Patent Grant
10568845
Fentanyl and fentanyl-analogous substances such as sulfentanyl, carfentanyl, lofentanyl and alfentanyl are extremely efficacious analgesics. The requirement for only a low dose and their physicochemical properties such as the n-octanol/water partition coefficient, melting point and the molecular weight make possible the transdermal administration of these substances in an efficacious amount and their pharmacokinetic properties such as the rapid metabolization and the relatively narrow therapeutic index make transdermal administration desirable.
In fact, a TTS containing fentanyl as active compound has been on the market for some years. This system is a “reservoir system”. A reservoir system is understood here as meaning a system which contains the active compound in a liquid or gelatinous preparation in a sachet formed from an impermeable film, which serves as a back layer, and an active compound-permeable membrane, the membrane additionally being provided with an adhesive layer for fixing the system to the skin. In this specific case, fentanyl is dissolved in a mixture of ethanol and water. Further details of this system can be taken from U.S. Pat. No. 4,588,580 or DE-C 35 26 339, which both contain a detailed description.
Reservoir systems, however, have the disadvantage that in the case of a leak in the reservoir sachet the active compound-containing reservoir filling comes in contact with the skin over a wide area and the active compound is absorbed in excessively high doses. This is very dangerous, especially in the case of fentanyl and its derivatives, since an overdose very rapidly leads to respiratory depression and therefore fatal incidents. A number of such fatal or near-fatal incidents are described in Clinical Pharmacokinet. 2000, 38(1), 59-89.
The object of this invention was now to make available a transdermal therapeutic system containing fentanyl or fentanyl analogs, which offers the user increased safety against an inadvertent absorption of overdoses.
This is possible according to the invention in that, instead of the reservoir system, a matrix system is employed in which the active compound is incorporated directly into a self-adhesive polyacrylate and thus, even in the case of damage to the system, cannot come into contact with the skin over a greater area than afforded by the TTS. In such a system, the active compound is generally completely, but to at least 80%, dissolved in molecularly disperse form in this polymer, the saturation solubility of the active compound in the polymer being between 3 and 20% by weight. Furthermore, it has surprisingly been shown that when using polyacrylate adhesives for the production of TTS containing fentanyl and its analogs, only adhesives without free carboxyl groups are suitable.
Such matrix systems in the simplest case consist of a back layer, which is impermeable to the active compound, of a self-adhesive active compound-containing layer and of a protective layer to be removed before use. In complicated embodiments of such systems is additionally also added a membrane controlling the release of active compound, which is normally further provided with an adhesive layer for fixing the system to the skin.
The active compound-containing layers of such a matrix system according to this invention consist of polyacrylates. Since free functional groups increase the saturation solubility of fentanyl and its derivatives in polyacrylate adhesives above the preferred range, the polyacrylate adhesives which are best suited are those which have no free functional groups and are only prepared from esters of acrylic and/or methacrylic acid and optionally other vinyl compounds without free functional groups such as vinyl acetate. However, in the synthesis of the adhesive, monomers having free hydroxyl groups such as 2-hydroxyethyl acrylate or 2-hydroxyethyl methacrylate can be tolerated up to a content of 20% by weight. Polyacrylates are prepared by free-radical polymerization using acrylic and/or methacrylic acid derivatives. Such derivatives are, for example, esters. By way of example of such derivatives, acrylic and methacrylic acid derivatives may be mentioned, in particular esters of alcohols having 1 to 8 C atoms, which optionally contain one hydroxyl group, such as 2-ethylhexyl acrylate, n-octyl acrylate, propyl acrylate, n- or isobutyl acrylate, 2-hydroxyethyl acrylate and dimethylaminoethyl acrylate or the corresponding methacrylates. Additionally, other polymerizable vinyl compounds without free functional groups such as, for example, vinyl acetate can also be used, e.g. in amounts of up to 50% by weight. The polymers thus prepared are also described as random copolymers, as solely the quantitative distribution of the monomers employed and chance decide the composition of the polymer chains.
If the polymers contain free hydroxyl groups, the possibility exists of additionally crosslinking the polymer chains by polyvalent cations such as Al3+ or Ti4+ or reactive substances such as melamine. Use is made of this possibility in order to increase the molecular weight and thus to improve the cohesion of the polymers. The possibility of the crosslinkage of polyacrylates, in particular of polyacrylate adhesives, is particularly valuable if the plasticizing action of the active compound dissolved in the polymers or the plasticizing action of other auxiliaries has to be compensated. The adhesive is usually used in the form of a solution. Solvents used are, for example, ethyl acetate, hexane or heptane, ethanol or their mixtures. These are removed during the preparation of the TTS.
Table 1 shows the results of permeation studies which have been obtained using an adhesive with and an adhesive without free carboxyl groups (but without hydroxyl groups). In both adhesives, the active compound was incorporated in a concentration of 5 percent by weight. The permeation study was carried out by means of the Franz diffusion cells known to the person skilled in the art and using human skin.
The results show that a neutral adhesive without free carboxyl groups is markedly superior to a carboxyl group-containing adhesive with respect to the permeation rates achievable.
An important characteristic of each active compound-containing polymer in TTS technology is the saturation solubility of the chosen polymer for the respective active compound. This parameter is important because the thermodynamic activity of the active compound in the matrix does not depend on the absolute amount of active compound dissolved, but rather on the ratio of the actual concentration to the saturation concentration. Since the active compound on application of the TTS to the skin must disperse in the skin and in the process bring into line not concentrations, but activities, it is important for achieving a permeation rate which is as high as possible to choose as high as possible a thermodynamic activity of the active compound in the TTS. This means that the solubility of the active compound in the active compound-containing parts of the TTS must not be too high, since otherwise the active compound concentration in the TTS must be quite high in order to achieve an adequately high thermodynamic activity. This is unadvantageous if the active compound disadvantageously influences the physical properties of the active compound-containing parts of the system in the high concentration and/or the active compound is very expensive. In the case of fentanyl, both reasons are true, it additionally still having to be taken into consideration that fentanyl and its derivatives belong to the narcotics and for this reason alone it is therefore desirable to incorporate as little active compound in the TTS as possible and/or to make the utilization of active compound, i.e. the ratio of active compound released during the wearing time of the TTS to the content of the unworn TTS, as large as possible.
