Stability with respect to the form the active um Such as, e.g., about 0.1 um to about 750 um, about 0.1 um Substance has in the composition; if the active Substance to about 500 um, typically from about 0.5 um to about 500 is dissolved (molecularly dispersed) in the polymeras a um, more typically from about 1 um to about 500 um, espe Solid dispersion. In such cases precipitation or otherwise cially from about 5 um to about 500 um. formation of crystals of the active Substance in the com 0159. In another embodiment of the invention, a compo position is an indication of a stability problem. sition comprises active Substance that at least partially is 0170 5) Physical and chemical stability of the pharma present in amorphous form with a mean particle size of at ceutically acceptable polymer and excipients employed least about 0.01 um Such as, e.g., from about 0.01 um to about 500 um, from about 0.05um to about 500 um, from about 0.1 0171 In particular, the active substance or substances um to about 500 um, from about 0.5 um to about 500 um, maybe stabilized in the dosage form in its amorphous form. about 1 um to about 500 um, typically from about 0.5um to The amorphous state and/or the solid dispersion is stabilized about 300 um, more typically from about 1 um to about 200 either by a very careful choice of the concentration of the um, especially from about 1 um to about 100 um. active Substance in the composition and/or by addition of 0160 The at least one therapeutically, prophylactically Suitable stabilizing agents acting by stabilizing one or more of and/or diagnostically and/or biologically active Substance the conditions mentioned above under items 1) to 5). will suitably be present in an amount of up to about 80%, 0172. In regards to condition 4) the stability may be typically up to about 70%, up to about 60% or up to about retrieved by several mechanisms of which the most important 50%, such as, e.g., from 0.1% to 80%, such as from 0.25% to a 75%, such as from 0.5% to 60%, such as from 0.75% to 50%, 0173 a) Physical stabilization by decreasing the such as from 1% to 40%, such as from 1.5% to 35%, such as molecular mobility of the components, i.e. Suitable from 1.75% to 30% by weight of the composition or layer. excipients and the active Substance of the formulation US 2010/0239667 A1 Sep. 23, 2010

0.174 b) Chemical stabilization by increasing the appar exchange resins, citrus pulp, Veegum, glycolate, natural ent solubility of the active substance in the matrix for sponge, bentonite. Sucralfate, calcium hydroxyl-apatite or mulation. mixtures thereof, effervescent agents (carbonate release) 0175 Thus a stabilizing agent may serve more than one Such as citric acid, anhydrous, citric acid, monohydrate, dex purpose, it may stabilize the amorphous state of the active trates, fumaric acid, potassium bicarbonate, sodium bicar Substance in the composition in order to avoid, reduce or bonate, Sodium citrate, dehydrate, tartaric acid or mixtures delay any recrystallization, it may stabilize the active Sub thereof. stance or other ingredients towards proteolytic or oxidative 0181 Furthermore, the composition may comprise one or degradation or it may have an anti-plasticizing effect. more agents selected from the group consisting of Sweetening 0176 A stabilizing agent may also contribute to an improved solubility of the active substance. Without being agents, flavouring agents and colouring agents, in order to bound to any theory it may be assumed that the stabilizing provide an elegant and palatable preparation. Examples are agent together with the polyethylene glycol and/or polyeth maltol, citric acid, water soluble FD&C dyes and mixtures ylene oxide represent the dispersion medium wherein the thereof with corresponding lakes and direct compression Sug solubility of the active substance may be higher than in the ars such as Di-Pac from Amstar. In addition, coloured dye polyethylene glycol and/or polyethylene oxide alone. The migration inhibitors such as tragacanth, acacia or attapulgite same may apply with respect to the stability of the amorphous talc may be added. Specific examples include Calcium car form of the active substance. bonate, 1,3,5-trihydroxybenzene, Chromium-cobalt-alu 0177 Pharmaceutically Acceptable Excipients minium oxide, ferric ferrocyanide, Ferric oxide, Iron ammo 0.178 The composition may also contain other excipients nium citrate, Iron (III) oxide hydrated, Iron oxides, Carmine as well, e.g. in order to improve the technical properties of the red, Magnesium carbonate and Titanium dioxide. composition so that it may be easier to produce or in order to 0182 Plasticizer may be incorporated in the composition. improve the properties of the composition Such as release rate A Suitable plasticizer is selected from Such as e.g. mono- and of the active substance, stability of the active substance or of di-acetylated monoglycerides, diacetylated monoglycerides, the composition itself etc. acetylated hydrogenated cottonseed glyceride, glyceryl 0179 A suitable pharmaceutically acceptable excipient cocoate, Polyethylene glycols or polyethylene oxides (e.g. for use in a composition of the invention may be selected from with a molecular weight of about 1,000-500,000 daltons), the group consisting of fillers, diluents, disintegrants, dipropylene glycol salicylate glycerin, fatty acids and esters, glidants, pH-adjusting agents, Viscosity adjusting agents, phthalate esters, phosphate esters, amides, diocyl phthalate, solubility increasing or decreasing agents, osmotically active phthalylglycolate, mineral oils, hydrogenated vegetable oils, agents and solvents. Vegetable oils, acetylated hydrogenated Soybean oil glycer 0180 Suitable excipients include conventional tablet or ides, Castor oil, acetyl tributyl citrate, acetyl triethylcitrate, capsule excipients. These excipients may be, for example, methyl abietate, nitrobenzene, carbon disulfide, 13-naphtyl diluents such as dicalcium phosphate, calcium sulfate, lactose salicylate, sorbitol, sorbitol glyceryl tricitrate, fatty alcohols, or Sucrose or other disaccharides, cellulose, cellulose deriva cetostearyl alcohol, cetyl alcohol, Stearyl alcohol, oleyl alco tives, kaolin, mannitol, dry starch, glucose or other monosac hol, myristyl alcohol. Sucrose octaacetate, alfa-tocopheryl charides, dextrin or other polysaccharides, Sorbitol, inositol polyethylene glycol succinate (TPGS), tocopheryl derivative, or mixtures thereof binders such as alginic acid, calcium diacetylated monoglycerides, diethylene glycol monostear alginate, Sodium alginate, starch, gelatin, Saccharides (in ate, ethylene glycol monostearate, glyceryl monooleate, cluding glucose, Sucrose, dextrose and lactose), molasses, glyceryl monostearate, propylene glycol monostearate, mac panwar gum, ghatti gum, mucilage ofisapolhusk, carboxym rogol esters, macrogol Stearate 400, macrogol Stearate 2000, ethylcellulose, methylcellulose, Veegum, larch arabolactan, polyoxyethylene 50 Stearate, macrogol ethers, cetomacrogol polyethylene glycols, ethylcellulose, water, alcohols, waxes, 1000, lauromacrogols, nonoxinols, octocinols, tyloxapol, polyvinylpyrrolidone such as, e.g., PVP K90 or mixtures poloxamers, polyvinyl alcohols, polysorbate 20, polysorbate thereof: lubricants such as talc, silicium dioxide, magnesium 40, polysorbate 60, polysorbate 65, polysorbate 80, polysor Stearate, calcium Stearate, Stearic acid, hydrogenated veg bate 85, sorbitan monolaurate, sorbitan monooleate, sorbitan etable oils, Sodium benzoate, Sodium chloride, leucine, car monopalmitate, Sorbitan monostearate, Sorbitan sesqui bowax 4000, magnesium laurylsulfate, Sodium laurilsulfate, oleate, Sorbitan trioleate, Sorbitan tristearate and Sucrose Stearyl alcohol, Polysorbate 20, Polysorbate 60, Polysorbate esters, amyl oleate, butyl oleate, butyl stearate, diethylene 80, Macrogol stearate, Macrogol lauryl ether, Stearoyl mac glycol monolaurate, glycerol tributyrate, Cumar W-1, Cumar rogolglycerides, Sorbitan Stearate, Sorbitan laurate, Mac MH-1, Cumar V-1, Flexol B-400, monomeric polyethylene rogol glycerol hydroxyStearat, colloidal silicon dioxide and ester, Piccolastic A-5, Piccalastic A-25, Beckolin, Clorafin mixtures thereof, disintegrants such as starches, clays, cellu 40, acetyl tributyl citrate, acetyl triethyl citrate, benzyl ben lose derivatives including microcrystalline cellulose, methyl Zoate, butoxyethyl Stearate, butyl and glycol esters of fatty cellulose, carboxymethylcellulose calcium, carboxymethyl acids, butyl diglycol carbonate, butyl ricinoleate, butyl cellulose sodium, cellulose, crosscarmellose sodium, gums, phthalyl butyl glycolate, camphor, dibutyl sebacate, dibutyl aligns, various combinations of hydrogencarbonates with tartrate, diphenyl oxide, glycerine, HB-40, hydrogenated weak acids (e.g. sodium hydrogencarbonate/tartaric acid or methyl ester of rosin, methoxyethyl oleate, monoamylphtha citric acid) crosprovidone, sodium starch glycolate, agar, alg late, Nevillac 10, Paracril 26, technical hydroabietyl alcohol, inic acid, calcium alginate, sodium alginate, chitosan, colloi triethylene glycol dipelargonate, Solid aliphatic alcohols, dal silicon dioxide, docusate Sodium, guar gum, low-substi nitrobenzene, carbon disulfide, B-naphtyl salicylate, phthalyl tuted hydroxypropyl cellulose, hydroxypropyl Starch, glycolate, dioctyl phthalate, and mixtures thereof. Other suit magnesium aluminium silicate, polacrilin potassium, povi able plasticizers appear from EP-B-0 746 310 to which ref done, Sodium starch glycolate, pregelatinized Starch, cation erence is made. US 2010/0239667 A1 Sep. 23, 2010

