Prolonged delivery of active substance employing an implanted system

The subject of the invention is an implanted device for delivering an active substance, especially susceptible to degradation, to the fluid surrounding the implant site. More particularly, the invention relates to an implant device for the extended delivery of a biologically active substance into a liquid environment in a natural or artificial body cavity.

One of the needs in the field of chronic disease treatment was to ensure long-term delivery of the active substance at a controlled rate over longer periods of time.

Different approaches have been tried to solve the problem of administering active substances. In one approach, implanted diffusion systems were used. Subcutaneous contraceptive implants are described by Philip D. Damey in Current Opinion in Obstetries and Gynecology 1991, 3: 470-476. The contraceptive Norplant required 6 silastim 2 capsules filled with levonorgestrel to be placed under the skin. Pre-conception protection for up to 5 years was obtained. Such implants work on the principle of ordinary diffusion, i.e. the active substance diffuses through the polymer material at a rate that is regulated by the formulation properties of the active substance and the polymer material. Further, Damey discloses biodegradable implants such as Capranor® and noretindron lozenges. These systems are designed to provide a contraceptive for approximately one year, after which they dissolve. The Capranor® system consists of capsules of poly (s-caprolactone), which are filled with levonorgestrel and of tablets that are 10% pure cholesterol with 90% norethindrone.

Implanted diffusion pumps for intravenous, intraarterial, intrathecal, intraperitoneal, spinal and epidural delivery have also been disclosed. Diffusion pumps are usually surgically inserted into the subcutaneous pocket of the lower abdomen. In the BBI Newsletter, volume 17, No. 12, pages 209-211, 1994, analgesic systems for chemotherapy and insulin delivery are described. These systems provide more accurate regulation of active substance delivery than conventional diffusion systems.

One particularly promising approach involves the osmotically driven device described in US 3,987,790, US 4,865,845, US 5,057,318, US 5,059,423, US 5,112,614, US 5,137,727, US 5,234,692 and US 5,234,693. These devices can be implanted in animals to release the active substance in a controlled manner for a given period of administration. Generally, these devices function by soaking up the liquid from the external medium and releasing the right amount of active substance into the given liquid medium.

Although implants as such have already found use in humans and in veterinary medicine, there is currently a need for devices capable of delivering active substances that ensure that a human will receive a controlled dose over an extended period of time.

EP 373.867 describes an implantation kit having two compartments assembled together, separated by a movable impermeable element. One compartment contains the active substance and the other contains delivery aids. The compartment containing the active substance has walls made of impermeable material and an opening that releases the active substance into the environment, while the compartment with the active substance delivery aid has walls that are semi-permeable to the surrounding fluid. Fluid from the environment entering the second compartment generates osmotic potential by pushing on the element separating the compartments and pushing the active substance into the environment.

EP 627.231 describes an implantation device that pulses the active substance into the environment in a pulsating manner. The active substance and the activation mechanism are located in separate compartments separated from each other by a movable partition wall. Pulse delivery is achieved by means of a web of flexible material placed on the venturi. The elastic material is strong enough to seal the orifice when the pressure in the device is lower than the threshold, while when the internal pressure exceeds the threshold pressure, the web stretches.

189 137

Implanted osmotic systems for humans should be reduced in size; the strength of the device must be sufficient to ensure a durable system. Accurate and reproducible dosing rates and the required duration must be ensured, and the period from implantation to the start of uniform dosing must be minimized. Active substances, in particular highly potent unstable substances, must maintain their purity and activity for extended periods of time at elevated body temperatures.

The device according to the invention fulfills these conditions.

According to the invention, the implanted device for supplying the active substance to the fluid surrounding the implant site has a liquid-impermeable container housing, inside which a piston is located dividing the container into two open-ended chambers; one chamber is provided for the formulation of the active substance and is closed by an outlet valve regulating the back diffusion effectively sealing and isolating the active substance from ambient fluids; while the second chamber is provided for a water-intumescent agent and has an end equipped with a semi-permeable plug through which fluid from the environment passes, causing the intumescent agent to swell and pressure on the piston towards the first chamber

Preferably the container of the device is made at least partly of metal, with the container part in contact with the active substance must be non-reactive towards the active substance. Preferably, this part is made of titanium and its alloys with a content of at least 60% titanium.

The piston dividing the container into two chambers is generally made of a thermoplastic elastomer, for example such as C-Flex® TPE.

The chamber containing the formulation of the active substance released into the fluid surrounding the implant site is provided with an outlet valve through which the active substance exits outside into the fluid surrounding the implant site.

The second chamber contains a water-swellable agent, and as a swelling agent, it contains NaCl, a gelling osmopolymer, granulation and processing aids, and optionally as an addition of PEG 400. A plug of semipermeable material closing this chamber is placed in the open end of this chamber. The plug usually has a length to diameter ratio in the range of: 10 to 10: 1, preferably 1: 4 to 4: 1.

Preferably, the plug of semi-permeable material is built into the cavity of the chamber, wherein the cavity of the chamber may have a cylindrical, stepped, spiral, threaded or spaced configuration.

A very important element of the implanted device for supplying the active substance, especially susceptible to degradation, is an integral valve that regulates back diffusion. The task of the outlet valve is to provide protection of the active substance against premature contact with ambient fluids at the implant site.

The outlet valve regulating the back diffusion into the fluid surrounding the implant site has the shape of a stem element with an external thread adapted to the smooth inner surface of the chamber and between the smooth inner surface of the chamber and the threaded element determines the flow path, its length, internal shape and area, where are they are configured so that the average linear speed of the active substance at the outlet of the outlet valve is greater than the rate of fluid inflow from the vicinity of the implant.

