CA2244997C - Sustained delivery of an active agent using an implantable system - Google Patents

Abstract

The invention is directed to a device for delivering an active agent formulation for a predetermined administration period. An impermeable reservoir is divided into a water- swellable agent chamber and an active agent formulation chamber. Fluid from the environment is imbibed through a semipermeable plug into the water-swellable agent chamber and the active agent formulation is released through a back-diffusion regulating outlet. Delivery periods of up to 2 years are achieved.

Description

WO 97!27840 PCT/LTS97/00722 IMPLANTABLE SYSTEM

Technical Field s This invention is related to the sustained delivery of a biologically active agent. More particularly, the invention is directed to an implantable s delivery system for the prolonged delivery of an active agent to a fluid s environment in a natural or artificial body cavity.
11 Background of the Invention 13 Treatment of disease by prolonged delivery of an active agent at a 1a controlled rate has been a goal in the drug delivery field. Various approaches 1s have been taken toward delivering the active agents.
1s One approach involves the use of implantable diffusional systems. For 1~ example, subdermal implants for contraception are described by Philip D.
1s Darney in Current Opinion in Obstetrics and Gynecology 1991, 3:470-476.
1s Norpiant~ requires the placement of 6 levonorgestrel-filled silastic capsules zo under the skin. Protection from conception for up to 5 years is achieved.
The z1 implants operate by simple diffusion, that is, the active agent diffuses through zz the polymeric material at a rate that is controlled by the characteristics of the zs active agent formulation and the polymeric material. Darney further describes za biodegradable implants, namely CapranorT"" and norethindrone pellets.
zs These systems are designed to deliver contraceptives for about one year and as then dissolve. The CapranorTM systems consist of poly(s-caprolactone) z7 capsules that are filled with levonorgestrel and the pellets are 10% pure za cholesterol with 90% norethindrone.
zs Implantable infusion pumps have also been described for delivering so drugs by intravenous, intra-arterial, intrathecal, intraperitoneal, intraspinal and s1 epidural pathways. The pumps are usually surgically inserted into a ~ subcutaneous pocket of tissue in the lower abdomen. Systems for pain 2 management, chemotherapy and insulin delivery are described in the 881.
s Newsletter, Vol. 17, No. 12, pages 209-211, December 1994. These systems 4 provide for more accurately controlled delivery than simple diffusions!
s systems.
,, s One particularly promising approach involves osmotically driven ~ devices such as those described in U.S. Patent Nos. 3,987,790, 4,885,845, a 5,057,318, 5,059,423, 5,112,814, 5,137,727, 5,234,892 and 5,234,693.
s These devices can be implanted ~o into an animal !o release the active agent in a controlled manner.for a ~ predetermined administratbn period. In general, these devices operate by ~z imbibing fluid from the outside environment and releasing. corresponding ~3 amounts of the active agent ,s The above-described devices have been useful for delivering alive ~s agents to a fluid environment of use. Although these devices have found is application for human and veterinary purposes, there remains a need for ,~ devices that are capable of delivering active agents, particularly potent ~e unstable agents, reliably to a human being at a controlled rate over a ~a prolonged period of time. .
so z~ $~~marv of the Invention x~ Implantable osmotic systems for delivery of an active agent to an a animal arse Hrell known. Adaptation of these systems for human use raises a is number of difficult issues. The size of the device may need fio be decreased 2s for human impiantaflon. The strength of the de~rice must be suffiaent to rr ensure a robust system. Accurate and reproduabk delivery rates and 28 durations must be ensured and the.period from implantation to start-up of Za delivery must be minimized. The active agent must return ita purity and 3o activity for extended periods of time at the elevated temperatures s~ encountered in the body cavity. ' .

2a According to one aspect of the present invention, there is provided a fluid-imbibing device for delivering an active agent to a fluid environment of use, said fluid-imbibing device comprising a water-swellable semipermeable plug that conforms to an interior surface of an end of an impermeable reservoir and creates a liquid-tight seal between the water-swellable semipermeable plug and the interior surface and an active agent to be displaced from the fluid-imbibing device when the water-swellable semipermeable plug swells.
According to another aspect of the present invention, there is provided the device as described above, further comprising a piston received within the interior surface of the impermeable reservoir, wherein the piston divides the reservoir into an active agent containing chamber and a water-swellable agent containing chamber.
According to still another aspect of the present invention, there is provided the device as described above, further comprising: (a) a piston that divides the reservoir into a first and a second chamber, the first and second chambers each having an open end; (b) a water-swellable semipermeable plug in the first chamber; and (c) the active agent in the second chamber, wherein the water-swellable semipermeable plug is located in the open end of the first chamber.
According to yet another aspect of the present invention, there is provided the device as described above wherein the water-swellable semipermeable plug contains at least about 64 mg NaCl.
According to a further aspect of the present invention, there is provided the device as described above wherein the water-swellable semipermeable plug contains 2b NaCl, a gelling osmopolymer and tabletting agents and viscosity modifying agents.

- ~ Accordingly, in one aspect, the invention is a fluid-imbibing device for 2 delivering an active agent formulation to a fluid environment of use. The 3 device comprises a water-swellable, semipermeable material that is received in sealing relationship with the interior surface at one end of an impermeable s reservoir. The device further contains an active agent to be displaced from s the device when the water-swellable material swells.
In another aspect, the invention is directed to an implantable device for 8 delivering an active agent to a fluid environment of use. The device s comprises a reservoir and a back diffusion regulating outlet in a mating relationship. The flow path of the active agent comprises a pathway formed » between the mating surfaces of the back diffusion regulating outlet and the reservoir.
13 In yet another aspect, the present invention is directed to a device for storing an active agent in a fluid environment of use during a predetermined ~s administration period, the device comprising a reservoir containing an active 1s agent. The reservoir is impermeable and formed at least in part from a metallic material. The portion of the reservoir contacting the active agent is ~a non-reactive with the active agent, and is formed of a material selected from 19 the group consisting of titanium and its alloys.
2o In a further aspect, the invention is an implantable fluid-imbibing active 21 agent delivery system that comprises an impermeable reservoir. The as reservoir contains a piston that divides the reservoir into an active agent zs containing chamber and a water-swellable agent containing chamber. The 2a active agent containing chamber is provided with a back-diffusion regulating as outlet. The water-swellable agent containing chamber is provided with a as semipermeable plug. Either the plug or the outlet is releasable from the z7 reservoir at an internal pressure that is lower than the maximum osmotic as pressure generated by the water-swellable agent.
~ 2s The invention is further directed to a fluid-imbibing implantable active so agent delivery system where the time to start-up of delivery is less than 10%
~ of the predetermined administration period.