From this point of view, the saturation solubility of the active compound-containing layers for a three-day TTS should not be below 3 percent by weight and not above 20 percent by weight. At higher saturation solubilities, even with a high specific permeation rate, the utilization of active compound is too poor, and the TTS is not readily marketable for commercial reasons because of the expensive active compound. Preferably, for these reasons the saturation solubility is between 4 and 12 and particularly preferably between 5 and 10, percent by weight.
The saturation solubility of fentanyl and its analogs can additionally be reduced by the addition of substances which do not have good dissolving properties for the active compound. Such substances are, for example, liquid hydrocarbons such as dioctylcyclohexane, liquid paraffin, hydrocarbon resins such as polyterpenes, in particular polypinene, or polar substances such as glycerol, di- and triglycerol or polyethylene glycols, e.g. having a molecular weight from 200 to 1000. These substances can form a homogeneous mixture with the polyacrylate adhesive or else be contained therein as a separate phase. Glycerol and its derivatives especially are already present in low concentrations in the matrix as a separate phase, e.g. in the form of droplets. By means of the addition of such substances, it is in particular also possible to compensate the higher saturation solubility in adhesives having free hydroxyl groups.
Table 2 contains some data regarding the saturation solubilities of fentanyl in some of these substances.
The influence of such additives can be recognized by means of comparative permeation studies.
In table 3, the results of permeation studies with matrices based on a neutral polyacrylate adhesive having free hydroxyl groups with and without such additives and of a polyacrylate adhesive without other free functional groups are compared. All formulations contain fentanyl in a concentration of 5% by weight.
The results of the permeation study show that the permeation rate can be significantly improved by the addition of substances reducing the solubility of the active compound in the matrix. Approximately the same results are achieved by the use of an adhesive without free functional groups, which even without additives has a low dissolving capacity for the active compound.
From the permeation data, the respective TTS sizes can be calculated for various TTS strengths. The results are listed in table 4.
The result of the calculation shows that carboxyl group-containing adhesives at a fentanyl concentration of 5% even at the lowest dose lead to TTS which are too large for practical use. Although quite large TTS are also calculated in the case of the hydroxyl group-containing adhesives, the possibility exists here due to the increase in the fentanyl concentration to arrive at TTS having a size suitable for practical use with concentrations which are not too high, i.e. at most 20%. Simplified, it can be assumed here that the thermodynamic activity and thus also the permeation rates depend linearly on the concentration, as long as the active compound is present completely dissolved.
By use of the solubility-lowering auxiliaries in formulations having hydroxyl group-containing polyacrylate adhesives or by the use of polyacrylate adhesives without free functional groups, even at a fentanyl concentration of 5%, TTS are obtained which have an acceptable size, even in the highest dose of 100 μg/h. Of course, the possibility also offers itself here of further reducing the system area by increasing the fentanyl concentration.
Fentanyl and its derivatives, as already mentioned at the outset, have a narrow therapeutic index. This means that for the action, on the one hand, a certain threshold value which must be exceeded with respect to the plasma concentration, on the other hand unacceptable side-effects rapidly occur at higher concentrations. It is therefore advantageous if the system additionally contains a control membrane and thus the active compound flow through the skin is restricted to a maximum value independently of the individual skin condition. Such membranes preferably consist of a copolymer of ethylene and vinyl acetate (EVA polymer) or are microporous films based on polyethylene or polypropylene. The prior art includes membranes of this type. In the case of the EVA polymers, the active compound permeability depends on the content of vinyl acetate and the thickness of the membrane. Membranes having a VA content of between 2 and 25 percent by weight and a thickness of between 25 and 100 μm, preferably between 40 and 100 μm, are customary, there being scarcely any limitations in practice with respect to the vinyl acetate content and the thickness. For the particular formulation, both parameters must be chosen accordingly in order to guarantee restriction to the desired maximum flow from the TTS. In the case of the microporous membranes, the substance transport does not take place through the polymer, but only through the pores found in these membranes. The number and size of the pores in this case determines the maximum release rate of the TTS.
Customarily, such membranes are provided with an adhesive film for fixing the TTS to the skin. Adhesive films based on self-adhesive polyacrylates or self-adhesive polysiloxanes are particularly suitable for fentanyl and its derivatives. The advantage of polysiloxanes here is that the active compound in these polymers is very poorly soluble and therefore the active compound loading of the TTS does not have to be increased unnecessarily by the use of an additional adhesive film. Adhesive films of this type, however, can also be used in systems which contain no membranes, but matrix layers having lower adhesive power.
As in any TTS, of course, there is also the possibility here of reducing the barrier properties of the human horny layer by the use of permeation-promoting substances. Such substances are, for example, fatty acids, fatty alcohols, fatty acid esters, esters of glycerol with medium- or long-chain fatty acids and glycols such as 1,2-propanediol. All substances can be employed here which are physiologically acceptable and compatible with the active compound and the other excipients.
In summary, it is to be observed the matrix systems within the meaning of this invention show satisfactory to good permeation rates and also make possible the production of TTS having an acceptable size. At the same time, an endangering of the patient by an excessively high absorption of active compound as a result of a leak is impossible. Overall, matrix systems based on polyacrylate adhesives within the meaning of this invention are thus an important advance in relation to the known prior art for fentanyl and its analogs with respect to patient safety.
Fentanyl (free base) is dissolved in the solution of the adhesive in heptane/ethyl acetate. The amount of fentanyl is in this case calculated such that, based on the solids content of the adhesive solution, a concentration of 5.0% results. The resulting material is coated using a doctor blade onto a siliconized polyester film protective layer to be removed before use, in a thickness such that, after the removal of the solvent, a weight of the coating of about 80 g/m2 results. After the removal of the solvent, the dried film is laminated with a thin polyester film (back layer of the TTS), and the finished TTS are stamped out of the complete laminate.
5.0 g of fentanyl, 15.0 g of polypinene, 10.0 g of glycerol, 15.0 g of dioctylcyclohexane and 110 g of the adhesive solution having a solids content of 50.0% are combined and stirred until the fentanyl has dissolved.