0183 The use of a plasticizer will often be desirable in acid, citric acid, tartaric acid, acrylic acid, benzoic acid, malic order to improve the processibility of the coating. The plas acid, maleic acid, Sorbic acid etc., aspartic acid, glutamic acid ticizer may also be a non-ionic Surfactant, e.g. a non-ionic etc. Surfactant as the one mentioned above. 0188 Examples of suitable organic acids include acetic 0184 Preferred stabilizers (chemical) include TPG e.g. in acid/ethanoic acid, adipic acid, angelic acid, ascorbic acid/ the form of TPGS due to surfactant properties, BHA, BHT, Vitamin C, carbamic acid, cinnamic acid, citramalic acid, t-butyl hydroquinone, calcium ascorbate, gallic acid, hydro formic acid, fumaric acid, gallic acid, gentisic acid, gluta quinone, maltol, octyl gallate, Sodium bisulfite, Sodium met conic acid, glutaric acid, glyceric acid, glycolic acid, glyoxy abisulfite, tocopherol and derivates thereof, citric acid, tar lic acid, lactic acid, leVulinic acid, malonic acid, mandelic taric acid, and ascorbic acid. Other stabilisers include acid, oxalic acid, oxamic acid, pimelic acid, and pyruvic acid. trivalent phosphorous like e.g. phosphite, phenolic antioxi 0189 Examples of suitable inorganic acids include pyro dants, hydroxylamines, lactones such as Substituted benzo phosphoric, glycerophosphoric, phosphoric Such as ortho and furanones. Hindered phenols, thiosynergists and/or hindered metaphosphoric, boric acid, hydrochloric acid, and Sulfuric amines, acids (ascorbic acid, erythorbic acid, etidronic acid, acid. hypophosphorous acid, nordihydroguaiaretic acid, propionic 0190. Examples of suitable inorganic compounds include acid etc.), phenols, dodecyl gallate, octyl gallate, 1,3,5-trihy aluminium. droxybenzene, organic and inorganic salts (calcium ascor 0191 Examples of organic bases are p-nitrophenol, suc bate, Sodium ascorbate, Sodium bisulphite, Sodium met cinimide, benzenesulfonamide, 2-hydroxy-2cyclohexenone, abisulfite, Sodium Sulfite, potassium bisulphite, potassium imidazole, pyrrole, diethanolamine, ethyleneamine, tris (hy metabisulphite), esters (calcium ascorbate, dilauryl thio droxymethyl)aminomethane, hydroxylamine and derivates dipropionate, dimyristyl thiodipropionate, distearyl thio of amines, sodium citrate, aniline, hydrazine. dipropionate), pyranon (maltol), and vitamin E (tocopherol, 0.192 Examples of inorganic bases include aluminium D-O-tocopherol, DL-C-tocopherol, tocopheryl acetate, d-C.- oxide Such as, e.g., aluminium oxide trihydrate, alumina, tocopheryl acetate, dl-C-tocopheryl acetate. However, other Sodium hydroxide, potassium hydroxide, calcium carbonate, anti-oxidative agents known in the art may be used according ammonium carbonate, ammonium hydroxide, KOH and the to the present invention. Other suitable stabilizer is selected like. from Such as e.g. Sorbitol glyceryl tricitrate. Sucrose octaac 0193 Suitable pharmaceutically acceptable salts of an etate. organic acid is e.g. an alkali metal salt or an alkaline earth 0185. Modifier may be incorporated in the composition. A metal salt Such as, e.g. sodium phosphate, Sodium dihydro Suitable modifier is selected from Such as e.g. fatty acids and genphosphate, disodium hydrogenphosphate etc., potassium esters, fatty alcohols, cetyl alcohol, Stearyl alcohol, mineral phosphate, potassium dihydrogenphosphate, potassium oils, hydrogenated vegetable oils, vegetable oils, acetylated hydrogenphosphate etc., calcium phosphate, dicalcium phos hydrogenated soybean oil glycerides, Castor oil, phosphate phate etc., sodium sulfate, potassium sulfate, calcium sulfate, esters, amides, phthalate esters, glyceryl cocoate oleyl alco Sodium carbonate, Sodium hydrogencarbonate, potassium hol, myristyl alcohol. Sucrose octaacetate, diacetylated carbonate, potassium hydrogencarbonate, calcium carbonate, monoglycerides, diethylene glycol monostearate, ethylene magnesium carbonate etc., Sodium acetate, potassium glycol monostearate, glyceryl monooleate, glyceryl acetate, calcium acetate, Sodium Succinate, potassium Succi monostearate, propylene glycol monostearate, macrogol nate, calcium Succinate, Sodium citrate, potassium citrate, esters, macrogol Stearate 400, macrogol Stearate 2000, poly calcium citrate, sodium tartrate, potassium tartrate, calcium oxyethylene 50 Stearate, macrogol ethers, cetomacrogol tartrate etc. 1000, lauromacrogols, poloxamers, polyvinyl alcohols, Sor 0.194. A suitable inorganic salt for use in a matrix compo bitan monolaurate, Sorbitan monooleate, Sorbitan mono sition of the invention is sodium chloride, potassium chloride, palmitate, Sorbitan monostearate, Sorbitan sesquioleate, Sor calcium chloride, magnesium chloride etc. bitan trioleate, sorbitan tristearate, ethylcellulose, cellulose 0.195 Saccharides such as glucose, ribose, arabinose, acetate, cellulose propionate, cellulose nitrate, cellulose Xylose, lyxose, Xylol, allose, altrose, inosito, glucose, Sorbi derivative selected from the group consisting of methylcellu tol, mannose, gulose, Glycerol, idose, galactose, talose, man lose, carboxymethylcellulose and salts thereof, cellulose nitol, erythritol, ribitol, xylitol, maltitol, isomalt, lactitol, acetate phthalate, microcrystalline cellulose, ethylhydroxy Sucrose, fructose, lactose, dextrin, dextran, amylose, Xylan. ethylcellulose, ethylmethylcellulose, hydroxyethylcellulose, 0196. Polyethylene glycol derivatives such as e.g. poly hydroxyethylmethylcellulose, hydroxypropylcellulose, ethylene glycol di(2-ethyl hexoate), polyethylene glycols hydroxypropylmethylcellulose, hydroxymethylcellulose and (200-600 daltons) or polyethylene oxides, e.g. with a molecu hydroxymethylpropylcellulose, cellulose acetate, polylactic lar weight of about 800-500,000 daltons, typically about acid or polyglycolic acid and copolymers thereof, methacry 1,000-100,000 daltons, more typically 1,000-50,000 daltons, 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. 0186. Other suitable modifier may be selected from the 0.197 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 0187. 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. US 2010/0239667 A1 Sep. 23, 2010 20