Usually the outlet valve is made of polyethylene and has a spiral-shaped flow path with a diameter of 0.08 to 0.5 mm and a length of 20 to 70 mm.

In a preferred embodiment, the implanted device for supplying the active substance to the fluid surrounding the implant site has a container housing made of titanium alloy, divided into two chambers by a piston made of thermoplastic elastomer. The active substance formulation contained in one chamber contains 65 mg of leuprolide in the form of a solution of leuprolide acetate in dMSO, and the water-swellable formulation placed in the other chamber is an osmotic mechanism

189 137 based on NaCl and PET additive. The semi-permeable plug closing the chamber with water-swelling agent is made of polyurethane with 20% water intake; and the active substance closing valve, the back diffusion control valve, is a polyethylene element that defines a spiral flow path, the implanted device being designed to continuously deliver about 150 pg of leuprolide daily for about 1 year, after subcutaneous implantation.

In practical implementation, the device that soaks up fluid from the implant site contains a water-swellable, semi-permeable material that is tightly fitted to the inner surface of one part of the impermeable container, and while the piston swells, it moves and displaces the active substance formulation from the device. The active substance flow path is created between the cooperating surfaces of the back diffusion controlled outlet valve and the container. In this way, the active substance is delivered to the fluid environment of the implanted implant.

The implanted device stores the active substance in the liquid environment of the implant for a given period of administration. The container is impermeable and formed, at least partly from metal. The part of the container in contact with the active substance must not be reactive with the active substance. A suitable material is a metal selected from the group consisting of titanium and its alloys.

Due to the fact that the open end of the water-swelling chamber contains a semi-permeable membrane, and the open end of the chamber with active substance contains a back-diffusion-controlled outlet valve, the system effectively seals the chamber of active substance and isolates it from the surrounding environment. This is possible due to the use of a diffusion-controlled outlet valve on the one hand, defining a flow path whose length, internal cross-section and surface defining the predicted average linear velocity of the active substance higher than the linear, directed into the interior, the flow of liquid from the surrounding environment, and on the other hand using a semi-permeable plug, which swells in water and expands linearly in the delivery system, causing pumping to begin.

In the device according to the invention, the period until the start of uniform delivery of the active substance is less than 10% of the prescribed administration period.

The invention is particularly recommended as an implanted leuprolide delivery system.

To better illustrate the invention, drawings are provided of an implanting device for delivering an active substance, not shown to scale. The same reference numbers refer to the corresponding structural components in various designs.

Figures 1 and 2 show two embodiments of the device according to the invention in partial cross-section; Figure 3 is an enlarged cross-sectional view of the outlet valve regulating the back diffusion of Figure 1; Fig. 4 is a graph illustrating the effect of bore diameter and length on drug diffusion; figures 5, 6, 7 and 8 are enlarged cross-sectional views of further embodiments of the semi-permeable stopper at the end of the container according to the invention; FIG. 9, 10 and 11 are graphs of drug release rates for leuprolide (Fig. 9) and blue dye systems with different membranes (Figs. 10 and 11).

More specifically, the present invention includes a device for delivering the active substance to the fluid environment of the implant, in which the active substance must be protected from the liquid environment until delivery. The device ensures extended and regular delivery.

As used herein, the term "active substance" means the active substance (s) optionally in combination with pharmaceutically acceptable carriers and optionally additional ingredients such as antioxidants, stabilizing agents, permeability enhancers, etc.

The term "prescribed administration period" means a period longer than 7 days, generally between 30 days and 2 years, preferably longer than about 1 month and usually between about 1 month and 12 months.

The term time to "start" delivery means the time from implant insertion until the active substance begins to be delivered at a rate not less than approximately 70% of the intended steady state speed.

The term "impermeable" means that the material is sufficiently impermeable to ambient fluids as well as to the ingredients contained in the dispensing device, so that the migration of such materials into or out of the device through the impermeable device is so small that it generally has no adverse effect on the operation of the device during the delivery period.

The term "semi-permeable" means that the material is permeable to external fluids, but essentially impermeable to other components contained within the dispensing device and the surrounding environment.

The term "therapeutically effective amount" or "therapeutically effective rate" refers to the amount or rate of delivery of the active substance needed to obtain the desired biological or pharmacological effect.

The active substance delivery device according to the invention finds use where the extended and regular delivery of the active substance is desired. In many cases, the active substance is susceptible to degradation as a result of the action of the surrounding environment before it is assimilated, and the device according to the invention providing the given substance protects against such action.

Figure 1 shows one embodiment of the device according to the invention. Figure 1 shows a system 10 which has an impermeable container 12. The container 12 is divided into two chambers by a piston 16. The first chamber 18 contains the active substance and the second chamber 20 contains a soaking agent, which swells when exposed to fluid. The back-diffusion-controlled outlet valve 22 is inserted into the open end of the first chamber 18 and the water-swellable semi-permeable plug 24 is introduced into the open end of the second chamber 20. In Fig. 1, the back-diffusion controlled outlet valve 22 is shown as a male threaded fitting to the smooth inner surface of the container 12, forming a spiral flow path between them 34. Stroke (x), height (y) and cross-sectional area and shape of the spiral path 34 formed between the matched surfaces of the back-diffusion-controlled outlet valve 22 and container 12, as shown in Figure 3, are factors that affect the efficiency of the path 34 preventing backward diffusion of the external fluid into the active substance in chamber 18 and back pressure in the device. The geometry of outlet valve 22 prevents water from diffusing into the container. In general, it is desirable for these characteristics to be selected so that the length of the spiral flow path 34 and the local flow rate of the active substance are sufficient to prevent backward diffusion of the external fluid through the flow path 34 without significantly increasing the back pressure so that, following initiation, the release rate of the substance active osmotic pumping speed was managed.

