HK1093449B - Sustained delivery of an active agent using an implantable system - Google Patents

Description

Sustained release of active substances using implantable systems

The present invention is a divisional application of the chinese patent application having the title of 'sustained release of active substance using implantable system' with application number 2004100070640.

Technical Field

The present invention relates to the slow release of biologically active substances. And more particularly to an implantable delivery system for the sustained delivery of an active agent to a fluid environment within a natural or artificial body cavity.

Background

The sustained release of active substances at a controlled rate for the treatment of diseases has been a goal in the field of drug delivery. Various methods have been used to release the active substance.

One approach is to use an implantable diffusion system. For example, Philip d.darney has been reported in infertility and Obstetrics Current (Current Opinion in obstercs and gynecomology) 1991, 3: 470-.6 silastic capsules containing levonorgestrel were implanted subcutaneously. Preventing conception for 5 years. The implant operates in a simple diffusion mode, i.e., the active substance diffuses through the polymeric material, the rate of which is controlled by the composition of the active substance and the properties of the polymeric material. Darney further describes the name Capranor^TMAnd norethindrone pellets. These systems are designed to release the contraceptive for about one year and then dissolve. Capranor^TMThe system included poly (epsilon-caprolactone) capsules with levonorgestrel contained therein and pellets of 10% pure cholesterol and 90% norethindrone.

Implantable infusion pumps have also been reported to deliver drugs via intravenous, intra-arterial, intrathecal, intraperitoneal, intraspinal and epidural routes. Infusion pumps are typically surgically implanted into the pocket of subcutaneous tissue of the lower abdomen. Systems for controlling pain, chemotherapy and insulin release are described in BBI Newsletter, Vol.17, No. 12, p.209-211, month 12 of 1994. These systems can provide more precise controlled release than simple diffusion systems.

One particularly promising approach includes osmotic drive devices such as those described in U.S. patent nos. 3987790, 4865845, 5057318, 5059423, 5112614, 5137727, 5234692, and 5234693, which are incorporated herein by reference. These devices can be implanted in animals to release the active agent in a controlled manner over a predetermined period of administration. Typically, these devices operate by imbibing a liquid from the external environment and releasing a corresponding amount of the active substance.

The above-described devices can be used to release active substances into the liquid environment of use. While these devices have found application for human and veterinary purposes, there remains a need for devices that are capable of releasing active substances, particularly substances that are extremely unstable, so that they can be reliably released at a controlled rate to humans over a sustained period of time.

Disclosure of Invention

It is well known to use implantable osmotic systems to deliver active agents to an animal. Adapting these systems to humans creates a series of challenges. The size of devices for human implantation needs to be reduced. The strength of the device must be sufficient to ensure the integrity of the system. Precise and reproducible release rates and durations are to be ensured, and the time interval from implantation to initiation of release is to be minimized. In case of exposure to elevated temperatures within the body cavity, the active substance must reproduce its purity and activity over a prolonged period of time.

Accordingly, one aspect of the present invention is a liquid-imbibing device for delivering an active agent formulation to a liquid environment of use. The device comprises a water-swellable, semi-permeable material mounted in a sealed manner to the inner wall at one end of an impermeable reservoir. The device also includes an active substance that is expelled from the device when the water-swellable material swells.

In another aspect, the present invention relates to an implantable device for releasing an active agent into a fluid environment of use. The device includes a reservoir and a mating back-diffusion regulating outlet. The flow path of the active substance includes a passage formed between the connecting surface of the back-diffusion regulating outlet and the reservoir.

In another aspect, the invention relates to a device for storing an active substance in a liquid environment of use during a predetermined administration period, the device comprising a reservoir containing the active substance. The reservoir is impermeable and is at least partially made of a metallic material. The portion of the reservoir contacting the active material is non-reactive with the active material and is made of a material selected from the group consisting of titanium and alloys thereof.