- ~ In another aspect, the invention is directed to a method for preparing a 2 fluid-imbibing implantable active agent delivery system. The method 3 comprises injection molding a semipermeable plug into the end of an 4 impermeable reservoir such that the plug is protected by the reservoir.
s In still another aspect, the invention is directed to an impermeable s active agent delivery system for delivering an active agent that is susceptible z to degradation. The reservoir contains a piston that divides the reservoir into s a water-swellable agent chamber and an active agent chamber. The open s end of the water-swellable agent chamber contains a semipermeable ~o membrane and the open end of the active agent chamber contains a back-diffusion regulating outlet. The system effectively seals the active agent ~2 chamber and isolates it from the environment of use.
~s In a further aspect, the invention is directed to a back-diffusion ~4 regulating outlet useful in an active agent delivery system. The outlet defines ~s a flow path wherein the length, inferior cross-sectional shape and area ~s provide for an average linear velocity of active agent that is higher than the linear inward flow of fluid in the environment of use.
The invention is also directed to a semipermeable plug useful in an active agent delivery system. The plug is water-swellable and must expand 20 linearly in the delivery system to commence pumping upon insertion of the 2~ system into the fluid environment of use.
22 The invention is further directed to impiantable delivery systems useful 23 for delivering leuprolide.

25 Descri,~tion of the Drawinc_as 2s 27 The figures are not drawn to scale, but are set forth to illustrate various , 2s embodiments of the invention. Like numbers refer to like structures.
2a Figs. 1 and 2 are partial cross-sectional views of two embodiments of so the delivery device of the invention.

1 Fig. 3 is an enlarged cross-sectional view of the back-diffusion 2 regulating outlet of Fig. 1.
s Fig. 4 is a graph that shows the effect of orifice diameter and length on 4 drug diffusion.
s Figs. 5, 6, 7 and 8 are enlarged cross-sectional views of further s embodiments of the semipermeable plug end of the reservoir according to the 7 invention.
s Figs. 9, 10 and 11 are graphs of release rates for systems with leuprolide (Fig. 9) and with blue dye and with different membranes (Figs. 10 1o and 11).

1z Detailed Description of the Invention 1a The present invention provides a device for the delivery of an active 1s agent to a fluid environment of use in which the active agent must be 1s protected from the fluid environment until it is delivered. Prolonged and 17 controlled delivery is achieved.

19 Definitions a1 The term "active agent" intends the active agents) optionally in az combination with pharmaceutically acceptable carriers and, optionally a3 additional ingredients such as antioxidants, stabilizing agents, permeation 2a enhancers, etc.
is By a "predetermined administration period" is intended a period of zs greater than 7 days, often between about 30 days and 2 years, preferably a~ greater than about 1 month and usually between about 1 month and 12 2s months.
29 By the time to "start-up" of delivery is intended the lime from insertion so into the fluid environment of use until the active agent is actually delivered at 31 a rate not less than approximately 70% of the intended steady-state rate.