Figure 2 illustrates a second embodiment of the device according to the invention with a container 12, a piston 16 and a plug 26. In this embodiment, the flow path 36 is formed between the outlet diffusion controlled valve 40 and threads 38, at the inner surface of the container 12. Heights of the threaded portions of the diffusion controlled valve backflow 40 and container 12 are different so that a flow path 36 between container 12 and outlet diffusion controlled valve 40 is created

The water-swellable semi-permeable plugs 24 and 26, shown in Figures 1 and 2, are so inserted into the container that the container wall concentrically surrounds and protects the plug. In Fig. 1, the top portion 50 of the plug 24 is exposed to the surrounding environment and can form a flange top cover 56 overlapping the container end 12. The semi-permeable plug 24 is resiliently engaged on the inner surface of the container 12 and in Fig. 1 is shown as having elongated projections 60 that serve to frictionally engage the semipermeable plug 24 within the container 12. In addition, the elongated projections 60 serve to produce a secondary peripheral seal that functions before the semipermeable plug 24 expands due to hydration. Clearance

189 137 between the longitudinal projections 60 and the inner surface of the container 12 counteracts that the hydration swelling causes stress on the container 12, which can cause tensile damage to the container 12 or compression, or shear damage to the plug 24. Fig. 2 shows a second embodiment of a semi-permeable plug 26, where the plug is injection molded in the upper portion of the container and where the top of the semi-permeable plug 26 is in line with the top 62 of the container 12. In this embodiment, the diameter of the plug is significantly smaller than the diameter of the container 12. In both embodiments, the plug 24 and 26 will swell upon exposure to fluid in the body cavity, creating an even more accurate seal with container 12.

The new configuration of components in the above embodiments provides an implanted device that is extremely suitable for implantation in humans and can be a dispensing device that is able to store unstable formulations at body temperatures for extended periods of time, with start times less than 10% of the administration period, and can be designed to be highly reliable and with a predictable manner of possible damage.

The impervious container 12 must be strong enough to be sure that it will not leak, crack, break or deform and that it does not release the active substance contained as a result of the stresses to which it could be subjected during use. In particular, it should be designed to withstand the maximum osmotic pressure that can be generated by water intumescent in chamber 20. The container 12 must also be chemically inert and biocompatible, i.e. it must be non-reactive towards the active substance as well as towards the body. In general, suitable materials include non-reactive polymers or a biocompatible metal or alloy. The polymers may be acrylonitrile polymers such as acrylonitrile butadiene styrene terpolymer and the like; halogenated polymers such as polytetrafluoroethylene, polychlorotrifluoroelylene, tetrafluoroethylene and hexafluoropropylene copolymer; polyimide; polysulfone; polycarbonate; polyethylene; polypropylene; polychlorovinyl acrylic copolymer; polycarbonate-acrylonitrile-butadiene-styrene copolymer; polystyrene; and similar. The rate of penetration of water vapor through the compositions suitable for forming the container is given in J Pharm. Sci, volume 29, pp. 1634-37 (1970), Ind. Eng. Chem, vol. 45, pp. 2296-2306 (1953); Materials Engineering, volume 5, pp. 38-45 (1972); Ann. Book of ASTM Stds, vol. 8.02, pp. 208-211 and pp. 584-587 (1984); and Ind. and Eng Chem, vol. 49, pp. 1933-1936 (1957). These polymers are known, see Handbook of Common Polymers, Scott and Roff, CRC Press, Cleveland Rubber Co., Cleveland, OH. Metal materials useful for the invention include stainless steel, titanium, platinum, tantalum, gold and their alloys as well as gilded iron alloys, platinum iron alloys, chromium cobalt alloys and titanium nitride coated stainless steel. A container made of titanium or a titanium alloy with a titanium content above 60%, often above 85% titanium is particularly advantageous for most applications where dimensions are important due to its high shape retention capacity, high load capacity and long life, and for those uses where the formulation is sensitive to body chemistry at the implantation site or when the body is sensitive to the formulation. Preferred systems maintain at least 70% of the active substance for 14 months at 37 ° C and have a storage stability of at least about 9 months, or more preferably at least two years at 2-8 ° C. Most preferably the systems can be stored at room temperature. In some embodiments and for applications other than those disclosed above, the fluid soaking and swelling equipment when the formulation 18 is not stable in the chamber 18, especially proteins and / or peptide formulation, then the metal elements in contact with the formulation must be made of titanium or its alloys, such as disclosed above.

The devices of the invention have a sealed chamber 18 that effectively isolates the formulation from the fluid of the environment. The container 12 is made of a rigid, impermeable and durable material. The water-swellable semi-permeable plug 24 is of a less hard material and adapts to the shape of the container, forming, after wetting, a matched seal with the inside of the container 12. The flow path 34 isolates the chamber 18 from backward diffusion of environmental fluid. The piston 16 isolates the chamber 18 from liquids

189 137 environments that can flow into chamber 20 through semi-permeable plugs 24 and 26 such that during steady state use, the active substance is secreted through outlet 22 at a rate corresponding to the rate at which water from environment d flows into the water swellable material in chamber 20 through semi-permeable plugs 24 and 26. As a result, the plug and active substance are protected from damage and their functionality will not be affected, even if the container is deformed. In addition, the use of sealants and adhesives is avoided and the problem of biocompatibility and ease of manufacture is solved

The semi-permeable plug is made of materials that are semi-permeable and that adapt to the shape of the container during wetting and adhere to the rigid surface of the container. The semi-permeable plug increases during hydration when placed in a liquid environment, so that a seal is formed between the matching surfaces of the plug and container. The seal strength between container 12 and outlet valve 22 and container 12 and 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 10 times the operating pressure of the chamber 20 osmotic agent. In a further alternative, the plugs 24 and 26 may be released from the container at an internal pressure that is lower than the pressure needed to release the back-diffusion controlled outlet valve. In this protection against damage, the water swelling chamber is opened and unsealed, thus avoiding the release of the diffusion-controlled outlet valve and the accompanying dispersion of large amounts of active substance. In other cases, when the damage protection system requires the release of the active substance rather than the water swelling agent, the semi-permeable plug must be released at a pressure that is higher than the outlet valve.

