Title of Invention

DRUG DELIVERY SYSTEM

Abstract

ABSTRACT 3119/CHENP/2005 "A DRUG DELIVERY SYSTEM'' The present invention relates to a drug delivery system comprising at least one compartment consisting of (i) a drug loaded thermoplastic polymer core, (ii) a drug- loaded thermoplastic polymer intermediate layer and (iii) a non-medicated thermoplastic polymer skin covering the intermediate layer, wherein said intermediate layer is loaded with crystals of a first pharmaceutically active compound and wherein said core is loaded with a second pharmaceutically active compound in dissolved form.

Full Text

ai c c c Drug delivery system FIELD OF THE INVENTION The present invention relates to the field of female contraception and hormone replacement therapy. Tbe present invention relates to a drug delivery system (device) for the simultaneous release of two or more active substances and more particularly to a ring shaped vaginal drug delivery system, which system releases the active substances in a substantially cocstant ratio over a prolonged period of time. Since the invention pertains to a drug delivery article for intra-vaginal use, its use is focussed on typically female medical indications, such as contraception and hormone-replacement The article according to the invention is particularly in the form of a ring, and will hereinafter be referred to as a vagmal ring. BACKGROUND OF THE INVENTION Vaginal rings are known. Background art in &is respect includes the following patent documents. U.S. Patents Nos. 3,995,633 and 3,995,634, describe separate, preferably spherical or cylindrical, reservoirs containing different active substances which are assembled in specially constructed holders. U.S. Patent No. 4,237,885 describes a tube or coil of polymeric material which is divided into portions by means of a plurality of "spacers" provided in the tube, after which each of he separate tube portions is filled with a different active substance in a silicone fluid and the wo ends of the tube are subsequently connected to one another. In this release system, lowever, transport (diflusion) of active material from one reservoir to the other takes place hrough the wall of the tube, especially iq)on prolonged storage, so that the pre-set fixed elease ratio between the active substances in question will change over a period of time. European patent publication 0,050,867 discloses a two-layered vaginal ring which comprises a pharmacologically acceptable supporting ring covered by two layers preferably of silicone elastomers whereby the inner layer is a silicone elastomer loaded with an active substance. US Patent No. 4,292,965 describes a ring shaped vaginal delivery system of three layers made of silicone elastomers. US Patent 4,596,576 describes a two-compartment vaginal ring wherein each compartment contains a different active substance. To achieve a suitable ring with a constant release ratio between the various active substances, the end portions of die compartments are joined by glass stoppers. Patent Publication WO 97/02015 describes a two-compartments device, a first compartment consisting of a core, a medicated middle layer and a non medicated outer layer, and a second compartment consisting of a medicated core and a non mecUcated outer layer. EP 876 815 discloses a vaginal ring (Nuvaring®) which is designed for ttie simultaneous release of a progestogenic steroid compound and an estrogenic steroid compoimd in a fixed physiological ratio over a prolonged period of time. The drug delivery system comprises one compartment comprising a Ihennoplastic polymer core containing the mixture of the progestogenic and estrogenic compounds and a thermoplastic polymer skin, the progestogenic compound being initially dissolved in the polymer core material in a relatively low degree of supersaturation. From the above disclosures, it is clear that e.g. the material, the layers and the compartments ire all aspects of a ring device which play a role in the designs that have been developed. \]1 choices are usually made with a view to obtain a constant release pattern, which is 'implicated when two or more active substances are involved. The latter is of particular roportance m the field of contraception, as for this puipose often a combination of a 3 progestagen and an estrogen is used Also in hormone replacement, however, it is desired to have rings which deliver combinations of drugs. Among the above disclosures, EP 876 815 clearly sets a standard; it involves a one-compartment design, it obviates the need for silastic polymer by using EVA combinations, and it releases two or more active substances in a substantially constant ratio to one anotiier over a prolonged period in time. As any product of technology at all times however, also the latter