0198 Preparation of a Composition of the Present Inven together with the active substance and the conversion from tion the crystalline state to the amorphous state requires addition 0199. A composition of the invention may be produced by of energy (heating). various methods which are either known perse in the phar 0208 Normally, when preparing a composition according maceutical industry or which, for example, are used in the to the invention heating is employed for e.g. an injection production of polymer-based materials, depending upon the moulding process. During heating it has been observed that desired embodiment and the materials employed in the com PEO in various qualities forms free radicals that results in the position in question. One advantage of the composition formation of interalia formaldehyde and formic acid. These according to the invention is that it may be produced by products may often lead to further degradation e.g. of the methods, which are relatively simple and inexpensive. active Substance present in the composition and it is therefore 0200 Suitable preparation methods for compositions necessary to take the necessary precautions in this respect. according to the invention include extrusion, injection moul Oxidative free radicals degradation by hydroperoxides can be ding, tabletting, capsule filling, thermoforming, spray coat catalysed by certain transition metal ions, especially those of ing, micro encapsulation and other methods Suitable for copper, cobalt and manganese. Thus, employment of PEO preparation of controlled release compositions. qualities devoid of or only containing a very small amount of 0201 Compositions according to the invention may be Such transition metal ions may improve stability. Another prepared in numerous ways giving rise to different release possibility is to use component in a quality that ensures that mechanisms. Particularly the composition may be prepared free radicals formed, if any, do not significantly increase the by 1, 2 or multiple component injection mouldings, by con degradation of the active Substance in the composition. Such ventional tablet compression, by tablet compression and a quality could e.g. be a quality containing an antioxidant that afterward temperature curing, by micro encapsulation, by 1, 2 functions by preventing the formation of free radical during or multiple component extrusions, by capsule filling or by heating or by Scavenging any free radicals formed. Another thermoforming. In cases were a preparation is needed in order possibility is to add such antioxidant to the formulation to make the controlled release properties before/after the before any heating takes place. above mentions preparation steps, the preparation may also 0209. A composition according to the invention may comprise separate steps as for example wet granulation, dry therefore further comprise one or more antioxidants that granulation, melt granulation, pelletizing, roller compaction, inhibits the formation of peroxides and/or inactivates any spray coating, electrostatic coating or other forms of con peroxides present. trolled release preparation methods. 0210 Suitable antioxidants for use includes beta-caroten 0202 In a particular example the composition is prepared (a vitamin A precursor), ascorbic acid, ascorbyl palmitate, by two/three component injection moulding of a matrix and a butylated hydroxyanisole, butylated hydroxytoluene, hypo coat partly covering the matrix and exposing two ends of the phosphorous acid, monothioglycerol, potassium met composition for erosion governed release. abisulfite, Sodium metabisulfite, propyl gallate, Sodium form 0203 During the injection moulding process it is possible aldehyde sulfoxylate, sodium thiosulfate, sulfur dioxide, to place separately prepared components and include these in tocopherol, tocopherol acetate, tocopherol hemisuccinate, the final product by insert-moulding or similar methods. Fur TPGS or other tocopherol derivatives, sulfides, phosphine ther separately prepared components from injection mould etc. Other suitable antioxidants are described herein. ing or other processes e.g. tablets, pellets etc. can be 0211. It is believed that the amorphous state of the active assembled in a separate, automated assembly process. Substance is furthermore favoured by the processing proce 0204. A composition may also be produced by, for dures of the preparation of the product according to the example, injection moulding, co-extrusion of the coating present invention, which in a preferred embodiment involves with the matrix composition and the active Substance, extru injection moulding of the pharmaceutical units. sion and dip coating, injection moulding and dip coating, or 0212 For further details reference is made to the experi by extrusion or injection moulding and solvent coating by mental section herein. spraying or dipping, electrostatic coating. Multiple compo 0213. Other Specific Embodiments of the Invention nent injection moulding, or a combination of these methods. 0214. In the following is described various embodiments 0205 The injection moulding technique have the advan of the present invention. These embodiments illustrate the tage of simultaneous mixing and heating the components flexibility of the technology to obtain different release pat during increased pressure in a one step procedure without terns and the flexibility with respect to including two or more, exposure to air and moisture because the injection moulding the same or different, active Substances in a composition of is performed in a single closed compartment from the time the the invention in order to obtain a composition that releases the blend has entered the machine to the final pharmaceutical active Substance in a different manner dependent on in which units are ejected ready for packaging. layer the active Substance is present. Accordingly, a compo 0206. In a further aspect of the invention, the blending sition of the present invention can be designed to have release process may be followed by an extrusion step for obtaining properties including burst release (very fast release of Sub pellets suitable for feeding of the injection moulding stantially the whole content in that part of the composition), machines. The extruding step may secure a more intimate controlled release (typically prolonged or extended release), blending and thereby higher reproducibility of the final phar delayed release (i.e. release only after a certain lag time) and maceutical product. immediate release (relatively fast release). Thus, the follow 0207. It should also be mentioned that the present technol ing types can be obtained: ogy also can be applied when it is desired to have an amor 0215. If only one active substance is present in the com phous form of the active Substance in the composition, position: because the most convenient process for the preparation of a 0216 Delayed release immediate release composition of the invention involves heating of the polymer 0217 Delayed release—controlled release US 2010/0239667 A1 Sep. 23, 2010 21

0218 Burst release—delayed release immediate release 0246 A third componentp mayy also be ppresent comprisinpr1S1ng 0219 Burst release—delayed release—controlled release 0247 a) a polymer or a mixture of polymers, 0220 Burst release immediate release 0248 b) optionally, one or more pharmaceutically 0221 Burst release—controlled release acceptable excipients. 0222 Controlled release Immediate release 0249 Due to the nature of the composition of the inven 0223 Controlled release—controlled release tion, it is possible to obtain a Substantially controlled pulsa tile?burst release, optionally in combination with a constant 0224. If e.g. two different active substances (S1 and S2) rate of release of the active substance over a specific period of are present, the following can be designed: time. The amount of drug release corresponds to the dosage 0225 Delayed release for S1, but controlled release for necessary for the treatment in question, so that adherence to a S2 immediate release for S1 strict dosage regimen, e.g. requiring administration of a drug 0226 Delayed release for S1, but controlled release for at set intervals up to several times a day, may be dispensed S2—controlled release for S1 with. It is possible to combine two or more active substances 0227 Burst release for S1 and/or S2 delayed release for each following and independent release pattern however the S1, but controlled release for S2 immediate release S1 release pattern of Such Substances may also be identical. 0228 Burst release for S1 and/or S2 delayed release for 0250. The matrix of the outer layer of a pharmaceutical S1, but controlled release for S2-controlled release for S1. composition of the invention may be designed to release an 0229 Burst release for S1 and/or S2 immediate release active Substance, if any, in a controlled manner Such as by a for S1 and/or S2 Zero order release mechanism. Accordingly, the composition 0230 Burst release for S1 and/or S2 controlled release is also suitable for controlled release of an active substance, for S1 and/or S2 from multiple units i.e. first a controlled release of an active substance (from the 0231 Controlled release for S1 and/or S2 Immediate matrix, layer B) and then a relatively fast release of the same release for S1 and/or S2 or different active substance (from the Layer A) or other suitable release combinations. In the present context the term 0232 Controlled release for S1 and/or S2-controlled “controlled release' is used to designate a release a desired release for S1 and/or S2 from multiple units rate during a predetermined release period. Terms like “modi 0233. A person skilled in the art will know how to obtain fied”, “delayed, “sustained”, “prolonged”, “extended” etc. other combinations in view of the guidelines given herein. release are in the present context synonyms to the term “con 0234. In a specific embodiment, the present invention pro trolled release'. Normally, the term relates to compositions vides a composition for controlled delivery of at least one that have a slower release of the active ingredient than that of active substance. It is possible to include two or more differ a plain tablet or a tablet designed for immediate release. A ent active Substances in the composition of the invention, person skilled in the art knows of these terms. adapted to enable release at different concentrations, intervals 0251. In order to more detailed explain the invention; ref and/or release rates. erence is made to (EP 0406315, EP 0493513, WO 2006/ 0235 Apart from the content of an active substance in the 128471) herein although the invention is not limited to this inner layer, the same and/or a different active substance (sec type and shape of the composition. However, the general idea ond active Substance) can be substantially homogeneously is to have a layered composition, wherein the layers are sepa dispersed in the outer layer (the polymer matrix), in which rate layers. case a substantially Zero order release of the second active 0252) However, a person skilled in the art will understand substance is obtained. Alternatively or in addition, a burst that other forms may fulfil the same objective. The most release of the same or a different active substance may be simplified versions of the pharmaceutical composition obtained in a composition of the invention which comprises according to the invention are either a sphere or an oval alternating layers. In a composition comprising alternating shaped first fraction Surrounded by a sphere oran oval shaped layers, the alternating layers may comprise, respectively, second fraction, reference is made to (EP 0406315, EP none, one, two or more different active Substances. 0493513, WO 2006/128471). 0236. As described in detail above, an inner layer com 0253. In one embodiment of the invention a double burst prises a quick release function obtained by e.g. fast disinte unit is presented by having a layered composition placed gration, exploding and/or effervescent effects. The first frac inside an immediate release tablet matrix in Such a way that tion comprises the outer matrix is eroded or disintegrated, exposing the lay 0237 a) a disintegration agent, an exploding agent, an ered composition, as shown in FIG. 1. effervescent agent or a mixture thereof 0254. In one embodiment of the invention, the inner layer 0238 b) optionally, an active substance of a composition according to the invention comprises an 0239 c) optionally, multiple units comprising an active active substance. The release of the active substance is Substance and, delayed because the outer layer must erode before the first 0240 d) optionally, one or more pharmaceutically fraction is exposed to the gastrointestinal fluids after oral acceptable excipients administration. 0241 The outer layers (matrix compositions) comprise 0255. In one embodiment of the invention it is possible to obtain a substantially controlled burst release, optionally in 0242 a) a polymer or a mixture of polymers, combination with a constant rate of release over a specific 0243 b) optionally, an active substance and, period of time. It is possible to combine two or more active 0244 c) optionally, multiple units comprising an active Substances each following and independent release pattern Substance and, however the release pattern of Such substances may also be 0245 d) optionally, one or more pharmaceutically identical. It may in certain cases be desirable to incorporate a acceptable excipients. mixture of two active substances into the matrix in order to US 2010/0239667 A1 Sep. 23, 2010

release both active substances in the matrix with the same 0261 5. A burst release layer B): release rate. In other cases it is desirable to have different release rates of the two active Substances. In such cases the composition may be composed of two different matrixes, each with different release characteristics. In yet another case Ingredient % Wiw the release of the active Substances may be sequential. Such that during the initial dissolution phase one active Substance PEO 100 OOO 5 S1 is released and then the other S2. In this case the second Poloxamer 188 5 release is onset after a lag defined by the first release. Maltitol 15 0256 More specifically, without limiting the invention Active substance 75 thereto, the invention is illustrated by the embodiments men tioned below. Various different formulations of layers A) and B) are given and any combination of layers A) and B) is 0262 6. A controlled release layer B): contemplated (i.e. any of the layer B) of 1, 2, 5-9 may be combined with any of layer A) 3, 4, 10-14, and the multiple unit formulations 15 or 16 may be part of either layer A) or B), Ingredient % Wiw and the coat formulations 17 or 18 may be applied to any of the combined formulations): E. 2OO 's s 0257 1. A burst release layer B) or multiple units: syst 10 Active substance 40