In any case, the semi-permeable plug must be long enough to seal tightly against the container wall under operating conditions. It should therefore have an aspect ratio of 1:10 to 10: 1 length to diameter, preferably at least 1: 2 length to diameter and often between 7:10 and 2: 1. The plug must be able to absorb water in an amount of 0.1% to 200% by weight. The diameter of the plug tightly fits inside the container before hydration, as a result of the tight contact of one or more peripheral zones, and will expand at this point as a result of wetting, creating an even tighter seal with the container. The polymeric materials from which the semi-permeable plug can be made vary depending on the absorption rate and configuration requirements of the device, and include, for example, plasticized cellulosic materials, strengthened methylmethacrylates such as hydroxyethyl methacrylate (HEMA) and elastomeric materials such as polyurethanes and polyamides, copolymers polyether-polyamide, thermoplastic copolyesters and the like.

The piston 16 separates the water swelling agent in the chamber 20 from the active substance in the chamber 18 and must be able to move tightly under the pressure prevailing in the container 12. The piston is preferably made of a material with a lower hardness than the container 12 so that it deforms to match the container light to provide an elastic fluid-tight seal with the container 12. The materials of which the piston is made are preferably elastomeric materials that are impermeable and include, for example, polypropylene, rubbers such as EPDm, silicone rubber, butyl rubber and the like, and thermoplastic elastomers such plasticized polyvinyl chloride, polyurethanes, Santoprene®, C -Flex® TPE (Consolidated Polymer Technologies Inc.) and the like. The piston can be designed as self-loading or pressure-loaded.

The outlet diffusion controlled valve 22 defines the delivery path along which the active substance flows from chamber 18 to the implantation site, where absorption of the active substance occurs. The seal between the outlet 22 and the container 12 can be designed to withstand the maximum osmotic pressure generated within the device or to protect against damage as described above. In a preferred embodiment, the pressure required to release the controlled outlet

189 Back diffusion 22 is at least 10 times the pressure required to move the piston 16 and / or at least 10 times the pressure in the chamber 18.

The active substance outlet path is the path 34 formed between the matched surfaces of the back-diffusion controlled outlet valve 22 and container 12. The length of the road, the shape of the internal section and the surface of the outlet path 34 or 36 is chosen so that the average linear velocity of the exiting active substance is higher than the linear velocity towards the inside of the material stream from the surrounding environment by diffusion or osmosis, weakening or slowing back diffusion and its harmful interior contaminating, destabilizing, diluting or otherwise formulating effects. The release rate of the active substance can be modified by changing the geometry of the outlet pathway, which relationship is shown below.

The convective outflow of active substance from the outlet valve 22 is determined by the degree of pumping of the system, and the active substance concentrations in chamber 20 can be represented as follows:

Qca = (Q) (Ca) (1) where

Qca means convective transport of substance A in mg / day

Q is the total convective transport of the substance and its diluents in cm³/ day Ca is the concentration of substance A in the formulation within chamber 20 in mg / cm³The diffusion flow of substance A through the material in the outlet valve 22 is a function of the substance concentration, the flow path configuration 34 or 36, the substance diffusion coefficient and the flow path length 34 or 36, and can be represented as follows:

Qda = D π r² ACa / L (2) where

Qda means diffusion transport of substance A in mg / day

D is the diffusion coefficient through the material on a 34 or 36 way path in cm²/ day r is the effective internal radius of the flow path in cm

ACa is the difference between the concentration of substance A in the container and in the body outside the outlet 22 in mg / cm3

L is the length of the flow path in cm.

Generally, the concentration of the substance in the container is much higher than the concentration of the substance in the body outside the opening, so that the difference ACa can be approximated as the concentration of the substance within the Ca container.

Qda = D π r² Ca / L (3)

It is generally desirable to keep the substance diffusion flux less than 10% of the convective flow. This is as follows:

Qda / Qca = D π r² Ca / QCaL = D π r2 / QL <0,1 (4)

Equation 4 indicates that the relative diffusion flux decreases with increasing volumetric s ^^ t ^ 1 ^ <^^^ and flow and length of the path, and increases with increasing diffusion coefficient and channel radius, and is independent of the concentration of Rku. Equity 4 is plotted in Fig. 4 as a function of length (L) and diameter (d) for D = 2 x 10⁶ cm2 / sec. and Q = 0.36 μΐ / day.

The water diffusion stream when the opening opens into the chamber 18 can be approximated as follows:

Qwd (res) = CoQe⁽-^QI7DWA) (5)

189 137 where

Ce is the water concentration profile in mg / cm³

Q is the mass flow rate in mg / day

L is the length of the flow path in cm

D_in is the water diffusion coefficient of the material over the flow path in cm²/ day A is the cross-sectional area of ​​the flow path in cm2

The hydrodynamic pressure drop along the opening can be calculated as follows:

in;

The simultaneous solution of equations (4), (5) and (6) gives the values ​​presented in Table 1, in which:

Q = 0.38 μΐ / day

Ca = 0, -4 migiel

L = 5 cm

Da = 2.00 E-06 cm²/knot.