can still be improved upon. The drug delivery device disclosed in EP 876815 is physically stable only when stored below room temperature. It requires storage and transport below room temperature which is expensive and requires a lot of attention. Moreover, if not stored below room temperature, steroid eventually crystalUzes out onto the skin of the device which may lead to uncontrollable and high burst release. The subject improved dmg delivery system solves this problem since it is physically stable under room temperature conditions and thus does not need special storage and transportation conditions. Moreoever, in the subject improved drug delivery system, it is possible to adjust the release rate of more than one pharmaceutically active con:Q)ound independently from one another, while maintaining the physical stability of the system. SUMMARY OF THE INVENTION The subject invention provides a tiiree-layer design vaginal ring, physically stable at room temperature, from which at least two pharmaceutically active compounds can be released independenfly from one another. The ring comprises at least one compartment comprising (i) a medicated thermoplastic poly¬mer core, (ii) a medicated thermoplastic polymer intermediate layer and (iii) a non-medicated Ihermoplastic polymer sldn covering the intermediate layer. The intermediate layer is medicated (loaded) with (a) crystals of a first active substance and wife (b) a second active substance in dissolved form. The core is loaded with the second active substance as well, optionally in the same concentration as in the intramediate layer. FIGURES Figure 1: In vitro release rates of etonogestrel (ENG) for all 4.0 mm batches. Figure 2: In vitro release rates of etonogestrel for all 3.5 mm batches. Figure 3: In vitro release rates of ethinyl estradiol (BE) for all 4.0 mm batches. Figure 4: In vitro release rates of ethinyl estradiol for all 3.5 mm batches. Figure 5: Schematic description of a vaginal ring of the subject invention. Figure 6: In vitro-release rates of etonogestrel and ethinyl estradiol from one Al ring. Figure?: In vitro-release rates of etonogestrel and ethinyl estradiol fttjm one A2 ring. Figure 8: In vitro-release rates of etonogestrel and ethinyl estradiol from one A3 ring. Figure 9: In vitro-release rates of etonogestrel and ethinyl estradiol from one A4 ring. Figure 10: In vitro-release rates of etonogestrel and ethinyl estradiol fi-om one Bl ring. Figure 11: In vitro-release rates of etonogestrel and ethinyl estradiol fi»m one B2 ring. Figure 12: In vitro-release rates of etonogestrel and ethinyl estradiol fiom one B3 ring. Figure 13: ID vitro-release rates of etonogestrel and ethinyl estradiol horn one B4 ring. Figure 14: In vitro release rates of etonogestrel for fibre variants E, F, G, H and L Figure 15: In vitro release rates of etonogestrel for fibre variants J, K, L, W and X. Figure 16: In vitro release rates of etonogestrel for fibre variants M, N, O, P and Q. Figure 17: In vitro release rates of etonogestrel for fibre variants R, S, T, U and V. Figure 18: In vitro release rates of ethinyl estradiol for fibre variants E, F, G, H and I. Figure 19: - In vitro release rates of ethinyl estradiol for fibre variants J, K, L, W and X. Figure 20: In vitro release rates of ethinyl estradiol for fibre variants M, N, O, P and Q. In vitro release rates of ethinyl estradiol for fibre variants R, S, T, U and V. DETAILED DESGRIPTION OF THE INVENTION Fick*s law of difiusion governs the release of compounds, such as contraceptive steroids fi-om a ring. According to this law, the amoimt of mass transferred over the boundary is an inverse fimction of the distance across the boundary. In a two-layer design, the steroid nearest to the outer layer (the skin) will diffuse first and this results in depletion of the outer core and hence toe diffusion distance will increase. The depletion of the outer core layer and the resulting increase of the di£flision distance will result in a decrease of the release rate. When speaking about the release rate of one drug substance, the problem of depletion and increase of the dif&ision distance can be overcome by concentrating the dmg substance in an intermediate layer between a placebo skin and a placebo core. Since the drug substance is tiien concentrated in a relatively thin layer, lengthening of the diffusion distance during release is minimal, resulting in a more constant release rate over time. The release rate of a cylindrical reservoir/membrane design is: dM,2w;LDj,Ki^AC dt Ln (ro / T| ) L = the length of the cylinder Dp = tile dififiision co-efficient of the compound in a skm polymer Kfvi = partition coefficient of the steroid between the skin and core polymer AC = the difference in concentration between the core (or intermediate