Ingredient % Wiw 0263 7. A controlled release layer B): Homopolymer (e.g. 20,000-100,000 daltons 5-70 PEO) Co-polymer (e.g. 1,000-16,000 daltons 5-70 Poloxamer) Ingredient % Wiw Active Substance O. 1-80 Filler Up to 100% PEO SOOOOO 2O Poloxamer 407 50 Mannitol 2 0258 2. A controlled release layer B) or multiple units: Active substance 28

Ingredient % Wiw 0264 8. A controlled release layer B): Homopolymer (e.g. 100,000-700,000 daltons 5-70 PEO) Co-polymer (e.g. 1,000-30,000 daltons 5-70 Ingredient % Wiw Poloxamer) Active Substance O. 1-80 0. PEO 700 OOO 2O Filler Up to 100% Poloxamer 407 50 Sorbitol 2 0259) 3. A burst release inner layer A): ActiveCWESS8iCo subst 28

Ingredient % Wiw 0265 9. A controlled release layer B): Homopolymer (e.g. 1,000-16,000 daltons 5-70 PEO) Co-polymer (e.g. 2,000-30,000 daltons 5-70 Ingredient % Wiw Poloxamer) Swelling agent S-80% PEO 100 OOO 52 Active Substance O. 1-80 Poloxamer188 10 Filler Up to 100% Eudragit RL 10 Active substance 28 0260 4. A burst release inner layer A): 0266 10. A burst release inner layer A):

Ingredient % Wiw Homopolymer (e.g. 1,000-16,000 daltons 5-70 Ingredient 0.% ww PEO) Croscarmellose 2O Co-polymer (e.g. 2,000-30,000 daltons 5-70 Lactose 2O Poloxamer) PEO 100 OOO 5 Effervescent agent S-80% Poloxamer 188 5 Active Substance O. 1-80 Active substance 50 Filler Up to 100% US 2010/0239667 A1 Sep. 23, 2010

0267 11. A burst release inner layer A): 0273) 17. Controlled release multiple units coated with Eudragit RL30D/RS 30D:

Ingredient % Wiw Ingredient % Wiw Starch 2O Lactose 2O PEO 100 OOO 5 PEG 1500 5 Poloxamer 188 5 Poloxamer 188 5 Povidone 2O Active Substance 50 Active substance 70

0268 12. A burst release inner layer A): 0274 18. Coat with a solid content of 20%

Ingredient % Wiw

PEO 1 OOOOO 5 Ingredient % Wiw Poloxamer 188 5 Eudragit RL30D 3.9 Citric Acid 10 Eudragit RS 30D 35.3 NaHCO 10 Talc 5.9 Active Substance 70 Triethyl citrate 2.33 Water 52.5 0269 13. A burst release inner layer A): 0275. In the appended FIGS. 15-24 are given release pro files obtainable by compositions of the present invention. Ingredient % Wiw 0276. Other specific embodiments are listed in the follow 1ng: PEO 1 OOOOO 5 0277 1. A layered pharmaceutical composition compris Poloxamer 188 5 Povidone 2 1ng Citric Acid 1O 0278 A) a solid inner layer comprising NaHCO 10 0279 i) a substantially water soluble and/or crystalline Active Substance 68 polymer or a mixture of substantially water soluble and/or crystalline polymers, the polymer being a polyglycol in the 0270 14. A burst release inner layer A): from of one of a) a homopolymer having a MW of at the most about 16,000 daltons, and b) a copolymer having a MW of at the most about 30,000 daltons, and 0280 ii) an active substance, Ingredient % Wiw 0281 the solid inner core being sandwiched between two PEO 1 OOOOO 5 outer layers B1 and B2), each outer layer comprising Poloxamer 188 5 Povidone 2 0282 iii) a substantially water soluble and/or crystalline Citric Acid 10 polymer or a mixture of substantially water soluble and/or NaHCO 10 crystalline polymers, the polymer being a polyglycol in the Active Substance 68 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 0271 15. Burst release multiple units: least about 2,000 daltons, 0283 and i) of layer Abeing different from iii) of layer B. 0284 the layered composition being coated with a coating C) that has at least one opening exposing at least one Surface Ingredient % Wiw of said outer layer, the coating being Substantially insoluble in PEO 1 OOOOO 5 and impermeable to fluids and comprising a polymer. Poloxamer 188 5 0285 2. A composition according to item 1, wherein A) Povidone 2O further comprises one or more disintegration/exploding Active Substance 70 agents, one of more effervescent agents or a mixture thereof. 0286 3. A composition according to item 2, wherein the 0272 16. Controlled release multiple units: disintegrant/exploding is Sodium starch glycolate, Povidone, Sodium alginate, Alginic acid, Calcium alginate, Carboxym ethylcellulose calcium, Carboxymethylcellulose sodium, Powdered cellulose, Chitosan, Croscarmellose sodium, Ingredient % Wiw Crospovidone, Hydroxypropyl starch, Hydroxypropyl cellu PEO 1 OOOOO 5 lose low-substituted, Magnesium aluminium silicate, Meth Poloxamer 407 15 Ethylcellulose 70 ylcellulose, Microcrystalline cellulose, pregelatinized starch, Active Substance 10 Docusae sodium, Guar gum, Polacrilin potassium or the like. 0287. 4. A composition according to item 2, wherein the effervescent agent is Effer-Soda, Citric acid, Citric acid, US 2010/0239667 A1 Sep. 23, 2010 24 monohydrate, Dextrates, Fumaric acid, Potassium bicarbon 0302 18. A composition according to any of the preceding ate, Sodium bicarbonate, Sodium citrate dehydrate, Tartaric items, wherein the concentration of the one or more efferves acid or the like. cent agent, if present, is from about 5% w/w to about 80% 0288 5. A composition according to any of the preceding w/w such as, e.g., from about 10% w/w to about 70% w/w, items, wherein the outer layer B1 and/or B2 when exposed to from about 15% w/w to about 60% w/w or from about 20% an aqueous medium erodes at a Substantially constant rate. w/w to about 50% w/w. 0289 6. A composition according to any of the preceding (0303. Outer Layer items, wherein the active Substance in A) is Subject to release 0304. 19. A composition according to any of the preceding after a lag time corresponding to the erosion time of the layer items, wherein polymer iii) comprises one or more of a poly B1 and/or B2. ethylene glycol, a polyethylene oxide and/or a copolymer of 0290 7. A composition according to any of the preceding ethylene oxide and propylene oxide including poly(ethylene items, wherein the inner layer A) without B) and C) disinte glycol-b-(DL-lactic acid-co-glycolic acid)-b-ethylene glycol grates within at the most 60 min Such as, e.g., at the most (PEG-PLGA PEG), poly((DL-lactic acid-co-glycolic acid)- about 30 minor at the most about 15 min, when subjected to g-ethylene glycol) (PLGA-g-PEG), and polyethylene oxide a disintegration test according to Ph. Eur. polypropylene oxide (PEO-PPO). 0291 8. A composition according to any of the preceding 0305 20. A composition according to item 19, wherein the items having a cylindrical shape optionally with one or more polyethylene glycol or a polyethylene oxide has a molecular tapered ends. weight from about 100,000 to about 700,000. 0292 9. A composition according to any of the preceding 0306 21. A composition according to item 19, wherein the items, wherein the coating C) appears as a Substantially intact copolymer of ethylene oxide and propylene oxide comprises empty shell when the composition has been Subjected to a up to about 30% w/w of the propylene oxide based block, and dissolution test according to Ph. Eur, by which the outer layer has a molecular weight of from about 5,000 to about 15,000 B) erodes and the inner layer A) disappears from the compo daltons. sition optionally by means of one or more disintegration 0307 22. A composition according to any of the preceding agents, explosion agents, effervescent agents or a mixture items, wherein the concentration of polymer iii) in layer B) is thereof. from about 5% w/w to about 100% w/w. 0293 10. A composition according to any of the preceding 0308 23. A composition according to any of the preceding items, wherein the polymers i) and iii), and the polymer items, wherein layer B1) and/or B2) contain a second active contained in the coating C) are thermoplastic. Substance. 0294 Inner Layer 0309 24. A composition according to item 23, wherein the 0295) 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 content of second active Substance in layer B). a MW of at least about 1,000 daltons such as, e.g., a 0310 Coating homopolymer having a MW in a range from about 1,000 to 0311 25. A composition according to any of the preceding about 15,000 daltons, from about 1,000 to about 12,000 dal items, wherein the polymer comprised in the coating is tons, from about 1,500 to about 10,000 daltons, from about selected from the group consisting of ethylcellulose, cellu 1,500 to about 8,000 daltons. lose acetate, cellulose propionate, cellulose nitrate, polya 0296 12. A composition according to any of the preceding mide, polyethylene, polyethylene terephtalate, polypropy items, wherein polymer i) comprises a copolymer having a lene, polyurethane, polyvinyl acetate, polyvinyl chloride, MW of at the most about 25,000 daltons such as, e.g., at the silicone rubber, latex, polyhydroxybutyrate, polyhydroxyval most about 20,000 daltons, at the most about 15,000 daltons, erate, teflon, polylactic acid or polyglycolic acid and copoly at the most about 10,000 daltons, at the most about 5,000 mers thereof, copolymers including ethylene vinyl acetate, daltons, at the most about 2,000 daltons. styrene-butadienstyrene and styrene-isoprene-styrene. 0297 13. A composition according to any of the preceding 0312 26. A composition according to any of the preceding items, wherein the active Substance in A) is present at least items, wherein the coating does not completely crumble or partly in solid or dissolved form. erode before the layer B) has completely eroded and the layer 0298. 14. A composition according to any of the preceding A) is released. items, wherein the active Substance in A) is present inform of 0313 The invention is further illustrated in the following pellets, beads, flakes, mini-tablets, granules, microspheres, non-limiting examples. nanoparticle, crystals or the like. 0299. 15. A composition according to claim 14, wherein DESCRIPTION OF THE FIGURES the active substance containing pellets, beads, flakes, mini tablets, granules, microspheres, nanoparticles, crystal or the 0314 FIG. 1, illustrate double burst unit, with a delay like are dispersed in the polymeri). between the two bursts 0300 16. A composition according to any of the preceding 0315 FIG. 2, illustrate simple combination formulation items, wherein the concentration of the polymer i) in inner 0316 FIG.3, releases of Hydrocodone and Morphine with layer A) is from about 5% w/w to about 100% w/w. burst-controlled release behaviour see preparation 4 0301 17. A composition according to any of the preceding 0317 FIG. 4, releases of Oxycodone and Morphine with items 2-16, wherein the concentration of the one or more controlled-controlled release behaviour see preparation 5 disintegration/exploding agent, if present, is from about 5% 0318 FIG. 5, illustrate double burst unit, with a delay w/w to about 80% w/w such as, e.g., from about 10% w/w to between the two bursts about 70% w/w, from about 15% w/w to about 60% w/w or 0319 FIG. 6, release of Paracetamol with double burst from about 20% w/w to about 50% w/w. release behaviour see example 2 US 2010/0239667 A1 Sep. 23, 2010