μ = 5.00 E + 02 cp

Cw0 = 0 mg / μΐ

D_in = 6.00 E + 06 c ^ i²/ ^^ k.

Table 1

<td></td><td></td><td colspan="3">Diffusion and pumping of the drug</td><td colspan="2">Water intrusion</td><td>Decrease pressure</td>

<td>Effective.</td><td></td><td>Speed pumping</td><td>Diffusion</td><td>Dyf./konw.</td><td></td><td></td><td></td>

<td>Diameter bore</td><td>Section</td><td>QCa</td><td>QDA</td><td>QDA / QCa</td><td>QD_IN</td><td>Qdw</td><td>Delta P.</td>

<td>(Mm)</td><td>Area (mm ")</td><td>mg / day</td><td>mg / day</td><td></td><td>mg / day</td><td>mg / year</td><td>kpa</td>

<td> 1</td><td> 2</td><td> 3</td><td> 4</td><td> 5</td><td> 6</td><td> 7</td><td> 8</td>

<td> 0,0254</td><td> 0,00051</td><td> 0,152</td><td> 0,0001</td><td> 0,0005</td><td> 0</td><td> 0</td><td> 10,74240</td>

<td> 0,0508</td><td> 0,00203</td><td> 0,152</td><td> 0,0003</td><td> 0,0018</td><td>1,14-79</td><td>4,16-77</td><td> 0,67144</td>

<td> 0,0762</td><td> 0,00456</td><td> 0,152</td><td> 0,0006</td><td> 0,0041</td><td>4.79-36</td><td>1.75 33</td><td> 0,13259</td>

<td> 0,1016</td><td> 0,00811</td><td> 0,152</td><td> 0,0011</td><td> 0,0074</td><td>8.89-21</td><td>3,25-18</td><td> 0,04199</td>

<td> 0,1270</td><td> 0,01267</td><td> 0,152</td><td> 0,0018</td><td> 0,0115</td><td>1.04 13</td><td>3.79-11</td><td> 0,01717</td>

<td> 0,1524</td><td> 0,01824</td><td> 0,152</td><td> 0,0025</td><td> 0,0166</td><td>7,16-10</td><td>2.16-07</td><td> 0,00827</td>

<td> 0,1778</td><td> 0,02483</td><td> 0,152</td><td> 0,0034</td><td> 0,0226</td><td>1.48-07</td><td>5,4E-05</td><td> 0,00448</td>

<td> 0,2032</td><td> 0,03243</td><td> 0,152</td><td> 0,0045</td><td> 0,0295</td><td>4,7E-06</td><td> 0,001715</td><td> 0,00262</td>

<td> 0,2286</td><td> 0,04105</td><td> 0,152</td><td> 0,0057</td><td> 0,0373</td><td>5,04-05</td><td> 0,018381</td><td> 0,00165</td>

189 137

cd table i

<td> 1</td><td> 2</td><td> 3</td><td> 4</td><td> 5</td><td> 6</td><td> 7</td><td> 8</td>

<td> 0,254</td><td> 0,05068</td><td> 0,152</td><td> 0,0070</td><td> 0,0461</td><td> 0,000275</td><td> 0,100263</td><td> 0,00110</td>

<td> 0,2794</td><td> 0,06132</td><td> 0,152</td><td> 0,0085</td><td> 0,0558</td><td> 0,000964</td><td> 0,351771</td><td> 0,00076</td>

<td> 0,3048</td><td> 0,07298</td><td> 0,152</td><td> 0,0101</td><td> 0,0664</td><td> 0,002504</td><td> 0,913839</td><td> 0,00055</td>

<td> 0,3302</td><td> 0,08564</td><td> 0,152</td><td> 0,0118</td><td> 0,0779</td><td> 0,005263</td><td> 1,921027</td><td> 0,00034</td>

<td> 0,3556</td><td> 0,09933</td><td> 0,152</td><td> 0,0137</td><td> 0,0903</td><td> 0,00949</td><td> 3,463836</td><td> 0,00028</td>

<td> 0,381</td><td> 0, 11402</td><td> 0,152</td><td> 0,0158</td><td> 0,1037</td><td> 0,015269</td><td> 5,573195</td><td> 0,00021</td>

<td> 0,4064</td><td> 0,12973</td><td> 0,152</td><td> 0,0179</td><td> 0,1180</td><td> 0,022535</td><td> 8,225224</td><td> 0,00014</td>

<td> 0,4318</td><td> 0,14646</td><td> 0,152</td><td> 0, 0202</td><td> 0,1332</td><td> 0,031114</td><td> 11,35656</td><td> 0,00014</td>

<td> 0,4572</td><td> 0,16419</td><td> 0,152</td><td> 0,0227</td><td> 0,1493</td><td> 0,040772</td><td> 14,88166</td><td> 0,00007</td>

<td> 0,4826</td><td> 0,18295</td><td> 0,152</td><td> 0,0253</td><td> 0,1664</td><td> 0,051253</td><td> 18,70728</td><td> 0,00007</td>

<td> 0,508</td><td> 0,20271</td><td> 0,152</td><td> 0,0280</td><td> 0,1844</td><td> 0,062309</td><td> 22,7427</td><td> 0,00007</td>

Calculations indicate that a hole diameter between about 0.076 and 0.254 mm and a length of 2 to 7 cm is optimal for the device in the given operating conditions. In a preferred embodiment, the pressure drop along the orifice is less than 10% of the pressure required to release the backward diffusion controlled outlet valve 22.