layer) and the sink ro = is the overall radius, i.e. the radius of the Qflinder including the skin - ri = is the radius of the core The equation shows that zero order release is obtained ^en tiie term on the ri^t hand side of the equation is constant, i.e. not a fimction of time. Lengthening of tiie diffusion distance due to dqiletion of flie core is insignificant in a three-layer design containing one drug y substance and hence the term (ro / rj) may be considered abnost constant. In case the steroid in the intermediate layer is present in the dissolved state, the concentration gradient (AC) -will steadily decrease in time and consequently the release rate dM/dt will decrease (deviate from zero order release kinetics). The subject invention provides a drug delivery system comprising at least two active dmg substances. The subject invention provides a drug delivery system, ^ically a substantially ring-shaped form intended for vaginal administration, which comprises at least one compartment consisting of (i) a thermoplastic polymer core, (ii) a tiieimqplastic polymer intermediate layer and (iii) a thermoplastic polymer skin covering the intermediate layer, wherein said intermediate layer comprises (a) crystals of a first pharmaceutically active compound and (b) a second pharmaceutically active compound in dissolved state and wherein said core comprises said second compound as well, optionally in the same concentration as in the intermediate layer. The essence of this novel three-layered ring of the subject invention lies in the provision of the possibility to adjust the release rates of more than one pharmaceutically active compound independenfly from each ottier while maintaining the physical stability of the ring at room temperature. This is acconiphshed by (1) incorporating crystalline reservoirs of the (first) compound in the intermediate layer of the ring, (2) loading both the intermediate layer and the core of the ring with the second compound in dissolved form, thereby enlarging the compound reservoir, and (3) defining the thickness of tiie skin of tiie ring. In a specific embodiment of the subject invention, tiie compounds are steroids. For the sake of ease, we hereinafter refer to steroids, although also non-steroidal compounds are contemplated by the subject invention as well. The steroid molecules incorporated in the crystalline lattice are in dynamic equilibrium with the steroid dissolved in the polymer of the intermediate layer. When no diffusion occurs, the ^ steroid concentration in flie polymer will equal or come close to the equilibrium concentration. After the ring has been put in a sink, steroid will start to diffuse out of the ring and the concentration of the steroid dissolved in the polymeric intermediate layer will drop slightly. As a consequence thereof, the steroid crystals will start to dissolve. Thus, tiie decrease of the concentration gradient due to diffusive transport out of the ring is counterbalanced by the stat>id in the crystalline reservoir. Figures 1 and 2 illustrate this stabilizing eflFect of crystals in the intermediate layer. In the beginning, the slope of the release curve is very flat, Le. indicates that the release is almost zero order up to day 10. Then, after day 10, the release curve suddenly becomes much steeper, i.e. the release rate becomes more time dependent O^ss zero order). Apparendy this moment coincides with the moment that flie size and amount of crystals in the polymer matrix has decreased beyond a certain point and &om this point on the loss of steroid due to dif^ion outside the ring can no longer be adequately counterbalanced by crystals going into dissolution. When the majority of ciystals are dissolved the concentration gradient is no longer stabilized and hence a steeper curve is seen. The stabilization of &e conc^tration gradient by this mechanism functions when tiie dissolving of the steroid crystals proceeds fast compared to the loss of steroid due to division. So, tiie concentration drop is counter balanced to a certain extent, and the net effect will be zero provided the crystals dissolve relatively fast in the polymer. In other words, the subject three-layer design is a three-layered ring comprising at least one compartment consisting of (i) an intermediate layer loaded with two steroids, one (steroid A) partly present in the crystalline phase and partly dissolved in the polymer and the other (steroid B) entirely dissolved in the polymer, (ii) a core loaded with steroid B (entirely dissolved and optionally in the same concentration as in tiie intermediate layer) and (iii) a placebo skin. In the subject three-layered ring, steroid B is not only accommodated in the intermediate layer, but also in tiie core. In one embodiment of the subject invention, tiie