0320 FIG. 7, illustrate unit exhibiting controlled-burst or Titanium dioxide to an MTI-Mixer at a temperature about burst-burst release behaviour 19-21° C. Mixing rate is 1000 rpm. The mixer is stopped 0321 FIG. 8, release of Morphine with controlled-burst when the temperature reaches 40-50° C. and the adhered release behaviour see example 3 material is manually incorporated into the mixture. The mix 0322 FIG. 9, release of Morphine with controlled-burst ture is left to cool for about 10 minutes. The mixing is then release behaviour see example 4 finalized with a short high-speed mix in order to minimize 0323 FIG. 10, illustrate unit exhibiting controlled-con lumps formation. The mixture is then allowed to cool to room trolled or burst-controlled release behaviour temperature, after which it has a suitable consistency for 0324 FIG. 11, release of Morphine with controlled-con being fed into an injection moulding machine. trolled release behaviour see example 0345 Example of a coat composition; 0325 FIG. 12, release of Morphine pellets see example 5 0326 FIG. 13, release of Morphine with controlled-con trolled release behaviour see example 6 0327 FIG. 14, release of Morphine with burst-controlled Batch: 58-014-01-013 Batch: 08-0017-058 release behaviour see example 7 Material %(wfw) %(wfw) 0328 FIG. 15, illustrate burst-lag-burst release character Ethylcellulose 79 86.5 istics Cetostearyl alcohol 2O 12.5 0329 FIG. 16 illustrate burst-controlled-burst release Titanium dioxide 1 1 characteristics 0330 FIG.17 illustrate burst-controlled release character (0346 Small Scale Preparation istics 0347 A mixture may be prepared by simple volumetric 0331 FIG.18 illustrate controlled-burst release character mixing of the components. 3 g of the mixture is then feeded istics into a table top injection molding machine (Haake MiniJet II, 0332 FIG. 19 illustrate lag-burst release characteristics Thermo Electron, Karlsruhe, Germany) and molded directly 0333 FIG. 20 illustrate controlled-controlled release into a pre-molden shell and/or matrix. Typical settings in the characteristic MiniJet are: Temperature 90-120° C. and pressure 600-800 0334 FIG. 21 illustrate controlled-controlled release bar. characteristic 0348 Preparation of Dosage Unit 0335 FIG. 22 illustrate releases of two active substances 0349 The final dosage units may be prepared according to with the same release characteristics two different methods. In one method, the coat and the matrix 0336 FIG. 23 illustrate releases of two active substances are moulded individually followed by a manually incorpora with different release characteristics tion of the moulded matrix plug into the moulded coat. The 0337 FIG. 24 illustrate releases of two active substances injection moulding machine used is an Arburg Allrounder 220 with sequential release characteristics S 250/60. In the second method, the coat and matrix are moulded in one process where the coat is moulded in a first EXAMPLES step and the matrix is moulded directly into the coat in a Dissolution Method for Testing Dosage Units second step (co-moulding or 2-component moulding). The According to the Invention injection moulding machine used is Arburg Allrounder 420 V 800-60/35. 0338. Dissolution testing is performed according to USP 0350 Preparation 1 30, NF 25 (711), and apparatus 2 (paddle method). The dis 0351 Pellets for the inner layer A of a dosage unit accord solution medium may consist of 0.1 M HCl or phosphate ing to the invention (PHH 0120-063) buffer e.g. pH 6.8, pH 6.8 & 40% ethanol or pH 7.2. The 0352 Pellets were prepared by mixing Poloxamer 188 volume of dissolution medium is typically 900 ml or 1000 ml (48% w/w), Eudragit RL (24% w/w) and Hydrocortisone and the paddle speed is 50 rpm. Samples are withdrawn at (28% w/w) in a beaker on a heat stage set at 150°C. The melt Suitable time points and analysed for content of active Sub was applied to a punched plate (hole size 1 mm) and pellets of stance by means of on-line UV detection or HPLC with UV diameter 1 mm was formed. The pellets disintegrated in cold detection. MQ water in less than 1 h. 0339 Methods 0353 Preparation 2 0340. A general method for preparation dosage unit is 0354 An inner layer A for a dosage unit according to the described below. invention prepared by direct compression (PHH-0120-061-2) 0341 Preparation of a Matrix Composition 0355 Pellets (batch 108-009-05-001C) comprising 0342. An accurate amount of the polymer is loaded into a Hydrocortisone (55% w/w), PEG 8000 (40% w/w) and PVP MTI mixer followed by an accurate amount of the active C15 (5% w/w) was prepared by hot melt extrusion followed Substance and of the pharmaceutically acceptable excipients by grinding. The pellets were sieved to reach a final size of (s), if any. The mixing is performed at 900-2000 rpm and at a 1000 um-1200 Lum. 35-37 mg pellets were mixed with 206 time period up to 20 min. At the start of the mixing the 230 mg filler material comprising Lactose (StarLacR). The temperature is about 19-21 C. and the final temperature of material was placed in an IR-tablet preparing device and the mixture is about 30-50° C. The mixture is then allowed to compressed at a pressure of 5 metric tons. cool to room temperature and is ready to be fed into an 0356. Dissolution shows that the tablet is completely dis injection moulding machine. integrated after 18 minutes leaving the pellets for slower 0343 Preparation of the Coating Composition dissolution. Upon testing with an USP2 apparatus using 900 0344. The coating composition is prepared by first adding ml phosphate buffered media, pH 6.8 and 50 RPM the fol the Ethylcellulose then Cetostearyl alcohol, and finally the lowing release profile was obtained. US 2010/0239667 A1 Sep. 23, 2010 26