WO 97!27840 PCT/US97/00722 - ~ The term "impermeable" intends that the material is sufficiently z impermeable to environmental fluids as well as ingredients contained within s the dispensing device such that the migration of such materials into or out of the device through the impermeable device is so low as to have substantially s no adverse impact on the function of the device during the delivery period.
s The term "semipermeable" intends that the material is permeable to z external fluids but substantially impermeable to other ingredients contained s within the dispensing device and the environment of use.
s As used herein, the terms "therapeutically effective amount" or ~o "therapeutically effective rate" refer to the amount or rate of the active agent needed to effect the desired biologic or pharmacologic effect.
12 The active agent delivery devices of the invention find use where the ~s prolonged and controlled delivery of an active agent is desired. In many ~a cases the active agent is susceptible to degradation if exposed to the ~s environment of use prior to delivery and the delivery devices protect the agent from such exposure.
~7 Fig. 1 shows one embodiment of the device according to the invention.
In Fig. 1 a fluid-imbibing system 10 is shown that comprises an impermeable reservoir 12. The reservoir 12 is divided into two chambers by a piston 16.
zo The first chamber 18 is adapted to contain an active agent and the second z~ chamber 20 is adapted to contain a fluid-imbibing agent. A back-diffusion zz regulating outlet 22 is inserted into the open end of the first compartment z3 and a wafer-swellable semipermeable plug 24 is inserted into the open end of z4 the second chamber 20. In Fig. 1, the back-diffusion regulating outlet 22 is zs shown as a male threaded member in a mating relationship with the smooth zs interior surface of the reservoir 12 thereby forming therebetween helical flow z7 path 34. The pitch (x), the amplitude (y), and the cross-sectional area and , zs shape of the helical path 34 formed between the mating surfaces of the back-zs diffusion regulating outlet 22 and the reservoir 12 as shown in Fig. 3 are so factors that affect both the efficiency of path 34 preventing back-diffusion of s~ external fluid into the formulation in chamber 18 and the back pressure in the ~ device. The geometry of outlet 22 prevents water diffusion into the reservoir.
z In general, it is desired that these characteristics be selected so that the s length of the helical flow path 34 and the velocity of flow of active agent a therethrough is sufficient to prevent back-diffusion of external fluid through the s flow path 34 without significantly increasing the back pressure, so that, s following start-up, the release rate of the active agent is governed by the osmotic pumping rate.
s Fig. 2 is a second embodiment of the device of the invention with a s reservoir 12, piston 16 and plug 26. In this embodiment, the flow path 36 is ~o formed between a threaded back-diffusion regulating outlet 40 and threads formed on the interior surface of the reservoir 12. The amplitudes of the threaded portions of the back-diffusion regulating outlet 40 and reservoir 12 ~s are different so that a flow path 36 is formed between the reservoir 12 and the 14 back-diffusion regulating outlet 40.
Ts The water-swellable semipermeable plugs 24 and 26 shown in Figs. 1 ~s and 2 respectively are inserted into the reservoir such that the reservoir wall concentrically surrounds and protects the plug. In Fig. 1, the top portion 50 of ~s the plug 24 is exposed to the environment of use and may form a flanged end cap portion 56 overlaying the end of reservoir 12. The semipermeable plug ao 24 is resiliently engaged with the interior surface of the reservoir 12 and in 21 Fig. 1 is shown to have ridges 60 that serve to frictionally engage the semipermeable plug 24 with the interior of reservoir 12. In addition, the 23 ridges 60 serve to produce redundant circumferential seals that function 24 before the semipermeable plug 24 expands due to hydration. The clearance is between ridges 60 and the interior surface of the reservoir 12 prevents is hydration swelling from exerting stresses on the reservoir 12 that can result in 2~ tensile failure of the reservoir 12 or compression or shear failure of the plug za 24. Fig. 2 shows a second embodiment of the semipermeable plug 26 where . zs the plug is injection molded into the top portion of the reservoir and where the so top of the semipermeable plug 26 is flush with the top 62 of the reservoir 12.
31 !n this embodiment, the diameter of the plug is substantially less than the diameter of the reservoir 12. In both embodiments the plugs 24 and 26 will 2 swell upon exposure to the fluid in body cavity forming an even tighter seal s with the reservoir 12.
a The novel confrgurations of the components of the above-described s embodiments provide for implantable devices that are uniquely suited for s implantation info humans and can provide delivery devices which are capable z of storing unstable formulations at body temperatures for extended periods of s time, which devices have start-up times of less than 10% of the administration s period and can be designed to be highly reliable and with predictable fail safe ~o modes.
11 Reservoir 12 must be sufficiently strong to ensure that it will not leak, crack, break or distort so as to expel its active agent contents under stresses is it would be subjected to during use while being impermeable. In particular, it ~a should be designed to withstand the maximum osmotic pressure that could be generated by the water-swellable material in chamber 20. Reservoir 12 must ~s also be chemically inert and biocompatible, that is, it must be non-reactive with the active agent formulation as well as the body. Suitable materials ~a generally comprise a non-reactive polymer or a biocompatible metal or alloy.
1s The polymers include acrylonitrile polymers such as acryionitrile-butadiene-ao styrene terpolymer, and the like; halogenated polymers such as 2~ polytetrafluoroethylene, polychlorotrifluoroethylene, copolymer as tetrafluoroethylene and hexafiuoropropylene; polyimide; polysulfone;
Zs polycarbonate; polyethylene; polypropylene; polyvinylchloride-acrylic ~4 copolymer; polycarbonate-acryionitriie-butadiene-styrene; polystyrene; and as the like. The water vapor transmission rate through compositions useful for 2s forming the reservoir are reported in J. Pharm. Sci., Vol. 29, pp. 1634-37 27 (1970), Ind. Eng. Chem., Vol. 45, pp. 2296-2306 (1953); Materials , is Engineering, Vol. 5, pp. 38-45 (1972); Ann. Book ofASTM Stds., Voi. 8.02, 2s pp. 208-211 and pp. 584-587 (1984); and lnd. and Eng. Chem., Vol. 49, pp.
ao 1933-1936 (1957). The polymers are known in the Handbook of Common 3~ Polymers by Scott and Roff, CRC Press, Cleveland Rubber Co., Cleveland, - ~ OH. Metallic materials useful in the invention include stainless steel, titanium, z platinum, tantalum, gold and their alloys as welt as gold-plated ferrous alloys, s platinum-plated ferrous alloys, cobalt-chromium alloys and titanium nitride coated stainless steel. A reservoir made from titanium or a titanium alloy s having greater than 60%, often greater than 85% titanium is particularly s preferred for the most size-critical applications, for high payload capability and for long duration applications and for those applications where the formulation s is sensitive to body chemistry at the implantation site or where the body is a sensitive to the formulation. Preferred systems maintain at least 70% active ~o agent after 14 months at 37°C and have a shelf stability of at least about 9 months, or more preferably at least about two years, at 2-8°C. Most ~z preferably, systems may be stored at room temperature. In certain ~s embodiments, and for applications other than the fluid-imbibing devices 14 specifically described, where unstable formulations are in chamber 18, particularly protein andlor peptide formulations, the metallic components to which the formulation is exposed must be formed of titanium or ifs alloys as 17 described above.
~s The devices of this invention provide a sealed chamber 18 which effectively isolates the formulation from the fluid environment. The reservoir ao 12 is made of a rigid, impermeable and strong material. The wafer-swellable z~ semipermeable plug 24 is of a lower durometer material and will conform to zz the shape of the reservoir to produce a liquid-tight sea( with the inferior of zs reservoir 12 upon wetting. The flow path 34 isolates chamber 18 from back-za diffusion of environmental fluid. Piston 16 isolates chamber 18 from the zs environmental fluids that are permitted to enter chamber 20 through zs semipermeable plugs 24 and 26 such that, in use at steady-state flow, active z7 agent is expelled through outlet 22 at a rate corresponding to the rate at a za which water from the environment flows into the water-swellable material in za chamber 20 through semipermeable plugs 24 and 26. As a result, the plug so and the active agent formulation will be protected from damage and their 31 functionality will not be compromised even if the reservoir is deformed. In addition, the use of sealants and adhesives will be avoided and the attendant z issues of biocompatibility and ease of manufacture resolved.
s Materials from which the semipermeable plug are made are those that a are semipermeable and that can conform to the shape of the reservoir upon s wetting and adhere to the rigid surface of the reservoir. The semipermeable s plug expands as it hydrates when placed in a fluid environment so that a seal is generated between the mating surfaces of the plug and the reservoir. The s strength of the seals between the reservoir 12 and the outlet 22 and the a reservoir 12 and the plugs 24 and 26 can be designed to withstand the maximum osmotic pressure generated by the device. In a preferred alternative, the plugs 24 and 26 may be designed to withstand at least 10X
~z the osmotic agent compartment 20 operating pressure. fn a further ~s alternative the plugs 24 and 26 may be releasable from the reservoir at an ~a internal pressure that is lower than the pressure needed to release the back ~s diffusion regulating outlet. In this fail safe embodiment, the water-swellable ~s agent chamber will be opened and depressurized, thus avoiding dispelling the diffusion regulating outlet and attendant release of a large quantity of the ~s active agent. In other cases, where a fail-safe system requires the release of the active agent formulation rather than the water-swellable agent zo formulation, the semipermeable plug must be releasable at a pressure that is z, higher than the outlet.
zz In either case, the semipermeable plug must be tong enough to zs sealably engage the reservoir wall under the operating conditions, that is, it za should have an aspect ratio of between 1:10 and 10:1 length to diameter, zs preferably at least about 1:2 length to diameter, and often between 7:10 and zs 2:1. The plug must be able to imbibe between about 0.1 % and 200% by z7 weight of water. The diameter of the plug is such that it will sealingly fit inside zs the reservoir prior to hydration as a result of seating contact at one or more zs circumferential zones and will expand in place upon wetting to form an even so tighter seal with the reservoir. The polymeric materials from which the semipermeabfe plug may be made vary based on the pumping rates and - ~ device configuration requirements and include but are not limited to z plasticized cellulosic materials, enhanced polymethyimethacrylate such as s hydroxyethylmethacrylate (HEMA) and elastomeric materials such as a polyurethanes and pofyamides, polyether-poiyamide copolymers, s thermoplastic copolyesters and the like.
s The piston 16 isolates the water-swetlable agent in chamber 20 from the active agent in chamber 18 and must be capable of sealably moving s under pressure within reservoir 12. The piston 16 is preferably made of a a material that is of lower durometer than the reservoir 12 and that will deform ~o to fit the lumen of the reservoir to provide a fluid-tight compression seal with 11 the reservoir 12. The materials from which the piston are made are 12 preferably elastomeric materials that are impermeable and include but are not ~a limited to polypropylene, rubbers such as EPDM, silicone rubber, butyl ~4 rubber, and the like, and thermoplastic elastomers such as plasticized 15 potyvinytchloride, polyurethanes, Santoprene~, C-Flexes TPE (Consolidated ~s Polymer Technologies Inc.), and the like. The piston may be of a self loading ~7 or compression-loaded design.
is The back-diffusion regulating outlet 22 forms the delivery pathway ~s through which the active agent flows from the chamber 18 to the implantation 2o site where absorption of the active agent takes place. The seal between the z~ outlet 22 and the reservoir 12 can be designed to withstand the maximum ~2 osmotic pressure generated within the device or to fail-safe in the modes is described above. In a preferred embodiment, the pressure required to 2a release back-diffusion regulating outlet 22 is at least 1 OX the pressure is required to move piston 16 and/or at least 10X the pressure in chamber 18.
Zs The exit flow path of the active agent is the pathway 34 formed z~ between the mating surtaces of the back-diffusion regulating outlet 22 and the zs reservoir 12. The pathway length, interior cross-sectional shape and area of . is the outlet path 34 or 36 are chosen such that the average linear velocity of so the exiting active agent is higher than that of the linear inward flux of materials s~ in the environment of use due to diffusion or osmosis, thereby attenuating or moderating back-diffusion and its deleterious effects of contaminating the z interior of the pump, destabilizing, diluting, or otherwise altering the s formulation. The release rate of active agent can be modified by modifying 4 the outlet pathway geometry, which relationship is shown below.
s The connective flow of active agent out of outlet 22 is set by the , s pumping rate of the system and the concentration of active agent in chamber 20 and can be represented as follows:
s Qca = (Q) (Ca) (1 ) ~o where Qua is the connective transport of agent A in mg/day ~z Q is the overall connective transport of the agent and its is diluents in cm3/day a Ca is the concentration of agent A in the formulation within T5 chamber 20 in mg/cm3 ~s m The diffusive flow of agent A through the material in the outlet 22 is a ~a function of agent concentration, cross-sectional configuration of flow path ~s or 36, agent diffusivity and length of flow path 34 or 36, and can be zo represented as follows:
zt az Qaa = D ~ r2 0 Ca/L (2) zs where a4 Qua is the diffusive transport of agent A in mg/day as D is the diffusivity through the material in path 34 or 36 in zs cmz/day z7 r is the effective inner radius of the flow path in cm , zs OCa is the difference between the concentration of agent A in zs the reservoir and in the body outside of the outlet 22 in so mg/cm3 s~ L is the length of the flow path in cm 2 In general, the concentration of agent in the reservoir is much greater s than the concentration of agent in the body outside of the orifice such that the difference, ~Ca can be approximated by the concentration of agent within the s reservoir, Ca.