The resulting material is coated using a doctor blade onto a siliconized polyester film (protective layer to be removed before use) in a thickness such that, after the removal of the solvent, a weight of the coating of about 80 g/m2 results. After the removal of the solvent, the dried film is laminated with a thin polyester film (back layer of the TTS) and the finished TTS are stamped out of the complete laminate.
| Number | Date | Country | Kind |
|---|---|---|---|
| 101 41 650 | Aug 2001 | DE | national |
| Filing Document | Filing Date | Country | Kind | 371c Date |
|---|---|---|---|---|
| PCT/EP02/07664 | 7/10/2002 | WO | 00 | 2/20/2004 |
| Publishing Document | Publishing Date | Country | Kind |
|---|---|---|---|
| WO03/018075 | 3/6/2003 | WO | A |
| Number | Name | Date | Kind |
|---|---|---|---|
| 965861 | Berwanger | Aug 1910 | A |
| 2618708 | Ostline | Nov 1952 | A |
| 2884126 | Ulrich | Apr 1959 | A |
| RE24906 | Ulrich | Dec 1960 | E |
| 3886126 | McKenna | May 1975 | A |
| 3900610 | McKenna | Aug 1975 | A |
| 4053604 | Jaramillo | Oct 1977 | A |
| 4486423 | Kenyhercz et al. | Dec 1984 | A |
| 4508715 | Booth et al. | Apr 1985 | A |
| 4588580 | Gale et al. | May 1986 | A |
| 4599342 | Hann et al. | Jul 1986 | A |
| 4626539 | Aungst et al. | Dec 1986 | A |
| 4645502 | Gale et al. | Feb 1987 | A |
| 4758434 | Kydonieus et al. | Jul 1988 | A |
| 4822802 | Levy et al. | Apr 1989 | A |
| 4879297 | Mahjour et al. | Nov 1989 | A |
| 4882163 | Guse et al. | Nov 1989 | A |
| 4906463 | Cleary et al. | Mar 1990 | A |
| 4911707 | Heiber et al. | Mar 1990 | A |
| 4911916 | Cleary et al. | Mar 1990 | A |
| 4915950 | Miranda et al. | Apr 1990 | A |
| 4927408 | Haak et al. | May 1990 | A |
| 4938759 | Enscore et al. | Jul 1990 | A |
| 5000886 | Lawter et al. | Mar 1991 | A |
| 5069909 | Sharma et al. | Dec 1991 | A |
| 5080646 | Theeuwes et al. | Jan 1992 | A |
| 5120532 | Wells et al. | Jun 1992 | A |
| 5121695 | Feuz et al. | Jun 1992 | A |
| 5122127 | Stanley et al. | Jun 1992 | A |
| 5167616 | Haak et al. | Dec 1992 | A |
| 5180716 | Yaksh et al. | Jan 1993 | A |
| 5187849 | Kobayashi et al. | Feb 1993 | A |
| 5203768 | Haak et al. | Apr 1993 | A |
| 5236714 | Lee et al. | Aug 1993 | A |
| 5254346 | Tucker et al. | Oct 1993 | A |
| 5260066 | Wood et al. | Nov 1993 | A |
| 5279594 | Jackson et al. | Jan 1994 | A |
| 5288497 | Stanley et al. | Feb 1994 | A |
| 5288498 | Stanley et al. | Feb 1994 | A |
| 5387466 | Therriault et al. | Feb 1995 | A |
| 5405997 | Hester, Jr. et al. | Apr 1995 | A |
| 5416191 | Cheronis et al. | May 1995 | A |
| 5451408 | Mezei et al. | Sep 1995 | A |
| 5456923 | Nakamichi et al. | Oct 1995 | A |
| 5462744 | Gupte et al. | Oct 1995 | A |
| 5465151 | Wybourne et al. | Nov 1995 | A |
| 5474783 | Miranda et al. | Dec 1995 | A |
| 5482965 | Rajadhyaksha et al. | Jan 1996 | A |
| 5497763 | Lloyd et al. | Mar 1996 | A |
| 5507277 | Rubsamen et al. | Apr 1996 | A |
| 5522385 | Lloyd et al. | Jun 1996 | A |
| 5543407 | Guodong et al. | Aug 1996 | A |
| 5554381 | Roos et al. | Sep 1996 | A |
| 5558879 | Chen et al. | Sep 1996 | A |
| 5560922 | Chien et al. | Oct 1996 | A |
| 5562607 | Gyory et al. | Oct 1996 | A |
| 5569450 | Duan et al. | Oct 1996 | A |
| 5589480 | Elkhoury et al. | Dec 1996 | A |
| 5589498 | Mohr et al. | Dec 1996 | A |
| 5608035 | Yanofsky et al. | Mar 1997 | A |
| 5619984 | Hodson et al. | Apr 1997 | A |
| 5635204 | Gevirtz et al. | Jun 1997 | A |
| 5656286 | Miranda et al. | Aug 1997 | A |
| 5686112 | Liedtke et al. | Nov 1997 | A |
| 5693335 | Xia et al. | Dec 1997 | A |
| 5697896 | McNichols et al. | Dec 1997 | A |
| 5714162 | Muller | Feb 1998 | A |
| 5730999 | Lehmann et al. | Mar 1998 | A |
| 5762952 | Barnhart et al. | Jun 1998 | A |
| 5769778 | Abrams et al. | Jun 1998 | A |
| 5770222 | Unger et al. | Jun 1998 | A |
| 5785599 | Reik et al. | Jul 1998 | A |
| 5785989 | Stanley et al. | Jul 1998 | A |
| 5788980 | Nabahi et al. | Aug 1998 | A |
| 5804213 | Rolf et al. | Sep 1998 | A |
| 5820876 | Hoffmann et al. | Oct 1998 | A |
| 5858410 | Muller et al. | Jan 1999 | A |
| 5861149 | Ritter et al. | Jan 1999 | A |
| 5861439 | Gyory et al. | Jan 1999 | A |
| 5871460 | Phipps et al. | Feb 1999 | A |
| 5880132 | Hill et al. | Mar 1999 | A |
| 5885564 | Zastrow et al. | Mar 1999 | A |
| 5886164 | Bird et al. | Mar 1999 | A |
| 5891842 | Kream et al. | Apr 1999 | A |
| 5910301 | Farr et al. | Jun 1999 | A |
| 5919473 | Elkhoury et al. | Jul 1999 | A |
| 5932227 | Higo et al. | Aug 1999 | A |