In yet another aspect, the invention is an implantable, fluid-imbibing, active agent delivery system including an impermeable reservoir. The reservoir has a piston which divides the reservoir into a chamber containing the active substance and a chamber containing the water-swellable substance. The chamber containing the active substance is provided with a back-diffusion regulating outlet. The chamber containing the water-swellable agent is provided with a semipermeable plug. The plug or outlet tube may be disconnected from the reservoir at an internal pressure that is below the maximum osmotic pressure generated by the water-swellable agent.

The invention also relates to a liquid-imbibing, implantable active agent delivery system, the initiation time of delivery of which is less than 10% of the intended administration period.

In another aspect, the invention relates to a method of preparing an implantable, liquid-imbibing active agent delivery system. The method includes injection molding a semipermeable plug into the end of the impermeable reservoir such that the plug is protected by the reservoir.

In another aspect, the present invention relates to an impermeable active agent delivery system for delivering an active agent that is susceptible to degradation. The reservoir has a piston dividing the reservoir into a water-swellable agent chamber and an active agent chamber. The open end of the water-swellable agent chamber is provided with a semi-permeable membrane and the open end of the active agent chamber is provided with a back-diffusion regulating outlet. The system effectively seals the active substance compartment and isolates it from the application environment.

In another aspect, the invention relates to a back-diffusion regulating outlet for an active agent delivery system. The outlet tube defines a flow path, its length, shape and area of internal cross-section, providing an average linear flow velocity of the active substance that is greater than the linear inward flow of liquid in the environment of use.

The invention also relates to a semipermeable plug for an active substance delivery system. The plug is water-swellable and must be linearly swellable in the delivery system in order to start pumping after the system is implanted in the fluid environment of the application.

The invention also relates to an implantable delivery system for delivering Leuprolide (Leuprolide).

Drawings

All figures are not drawn to scale and are intended to illustrate various embodiments of the present invention. Like structures are indicated by like numerals.

Figures 1 and 2 are partial cross-sectional views of two embodiments of the delivery device of the present invention.

Fig. 3 is an enlarged cross-sectional view of the back-diffusion regulating outlet of fig. 1.

Fig. 4 is a graph illustrating the effect of nozzle diameter and length on drug diffusion.

Fig. 5, 6, 7 and 8 are enlarged cross-sectional views of another embodiment of a semipermeable plug end of a reservoir according to the invention.

Figures 9, 10 and 11 are release rate profiles for systems employing leuprolide (figure 9) and blue dye and different membranes (figures 10 and 11).

Detailed Description

The present invention provides a device for releasing an active substance into an application liquid environment, wherein the active substance has to be protected from the liquid environment until it is released. Sustained and controlled release is achieved.

Definition of

The term "active agent" refers to an active agent optionally in combination with a pharmaceutically acceptable carrier and optionally with additional ingredients such as antioxidants, stabilizers, penetration enhancers, and the like.

By "predetermined administration time" is meant a period of time greater than 7 days, typically between about 30 days and 2 years, preferably about greater than 1 month and typically between 1 month and 12 months.

The time to "start" release refers to the time from implantation in the fluid environment of use to the time at which the active agent is actually released at a rate no less than about 70% of the expected steady state rate.

The term "impermeable" means that the materials are sufficiently impermeable to environmental fluids and to the components contained in the drug delivery device that migration of these materials into and out of the device through the impermeable device is so low that there is substantially no adverse effect on the function of the device during release.

The term "semipermeable" means that the material is permeable to external fluids but substantially impermeable to other components contained within the drug delivery device and the environment of use.

The term "therapeutically effective amount" or "therapeutically effective rate" as used herein refers to the amount or rate of active agent required to produce the desired biological or pharmacological effect.

The active substance release device of the present invention finds application where sustained and controlled release of an active substance is desired. In many cases, the active substance is susceptible to degradation if exposed to the environment of use prior to release, and the release device avoids such exposure.