0367 Preparation of a Burst Release Plug: 0368. The active plug comprised: Hydrocodone bitartarte, PEG 3350S, Sodium hydrogen carbonate and Citric acid, Time (min) Release (%) which were mixed. Afterwards the powder mixture fed to the 50 min 50 injection moulding machine. 245 min 8O 0369. The inactive (placebo) plug comprised: PEG 3350S, 490 min 90 Sodium hydrogen carbonate and Citric acid, which were mixed. Then the powder mixture was fed to the injection Preparation 3 moulding machine. 0357 0370. The Controlled Release Plug has the Composition: 0358 An inner layer A for a dosage unit according to the invention prepared by direct compression (PHH-0120-062-4) 0359 Pellets (batch 108-009-05-001 C) comprising Hydrocortison (55% w/w), PEG 8000 (40% w/w) and PVP Content % (w.fw) C15 (5% w/w) was prepared by hot melt extrusion followed Active plug by grinding. The pellets were sieved to reach a final size of Morphine sulphate pentahydrate 53 1000 um-1200 Lum. 35-37 mg pellets were mixed with 165 Mannitol 3 336 mg filler material comprising Lactose (StarLacR): PEO 3OOOOO 35 NaHCO:Citric Acid (1497:333:27.2% w/w). The material Poloxamer 188 9 was placed in an IR-tablet preparing device and compressed Inactive (placebo) plug at a pressure of 5 metric tons. PEO 3OOOOO 85 0360 Dissolution shows that the tablet disintegrates Poloxamer 407 15 immediately leaving the pellets for slower dissolution. Upon testing with an USP 2 apparatus using 900 ml phosphate 0371. The Burst Release Plug has the Composition: buffered media, pH 6.8 and 50 RPM the following release profile was obtained. Content % (w.fw) Active plug Time (min) Release (%) Hydrocodone bitartrate 53 40 min 50 PEG 335OS 41 185 min 8O Sodium hydrogen carbonate 3 435 min 90 Citric acid 3 Inactive (placebo) plug 0361 Preparation 4 PEG 335OS 94 Sodium hydrogen carbonate 3 0362. A dosage unit exhibiting Burst-controlled behav Citric acid 3 iour (MQV batch 1047-041, 1047-042 & 1047-044), see FIG. Shell 2. As both Morphine and Hydrocodone absorb at the same Ethylcellulose 86.5 wave length, it has been necessary to conduct two parallel Cetostearyl alcohol 12.5 experiments—each experiment applying a dosage unit with Titanium dioxide 1.O active Substance combined with placebo. The dosage units consisted of two plugs, one containing the active Substance, one being a placebo-formulation. Finally the results from the 0372. The dissolution behaviour as tested by USP2 appa ratus, (pH 6.8, 900 ml phosphate buffered media, 50 RPM), two experiments were pooled, thereby simulating one dosage See FIG. 3. unit consisting of the two active Substances, one plug which 0373) Preparation 5 exhibits burst release of Hydrocodone and the other con 0374. A dosage unit exhibiting Controlled-controlled trolled release of Morphine. behaviour (MQV batch 1047-041), see FIG. 2. As both active 0363 The shell was produced by injection moulding. The substances Morphine and Oxycodone absorb at the same plugs were injection moulded using the mini-jet at applying a wave length, it has been necessary to conduct two parallel temperature 110°C., a pressure of 800 bar and a cycle time of experiments—each experiment applying a dosage unit with 20s. The thickness and the diameter of the plug was 4.5 mm active Substance combined with placebo. The dosage units diameter. The exposed area of the matrix (i.e. two ends) is consisted of two plugs, one containing the active Substances, 35.04 mm and the length of the dosage unit is 9 mm. one being a placebo-formulation. Finally the results from the Preparation of a Controlled Release Plug: two experiments were pooled, thereby simulating one dosage 0364 unit consisting of Morphine and Oxycodone, both exhibiting 0365. The active plug comprised: PoloXamer 188, PEO controlled release behavior. 300 000, Morphine Sulphate pentahydrate and Mannitol, 0375. The shell was produced by injection moulding. The which were mixed. Afterwards the powder mixture fed to the plugs were injection moulded using the mini-jet at applying a injection moulding machine. temperature 110°C., a pressure of 800 bar and a cycle time of 0366. The inactive (placebo) plug comprised: PoloXamer 20s. The thickness and the diameter of the plug was 4.5 mm 407, PEO 300 000, which were mixed. Then the powder diameter. The exposed area of the matrix (i.e. two ends) is mixture was fed to the injection moulding machine. 35.04 mm and the length of the dosage unit is 9 mm. US 2010/0239667 A1 Sep. 23, 2010 27

0376 Preparation of Plug (for Controlled Release of Mor the un-dissolved pellets from the unit into the dissolution phine): media. From the pellets 50% release of Hydrocortison was 0377 The active plug comprised: PoloXamer 188, PEO reached within 4h from time of onset (end of delay). 300 000, Morphine Sulphate pentahydrate and Mannitol, which were mixed. Afterwards the powder mixture fed to the Example 2 injection moulding machine. 0378 Preparation of Plug (for Controlled Release of Oxy 0386 Dosage unit according to the invention exhibiting codone): double burst behaviours (batch 05-0126-110/05-0134-110), 0379 The active plug comprised: Oxycodone hydrochlo See FIG. 5. ride, PEO 200 000, Mannitol, PoloXamer 407, which were 0387. Shell, end plugs (layer B), delay plugs and centre mixed. Afterwards the powder mixture fed to the injection plug (inner layer A) were prepared by injection moulding and moulding machine. hand assembled. The procedure was as follows: 0380. In both cases the inactive (placebo) plug comprised: 0388 1 Locate the shell with injection side upward PoloXamer 407, PEO 300 000, which were mixed. Then the 0389 2 Place the first delay plug with the injection side powder mixture was fed to the injection moulding machine. down word at the top of the shell 0381. The dosage form (controlled release) consists of an active plug and a placebo plug, the composition is given 0390 3 Gently push the delay plug a few mm into the shell below: 0391 4 Place the inner plug at the delay plug and push it into the shell also moving the delay plug 0392 5 Place the second delay plug with the injection side upward at the inner plug and push it into the shell Content % (w.fw) 0393 6 One end plug is placed at each end of the shell Active plug 0394 The Dosage Form has the Composition: Morphine sulphate pentahydrate 53 Mannitol 3 PEO 3OOOOO 35 Poloxamer 188 9 Content % (w.fw) Oxycodone hydrochloride 53 End plug Mannitol 5 PEO 200 000 17 Paracetamol 8O Poloxamer 407 25 Peg 8000 10 Placebo plug Hard fat 4 Sodium bicarbonate 3.3 PEO 3OOOOO 85 Citric acid, monohydrate 2.7 Poloxamer 407 15 Delay plug Shell PEO 200 OOO 99.5 Ethylcellulose 86.5 BHT O.S Cetostearyl alcohol 12.5 Centre plug Titanium dioxide 1.O Paracetamol 75.2 Peg 8000 9.4 0382. The dissolution behaviour as tested by USP2 appa Hard fat 3.8 ratus, (pH 6.8, 900 ml phosphate buffered media, 50 RPM), Sodium bicarbonate 9.1 See FIG. 4. Citric acid, monohydrate 2.5 Shell Example 1 Ethylcellulose 79 0383 Dissolution of non-compressed inner layer A for a Cetostearoyl 2O dosage unit according to the invention (PHH-0120-067). Titanium dioxide 1 0384 Units were prepared by the following procedure: Pellets comprising Hydrocortison (55% w/w), PEG 8000 0395. The exposed area of the matrix is 77 mm (i.e. sum (40% w/w) and PVP C15 (5% w/w) was prepared by hot melt of surface area of the two ends) and the length of the shell is extrusion followed by grinding. The pellets were sieved to 22.7 mm. reach a uniform size. 36-38 mg pellets were mixed with 0396 The dissolution behaviour as tested by USP2 appa 170-175 mg filler material comprising lactose (StarLacR), ratus, (pH 6.8, 1000 ml phosphate buffered media, 50 RPM) NaHCO, and Citric Acid (18500:825:675% w/w). Shellcom was as follows (see FIG. 6): prising Ethyl cellulose (89% w/w), Cetostearyl alcohol (10% w/w) and Titanium dioxide (1% w/w) (batch 06-0010-058) was prepared by injection moulding. The dosage unit was hand assembled first with a 2 mm thick delay plug comprising Time (min) Release (%) PEO 200 000, the pellet/filler blend was added and then 15 49 another 2 mm thick delay plug comprising PEO 200 000. The 155 50 exposed area of the matrix is 77 mm and the length of the 211 70 shell is 22.7 mm. 218 75 241 92 0385 Dissolution analysis using USP2 apparatus, pH 6.8, 250 94 900 ml phosphate buffered media at 50 RPM showed a delay for more than 4 hours followed by the immediate release of US 2010/0239667 A1 Sep. 23, 2010 28