| 5948433 | Burton et al. | Sep 1999 | A |
| 5958379 | Regenold et al. | Sep 1999 | A |
| 5958446 | Miranda et al. | Sep 1999 | A |
| 5976547 | Archer et al. | Nov 1999 | A |
| 5980927 | Nelson et al. | Nov 1999 | A |
| 5985317 | Venkateshwaran et al. | Nov 1999 | A |
| 5993849 | Assmus et al. | Nov 1999 | A |
| 5998434 | Mitch et al. | Dec 1999 | A |
| 6004566 | Friedman et al. | Dec 1999 | A |
| 6004577 | Murdock et al. | Dec 1999 | A |
| 6024976 | Miranda et al. | Feb 2000 | A |
| 6039977 | Venkatraman et al. | Mar 2000 | A |
| 6049733 | Phipps et al. | Apr 2000 | A |
| 6063399 | Assmus et al. | May 2000 | A |
| 6074665 | Horstmann et al. | Jun 2000 | A |
| 6093419 | Rolf et al. | Jul 2000 | A |
| 6098619 | Britto et al. | Aug 2000 | A |
| 6139866 | Chono et al. | Oct 2000 | A |
| 6143278 | Elkhoury et al. | Nov 2000 | A |
| 6163720 | Gyory et al. | Dec 2000 | A |
| 6181963 | Chin et al. | Jan 2001 | B1 |
| 6203817 | Cormier et al. | Mar 2001 | B1 |
| 6210394 | Demopulos et al. | Apr 2001 | B1 |
| 6210705 | Mantelle et al. | Apr 2001 | B1 |
| 6214378 | Tanida et al. | Apr 2001 | B1 |
| 6219576 | Gupta et al. | Apr 2001 | B1 |
| 6221377 | Meyer et al. | Apr 2001 | B1 |
| 6221385 | Camu et al. | Apr 2001 | B1 |
| 6246904 | Murdock et al. | Jun 2001 | B1 |
| 6255502 | Penkler et al. | Jul 2001 | B1 |
| 6261582 | Needham et al. | Jul 2001 | B1 |
| 6264981 | Zhang et al. | Jul 2001 | B1 |
| 6267984 | Beste et al. | Jul 2001 | B1 |
| 6275728 | Venkatraman et al. | Aug 2001 | B1 |
| 6306876 | Carson et al. | Oct 2001 | B1 |
| 6310072 | Smith et al. | Oct 2001 | B1 |
| 6319510 | Yates et al. | Nov 2001 | B1 |
| 6355657 | Osborne et al. | Mar 2002 | B1 |
| 6375978 | Kleiner et al. | Apr 2002 | B1 |
| 6383471 | Chen et al. | May 2002 | B1 |
| 6425892 | Southam et al. | Jul 2002 | B2 |
| 6436433 | Muller | Aug 2002 | B1 |
| 6464688 | Harper et al. | Oct 2002 | B1 |
| 6465004 | Rossi-Montero et al. | Oct 2002 | B1 |
| 6579059 | Chen et al. | Jun 2003 | B2 |
| 6596261 | Adjei et al. | Jul 2003 | B1 |
| 6605060 | O'Neil et al. | Aug 2003 | B1 |
| 6610317 | Straub et al. | Aug 2003 | B2 |
| 6669953 | Kamiyama et al. | Dec 2003 | B1 |
| 6685964 | Bartholomaeus et al. | Feb 2004 | B1 |
| 6737080 | Schumann et al. | May 2004 | B1 |
| 6791003 | Choi et al. | Sep 2004 | B1 |
| 6841161 | Passmore et al. | Jan 2005 | B1 |
| 6868286 | Hine et al. | Mar 2005 | B1 |
| 6881208 | Phipps et al. | Apr 2005 | B1 |
| 7001609 | Matson et al. | Feb 2006 | B1 |
| 7026360 | Festo et al. | Apr 2006 | B1 |
| 7504114 | Kurita et al. | Mar 2009 | B1 |
| 7556823 | Miller, II et al. | Jul 2009 | B2 |
| 7700122 | Kolesnikov et al. | Apr 2010 | B1 |
| 20010006967 | Crain et al. | Jul 2001 | A1 |
| 20010011095 | Shuster et al. | Aug 2001 | A1 |
| 20010018072 | Unger et al. | Aug 2001 | A1 |
| 20010018457 | DiSanto et al. | Aug 2001 | A1 |
| 20010024658 | Chen et al. | Sep 2001 | A1 |
| 20010031787 | Hsu et al. | Oct 2001 | A1 |
| 20010033828 | Edwards et al. | Oct 2001 | A1 |
| 20010033858 | Zhang et al. | Oct 2001 | A1 |
| 20010033865 | Oshlack et al. | Oct 2001 | A1 |
| 20010037104 | Zhang et al. | Nov 2001 | A1 |
| 20010039343 | Mulvihill et al. | Nov 2001 | A1 |
| 20010047005 | Farrar | Nov 2001 | A1 |
| 20010053777 | Brecht et al. | Dec 2001 | A1 |
| 20020004063 | Zhang et al. | Jan 2002 | A1 |
| 20020004066 | Stanley et al. | Jan 2002 | A1 |
| 20020004484 | Pasternak et al. | Jan 2002 | A1 |
| 20020010127 | Oshlack et al. | Jan 2002 | A1 |
| 20020012677 | Levine et al. | Jan 2002 | A1 |
| 20020017296 | Hickle et al. | Feb 2002 | A1 |
| 20020019421 | Biberman et al. | Feb 2002 | A1 |
| 20020019563 | Webber et al. | Feb 2002 | A1 |
| 20020022054 | Sawada et al. | Feb 2002 | A1 |
| 20020028235 | Reed et al. | Mar 2002 | A1 |
| 20020032581 | Reitberg et al. | Mar 2002 | A1 |
| 20020037313 | Simon et al. | Mar 2002 | A1 |
| 20020042587 | Murdock et al. | Apr 2002 | A1 |
| 20020044966 | Bartholomaeus et al. | Apr 2002 | A1 |
| 20020045572 | Clemens et al. | Apr 2002 | A1 |
| 20020045636 | Clemens et al. | Apr 2002 | A1 |
| 20020052007 | Chang et al. | May 2002 | A1 |
| 20020052573 | Georgieff et al. | May 2002 | A1 |
| 20020053093 | Barak et al. | May 2002 | A1 |
| 20020055496 | McCoy et al. | May 2002 | A1 |
| 20020055704 | Scott et al. | May 2002 | A1 |
| 20020058050 | Sackler et al. | May 2002 | A1 |
| 20020058068 | Houze et al. | May 2002 | A1 |
| 20020058608 | Cormier et al. | May 2002 | A1 |
| 20020058809 | Emmanuel et al. | May 2002 | A1 |
| 20020071809 | Pather et al. | Jun 2002 | A1 |