The back-diffusion-controlled outlet valve 22 preferably forms a spiral flow path 34 or 36 resulting from the mechanically attached outlet-valve to the container without the use of adhesives or other sealants. The back-diffusion-controlled outlet valve is made of an inert and biocompatible material selected for example from metals including, for example, titanium , stainless steel, platinum and its alloys and cobalt-chromium alloys, and the like, and polymers including, for example, polyethylene, polypropylene, polycarbonate and polymethylmethacrylate, and the like. The flow path usually has a length between about 0.5 and 20 cm, preferably a length between and 10 cm, and a diameter between about 0.0254 and 0.508 mm, preferably between about 0.076 and 0.38 mm, allowing a flow of from about 0.02 to 50 μΐ / day, usually 0.2 to 10 μΐ / day and often 0.2 to 2.0 μΐ / day. In addition, a catheter or other system may be attached to provide delivery of the active substance formulation at a location distant from the implant to the end of the back-diffusion controlled outlet valve. Such systems are disclosed, for example, in US Patent Nos. 3,732,865 and US 4,340.054. In addition, the designed flow path may be useful in systems other than the fluid soak devices according to the invention.

The innovative device configuration described above also minimizes drug delivery delay from initiation to a steady state flow rate. This is achieved in part by configuring the semi-permeable plug 24 or 26. With water permeating through the semi-permeable plug, it swells. The radial expansion is limited by the rigid container 12, and therefore the expansion must be linear, pushing the swelling agent in the water in the chamber 20, which in turn pushes the piston 16. This allows pumping to begin ahead of time when water enters the water swelling agent, which otherwise it would be required before pumping can begin. For reliable acceleration of initiation, the flow path 34 can be pre-filled with the active substance from the chamber 18. Further, the outlet geometry 22 allows for initial delivery, which is affected by a drug concentration gradient including the outlet length. Start period is less than 25%

189 137 a predefined delivery period and is often less than about 10%, and usually shorter than about 5% of the predefined delivery period. In a preferred embodiment for an annual system, at least 70% of the steady state flow rate is reached on day 14.

The water-swellable formulation in chamber 20 is preferably a tissue-tolerant formulation whose high osmotic pressure and significant solubility propel the active substance over a long period of time while remaining in a saturated aqueous solution allowed by the semi-permeable membrane. The water swelling agent is preferably selected to be tolerated by the subcutaneous tissue, at least at pumping rates and hypothetically resulting concentrations that would allow unintended dosing from implanted devices left in the patient for a longer period than prescribed. In preferred embodiments, the water swelling agent should not diffuse or penetrate the semi-permeable plug 24 or 26 in a discernable amount (e.g. less than 8%) under normal operating conditions. Osmotic agents, such as NaCl with suitable tabletting agents (glidants and binders) and viscosity modifying agents, such as sodium carboxymethyl cellulose or sodium polyacrylate, are preferred water swelling agents. Other osmotic agents useful as water swelling agents include osmopolymers and osmogeners, and are disclosed, for example, in US Patent 5,413,572. The water swelling agent formulation may be in the form of a suspension, tablet, molded or extruded material, or other form known in the art. A liquid or gel additive or filler may be added to chamber 20 to remove air from the space around the osmotic motor. Removal of air from equipment should mean that delivery rates will be less affected by nominal external pressure changes (e.g., ± 50 kPa).

The device according to the invention is useful for delivering a wide range of active substances. These substances include, but are not limited to, pharmacologically active peptides and proteins, genes and gene products, other gene therapy factors and other small molecules. Polypeptides may include, among others growth hormone, somatotropin analogues, somatomedin-C, gonadotropic secretion hormone, lymphoid stimulating hormone, luteinizing hormone, LHRH, LHRH analogues such as leuprolide, nafareline and goserelin, LHRH agonist and antagonist, calcinone hormone secretion like chorionic gonadotropin, oxytocin, octreotide, somatotropin plus amino acid, vasopressin, adrenocorticotropic hormone, epidermal growth factor, prolactin, somatostatin, somatostatin plus protein, cosyntropin, lypressin, polypeptides such as thyrotropin secretion hormone, thyroid stimulating hormone, secretin, pancreozymin, enkephalin, glucagon, endocrine secreted internally and distributed with the blood stream, and the like. Further factors that may be provided include, αι-antitrypsin, factor VIII, factor IX and other coagulation factors, insulin and other peptide hormones, adrenocortical stimulating hormone, thyroid stimulating hormone and other pituitary hormones, interferon α, β and δ, erythropoietin , growth factors such as GCSF, GMCSF, insulin-like growth factor 1, tissue plasminogen activator, CD4, dDAVP, interleukin-1 receptor antagonist, tumor necrosis factor, pancreatic enzymes, lactase, cytokines, interleukin-1 receptor antagonist, interleukin-2, tumor necrosis factor receptor, tumor inhibiting proteins, cytotoxic proteins and recombinant antibodies and antibody fragments, and the like.

The above substances are useful in the treatment of various conditions including hemophilia and other blood disorders, growth disorders, diabetes, leukemia, hepatitis, kidney dysfunction, HIV infection, hereditary diseases such as cerebroside deficiency and adenosine deaminase deficiency, hypertension, septic shock, autoimmune diseases such as multiple sclerosis, Graves disease, lupus erythematosus systemic and rheumatoid arthritis, shock and debilitating disorders, cystic fibrosis, lactose intolerance, Crohn's disease, inflammatory bowel disease, gastrointestinal cancer and other cancers.