s Qaa = D ~t r2 Ca/L (3) s a It is generally desirable to keep the diffusive flux of agent at less than 10% of the connective flow. This is represented as follows:

Qda/Qca = D ~ ~ Ca/QCaL = D~ r2/QL 5 0.1 (4) 14 Equation 4 indicates that the relative diffusive flux decreases with 1s increasing volumetric flow rate and path length and increases with increasing 16 diffusivity and channel radius and is independent of drug concentration.

1~ Equation 4 is plotted in Figure 4 as a function of length (L) and diameter (d) 1s for D = 2 x 10-s cm2/sec and Q = 0.36 .!/day.

1s The diffusive flux of water where the orifice opens into chamber 18 Zo can be approximated as:

z1 22 Qwa (res) = CQe ~-owW,a~ (5) i3 where 24 C is the concentration profile of water in mg/cm3 zs Q is the mass flow rate in mg/day 2s L is the length of the flow path in cm a~ DW is the diffusivity of water through the material in the flow path in 2s cm2/day as A is the cross-sectional area of the flow path in cm2 1 The hydrodynamic pressure drop across the orifice can be calculated z as follows:

4 oP = (6) ~r4 s 7 Simultaneously solving equations (4), (5) and (6) gives the values s shown in Table 1 where:
s 1o Q = 0.38 wl/day 11 Ca = 0.4 mg/Etl 12 L =5cm 13 Da = 2.00 E-06 cm2/sec 14 ~, =5.00E+02cp CwD = 0 mg/~i,l 1s Dw = 6.00 E + 06 cm2/sec 1a Table 1 Dru Diffusionmping Water ntrusionPressure & Pu i Drap Effective Pump DiffusionDiffJConv rate OrificeCross QCs QDe QDe/QC, QD Qdw delta dia Sec P