| 20020077285 | Pasternak et al. | Jun 2002 | A1 |
| 20020081333 | Oshlack et al. | Jun 2002 | A1 |
| 20020086343 | Cameron et al. | Jul 2002 | A1 |
| 20020086890 | Levin et al. | Jul 2002 | A1 |
| 20020087193 | Riddle et al. | Jul 2002 | A1 |
| 20020099013 | Piccariello et al. | Jul 2002 | A1 |
| 20020099049 | Burch et al. | Jul 2002 | A1 |
| 20020102280 | Anderson et al. | Aug 2002 | A1 |
| 20020106329 | Leslie et al. | Aug 2002 | A1 |
| 20020106407 | Coleman et al. | Aug 2002 | A1 |
| 20020107265 | Chen et al. | Aug 2002 | A1 |
| 20020119187 | Cantor et al. | Aug 2002 | A1 |
| 20020123489 | Baxter et al. | Sep 2002 | A1 |
| 20020124272 | Messing et al. | Sep 2002 | A1 |
| 20020128248 | Salvemini et al. | Sep 2002 | A1 |
| 20020128591 | Kleiner et al. | Sep 2002 | A1 |
| 20020132794 | Lind et al. | Sep 2002 | A1 |
| 20020137761 | Crain et al. | Sep 2002 | A1 |
| 20020147197 | Newman et al. | Oct 2002 | A1 |
| 20020160043 | Coleman et al. | Oct 2002 | A1 |
| 20020164290 | Stefely et al. | Nov 2002 | A1 |
| 20020165248 | Wimmer et al. | Nov 2002 | A1 |
| 20020176841 | Barker et al. | Nov 2002 | A1 |
| 20020176888 | Bartholomaeus et al. | Nov 2002 | A1 |
| 20020177232 | Melker et al. | Nov 2002 | A1 |
| 20020179758 | Reed et al. | Dec 2002 | A1 |
| 20020183722 | Harper et al. | Dec 2002 | A1 |
| 20020187996 | Dewey et al. | Dec 2002 | A1 |
| 20020195493 | Dell et al. | Dec 2002 | A1 |
| 20020197324 | Watts et al. | Dec 2002 | A1 |
| 20020198484 | Young et al. | Dec 2002 | A1 |
| 20030004126 | Bountra et al. | Jan 2003 | A1 |
| 20030004177 | Kao et al. | Jan 2003 | A1 |
| 20030004554 | Riff et al. | Jan 2003 | A1 |
| 20030013689 | Helton et al. | Jan 2003 | A1 |
| 20030026829 | Venkatraman et al. | Feb 2003 | A1 |
| 20030027835 | Hamon et al. | Feb 2003 | A1 |
| 20030027936 | Murray et al. | Feb 2003 | A1 |
| 20030032001 | Broderick et al. | Feb 2003 | A1 |
| 20030032361 | Murasko et al. | Feb 2003 | A1 |
| 20030032947 | Harper et al. | Feb 2003 | A1 |
| 20030035775 | Klibanov et al. | Feb 2003 | A1 |
| 20030035831 | Modi et al. | Feb 2003 | A1 |
| 20030049300 | Terry et al. | Mar 2003 | A1 |
| 20030064093 | Jordan et al. | Apr 2003 | A1 |
| 20030088236 | Johnson et al. | May 2003 | A1 |
| 20030091620 | Fikstad et al. | May 2003 | A1 |
| 20030095992 | Erhardt et al. | May 2003 | A1 |
| 20030100507 | Gulati et al. | May 2003 | A1 |
| 20030119827 | Hickey et al. | Jun 2003 | A1 |
| 20030125343 | Gambacorti-Passerini et al. | Jul 2003 | A1 |
| 20030129219 | Hong et al. | Jul 2003 | A1 |
| 20030130203 | Christoph et al. | Jul 2003 | A1 |
| 20030138503 | Staniforth et al. | Jul 2003 | A1 |
| 20030139396 | Gibson et al. | Jul 2003 | A1 |
| 20030139698 | Hyson et al. | Jul 2003 | A1 |
| 20030166624 | Gale et al. | Sep 2003 | A1 |
| 20030170295 | Kim et al. | Sep 2003 | A1 |
| 20030187009 | Wentland et al. | Oct 2003 | A1 |
| 20030190290 | Ross et al. | Oct 2003 | A1 |
| 20030199426 | Carrara et al. | Oct 2003 | A1 |
| 20030216413 | Root-Bernstein et al. | Nov 2003 | A1 |
| 20030220497 | Hung et al. | Nov 2003 | A1 |
| 20030229263 | Connors et al. | Dec 2003 | A1 |
| 20040023249 | Balch et al. | Feb 2004 | A1 |
| 20040034059 | Grarup et al. | Feb 2004 | A1 |
| 20040034108 | Whittle et al. | Feb 2004 | A1 |
| 20040037882 | Johnson et al. | Feb 2004 | A1 |
| 20040081685 | Wright, IV et al. | Apr 2004 | A1 |
| 20040092531 | Chizh et al. | May 2004 | A1 |
| 20040096491 | Tateishi et al. | May 2004 | A1 |
| 20040101482 | Sanders et al. | May 2004 | A1 |
| 20040116352 | Chizh et al. | Jun 2004 | A1 |
| 20040121979 | Susilo et al. | Jun 2004 | A1 |
| 20040131665 | Wepfer et al. | Jul 2004 | A1 |
| 20040138461 | Mathew et al. | Jul 2004 | A1 |
| 20040146547 | Marcenyac et al. | Jul 2004 | A1 |
| 20040167060 | Wolpe et al. | Aug 2004 | A1 |
| 20040180080 | Furusawa et al. | Sep 2004 | A1 |
| 20040186417 | Phipps et al. | Sep 2004 | A1 |
| 20040208918 | Koch et al. | Oct 2004 | A1 |
| 20040213855 | Pettersson et al. | Oct 2004 | A1 |
| 20040234583 | Muller | Nov 2004 | A1 |
| 20040241218 | Tavares et al. | Dec 2004 | A1 |
| 20040241219 | Hille et al. | Dec 2004 | A1 |
| 20040258753 | Demeester et al. | Dec 2004 | A1 |
| 20050009796 | Goodchild et al. | Jan 2005 | A1 |
| 20050019381 | Petereit et al. | Jan 2005 | A1 |
| 20050048104 | Venkatraman et al. | Mar 2005 | A1 |
| 20050081440 | Sauvage et al. | Apr 2005 | A1 |
| 20050085440 | Birch et al. | Apr 2005 | A1 |
| 20050087198 | Bruno-Raimondi et al. | Apr 2005 | A1 |
| 20050176790 | Bartholomaus et al. | Aug 2005 | A1 |