concentration of steroid B is the same in tiie core and in the intermediate layer. By loading both core and intermediate layer with steroid B, the reservoir for steroid B is largely increased, allowing a feirly constant release rate of this steroid over a prolonged period (see figures 3 and 4). As a result of this design, the release rate of steroid A and the release rate of steroid B can be adjusted independently from each other. Moreover, by loading the core with steroid B, also back-difilusion of steroid B from the intermediate layer back to the core is prevented. Back-difiusion of steroid B would lead to a steadily decreasing concentration in fhe intermediate layer and thus a decreasing release profile upon storage (until even distribution of steroid B in core and intemiediate layer). Also steroid A may back-diffiise into the core. This is however less critical since the concentration of steroid A in the intermediate layer is stabilized because of its presence in crystalline form. In a special embodiment of the subject invention, steroid A, in dissolved form, can however also be loaded into the core. This will reduce (or eliminate) internal diflusion efibcts. Thus, the concept of this three-layer vaginal ring is to concentrate steroid in a relatively thin intermediate layer wherein part thereof will be present in the form of crystals dispersed in the thin intemiediate layer. The desired release rate of steroid A is obtained by adjusting the skin thickness. Hierefore, steroid A is incoiporated in crystalline form and steroid B in dissolved form thereby making it possible to adjust the concentration of steroid B to the already pre¬set skin thickness. Since the volume of the intermediate layer may be relatively small, this q>proach may lead to a relatively small content and may become depleted relatively fast A possible too fast depletion of the three-layered ring is prevented by loading fhe core wift the second steroid (B) as well. In a difTerent embodiment of the subject invention, the drug deliveiy system is a three-layered vaginal ring comprising at least one compartment consisting of (i) an intennediate layer loaded with steroid A partly present in the crystalline phase and partly dissolved in the polymer and (ii) a core loaded with steroid B which is entirely dissolved in the polymer and (iii) a placebo skin. This ring design, although containing only one steroid in the intennediate layer (as opposed to two steroids in the ring design described above), wili, after some time, turn into the same design as the ring described above wherein there are two steroids in the intennediate layer. This is because over a period of time, steroid B will diftiise into the intermediate layer and at a particular point in time will contain (i) an intermediate layer medicated with two steroids, one (steroid A) partly present in the ciystalline phase and partly dissolved in the polymer and the other (steroid B) entirely 10 dissolved in Ifae polymer, (ii) a core loaded with steroid B (entirely dissolved) and (iii) a placebo skin. The vagina] ring of the subject invention can be manu&ctured by the known process of extrusion, such as co-extrusion and/or blend-extrusion. The drug-loaded core, the drug-loaded intemsediate layer and the non-medicated outer layer are all co-extruded. The fibres Qxm obtained are cut into pieces of the required length and each piece is assembled to a ring-shaped device in any suitable manner. The rings are then packed for example in a suitable sachet, optionally after being sterilized or disinfected. The themioplastic polymer that can be used in practising the invention, may in principle be any thermoplastic polymer or elastomer material suitable for pharmaceutical use, such as low density polyethylene, efliylene-vinylacetate copolymers and styrene-butadiene-styrene copolymers. In a specific embodiment, ethylene-vinylacetate copolymer (poly-EVA) is used due to its excellent mechanical and physical properties (e.g. solubility of the steroids in the material). The poly-EVA material may be used for the core, the intermediate layer as well as the skin and can be any commercially available ethylene-vinylacetate copolymer, such as the products available under the trade names: Elvax, Evatane, Lupolen, Movriton, Ultrathene, Ateva and Vestypar. In one embodiment both core and intermediate layer are made out of the same polymer grade. In another embodiment, the core and the intermediate layer are not made out of the same polymer grade in order to allow for furdier flexibility of the ring. By electing different polymer grades for the core and the intermediate layer, fine-tuning of tiie flexibility of the ring is possible. The vaginal ring according to the inveniion Ciu^ i/o iijauafactuicd iu any size dsifsqmit^ In one embodiment, the