189 137

The active substances may be in the form of anhydrous or aqueous solutions, suspensions or may be multi-component with pharmaceutically acceptable excipients or carriers. The resulting liquid formulation can be stored for long periods of time at ambient temperature or at a reduced temperature, as well as stored in an implanted dispensing system. The formulations may contain pharmaceutically acceptable carriers and additional inert ingredients. The active substances may be in various forms, such as uncharged molecules, components of molecular complexes or pharmaceutically acceptable salts. Also, simple derivatives of these substances (such as prodrugs, ethers, esters, amides, etc.) that can easily hydrolyze at body pH, enzymes etc. can be used.

It should be understood that more than one active agent may be included in the active substance formulation in the device of the invention. The term "factor" does not preclude the use of two or more of such factors. The dispensing device of the invention may be used in humans or animals. The surrounding environment is a fluid environment and can be any subcutaneous site or body cavity, such as the peritoneum or uterus, and may or may not be equivalent to the destination point of delivery of the active agent formulation. During the therapy program, a subject may be provided with a single or several dispensing devices. The devices are designed to remain as implants during a given administration period. Unless devices are removed after administration, they may be designed to withstand the maximum osmotic pressure of the water swelling agent, or may be designed with a bypass channel to release pressure generated within the device.

The devices of the present invention are preferably sterilized before use, especially when they are to be implanted. This can be done separately by sterilizing each element, e.g. gamma radiation, steam sterilization or filtration sterilization and then aseptically assemble the final kit · '. Alternatively, devices can be assembled and then sterilized in the correct way.

Preparation of the device according to the invention

The container 12 was prepared by machining a metal rod or extrusion or polymer injection molding. The upper part of the container may be open as shown in Fig. 1, or may have a cavity as shown in Fig. 2.

When the container 12 is open, as shown in Fig. 1, the water swellable, semi-permeable plug 24 is mechanically incorporated from the outside of the container without the use of glue before or after the plunger and water swelling agent formulation. The container 12 may be provided with grooves or threads that engage with the ribs or threads of the plug 24.

If the container 12 comprises a cavity as shown in Fig. 2, the cavity may be cylindrical as shown in Fig. 5, it may be stepped as shown in Fig. 6, it may be helical as shown in Fig. 7 or it may have a spaced configuration as shown in Figure 8. The semi-permeable plug 26 is then inserted, built into, or otherwise mounted in the cavity so as to form a seal with the walls of the container.

Then, after installing the plug 26, either mechanically, by welding or by inserting, the water swelling agent is placed in the container, after which the piston is inserted, with the release of trapped air first. The device is filled with the active substance by means of a syringe or precision metering pump. A diffusion retarder is built into the device, usually by vortex or spiral action, or by axial pressure.

The following examples are presented to illustrate the invention and are not intended to limit the scope of the invention.

Examples

Example 1 - Preparation of a set with HDPE container

The device containing leuprolide acetate for the treatment of prostate cancer is assembled from the following components:

Container (HDPE) (5 mm outside diameter, 3 mm inside diameter)

Piston (Santoprene)

189 137

Lubricant (medical silicone fluid)

Compressed osmotic motor (60% NaCl, 40% sodium carboxymethyl cellulose)

Membrane plug (Hytrel polyether ester block copolymer, injection molded to desired shape)

Outlet valve controlled by a dyji. reverse (polycarbonate)

Active substance (0.78 g 60% propylene glycol and 40% leuprolide acetate)

Assembly

The piston and the inner surface of the container are lightly lubricated with silicone medical fluid. Piston 16 was inserted into the open end of chamber 20. Two osmotic motor tablets (40 mg each) were then placed on top of piston 16. After incorporation, the osmotic motor was rinsed from the end of the container. The membrane plug 24 was placed by aligning the container plug and gently pushing the plug into the container fully engage. The active substance was introduced into the syringe, which was used to fill chamber 18 from its open end by injecting material into the open tube until the formulation was about 3 mm from its edge. The filled container was centrifuged (with the outlet end "up") to remove any air bubbles that remained trapped in the formulation during filling. The outlet valve 22 is screwed into the open end of the container until it engages completely. By screwing in the outlet valve, excess formulation escaped outside the orifice ensuring uniform filling.

Example 2 - Placing the kit from Example 1

Placement of the kit of Example 1 was performed under aseptic conditions using a trocar, similar to that used for implantation of Norplant®, contraceptive implants, situating the kit under the skin. A typical implant site is the upper arm, 8-10 cm above the elbow.

The site was anesthetized and an incision was made through the skin. The incision was approximately 4 mm long. A trocar was inserted into the incision so that the tip of the trocar is 4 to 6 cm from the incision. Then the obturator was removed from the trocar and the set of Example 1 was inserted into the trocar. The device was moved to the open end of the trocar using an obturator. The obstrator was then held in place by immobilizing the device of Example 1 while the trocar was moved away from both the implanted set and the obturator. The obturator was then removed, leaving the implant in the right position behind it. The edges of the incision were secured by connecting the skin. The surface was covered and kept dry for 2 to 3 days.

Example 3 - Removing the set from Example 1

The kit from Example 1 is removed as follows: Locating the device is performed by palpating the upper arm with the tip of a finger. The area on one side of the implant is anesthetized and an approximately 4 mm perpendicular incision is made through the skin and fibrous tissue surrounding the implant area. The end of the device opposite the incision is pressed so that the end of the device closer to the incision extends in the direction of the incision. Further fibrous tissue is cut with a scalpel. After removal, the procedure of Example 2 is repeated to insert a new kit.

Example 4 - Delivery speed of the kit of Example 1

The glass tubes were filled with distilled water and then placed in a 37 ° C water bath. One set as described in Example 1 was placed in each tube and the tubes changed periodically. The delivery rate profile of the kit is shown in Figure 9. The kit has no start time because the kit has an initial rapid release period followed by a steady slow release state over a period of 200 days.