| 20050181032 | Wilkins et al. | Aug 2005 | A1 |
| 20050186141 | Gonda et al. | Aug 2005 | A1 |
| 20050208117 | Venkatraman et al. | Sep 2005 | A1 |
| 20050278195 | Getz et al. | Dec 2005 | A1 |
| 20060040869 | Roberts et al. | Feb 2006 | A1 |
| 20060116662 | McNichols et al. | Jun 2006 | A1 |
| 20070184097 | Kurita et al. | Aug 2007 | A1 |
| 20080038330 | Fleischer et al. | Feb 2008 | A1 |
| 20090238886 | O'Mahony et al. | Sep 2009 | A1 |
| 20090264855 | Phipps et al. | Oct 2009 | A1 |
| Number | Date | Country |
|---|---|---|
| 3526339 | Jan 1986 | DE |
| 4310012 | Sep 1994 | DE |
| 4438989 | Mar 1996 | DE |
| 19527925 | Feb 1997 | DE |
| 19912477 | Sep 2000 | DE |
| 10141650 | Nov 2002 | DE |
| 20220982 | Dec 2004 | DE |
| 20221087 | Jan 2005 | DE |
| 20221397 | Oct 2005 | DE |
| 0328806 | Aug 1989 | EP |
| 0415055 | Mar 1991 | EP |
| 0483105 | Apr 1992 | EP |
| 0622075 | Nov 1994 | EP |
| 0695177 | Feb 1998 | EP |
| 0 842 662 | May 1998 | EP |
| 0842662 | May 1998 | EP |
| 0842662 | May 1998 | EP |
| 0887075 | Dec 1998 | EP |
| 1225951 | Jun 2005 | EP |
| WO-9320165 | Oct 1993 | WO |
| WO-9415609 | Jul 1994 | WO |
| WO 9518603 | Jul 1995 | WO |
| WO 0226217 | Mar 1996 | WO |
| WO 9608229 | Mar 1996 | WO |
| WO-9608229 | Mar 1996 | WO |
| WO 9813085 | Apr 1998 | WO |
| WO-9813035 | Apr 1998 | WO |
| WO 9836740 | Aug 1998 | WO |
| WO 9902141 | Jan 1999 | WO |
| WO 0024386 | May 2000 | WO |
| WO-0041538 | Jul 2000 | WO |
| WO 0064418 | Nov 2000 | WO |
| WO-0064418 | Nov 2000 | WO |
| WO-0074661 | Dec 2000 | WO |
| WO-0126705 | Apr 2001 | WO |
| WO 0224157 | Mar 2002 | WO |
| WO 02074286 | Sep 2002 | WO |
| WO-03018075 | Mar 2003 | WO |
| Entry |
|---|
| Grond et al., “Clinical Pharmacokinetics of Transdermal Opioids”, Drug Delivery Systems, Clin. Pharmacokinet., vol. 38, No. 1, pp. 59-89, Jan. 2000. |
| Roy et al., “Controlled Transdermal Delivery of Fentanyl: Characterizations of Pressure-Sensitive Adhesives for Matrix Patch Design”, Journal of Pharmaceutical Sciences, vol. 85, No. 5, May 1996, referred to as XP-000583527. |
| U.S. Appl. No. 60/276,837, filed Mar. 16, 2001, Li et al. |
| Roy et al, “Solubility and Related Physicochemical Properties of Narcotic Analgesics”; Pharmaceutical Research, vol. 5, No. 9, 1988, pp. 580-583. |
| Handbook of Pressure Sensitive Adhesives, 2nd Edition, 1982, pp. 400, 401, 414-417. |
| Patent Abstracts of Japan, vol. 015, No. 001 (C-0793) and JP 02 255611. |
| Duro-Tak® Transdermal Grade Pressure Sensitive Adhesive, S.H. Steenhuis, National Starch & Chemical B.V., dated Feb. 2002. |
| Duro-Tak® Transdermal Grade Pressure Sensitive Adhesives Product Selection Guide, National Starch & Chemical, dated Jul. 22, 2003; and. |
| National Starch and Chemical Company Solubility Calculator, National Starch & Chemical, Adhesives Division, dated 2003. |
| U.S. Appl. No. 60/234,248, filed Sep. 19, 2000, Silverberg et al. |
| U.S. Appl. No. 60/236,973, filed Sep. 29, 2000, Adam Cantor. |
| U.S. Appl. No. 60/284,017, filed Apr. 16, 2001, Adam Cantor. |
| Confidential Letter of National Starch to Alza, dated Apr. 28, 2004. |
| Letter of National Starch to Johnson & Johnson Services, dated Jan. 12, 2005. |
| Internet printout of Nov. 2003; Solubility Calculator. |
| Kokubo et al., Interaction Between Drugs and Pressure-Sensitive Adhesives in Transdermal Therapeutic Systems, 1994, Pharmaceutical Research, vol. 11, No. 1, pp. 104-107. |
| Feldstein, et al., Hydrophilic Polymeric Matrices for Enhanced Transdermal Drug Delivery, 1996, International Journal of Pharmaceutics, vol. 131, pp. 229-242. |
| Otto-Albrecht Neumüller, Römpps Chemie-Lexikon, 1981, pp. 986-987. |
| Labtec GmbH, “Determiniation of solubility of fentanyl in polyacrylates,” Langenfeld, Germany, 2007 (Submitted in file history of EP 1418894). |
| Novis AG, Loslichkeit von Fentanyl Base im Polymer des Klebers Gelva 737, Jun. 15, 2007. |
| “Declaration of Hyun Suk Yu”, Feb. 2006. |
| National Starch & Chemical, “Transdermal Grade Pressure Sensitive Adhesives”, Bridgewater, NJ, 1999. |
| “Gelva Multipolymer Solution 737”, Nov. 13, 2000. |
| National Starch & Chemical, “Acrylic Polymers for transdermal systems”, Bridgewater, NJ, 1997. |
| Falbe et al., “Fentanyl”, Rompp Lexikon, Georg Thieme Verlang, 1997. |
| P. Liu et al., “A novel method for measuring solubility of a drug in an adhesive”, Pharmaceut. Res., 14, S317 (1997)—(Presented at the AAPS Annual Meeting, Boston MA, Nov. 19. |
| Jasti et al., “A novel method for determination of drug solubility in polymeric matrices”, Journal of Pharmaceutical Sciences, vol. 9, No. 8, pp. 2135-2141, Aug. 2004. |