ring has an outer diameter (outer circumference) of between 50 and 60 mm and in anotiier embodiment between 52 and 56 mm; the cross sectional diameter is between about 2.5 and 5 mm, in a specific embodiment between about 3.0 and 4.5 mm, and in anothCT embodiment between about 3.5 and 4.0 mm and in yet another embodiment is 4.0 mm. /I It is also an object of the subject invention to provide an inproved vaginal ring in which the intennediate layer and/or the core, in addition to steroids for contraception or hormone replacement, also comprises anti-microbials, e.g. to concomitently treat and/or prevent sexually-transmitted diseases (STD's) such as HIV, herpes, chlamydia and gonorrhoea. In the subject invention, the surface of the core body is more than 800 mm^ and in another embodiment more than 1000 mm^ and will typically be in the order of 1700-2200 mm^ though significantly larger surfaces are possible, provided that the design (physical dimensions) of the vaginal ring prevents inconvenience for flie subject It may sometimes be required to add a second compartment which is a placebo compartment or a compartment loaded with one or more other drugs. Such an extra compartment may be necessary for example in practising hormonal rq>lacement therapy, where the ratio between progestogen and estrogen is different from the ratio suitable for contraception. Such an extra compartment can also be necessary to admiiuster, in addition to the steroids, anti-microbial drugs to treat and/or prevent STD's such as AIDS, chlamydia, herpes and gonorrhoea. Any anti-microbial drug can be incorporated into a vaginal ring of tiie subject invention (in the intermediate layer and/or in the core and/or in an additional compartment). The anti¬microbial drug can be any anti-bacterial drug such as any antibiotic, any anti-viral agent, any anti-fimgal agent or any anti-protozoal agent An example of an anti-microbial drug contemplated to be incorporated into the vaginal ring of the subject invention is mandelic acid condensation polymer (Zanefeld et al (2002), Fertility and Sterility 78(5): 1107-1115). Another example is dapivirine (4-[[4-[2,4,6-trimelhylphenyl)aniino-2-pyrimidinyl]amino]benzonitrile). FigiWS sii6\^rs^i^iMti&iafes(Si|mon Of tttef^nffl rih^ of the subject invention. Ri WMH^"" diameter of the three-layered fibre. R2 is the radius of the core together with the intennediate layer and R3 is the radius of the core. The ratios of R1/R2 andRa/Rs described in that figure are defined as follows: In one embodiment, tiie drug delivery system is removed after about 21 days for an approximate one week period to permit menstruation. In other embodiments, tiie drug delivery system is removed after about 42, 63, 84,105, 126, 147,186, 189, 210, 231, 252, 273, 294,315,336 or 357 days for an approxhnate one week period to permit menstruation. After the approximate week to allow for menstruation, a new drag delivery system of the subject invention is inserted into the female vagina to provide contraception in the next female cyclus or cyclusses. The subject invention fiirther envisions a use of a drug delivery system of the subject invention for the manufacture of a contraceptive kit The subject invention ftmher encompasses a use of a drug deliveiy system of the subject invention for the manufacture of a medicament for hormone replacement therapy. The subject invention also provides a use of a drug delivery system of the subject invention for the manufacture of a combination preparation to provide contraception and to treat and/or prevent a sexually transmitted disease such as for example AIDS, herpes, chlamydia and gonorrhoea. The progestogenic steroidal conipound of the subject invention can be any suitable progestogen, such as desogestrel, etonogestrel, levonorgestrel, norgestimate, gestodene or any other steroidal compound with progestogenic activity. The estrogenic steroidal compound can be any suitable estrogen, such as estradiol, estriol, mestranol and ethinyl-estradiol. In a specific embodiment of the subject invention, the progestogen is etonogestrel. In a specific embodiment of the subject invention the estrogen for contraceptive use is ethinylestradibl. In aflbther embodiment, estradiol is the estrogen used for HRT. - In one embodiment of the subject invention, ethinyl estradiol is present in flie intermediate layer and in the core at about 0.05-1.5% by wei^t. In other embodiments, ethinyl estradiol is present in the intennediate layer and in the core at about 0.08-0.5% by weight, at about 0.09-0.20% by weight, at about 0.09-0.18% by weight or at about 0.09-0.15% by weight In one embodiment of the subject invention, etonogestrel is present in the intermediate layer at about 6-80% by weight. In other embodiments, etonogestrel is present in ibe