(mil) area m /day mg/day m !day m J si (mm2) ear l 0.000510.152 0.0001 0.0005 0 0 1.55800 2 0.002030.152 0.0003 0.0018 1.14E-794.16E-770.09738 3 0.004560.152 0.0006 0.0041 4.79E-381.75E-330.01923 4 0.008110.152 0.0011 0.0074 8.89E-213.25E-180.00609 5 0.012670.152 0.0018 0.0115 1.04E-1133.79E-110.00249 6 0.018240.152 0.0025 0.0166 7.16E-102.61 0.00120 7 0.024830.952 0.0034 0.0226 1.48E-075.4E-050.00065 8 0.032430.152 0.0045 0.0295 4.7E-06 0.0017150.00038 9 0.041050.152 0.0057 0.0373 5.04E-050.0183810.00024 10 0.050680.152 0.0070 0.0461 0.0002750.1002630.00016 11 0.061320.152 0.0085 0.0558 0.0009640.3517710.00011 12 0.072980.152 0.0101 0.0654 0.0025040.9138390.00008 -13 0.085640.152 0.0118 0.0779 0.0052631.9210270.00005 14 0.099330.152 0.0137 0.0903 0.00949 3.4638360.00004 15 0.114020.152 0.0158 0.1037 0.0152695.5731950.00003 16 0.129730.152 0.0179 0.1180 0.0225358.2252240.00002 17 0.146460.152 0.0202 0.1332 .03 11.356560.00002 18 0.164190.152 0.0227 0.1493 _ 14.881660.00001 _ 0.040772 19 0.182950.152 0.0253 0.1664 0.05125318.707280.00001 ' 20 0.202710.152 0.0280 0.1844 0.06230922.74270.00001 The calculations indicate that an orifice diameter of between about 3 2 and 10 mil and a length of 2 to 7 cm is optimal for a device with the operating 3 conditions described. In a preferred embodiment, the pressure drop across 4 the orifice is less than 10% of the pressure required to release the back-s diffusion regulating outlet 22.
s The back-diffusion regulating outlet 22 preferably forms a llelica!
~ pathway 34 or 36 incorporating a long flow path with a means of mechanically . a attaching the outlet into the reservoir without using adhesives or other s sealants. The back-diffusion regulating outlet is made of an inert and ~o biocompatible material selected from but not limited to metals induding but not limited to titanium, stainless steel, platinum and their alloys and coba8 ,2 chromium alloys and the like, and polymers induding but not limited to polyethylene, polypropylene, polycarbonate and polymethylmethacrylate and the like. The flow path is usually between about 0.5 and 20 cm long, .~s preferably between about 1 and 10 cm long and between about 0.001 and ~s 0.020 inches in diameter, preferably between about 0.003 and 0.015 inches to allow for a flow of between about 0.02 and 50 ~,I/day, usually 0.2 to 10 ~e ~Uday and often 0.2 to 2.0 pUday. Addiflonally, a catheter or other system ~s may be attached to the end of the back-diffusion regulating outlet to provide.
zo for delivery of the active agent formulation at a site removed from the implant.
z~ Such systems are known in the art and are described, for example, in U.S.
r~ Patent Nos. 3,732,865 and X4,340,054.
a~ Further, the flow path design may be useful in systems other than z4 the fluid-imbibing devices specifically described herein.
The inventive device configurations described above also allow for a ~s ~ minimal period of delay from start-up to steady-state flow rate. This is r accomplished in part as a result of the conflgurat<on of the semipermeabie isplug 24 or 26. As water is imbibed ~by the semipermeable plug, it swells. .
is Radial expansion is limited by the rigid reservoir 12, thus the expansion must ~o occur linearly, thereby pushing against the water-swellable agent in chamber s, 18, whicfi in tum pushes against the piston 16. This allows pumping to (7696-260 commence prior to the time that water reaches the water-swellable agent z which otherwise would be required before pumping could commence. ~ To 3 facilitate reliable start-up, the flow path 34 can be precharged with the active 4 agent in chamber 18. Further, the geometry of the outlet 22 allows for initial s delivery that is influenced by the concentration gradient of dnrg along the s length of the outlet. The start-up period is less than about 25% of the ~ predetermined delivery period and is often less than about 10% and usually a less than about 5% of the predetermined delivery period. In a prefen~ed s embodiment for a one year system, at least 70% of the steady-state flow rate ~o is achieved by day 14.
. The water-swellabie agent formulation in chamber 20 is preferably a ~2 tissue tolerable formulation whose high osmotic pressure and high solubility ~3 propels the active agent over a long period of time while remaining in v saturated solution in the water admitted by the semipermeable membrane.
~s The water-swellable agent is preferably selected for tolerability by ,s subcutaneous tissue, at least at pumping rates and hypothetically resulting ~ concentrations to allow inadvertent dispensing from implanted devices left in ,e the patient for a tonger than labeled period. In preferred embodiments, the s water swellable agent should not diffuse or permeate through the zo semipermeable plug 24 or 28 to any appreciable amount (e.g., less than 8%) z~ under normal operating conditions.. Osmotic agents, such as NaCI with appropriate tabletflng agents (lubricants and binders) and viscosity modifying z3 agents, such as sodium carboxymethylCeliulose or sodium potyacrylate are z4 preferred water-swellable agents. Other osmotic agents useful as the water zs. swellabie agent include osmopolymers and osmagents and are described, for zs example, in U.S. Patent No. 5,413,572.
z~ The water-swellable agent formulation can be a slurry, a tablet, a is molded or extruded material or other form known in the art. A liquid or gel is additive or filler may be added to chamber 20 to exclude air from spaces 3o around the osmotic engine. Exclusion of air from the devices should mean WO 97!27840 PCT/US97/00722 - ~ that delivery rates will be less affected by nominal external pressure changes z (e.g., t7 p.s.i._(t5 a.t.m.}).
s The devices of the invention are useful to deliver a wide variety of a active agents. These agents include but are not limited to pharmacologically s active peptides and proteins, genes and gene products, other gene therapy s agents, and other small molecules. The polypeptides may include but are not limited to growth hormone, somatotropin analogues, somatomedin-C, a Gonadotropic releasing hormone, follicle stimulating hormone, luteinizing 9 hormone, LHRH, LHRH analogues such as leuprolide, nafarelin and ~o goserelin, LHRH agonists and antagonists, growth hormone releasing factor, calcitonin, colchicine, gonadotropins such as chorionic gonadotropin, ~z oxytocin, octreotide, somatotropin plus an amino acid, vasopressin, ~s adrenocorticotrophic hormone, epidermal growth factor, prolactin, ~a somatostatin, somatotropin plus a protein, cosyntropin, lypressin, 15 polypeptides such as thyrotropin releasing hormone, thyroid stimulation ~s hormone, secretin, pancreozymin, enkephalin, glucagon, endocrine agents secreted internally and distributed by way of the bloodstream, and the like.
~a Further agents that may be delivered include a~antitrypsin, factor Vlll, factor 19 IX and other coagulation factors, insulin and other peptide hormones, adrenal ao cortical stimulating hormone, thyroid stimulating hormone and other pituitary z~ hormones, interferon a, (3, and 8, erythropoietin, growth factors such as Zz GCSF, GMCSF, insulin-like growth factor 1, tissue plasminogen activator, 23 CD4, dDAVP, interleukin-1 receptor antagonist, tumor necrosis factor, 24 pancreatic enzymes, lactase, cytokines, interleukin-1 receptor antagonist, zs interleukin-2, tumor necrosis factor receptor, tumor suppresser proteins, 2s cytotoxic proteins, and recombinant antibodies and antibody fragments, and 2~ the like.
as The above agents are useful for the treatment of a variety of conditions Zs including but not limited to hemophilia and other blood disorders, growth so disorders, diabetes, leukemia, hepatitis, renal failure, HIV infection, hereditary 31 diseases such as cerbrosidase deficiency and adenosine deaminase deficiency, hypertension, septic shock, autoimmune diseases such as 2 multiple sclerosis, Graves disease, systemic lupus erythematosus and s rheumatoid arthritis, shock and wasting disorders, cystic fibrosis, lactose a intolerance, Crohn's diseases, inflammatory bowel disease, gastrointestinal s and other cancers.
s The active agents may be anhydrous or aqueous solutions, suspensions or complexes with pharmaceutically acceptable vehicles or s carriers such that a flowable formulation is produced that may be stored for s long periods on the shelf or under refrigeration, as well as stored in an ~o implanted delivery system. The formulations may include pharmaceutically acceptable carriers and additional inert ingredients. The active agents may 12 be in various forms, such as uncharged molecules, components of molecular ~3 complexes or pharmacologically acceptable salts. Also, simple derivatives of ~a the agents (such as prodrugs, ethers, esters, amides, etc.) which are easily ~s hydrolyzed by body pH, enzymes, etc., can be employed.
It is to be understood that more than one active agent may be ~~ incorporated info the active agent formulation in a device of this invention and ~s that the use of the term "agent" in no way excludes the use of two or more ~s such agents. The dispensing devices of the invention find use, for example, ao in humans or other animals. The environment of use is a fluid environment 2~ and can comprise any subcutaneous position or body cavity, such as the 22 peritoneum or uterus, and may or may not be equivalent to the point of as ultimate delivery of the active agent formulation. A single dispensing device 2a or several dispensing devices can be administered to a subject during a as therapeutic program. The devices are designed to remain implanted during a as predetermined administration period. If the devices are not removed following 2~ the administration, they may be designed to withstand the maximum osmotic as pressure of the water-swellable agent or they may be designed with a bypass 2s to release the pressure generated within the device.
so The devices of the present invention are preferably rendered sterile 31 prior to use, especially when such use is implantation. This may be ~ accomplished by separately sterilizing each component, e.g., by gamma radiation, steam sterilization or sterile filtration, then aseptically assembling s the final system. Alternatively, the devices may be assembled, then 4 terminally sterilized using any appropriate method.
s Preparation of the Devices of the Invention s Reservoir 12 is prepared preferably by machining a metal rod or by s extrusion or injection molding a polymer. The top portion of the reservoir may ~o be open as shown in Fig. 1 or may contain a cavity as shown in Fig. 2.
11 Where the reservoir 12 is open as shown in Fig. 1, a water-swellable semipermeable plug 24 is inserted mechanically from the outside of the ~s reservoir without using an adhesive before or after insertion of the piston and ~a water-swellable agent formulation. Reservoir 12 may be provided with grooves or threads which engage ribs or threads on plug 24.
~s Where the reservoir 12 contains a cavity as shown in Fig. 2, the cavity may be cylindrical in shape, as shown in Fig. 5, it may be stepped, as shown ~s in Fig. 6, it may be helical, as shown in Fig. 7 or it may be in a spaced 19 configuration, as shown in Fig. 8. The semipermeable plug 26 is then Zo injected, inserted, or otherwise assembled into the cavity so that it forms a 2~ seal with the reservoir wall.
z2 Following insertion of the plug 26 either mechanically, by welding or by as injection, the water-swellable agent is assembled into the reservoir followed z4 by insertion of the piston, with appropriate steps taken to vent entrapped air.
z5 The active agent is flied into the device using a syringe or a precision is dispensing pump. The diffusion moderator is inserted into the device, usually z7 by a rotating or helical action, or by axial pressing.
zs The following examples are illustrative of the present invention. They - zs are not to be construed as limiting the scope of the invention.
Variations and so equivalents of these examples will be apparent to those of skill in the art in 31 light of the present disclosure, the drawings and claims herein.