| O'Neil et al. “Fentanyl”, The Merck Index, Forteenth Edition, p. 4001, 2006. |
| Satas, D., “Acrylic Adhesives”, Handbook of Pressure Sensitive Adhesive Technology, Satas & Associates, 2nd Edition (1989), pp. 397-456. |
| Tan, Hock S. et al., “Pressure-sensitive adhesives for transdermal drug delivery systems,” Pharm. Science and Tech. Today, Feb. 1999, pp. 60-69, vol. 2, No. 2. |
| Milker et al., “Vernetzung von Copolymeren auf Acrylatbasis”, 1984, pp. 85-91, 9, Muenchener Klebstoff-und Veredelungsseminar, Muenchen, Germany. |
| Milker et al., “Vernetzung von Copolymerisaten auf Acrylatbasis”, Adhaesion, 1985, pp. 29-32, 3, Germany. |
| Extract Communication From Cornelius, Bartenbach, Haesemann in Case No. 21 O 18429/06 LTS Lohmann Therapie-Systeme AG v. Novosis AG dated Oct. 4, 2007 (with English translation). |
| Mueller, W; Determination of saturatio solubilities of Fentanyl in Gelva 737, Durotak 387-4287 and Durotak 387-2287; Test Report from LTS Lohmann Therapie-Systeme, dated Jun. 21, 2007 (with English translation). |
| Salman, N; Solubility of Fentanyl Base in the Polymer base of the Adhesive Durotak 87-4098, Confidential Experimal Report, Ancino AG dated Mar. 3, 2009 pp. 1-4 (with English translation). |
| Christen, H R; Introduction to Chemistry, 9th Edition (1974) pp. 53-55 (with English translation). |
| Declaration of Dr. Walter Mueller (with English translation). |
| Duro-Tak Transdermal Grade Pressure Sensitive Adhesives, Product Selection Guide. |
| Klaffenbach and Becker, Determination of solubility of Fentanyl in polyacrylate copolymer DuroTak 87-4098, Study report dated Dec. 11, 2005 pp. 4-8. |
| Annex 2, European Patent No. 1418894, Transdermal Therapeutic System with Fentanyl, 1 Page. |
| Annex 3, European Patent No. 1418894, Saturation Solubility Testing for Fentanyl in National Starch Adhesives 87-2287 and 87-4287, Transdermal Therapeutic System with Fentanyl, 4 pages. |
| Attachment B, Hyun Suk Yu, Feb. 2006. |
| Attachment C, Millennial World Congress of Pharmaceutical Sciences, Abstracts, Hyun Suk Yu, Feb. 2006, 5 pages. |
| Breltonbach and Becker, Determination of solubility of Fentanyl in polyacrylate copolymer DuroTak 87-4098, Bird and Bird LLP, Exhibit A, Labtec, 2010, 8 Pages. |
| Castlemain, Scientific and Engineering consultancy, Jun. 2, 2010, Expert opinion, Gelva 737, Geoffrey Lee, 7 pages. |
| Declaration of Hyun Suk Yu, Dongbaek-woosung Apt. 1310-1201, Sanbon2-dong, Gunpo-si, Gyonggi-do, 435-745, Feb. 2006, 2 Pages. |
| Declaration of Subbu Venkatraman, Serial No: 7,405,630, 1990, 2 Pages. |
| Dissolution Test for Transdermal Patches, European Pharmacopoeia 6.0, 2008, pp. 275-277. |
| Duro-Tak Technical Information, Adhesive Transdermal, 2007, 1 page. |
| DURO-TAK® Transdermal Grade Pressure Sensitive Adhesive, DURO-TAK TM 387-2287/87-2287, Technical data sheet, Henkel, 2009, 3 pages. |
| European Search Report for Application No. EP;07001087, dated Jul. 25, 2007, 6 pages. . |
| Feature Analysis of Claim 1, Bird & Bird, Exhibit D1, 1 page. |
| Handbook of Pressure Sensitive Adhesive Technology, Third Edition, Donatas Satas, Satas & Associates, Warwick, Rhode Island, 1999, 12 pages. |
| Letter of National Starch & Chemical to Philip, dated Jan. 12, 2005. |
| Liron, Z and Cohen, S., “Percutaneous Absorption of Alkanoic Acids li: Application of Regular Solution Theory,” Journal of Pharmaceutical Sciences., 73(4):538-542, New York, NY : Elsevier,United States., (Apr. 1984). |
| Marsac,P.J et al.,, “Estimation of Drug-polymer Miscibility and Solubility in Amorphous Solid Dispersions Using Experimentally Determined Interaction Parameters,” Pharmaceutical Research, 26(1):139-151, Kluwer Academic Plenum Publishers , United States, (Jan. 2009). |
| Mullin, J.W., Crystallization, Fourth Edition, 2001, 6 pages. |
| Polymer Library Abstract Display, Accession Number- 091664, Gelva 737, Monsanto Polymer Products Co, 2008, Monsanto, Acrylic Resin Solution for Pressure Sensitive Adhesives, 6 pages. |
| Confidential Letter of National Starch & Chemical to Angela, dated Apr. 28, 2004. |
| Recordation of Assignment document, 700007637A, Sep. 26, 2001, 7 pages. |
| Publication List—Dr. Hans-Michael Wolff, Aug. 2017, 3 pages. |
| Reismann, S ans Lee, G., “Assessment of a Five-layer Laminate Technique to Measure the Saturation Solubility of Drug in Pressure-sensitive Adhesive Film.,” Journal of pharmaceutical sciences, 101(7):2428-2438, Elsevier, United States., (Jul. 2012). |