intermediate layer at about 6-70% by weight, at about 10-53% by wei^t, at about 10-30% by weight, at about 10-15% by weight, or at about 10-12% by weight The subject invention also provides a method of manufacturing the three-layered drug delivery system of the subject invention by: (i) Producing a loaded (medicated) homogenous polymer core granulate and a loaded (medicated) homogenous polymer intermediate layer granulate; (ii) Co-extruding the core granulate and the intermediate layer granulate with a polymer skin granulate to form the three-layered drug delivery system. The production of the loaded (medicated) homogenous polymer core granulate and loaded (medicated) homogenous polymer intermediate layer granulate comprises: (a) grounding the polymer, (b) dry powder mixing the grounded polymer with the active compounds to be loaded in the intermediate layer; (c) dry powder mixing the grounded polymer with the active compound to be loaded in the core; (d) blend extruding the resulting powder mixtures of steps (b) and (c); (e) cutting the resulting loaded polymer strands into granules, th^eby obtaining a core granulate and an intermediate layer granulate; (f| lubricating bolb core granulate and intermediate granulate with a lubricant; wherein stq)s (b) and (c) are int^iexchangeable. The present invention i&^furlher described in~&e following exan^)lc3 which are notin-any way intended to limit the scope of the invention as claimed. EXAMPLES EXAMPLE 1 - Preparation of the three-layered ring EXAMPLE 2 - PHYSICAL STABILITY The storage stability of NuvaRing® at normal storage temperature (up to 30°C) is limited due to the formation of steroid crystals on the surface of the skin of the vaginal ring, which leads to an increased on-set release, the so-called burst release and thus to a decreased physical stability. The burst release (day 1 release) of 8 batches of a ring of the subject invention was tested at time zero and after 12,18 and 24 months storage at 30°Cy75% R.H. in a closed aluminum foil laminate sachet (WO 99/30976). The burst release of 3 representative NuvaRing® batches was also tested at time zero and after 12,18 and 24 months storage at 30°C/7S% R.H. in said closed aluminum foil laminate sachet The release rate at time zero was determined by analyzing 12 rings per batch and the release rate after 12,18 and 24 months was determined by analyzing 6 rings per batch. The results of these analyses are described in Tables 4, S and 6. It is ^parent diat the burst release of all three NuvaRing® batches increases upon storage aheady after 12 months at 30°C. With exception of variant A3, all seven batches of a ring of the subject invention show a constant or a lower burst release after storage at 30°C. Visual examination of rings from batch A3, revealed that the inoease of the burst release is not due to the formation of steroid crystals on the sur&ce of the ring. The fact that the increase of tfie burst release of batch A3 is not due to crystal formation on the ring surface is also shown by the small differences observed between individual test result as indicated by the low RSD (relative standard deviation) value. EXAMPLE 3- improved tfaree-lavered ring versus ring described in US 4.292.965 This example illustrates the benefits of the subject improved three-layered ring relative to the three-layered ring described in US 4,292,965. In US 4,292,965 two steroids are accommodated in the intermediate layer; no steroid is present in the core. The essence of the unproved three-layer ring is that the release rate of two or more steroids can be adjusted independently fi'om one another and that the ring is able to sustain this release rate for a more prolonged period of time while maintaining physical stability at room teniperature conditions. This example demonstrates the advantage of the improved three-layered ring which also has a loaded core over a ring design with a non-medicated core as described in US 4,292,965. It is not possible to load more than one steroid in the intermediate layer in the crystalline form and have independ^it release. In order to adjust the release rate of two (or more) steroids from one compartment, only one steroid can be present in the crystalline phase and the o&et(s) has to be present in the dissolved phase. In case steroid A is partly present in the crystalline phase, the steroid m the crystalline lattice will be in dynamic equilibrium with dissolved steroid Since the concentration of steroid A is pre-determined, the release rate of steroid A can be adjusted by choosing the right skin thickness. Considering the iact that ihe skin thickness is already used as a means to adjust the release rate of steroid A, the release rate of the second component, steroid B can only be tuned by choosmg the appropriate