_ 1 a Examples a Example 1 - Preparation of a Device with an HDPE Reservoir s s A system containing leuprolide acetate for the treatment of prostate cancer was assembled from the following components:
s Reservoir (HDPE) (5 mm outside diameter, 3 mm inside diameter) a Piston (Santoprene~) 1o Lubricant (silicone medical fluid) 11 Compressed osmotic engine (60% NaCI, 40% sodium carboxymethyl 1z cellulose) 1s Membrane plug (Hytrel polyether-ester block copolymer, injection 1a molded to desired shape) 1s Back diffusion Regulating Outlet {pofycarbonate) 1s Active agent (0.78g of 60% propylene glycol and 40% leuprolide 17 acetate) 18 Assembfv 1a The piston and inner diameter of the reservoir were Lightly lubricated zo with silicon medical fluid. The piston 16 was inserted into the open end of a1 chamber 20. Two osmotic engine tablets (40 mg each) were then inserted on zz top of piston 16. After insertion, the osmotic engine was flush with the end of as the reservoir. The membrane plug 24 was inserted by lining up the plug with a4 the reservoir and pushing gently until the plug was fully engaged in the zs reservoir. Active agent was loaded into a syringe which was then used to fill as chamber 18 from its open end by injecting the material into the open tube until z~ the formulation was ~3 mm from the end. The filled reservoir was centrifuged zs (outlet end "up") to remove any air bubbles that have been trapped in the zs formulation during filling. The outlet 22 was screwed info the open end of the so reservoir until completely engaged. As the outlet was screwed in, excess s1 formulation exited out of the orifice ensuring a uniform fill.