| Chien, Y.W., “Transdermal Controlled Systemic Medications,” Controlled Drug-Delivery Research Center, Rutgers-The State University of New Jersey Piscataway, Marcel Dekker, Inc, New York and Basel, 1987, 14 Pages. |
| Material Safety Data Sheet, Gelva MultiPolymer Solution 737, Reference Number 0000000000625, 2001, Version 4.1/E, 2001, 9 pages. |
| National Starch and Chemical, A member of the ICI Group, Product Number 87-4098, Aug. 2007, 7 Pages. |
| Transmittal of Provisional Application, Level -2, Version 1.1, Composition of the Transdermal Delivery of Fentanyl, 56633USA99.002, 61 pages. |
| Venner Shipley, National Starch & Chemical, Transdermal Grade Pressure Sensitive Adhesives, 2007, Confidential Information, 3 Pages. |
| Yoon, H.J., et al., Transdermal Fentanyl Matrix Patch—Evaluation of a Parallel Binary Matrix System, Samyang Corporation, Taejeon, Korea, Attachment A, Hyun Suk Y.U, Apr. 19, 2000, 17 Pages. |
| Lederer and Keller, EP07001087, Third Party Observations, Mar. 8, 2013, 3 pages. |
| Transdermal Administration of Fentanyl and Analogs Thereof, Technical Field, ARC 2912, 27 Pages. |
| Transmittal of U.S. Appl. No. 60/236,973, Composition of the Transdermal Delivery of Fentanyl, 56032USA39.002, 49 pages. |
| Venkatraman, S and Gale, R., “Skin Adhesives and skin adhesion, 1. Transdermal drug delivery systems.,” Biomaterials, 19(13):1119-1136., Amsterdam : Elsevier Science, Netherlands, (Jul. 1998). |
| Wokovich,A.M et al. “Transdermal Drug Delivery System (Tdds) Adhesion as a Critical Safety, Efficacy and Quality Attribute,” European Journal of Pharmaceutics, 64(1):1-08, Elsevier Science , Netherland, (Aug. 2006 ). |
| Zaffaroni, A., “The Innovators: Delivering Drugs, ” Chemtech, 82-88, (Feb. 1980). |
| Muller, W., “Determination of saturation solubilities of Fentanyl in Gelva 737, Durotak 387-4287 and Durotak 387-2287,” Lohmann Therapy Systems, dated Jun. 21, 2007, 2 pages. |
| Salman, N., “Solubility of Fentanyl Base in the Polymer of Duro-Take® Adhesive 87-4098,” Acino AG, dated Mar. 3, 2009, 8 pages. |
| Muller, W., “Statement by Dr. Walter Muller,” LTS signed May 25, 2014, 8 pages. |
| Rompp, “Solutions: Breakdown,” retrieved from https://roempp.thieme.de/roempp4.0/do/data/RD-12-01485, edited by ROMPP author, dated Dec. 8, 2014, 13 pages. |
| Study Report, “Saturation concentration Fentanyl; Determination of the saturation concentration of Fentanyl in acrylic adhesives,” No. 2002326, valid from Oct. 14, 2014, 30 pages. |
| Wolff, H-M., et al., “Measurement of the Saturation Solubility of Fentanyl in a Polyacrylate,” LTS, dated Sep. 29, 2017, 45 pages. |
| Thieme Rompp, “Fentanyl,” retrieved from https://roempp.thieme.de/roempp4.0/do/data/RD-0600480, dated Aug. 16, 2017, 11 pages. |
| German Patent and Trademark Office, “Oral Proceeding Rulings in the utility model cancellation action of model No. 202 21 087,” dated Feb. 28, 2007, Munich, Germany, 17 pages. |
| German Patent and Trademark Office, “Oral Proceeding Rulings in the utility model cancellation action of model No. 202 21 160,” Sep. 5, 2007, Munich, Germany, 16 pages. |
| German Patent and Trademark Office, “Oral Proceeding Rulings in the utility model cancellation action of model No. 202 21 161,” Sep. 5, 2007, Munich, Germany, 15 pages. |
| Letter to the Patent Litigation Chamber, Munich District Court, “Reference Number 21 O 18429/06,” dated Feb. 2, 2007, 14 pages. |
| Letter to the Patent Litigation Chamber, Munich District Court, “Claim by LTS Lohmann Therapie- Systeme AG,” dated Oct. 11, 2006, 42 pages. |
| Prescribing Information, “Fentadolon Matrixpflaster,” last updated Jan. 2007, 10 pages. |
| Novosis AG., “Solubility of Fentanyl Base in Polymer of the Gelva 737 Adhesive,” dated Jun. 15, 2007, 8 pages. |
| Lohman Therapy Systems, “Determination of saturation solubilites of Fentanyl in Gelva 737, Durotak 387-4287 and Durotak 387-2287,” dated Jun. 21, 2007, 2 pages. |
| Antonietti, M., “Letter to Dr. Best,” dated Jan. 20, 2005, 14 pages. |
| Claims submitted Mar. 20, 2007, in European Patent Opposition EP1418894, signed Feb. 13, 2017, 5 pages. |
| Federal Patent Court, “Concerning the German Patent 101 41 650,” reference No. 3 Ni 22/04, dated Aug. 2005, 68 pages. |
| Test Report for EP 1 418 894 B1, dated Apr. 16, 2009, 9 pages. |
| Certified Korean Patent Application Priority Document No. 1999 43794. Date of Application Oct. 11, 1999, 57 pages. |
| Number | Date | Country | |
|---|---|---|---|
| 20040234584 A1 | Nov 2004 | US |