Example 5 - Delivery speed profiles

The glass tubes were filled with 35 ml distilled water and then placed in a 37 ° C water bath. After the test tubes reached this temperature, a single device as described in Example 1, but with the membrane materials described below and containing 1% FD&amp;C blue dye in water as the drug formulation, was placed

189 137 in each tube. At regular intervals, the set was transferred to new tubes. The amount of dye released was determined by measuring the concentration of blue dye in each tube using a spectrophotometer. The pumping rate was calculated from the total amount of dye released, the volume of water in the tube, the initial concentration of dye and the time intervals during which the kit remained in the tube. The results of two separate tests are shown in Figures 10 and 11. Fiuraa 10 will represent different sets with different stopper materials (Hyttre®, 2, 3 and 12 month systems), and Fig. 11 fm ^ t ^ issa ^ in m 4 sets with different stopper materials. These materials are:

Membrane Material month PPbax 25 (polylamide) months Pebax 22 ΦοΚιο ^) months Poiiueehm (HP60D) months Pebax 24 p ^ oińmikl)

The kits were able to deliver the substance for a period of 2 to 12 months depending on the membrane used.

Example 6 - Preparation of the device with a titanium container

Kits containing leuprolide acetate for the treatment of prostate cancer are assembled from the following components:

Container (titanium, Ti6A14V alloy) (4 mm outside diameter, 3 mm inside diameter)

Piston (C-Flex®).

Lubricant (medical silicone fluid).

Compressed osmotic motor (76.4% NaCl, 15.5% sodium carboxymethyl cellulose, 6% polyvinylpyrrolidone, 0.5% Mg stearate, 1.6% water)

PEG 400 (8 mg added to the osmotic motor to fill the airspace).

Membrane plug (polyurethane polymer, injection molded to desired shape).

Outlet valve controlled by backward diffusion (polyethylene).

Drug formulation (0.150 g 60% water and 40% leuprolide acetate).

Assembly

The piston and the inside surface of the container are lightly greased. The piston was inserted into the container about 0.5 cm from the membrane side. PEG 400 was added to the container. Then two osmotic motor tablets (40 mg each) were inserted into the container from the membrane side. After incorporation, the osmotic motor was flushed from the end of the container. The membrane plug was placed by aligning the plug with the container and gently pushing until the protruding plug element was not completely engaged in the container. The formulation was introduced into a syringe which was used to fill the container from its outlet end by injecting material into the open tube until the formulation was about 3 mm from its edge. The filled container was centrifuged (with the outlet end "up") to remove any air bubbles that were trapped in the formulation during filling. The outlet valve is screwed into the open end of the container until it engages completely. By screwing in the exhaust valve, excess formulation escaped outside the orifice, ensuring a homogeneous filling.

Example 7 - Preparation of a leuprolide acetate delivery kit with a titanium container

The kit containing leuprolide acetate for the treatment of prostate cancer is assembled from the following components:

Container (titanium, Ti6A14V alloy) (4 mm outside diameter, 3 mm inside diameter, length 4.5 cm).

Piston (C-Flex® TPE elastomer available from Consolidated Polymer Technologies, Inc.).

Lubricant (medical silicone fluid 360).

Tablet of compressed osmotic motor (76.4% NaCl, 15.5% carboxymets 16

189 137 sodium cellulose, 6% polyvinylpyrrolidone, 0.5% Mg stearate, 1.5% water, total 50 mg)

PEG 400 (8 mg added to the osmotic motor to fill the air spaces)

Membrane plug (polyurethane polymer 20% water injection molded to the desired shape, 3 mm in diameter x 4 mm in length).

Exhaust valve controlled by back diffusion (polyethylene, with 0.15 mm x 5 cm duct)

Drug formulation (leuprolide acetate dissolved in DMSO to a determined content of 65 mg leuprolide).

Assembly

The kit was assembled as in Example 6, using aseptic procedures for assembling γ-irradiated components and aseptic filling with filter sterilized leuprolide formulation in DMSO.

Release rate

These kits provide about 0.35 μΐ / day of leuprolide formulation containing on average 150 μμ of leuprolide in the amount delivered daily. At this rate, they ensure leuprolide delivery for at least one year. The system achieves approximately 70% of steady state delivery on day 14.

Implanting and removal

The sets are implanted under local anesthesia through an incision and trocar application as in Example 2, in patients suffering from advanced prostate cancer.

After one year, the sets are removed under local anesthesia as described in Example 3. Then other systems are inserted.

Example 8 - Treatment of prostate cancer

Leuprolide acetate, an LHRH agonist, acts as an active inhibitor of gonadotropin secretion when administered continuously at therapeutic doses. Animal and human studies indicate that following initial stimulation, chronic administration of leuprolide acetate causes a reduction in nuclear steroidogenesis. This effect is reversible if anxiety therapy is discontinued. Leuprolide acetate administration inhibits the growth of certain hormone-dependent tumors (prostate tumors in male Noble and Dunning rats and DMBA-activated breast tumors in female rats) as well as reproductive organs atrophy. In humans, administration of leuprolide acetate causes an initial increase in circulating luteinizing hormone (LH) and follicle stimulating hormone (FSH) levels leading to a transient increase in gonadal steroid levels (testosterone and dihydrotestosterone in men). However, continuous administration of leuprolide acetate causes a reduction in LH and FSH levels. In males, testosterone is limited to the castrate level. This reduction occurs two to six weeks after the start of administration, and castrate-typical testosterone levels in patients with prostate cancer have been shown over many years. Leuprolide acetate is inactive if given orally.

Kits were prepared as in Example 7, then implanted as described. Continuous administration of leuprolide for one year using these kits reduces testosterone to the level of castrate.

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