z .Example 2 - Insertion of the Device of Example 1 Insertion of the device of Example 1 is done under aseptic conditions s using a trocar similar to that used in the implantation of Norp(ant~
s contraceptive implants to position the device under the skin. The insertion area is typically in the inside of the upper arm, 8 to 10 cm above the elbow.
s The area is anesthetized and an incision is made through the skin.
s The incision is approximately 4 mm long. The trocar is inserted into the 1o incision until the tip of the trocar is at a distance of 4 to 6 cm from the incision.
11 The obturator is then removed from the trocar and the device of Example 1 1z inserted into the trocar. The device is then advanced to the open end of the 13 trocar using the obturator. The obturator is then held in position, thus 14 immobilizing the device of Example 1 while the trocar is withdrawn over both 1s the device and the obturator. The obturator is then removed, leaving the 1s implant behind in a well-controlled position. The edges of the incision are 17 then secured with a skin closure. The area is covered and kept dry for 2 to 1s days.

2o Example 3 - Removal of the Device of Example 1 z2 The device of Example 1 is removed as follows: The device is located 23 by fingertip palpation of the upper arm area. The area at one end of the 24 implant is then anesthetized and an approximately 4 mm, perpendicular zs incision is made through the skin and any fibrous capsule tissue surrounding is the implant area. The end of the device opposite the incision is pushed so - z7 that the device end proximal to the incision is urged out of the incision. Any 2s further fibrotic tissue is cut with a scalpel. Following removal, the procedure - zs of Example 2 can be followed to insert a new device.

1 Example 4 - Delivery Rate of the Device of Example 1 s Glass test tubes were filled with 35 ml distilled water and then placed a in a 37°C water bath. A single device as described in Example 1 was placed s in each test tube and the test tubes were changed periodically. The delivery s rate profile from the system is shown in Fig. 9. The system does not have any start-up time because the system exhibits a period of initial high release s followed by a lower steady state release for a period of 200 days.
s 1o Example 5 - Delivery Rate Profiles 12 Glass test tubes were filled with 35 ml distilled wafer which were then 1a placed in a 37°C water bath. After the test tubes had come up to 14 temperature, a single device as described in Example 1, but with membrane 1s materials described below and containing 1 % FD&C blue dye in wafer as the 1s drug formulation, was placed in each tube. Water from the test tube 17 permeated through the membrane causing the system to pump formulation 1s (blue dye) into the surrounding water in the test tube. At regular intervals, 1s systems were switched to fresh test tubes. The amount of dye released was zo determined by measuring the concentration of blue dye in each test tube z1 using a spectrophotometer. The pumping rate was calculated from the total dye released, the volume of water in the tube, the initial concentration of dye 2s and the interval over which the system was in the test tube. Results for two 24 different tests are shown in Figures 10 and 11. Figure 10 shows 3 different as systems with different plug materials (Hytrel~ 2, 3 and 12 month systems) and is Figure 11 shows 4 systems with different plug materials. These materials are:
a7 Membrane Material as 1 month Pebax 25 (Polyamide) 29 2 month Pebax 22 (Polyamide) so 3 month Polyurethane (HP60D) 31 12 month Pebax 24 (Polyamide) The systems were capable of delivering for a period of from 2 to 12 z months, depending on the membrane used.

a Example 6 - Preparation of a Delivery Device with a Titanium Reservoir s s A system containing leuprolide acetate for the treatment of prostate cancer was assembled from the following components:
s Reservoir (Titanium, Ti6A14V alloy ) (4 mm outside diameter, 3 mm s inside diameter) ~o Piston (C-Flex~) Lubricant (silicone medical fluid) .
12 Compressed osmotic engine (76.4% NaCI, 15.5% sodium carboxymethyl cellulose, 6% povidone, 0.5% Mg Stearate, 1.6%
water) 15 PEG 400 (8 mg added to osmotic engine to fill air spaces) Membrane plug (polyurethane polymer, injection molded to desired shape) Back diffusion Regulating Outlet (polyethylene) 19 Drug formulation (0.150g of 60% water and 40% leuprolide acetate) Zo g~semblv ii The piston and inner diameter of the reservoir were lightly lubricated.
2a The piston was inserted ~0.5 cm into the reservoir at the membrane end.
2s PEG 400 was added into the reservoir. Two osmotic engine tablets (40 mg 24 each) were then inserted into the reservoir from the membrane end. After Zs insertion, the osmotic engine was flush with the end of the reservoir. The 2s membrane plug was inserted by lining up the plug with the reservoir and z~ pushing gently until the retaining features of the plug were fully engaged in 2s the reservoir. Formulation was loaded into a syringe which was then used to 29 fill the reservoir from the outlet end by injecting formulation into the open tube so until the formulation was ~3 mm from the end. The filed reservoir was ~ centrifuged (outlet end "up") to remove any air bubbles that have been - ~ trapped in the formulation during filling. The outlet was screwed into the open 2 end of the reservoir until completely engaged. As the outlet was screwed in, a excess formulation exited out of the orifice ensuring a uniform fill.