Example 3 was moulded into a 3 mm thick, and a 4.5 mm diameter, hole 0397. A dosage unit according to the invention exhibiting metal filter to attain the plugs. Controlled-burst behaviour (MQV batch 1047-040), see FIG. 04.15 Preparation of Centre Plug (for Burst Release): 7. 0416 Sodium hydrogen carbonate, Citric acid and Mor 0398. The shell was produced by injection moulding. The phine Sulphate pentahydrate were mixed. Then the powder injection moulding machine used is a Haake Minijet II. End mixture was compressed to a plug (tablet) by direct compres plugs and centre plug were prepared by hand and hand Sion. Centre plugs of 3 mm thickness and a diameter of 4.5 assembled. Each plug had a thickness of 3 mm. mm were prepared. 0399. Preparation of End Plugs (for Controlled Release): 0417. The Procedure was as Follows: (0400 PoloXamer 338, PEO 200 000, Morphine Sulphate 0418) 1 Locate the shell with injection side upward pentahydrate and Mannitol were mixed. Afterwards the pow 0419 2 Place the first end plug with the injection side der mixture was heated to approximately 110°C. The melt down word at the top of the shell was moulded into a 3 mm thick, and a 4.5 mm diameter, hole 0420 3 Gently push the centre plug into the shell metal filter to attain the plugs. 0421 4 The last end plug is placed at the end of the shell 04.01 Preparation of Centre Plug (for Burst Release): 0422 The dosage form has the composition: 04.02 Explotab, Sodium Starch Glycolate & Sodium Car boxymethyl Starch, Maize starch and Morphine Sulphate pentahydrate were mixed. Then the powder mixture was com Content % (w.fw) pressed to a plug (tablet) by direct compression. Centre plugs of 3 mm thickness and a diameter of 4.5 mm were prepared. End plug 0403. The procedure was as follows: Morphine sulphate pentahydrate 16 0404 1 Locate the shell with injection side upward Mannitol 10 04.05 2 Place the first end plug with the injection side PEO 200 OOO 34 down word at the top of the shell Poloxamer 338 40 0406 3 Gently push the centre plug into the shell Centre plug 04.07 4 The last end plug is placed at the end of the shell Morphine sulphate pentahydrate 32 0408. The Dosage Form has the Composition: Citric acid 34 Sodium hydrogen carbonate 34 Shell Ethylcellulose 86.5 Content % (w.fw) Cetostearyl alcohol 12.5 End plug Titanium dioxide 1.O Morphine sulphate pentahydrate 16 Mannitol 10 0423. The exposed area of the matrix (i.e. two ends) is PEO 200 OOO 34 34.72 mm and the length of the dosage unit is 9 mm. Poloxamer 338 40 0424 The dissolution behaviour as tested by USP2 appa Centre plug ratus, (pH 6.8, 900 ml phosphate buffered media, 50 RPM), See FIG. 9. Morphine sulphate pentahydrate 32 Explotab 50 Maize starch 18 Example 5 Shell 0425. A dosage unit according to the invention exhibiting Ethylcellulose 86.5 Controlled-controlled behaviour (MQV batch 1047-043), see Cetostearyl alcohol 12.5 FIG 10. Titanium dioxide 1.O 0426. The shell was produced by injection moulding. End plugs and centre plug, comprising pellets, were prepared by 04.09. The exposed area of the matrix is 34.72 mm (i.e. hand and hand assembled. Each plug had a thickness of 3 mm. two ends) and the length of the dosage unit is 9 mm. 0427 Preparation of End Plugs (for Controlled Release): 0410 The dissolution behaviour as tested by USP2 appa 0428 PoloXamer 188, PEO 300 000, Mannitol and Mor ratus, (pH 6.8, 900 ml phosphate buffered media, 50 RPM), phine Sulphate pentahydrate were mixed. The material was See FIG. 8. melted to approximately 110°C., and the melt was moulded into a 3 mm thick, and a 4.5 mm diameter, hole metal filter to Example 4 attain the plugs. 0411. A dosage unit according to the invention exhibiting 0429 Preparation of Centre Plug (for Controlled Release): Controlled-burst behaviour (MQV batch 1047-045), see FIG. 0430 PoloXamer 188, PEO 300 000, Mannitol and Mor 7. phine Sulphate pentahydrate were mixed and processed on a 0412. The shell was produced by injection moulding. The melt extruder. The extruded strings were cooled and cut into injection moulding machine used is a Haake Minijet II. End pellets. The pellets were sieved to reach a uniform size. Pel plugs and centre plug were prepared by hand and hand lets were mixed with CrosPovidone to attain a centre plug of assembled. Each plug had a thickness of 3 mm. approximately 3 mm thickness and a 4.5 mm diameter. 0413 Preparation of End Plugs (for Controlled Release): 0431. The Procedure was as Follows: 0414 PoloXamer 338, PEO 200 000, Morphine Sulphate 0432 1 Locate the shell with injection side upward pentahydrate and Mannitol were mixed. Afterwards the pow 0433 2 Place the first end plug with the injection side der mixture was heated to approximately 110°C. The melt down word at the top of the shell US 2010/0239667 A1 Sep. 23, 2010 29

0434 3 Pellets and CrosPovidone were added into the 0450. The Dosage Form has the Composition: shell 0435 4 The last end plug is placed at the end of the shell 0436 The Dosage Form has the Composition: Content % (w.fw) End plug Content% (w.fw) Morphine sulphate pentahydrate 2O PEO 45 End plug Poloxamer 407 35 Pellets Morphine sulphate pentahydrate 53 Mannitol 3 Morphine sulphate pentahydrate 53 PEO3OOOOO 35 Mannitol 3 Poloxamer 188 9 PEO3OOOOO 35 Pellets Poloxamer 188 9 Centre plug Morphine sulphate pentahydrate 53 Mannitol 3 Pellets and 25% CrossPovidone were added PEO3OOOOO 35 Shell Poloxamer 188 9 Centre plug Ethylcellulose 86.5 Cetostearyl alcohol 12.5 Pellets and 25% CrossPovidone were added Titanium dioxide 1.O

Shell 0451. The exposed area of the matrix (i.e. two ends) is Ethylcellulose 86.5 34.72 mm and the length of the dosage unit is 9 mm. Cetostearyl alcohol 12.5 0452. The dissolution behaviour as tested by USP2 appa Titanium dioxide 1.O ratus, (pH 6.8, 900 ml phosphate buffered media, 50 RPM, See FIG. 13. 0437. The exposed area of the matrix (i.e. two ends) is 34.72 mm and the length of the dosage unit is 9 mm. Example 7 0438. The dissolution behaviours as tested by USP2 appa 0453 A dosage unit according to the invention exhibiting ratus, (pH 6.8 and pH 6.8/40% ethanol, 900 ml phosphate Burst-controlled behaviour (MQV batch 1047-046), see FIG. buffered media, 50 RPM), see FIG. 11. Furthermore, it is 10. demonstrated that these pellets are abuse resistant as the 0454. The shell was produced by injection moulding. End dissolution rate is significantly lower in alcohol-containing plugs and centre plug, comprising pellets, were prepared by media, see FIG. 12. hand and hand assembled. Each plug had a thickness of 3 mm. 0455 Preparation of End Plugs (for Burst Release): Example 6 0456 Morphine sulphate pentahydrate, PEG 3350S, Sodium hydrogen carbonate and Citric acid were mixed and 0439 A dosage unit according to the invention exhibiting melted to approximately 110°C., and the melt was moulded Controlled-controlled behaviour (MQV batch 1047-047, see into a 3 mm thick, and a 4.5 mm diameter, hole metal filter to FIG 10. attain the plugs. 0440 The shell was produced by injection moulding. End 0457 Preparation of Centre Plug (for Controlled Release): plugs and centre plug, comprising pellets, were prepared by 0458 PoloXamer 188, PEO 300 000, Mannitol and Mor hand and hand assembled. Each plug had a thickness of 3 mm. phine Sulphate pentahydrate were mixed and processed on a melt extruder. The extruded strings were cooled and cut into 0441 Preparation of End Plods (for Controlled Release): pellets. The pellets were sieved to reach a uniform size. Pel 0442. Morphine, PEO and PoloXamer 407 were mixed lets were mixed with CrosPovidone to attain a centre plug of thoroughly and melted to approximately 110°C., and the melt approximately 3 mm thickness and a 4.5 mm diameter. was moulded into a 2 mm thick, and a 4.5 mm diameter, hole 0459. The Procedure was as Follows: metal filter to attain the plugs. 0460 1 Locate the shell with injection side upward 0443 Preparation of Centre Plod (for Controlled Release): 0461) 2 Place the first end plug with the injection side 0444 PoloXamer 188, PEO 300 000, Mannitol and Mor down word at the top of the shell phine Sulphate pentahydrate were mixed and processed on a 0462. 3 Pellets and CrosPovidone were added into the melt extruder. The extruded strings were cooled and cut into shell pellets. The pellets were sieved to reach a uniform size. Pel 0463 4. The last end plug is placed at the end of the shell lets were mixed with CrosPovidone to attain a centre plug of 0464. The Dosage Form has the Composition: approximately 3 mm thickness and a 4.5 mm diameter. 0445 The Procedure was as Follows: 0446 1 Locate the shell with injection side upward 0447 2 Place the first end plug with the injection side Content % (w.fw) down word at the top of the shell End plugs 0448 3 Pellets and CrosPovidone were added into the Morphine sulphate pentahydrate 25 shell PEG 335OS 65 0449 4 The last end plug is placed at the end of the shell US 2010/0239667 A1 Sep. 23, 2010 30