concentration. Since steroid B is only present in the dissolved form, more steroid can be incorporated into the ring (while maintaining the same concentration gradient over the membrane) by increasing the volume of tiie reservoir (flie core). Thus, the volume of the reservoir detramines the amount of dissolved steroid B that can be loaded in the ring. For ring A2 of the subject invention (see example 1) tiie volume of Ae intermediate layer and core reservoir can be calculated as follows. The fibre dimensions of ring A2 are approximately; length 15.7 cm, diameter 4.0 mm, thickness intermediate layer about 60^m and skin about SO^m and the volume of the intermediate layer and the core of approximately Vint = 0.11 ml and Yam = 1-71 ml. The densities of both core and intermediate layer are relatively close to 1 g/ml and consequently the mass of the core and intemsediate layer are ^proximately 1.71 g and 0.11 g respectively. The concentration EE in the core and intermediate layer is q>proximately 0.095% m/m. and hence the core contains approximately 1620^g EE and the intermediate layer contains approximately 106^g of EE. Thus, in this particular case (A2) more than ^proximately 15 times more EE can be loaded in tiie improved three-layered design compared to a ring with a non-medicated core. The release of EE from ring A2 as flmction of time is presented in figure 3 and can be used to illustrate &e advantage of loading the core with EE. The semi-steady state release (release day 2 -21) is between 15 and 10 ^g/day and the content of the intermediate layer alone (106^g) would be insufficient to sustain a fairly constant release rate over a period longer than a few days. After less then 7 days the intermediate layer would be almost completely depleted and the release rate would drop aheady dramatically after a few days. Moreover, in a ring design such as that of US 4,292,965, due to internal diffusion into the core, a non-equilibrium situation is obtained and consequently ^e concentration EE in tiie intermediate layer will decrease, which results in a pharmaceutical product with an unstable release profile. However, when the core is loaded with the same concentration EE as in the intermediate layer the desired equilibrium situation is obtained This non-steady state behaviour due to internal dif!usion (also called back diffusion) is inherent to Ae three-l^er design according to US 4,292,965 while tiie improved three layer design eliminates also these undesired effects. were connected with a 3-compartment spinning block with 3 separate spinning pumps (to control the volume flow rate (melt flow) of each layer). The three melt flows were combined in a spinneret resulting in a fibre with 3 layers. A cqjillaiy of 3.6 mm was used All fibres were extruded at an extrusion temperature of 1 iCC. The spinning rate was adjusted to obtain the desired fibre diameter of 3, 4 or 5 mm. The desired layer tiiickness for skin and intermediate layer was obtained by adjustment of the spinning pumps. Each of the tri-layer fibre variants was produced by using the appropriate spinning rate and spinning pump settings (totally 20 variants, E-X). After approximately 20 minutes tri-layer co-extrusion of each variant, tiie tri-layer fibre was collected on a stainless steel reel for 120 minutes. The outer diameter of the fibre was measured on-line continuously using a laser micrometer and recorded. At the start and at the end of Hxese 120 minutes, the diameter of the fibre, thickness of the middle layer, and the thickness of the sldn was measured and recorded. The variants W and X were collected for only 30 minutes. The loaded fibres were processed at an extmsion speed of 2.00 m/min for variants E-V, at 3.59 m/min for variant W, and at 1.28 m/min for variant X, Fibre dimensions The intermediate layer thickness and skin thickness were determined for each fibre variant from fibre pieces of 4 samples during tiie trico-extrusion . The outer diameter was determined for each fibre variant from fibre pieces of 6 samples during processing on trico-extmded fibres. The outer diameter was determined by means of a laser thickness gauge (Zumbach). The intermediate layer and skin thickness were determined using a microscope (Jena). The results for the loaded batches are shown in Tables 9a, 9b and 9c. WE CLAIM: 1. A drug delivery system comprising at least one compartment consisting of (i) a drug loaded thermoplastic polymer core, (ii) a drug-loaded thermoplastic polymer intermediate layer and (iii) a non-medicated thermoplastic polymer skin covering the intermediate layer, wherein said intermediate layer is loaded with crystals of a first pharmaceutically active compound and wherein said core is loaded with a second pharmaceutically active compound in dissolved form. 2. The drug delivery system as claimed in claim 1, wherein the intermediate layer is additionally loaded with said second pharmaceutically active compound in dissolved form. 3. The drug delivery system as claimed in claim 1, which is physically stable at 18-30°C. 4. The drug delivery system as claimed in claim 2, wherein said second compound in the core is present in the same concentration as in the intermediate layer. 