Example 7 - Preparation of a Leuprolide Acetate Delivery Device with a s Titanium Reservoir a A system containing leuprolide acetate for the treatment of prostate s cancer was assembled from the following components:
Reservoir (Titanium Ti6A14V alloy) {4 mm outside diameter, 3 mm inside diameter, 4.5 cm length) ~2 Piston (C-Flexes TPE efastomer, available from Consolidated Polymer ~s Technologies, Inc.) ~a Lubricant (silicone medical fluid 360) Compressed osmotic engine tablet (76.4% NaCI, 15.5% sodium ~s carboxymethyl cellulose, 6% povidone, 0.5% Mg Stearate, 1.5%
i7 water, 50 mg total) is PEG 400 (8 mg added to osmotic engine to fill air spaces) ~s Membrane plug (polyurethane polymer 20% water uptake, injection 2o molded to desired shape 3 mm diameter X 4 mm length) 2~ Back-diffusion Regulating Outlet (polyethylene, with 6 mil X 5 cm 22 channel) 23 Drug formulation (leuprolide acetate dissolved in DMSO to a measured 2a content of 65 mg leuprolide) Ass~mblv 2s Systems were assembled as in Example 6, using aseptic procedures 27 to assemble y-irradiated subassemblies and filled aseptically with sterile 2s altered leuproiide DMSO formulation.
29 Release Rate so These systems delivered about 0.35 p.L/day leuprolide formulation ~ containing on average 150 ~cg leuprolide in the amount delivered per day - ~ They provide delivery ofi leuprolide at this rate for at least one year.
The 2 systems achieved approximately 70% steady-state delivery by day 14.
s ~mt~lantation and Removal a Systems will be implanted under local anesthetic and by means of an s incision and trocar as in Example 2 to patient suffering from advanced s prostatic cancer.
7 After one year, systems will be removed under local anesthetic as $ described in Example 3. New systems may be inserted at that time.
s 1o Example 8 - Treatment of Prostatic Cancer 12 Leuprolide acetate, an LHRH agonist, acts as a potent inhibitor of 1s gonadotropin secretion when given continuously and in therapeutic doses.
14 Animat and human studies indicate that following an initial stimulation, chronic 1s administration of leuprolide acetate results in suppression of testicular 1s steroidogenesis. This effect is reversible upon discontinuation of drug 17 therapy. Administration of leuprolide acetate has resulted in inhibition of the 1a growth of certain hormone-dependent tumors (prostatic tumors in Noble and 19 Dunning male rats and DMBA-induced mammary tumors in female rats) as ao well as atrophy ofi the reproductive organs. In humans, administration of z1 leuprolide acetate results in an initial increase in circulating levels of z2 futeinizing hormone (LH) and follicle stimulating hormone (FSH), leading to a is transient increase in levels of the gonadal steroids (testosterone and z4 dihydrotestosterone in males). However, continuous administration of zs leuproiide acetate results in decreased level of LH and FSH. in males, zs testosterone is reduced to castrate levels. These decreases occur within two z7 to six weefcs after initiation of treatment, and castrate levels of testosterone in Za prostatic cancer patients have been demonstrated for multiyear periods.
is Leuprolide acetate is not active when given orally.

- ~ Systems will be prepared as in Example 7, then inserted as described.
z The continuous administration of leuprolide for one year using these systems will reduce testosterone to castrate levels.
.a The above description has been given for ease of understanding only.
s No unnecessary (imitations should be understood therefrom, as modifications s will be obvious to those skilled in the art.

Claims (29)

CLAIMS:

1. A fluid-imbibing device for delivering an active agent to a fluid environment of use, said fluid-imbibing device comprising a water-swellable semipermeable plug that conforms to an interior surface of an end of an impermeable reservoir and creates a liquid-tight seal between the water-swellable semipermeable plug and the interior surface and an active agent to be displaced from the fluid-imbibing device when the water-swellable semipermeable plug swells.

2. The device of claim 1 wherein the aspect ratio of the plug is 1:10 to 10:1 length to diameter.

3. The device of claim 1 wherein the semipermeable material is assembled into an open end of the reservoir.

4. The device of claim 1 wherein the semipermeable material is assembled into a cavity in said reservoir.

5. The device of claim 4 wherein the cavity is of a shape selected from the group consisting of a cylindrical, stepped, helical threaded and spaced configuration.

6. The device of claim 1, further comprising a piston received within the interior surface of the impermeable reservoir, wherein the piston divides the reservoir into an active agent containing chamber and a water-swellable agent containing chamber.

7. A method for preparing a fluid-imbibing implantable active agent delivery system for delivering an active agent to a fluid environment of use for a predetermined administration period said method comprising injection molding a semipermeable plug into the end of an impermeable reservoir such that the semipermeable plug conforms to the interior surface of the end of the impermeable reservoir and creates a liquid-tight seal between the semipermeable plug and the interior surface.

8. The device of claim 1 or claim 6 wherein the semipermeable material is selected from the group consisting of plasticized cellulosic materials, polyurethanes and polyamides.

9. The device of claim 1 or claim 6 wherein the active agent is selected from the group consisting of a protein, a peptide and a gene therapy agent.

10. The device of claim 9 wherein the active agent is an LHRH agonist or antagonist.

11. The device of claim 9 wherein the active agent is leuprolide.

12. The device of claim 9 wherein the active agent is Factor VIII or Factor IX.

13. The device of claim 1, further comprising:
(a) a piston that divides the reservoir into a first and a second chamber, the first and second chambers each having an open end;
(b) a water-swellable semipermeable plug in the first chamber; and (c) the active agent in the second chamber, wherein the water-swellable semipermeable plug is located in the open end of the first chamber.

14. The device of any one of claims 1, 6 and 13 wherein the reservoir is titanium or a titanium alloy.

15. The device of claim 6 or claim 13 wherein the piston is formed of C-Flex® TPE.

16. The device of claim 13 wherein the water-swellable semipermeable plug contains at least about 64 mg NaCl.

17. The device of claim 13 wherein the water-swellable semipermeable plug contains NaCl, a gelling osmopolymer and tabletting agents and viscosity modifying agents.

18. The device of claim 13 further comprising an additive in the first chamber of the reservoir.

19. The device of claim 18 wherein the additive is PEG 400.

20. The device of claim 11 wherein the leuprolide formulation is leuprolide acetate dissolved in DMSO at an assayed content of 37% leuprolide.

21. The device of claim 13 wherein the second chamber contains 65 mg of leuprolide.

22. The device of claim 13 wherein the semipermeable plug is formed of polyurethane material with 20% water uptake.

23. The device of claim 13 which delivers about 0.35 µL leuprolide formulation per day.

24. The device of claim 23 which provides continuous delivery of leuprolide formulation for about one year.

25. The device of claim 13 which reaches at least about 70% steady-state delivery by day 14.

26. The device of claim 13 which delivers about 150 µg leuprolide per day.

27. Use of at least one device of claim 13 in the manufacture of a medicament for treating a subject suffering from prostatic cancer.

28. Use of at least one device of claim 13 for treating a subject suffering from prostatic cancer.

29. The device of claim 13 for use in treating a subject suffering from prostatic cancer.