sodium, Powdered cellulose, Chitosan, Croscarmellose -continued Sodium, Crospovidone, Hydroxypropyl Starch, Hydroxypro pyl cellulose low-substituted, Magnesium aluminium sili Content% (w.fw) cate, Methylcellulose, Microcrystalline cellulose, pregelati Sodium hydrogen carbonate 5 nized starch, Docusae sodium, Guar gum, Polacrilin Citric acid 5 potassium or a mixture thereof. Pellets 34. A composition according to claim 29, wherein the Morphine sulphate pentahydrate 53 effervescent agent is Effer-Soda, Citric acid, Citric acid, Mannitol 3 monohydrate, Dextrates, Fumaric acid, Potassium bicarbon PEO 3OOOOO 35 ate, Sodium bicarbonate, Sodium citrate dehydrate, Tartaric Poloxamer 188 9 acid or a mixture thereof. Centre plug 35. A composition according to claim 30, wherein the Pellets and 25% CrossPovidone were added multiple unit formulation comprises a Substantially water Shell soluble and/or crystalline polymer or a mixture of substan Ethylcellulose 86.5 tially water soluble and/or crystalline polymers, the polymer Cetostearyl alcohol 12.5 being a polyglycol in the from of one of (a) a homopolymer Titanium dioxide 1.O having a MW of at least about 100,000 daltons, and (b) a copolymer having a MW of at least about 2,000 daltons, or a 0465. The exposed area of the matrix (i.e. two ends) is mixture thereof. 34.72 mm and the length of the dosage unit is 9 mm. 36. A composition according to claim 29, wherein layer 0466. The dissolution behaviour as tested by USP2 appa (A) further comprises a filler. ratus, (pH 6.8, 900 ml phosphate buffered media, 50 RPM) 37. A composition according to claim 29, wherein layer See FIG. 14. (A) further comprises (v) a substantially water soluble and/or 1-28. (canceled) crystalline polymer or a mixture of substantially water 29. A layered pharmaceutical composition comprising soluble and/or crystalline polymers, the polymer being a three layers, wherein a solid inner layer (A) comprises: polyglycol in the form of one of (c) a homopolymer having a (i) an active substance, and MW of at the most about 16,000 daltons, and (d) a copolymer (ii) one or more disintegrants/exploding agents, one of having a MW of at the most about 30,000 daltons, or a mixture more effervescent agents or a mixture thereof, thereof. the solid inner layer (A) being sandwiched between two 38. A composition according to claim 37, wherein the outer layers (B1) and (B2), each outer layer comprising polymer (v) comprises a homopolymer having a MW of at (iii) a substantially water soluble and/or crystalline poly least about 1,000 daltons such as, e.g., a homopolymer having mer or a mixture of substantially water soluble and/or a MW in a range from about 1,000 to about 15,000 daltons, crystalline polymers, the polymer being a polyglycol in from about 1,000 to about 12,000 daltons, from about 1,500 to the form of one of (a) a homopolymer having a MW of at about 10,000 daltons, from about 1,500 to about 8,000 dal least about 100,000 daltons, and (b) a copolymer having tons, or a mixture thereof. a MW of at least about 2,000 daltons, or a mixture 39. A composition according to claim 37, wherein the thereof, and polymer (v) comprises a copolymer having a MW of at the (iv) an active substance, which is the same as in said Solid most about 25,000 daltons such as, e.g., at the most about inner layer (A), and the Solid inner layer (A) being 20,000 daltons, at the most about 15,000 daltons, at the most different from layer (B1) and (B2), the layered compo about 10,000 daltons, at the most about 5,000 daltons, at the sition being coated with a coating (C) that has at least most about 2,000 daltons. one opening exposing at least one Surface of said outer 40. A composition according to claim 29, wherein the layer, the coating being Substantially insoluble in and active Substance in Solid inner layer (A) is present in form of impermeable to fluids and comprising a polymer, and pellets, beads, flakes, mini-tablets, granules, microspheres, the composition having a cylindrical form optionally nanoparticle, crystals or the like. with one or more tapered ends, wherein the ratio between the surface area of one end surface of the cyl 41. A composition according to claim 29, wherein the inder and the length of the cylinder is in a range of from concentration of the one or more disintegrants/exploding 0.02 to 45 mm. agent in the solid inner layer (A) is from about 5% w/w to 30. A composition according to claim 29, wherein the about 80% w/w such as, e.g., from about 10% w/w to about active Substance in the Solid inner layer (A) is present in the 70% w/w, from about 15% w/w to about 60% w/w or from form of a multiple unit formulation. about 20% w/w to about 50% w/w. 31. A composition according to claim 30, wherein the 42. A composition according to claim 29, wherein the multiple unit formulation is a controlled release multiple unit concentration of the one or more effervescent agent in the formulation. solid inner layer (A) is from about 5% w/w to about 80% w/w 32. A composition according to claim 29, wherein the ratio such as, e.g., from about 10% w/w to about 70% w/w, from between the end surface area and the length of the cylinder is about 15% w/w to about 60% w/w or from about 20% w/w to in a range of from 0.1 to about 10 mm or from about 0.5 to about 50% w/w. about 8 mm. 43. A composition according to claim 29, wherein the 33. A composition according to claim 29, wherein the substantially water soluble and/or crystalline polymer, or a disintegrant/exploding agent is Sodium starch glycolate, mixture of substantially water soluble and/or crystalline poly Povidone, Sodium alginate, Alginic acid, Calcium alginate, mers, comprises one or more of a polyethylene glycol, includ Carboxymethylcellulose calcium, Carboxymethylcellulose ing derivatives Such as mono- and dimethoxypolyethylene US 2010/0239667 A1 Sep. 23, 2010 glycols (mPEGs), polyethylene oxide and/or a copolymer of tic acid or polyglycolic acid and copolymers thereof, copoly ethylene oxide and propylene oxide. mers including ethylene vinyl acetate, styrene-butadiensty 44. A composition according to claim 43, wherein the rene and styrene-isoprene-styrene. polyethylene glycol or a polyethylene oxide has a molecular 51. A composition according to claim 29, wherein the weight from about 100,000 to about 700,000. coating (C) does not completely crumble or erode before the 45. A composition according to claim 43, wherein the layer (B1) and/or (B2) has completely eroded and the layer copolymer of polyethylene glycol (PEG) and polypropylene (A) is released. 52. A composition according to claim 29, wherein the outer glycol (PPG) has a molecular weight of from about 4,000 to layer (B1) and/or (B2) when exposed to an aqueous medium about 15,000 daltons. erodes at a Substantially constant rate. 46. A composition according to claim 29, wherein the 53. A composition according to claim 29, wherein the concentration of polymer (iii) in layer (B1) and layer (B2) is active Substance in Solid inner layer (A) is subject to release from about 5% w/w to about 100% w/w. after a lag time corresponding to the erosion time of the layer 47. A composition according to claim 29, wherein the (B1) and/or (B2). release of the active substance contained in layer (B1) and 54. A composition according to claim 29, wherein the solid layer (B2) follows a zero order release pattern at least up to inner layer (A), without layers (B1) and (B2) and coating (C), 80% w/w release of the total content of active substance in disintegrates within at the most 60 min Such as, e.g., at the layer (B1) and layer (B2). most about 30 min or at the most about 15 min, when sub 48. A composition according to claim 29, wherein layer jected to a disintegration test according to Ph. Eur. (B1) and/or (B2) contain a second active substance different 55. A composition according to claim 29, wherein the from the active substance of layer (A). coating (C) appears as a Substantially intact empty shell when 49. A composition according to claim 48, wherein the the composition has been Subjected to a dissolution test release of the second active substance follows a Zero order according to Ph. Eur, by which the outer layers (B1) and (B2) release pattern at least up to 80% w/w release of the total erode and the inner layer (A) disappears from the composi content of second active Substance in layer (B1) and layer tion optionally by means of one or more disintegration agents, (B2). explosion agents, effervescent agents or a mixture thereof. 50. A composition according to claim 29, wherein the 56. A composition according to claim 29, wherein the polymer comprised in the coating (C) is selected from the substantially water soluble and/or crystalline polymer, or a group consisting of ethylcellulose, cellulose acetate, cellu mixture of substantially water soluble and/or crystalline poly lose propionate, cellulose nitrate, polyamide, polyethylene, mers, and the polymer contained in the coating (C) are polyethylene terephtalate, polypropylene, polyurethane, thermoplastic. polyvinyl acetate, polyvinyl chloride, silicone rubber, latex, polyhydroxybutyrate, polyhydroxyvalerate, teflon, polylac