5. The drug delivery system as claimed in claim 1, characterized in that the delivery system has a substantially ring-shaped form and is intended for vaginal administration. 6. The drug delivery system as claimed in claim 1, wherein said first active compound is a steroid and said second active compound is a steroid. 7. The drug delivery system as claimed in claim 6, wherein said first active steroid is a progestogen. 8. The drug delivery system as claimed in claim 6, wherein said second active steroid is an estrogen. 34 9. The drug delivery system as claimed in claim 7, wherein the progestogen is etonogestrel. 10. The drug delivery system as claimed in claim 8, wherein the estrogen is ethinyl estradiol. 11. The drug delivery system as claimed in claim 1, wherein the first active compound is etonogestrel and the second active compound is ethinyl estradiol. 12. The drug delivery system as claimed in claim 1, wherein the skin and optionally also the core and the intermediate layer comprise ethylene-vinylacetate copolymer as the thermoplastic polymer. 13. The drug delivery system as claimed in claim 12, wherein the core and the intermediate layer comprise the same grade of ethylene-vinylacetate copolymer as the thermoplastic polymer. 14. The drug delivery system as claimed in claim 12, wherein the core and the intermediate layer comprise a different grade of ethylene-vinylacetate copolymer as the thermoplastic polymer. 15. The drug delivery system as claimed in claim 1, wherein the core is additionally loaded with the first compound. 16. The drug delivery system as claimed in claim 9, wherein etonogestrel is present in the intermediate layer at 6-80% by weight. 17. The drug delivery system as claimed in claim 10, wherein ethinyl estradiol is present in the intermediate layer and in the core at 0.05-1.5% by weight. 35 18. The drug delivery system as claimed in claim 1, wherein the compartment is a fibre and Rl is the radius of the fibre, R2 the radius of the core together with the intermediate layer and R3 the radius of the core and wherein the ratio R1/R2 is between 1.0075-2.0000 and the ratio R2/R3 is between 1.0075- 2.0000. 19. The drug delivery system as claimed in claims 6-18, wherein the intermediate layer additionally contains an anti-microbial agent. 20. The drug delivery system as claimed in claims 6-18, wherein the core additionally contains an anti-microbial agent. 21. A drug delivery system according to any one of the preceding claims, wherein the device contains two compartments. 22. The drug delivery system as claimed in claim 21, wherein the second compartment contains an anti-microbial agent. 23. The drug delivery system as claimed in claims 19-22, wherein the anti-microbial agent is mandelic acid condensation polymer. 24. A method of manufacturing the three-layered drug delivery system of claim 1 comprising: (i) producing a loaded homogenous polymer core granulate and a loaded homogenous polymer intermediate layer granulate; (ii) co-extruding the core granulate and the intermediate layer granulate with a polymer skin granulate to form the three-layered drug delivery system. 25. A method according to claim 24, wherein step (i) comprises: (a) grounding the polymer; (b) dry powder mixing the grounded polymer with the active compound to be 36 loaded in the intermediate layer; (c) dry powder mixing the grounded polymer with the active compound to be loaded in the core; (d) blend exuding the resulting powder mixtures of steps (b) and (c); (e) cutting the resulting loaded polymer strands into granules, thereby obtaining a core granulate and an intermediate layer granulate; (f) lubricating both core granulate and intermediate granulate with a lubricant; wherein steps (b) and (c) are interexchangeable.

Documents:

3119-chenp-2005 abstract.pdf

3119-chenp-2005 claims-duplicate.pdf

3119-chenp-2005 claims.pdf

3119-chenp-2005 correspondences others.pdf

3119-chenp-2005 correspondences po.pdf

3119-chenp-2005 description(complete)-duplicate.pdf

3119-chenp-2005 description(complete).pdf

3119-chenp-2005 drawings-duplicate.pdf

3119-chenp-2005 drawings.pdf

3119-chenp-2005 form-1.pdf

3119-chenp-2005 form-18.pdf

3119-chenp-2005 form-26.pdf

3119-chenp-2005 form-3.pdf

3119-chenp-2005 form-5.pdf

3119-chenp-2005 form-6.pdf

3119-chenp-2005 pct search report.pdf

3119-chenp-2005 pct.pdf

3119-chenp-2005 petition.pdf