FIG. 1 shows an embodiment of the apparatus of the present invention. In fig. 1, a fluid-imbibing system 10 is shown which includes an impermeable reservoir 12. The reservoir 12 is divided into two chambers by a piston 16. The first chamber 18 is adapted to contain an active substance and the second chamber 20 is adapted to contain a liquid-imbibing substance. A back-diffusion regulating outlet 22 is inserted into the open end of the first compartment 18 and a water-swellable semipermeable plug 24 is inserted into the open end of the second chamber 20. The back-diffusion regulating outlet 22 is shown in fig. 1 as a male threaded member in position to engage the smooth inner surface of the reservoir 12 to form a spiral passageway 34 therebetween. The pitch (x), amplitude (y) and cross-sectional area and shape of the spiral channel 34 formed between the connecting surfaces of the reservoir 12 and the back-diffusion regulating outlet 22 as shown in fig. 3 are factors that affect the effectiveness of the channel 34 in preventing back-diffusion of external liquid into the composition in the chamber 18 and the back-pressure in the device. The geometry of the outlet tube 22 prevents diffusion into the reservoir. In general, these characteristics are selected so that the length of the spiral flow channel 34 and the flow rate of the active agent therethrough are sufficient to prevent back-diffusion of external fluids through the flow channel 34 without significantly increasing back pressure, so that the release rate of the active agent after actuation is controlled by the rate of osmotic pumping.

Fig. 2 shows a second embodiment of the device according to the invention with a reservoir 12, a piston 16 and a plug 26. In this embodiment, the flow path 36 is formed between a threaded back-diffusion regulating outlet 40 and threads 38 formed on the interior surface of the reservoir 12. The amplitude of the threaded portions of the back-diffusion regulating outlet 40 and the reservoir 12 are not the same so that a flow path 36 is formed between the reservoir 12 and the back-diffusion regulating outlet 40.

Water-swellable semipermeable plugs 24 and 26, shown in figures 1 and 2, respectively, are inserted into the reservoir such that the walls of the reservoir concentrically surround and protect the plugs. In fig. 1, the top portion 50 of the plug 24 is exposed to the environment of use and may form a flanged end cap portion 56 that covers the end of the reservoir 12. The semipermeable plug 24 is resiliently engageable with the interior surface of the reservoir 12 and is shown in fig. 1 as being provided with ridges 60 to function to frictionally engage the semipermeable plug 24 with the interior surface of the reservoir 12. In addition, the ridges 60 serve to create an additional circumferential seal that acts as a seal before the semipermeable plug 24 expands due to hydration. The clearance between the ridges 60 and the interior surface of the reservoir 12 prevents the hydration expansion from exerting stresses on the reservoir 12 that could cause the reservoir 12 to pull apart or crush or shear the plug 24. Fig. 2 shows a second embodiment of the semipermeable plug 26 wherein the plug is injection molded into the top of the reservoir and the top of the semipermeable plug 26 is flush with the top 62 of the reservoir 12. In this embodiment, the diameter of the plug is significantly smaller than the diameter of the reservoir 12. In both embodiments the plugs 24 and 26 will expand when exposed to fluid within the body cavity to form a tighter seal with the reservoir 12.

The novel configuration of the components of the above-described embodiments provides an implantable device that is well suited for implantation into the human body and ensures that the delivery device can store unstable compositions at body temperature for extended periods of time, has a start-up time of less than 10% of the administration period and can be designed to be highly reliable and to have a predictable fail-safe form.

The reservoir 12 must be strong enough to ensure that it does not leak, break or deform to release its active substance under the stresses it is subjected to during use, which should be impermeable. In particular, it should be designed to withstand the maximum osmotic pressure generated by the water-swellable material in chamber 20. The reservoir 20 should also be chemically inert and biocompatible, i.e. it must be non-reactive with the active substance ingredient and the human body. Suitable materials typically include non-reactive polymers or biocompatible metals or alloys. Polymers include acrylonitrile polymers such as acrylonitrile-butadiene-styrene terpolymers and the like; halogenated polymers such as polytetrafluoroethylene, polychlorotrifluoroethylene, tetrafluoroethylene, and hexafluoropropylene copolymers; a polyimide; polysulfones; a polycarbonate; polyethylene; polypropylene; polyvinyl chloride-acrylic acid copolymers; polycarbonate-acrylonitrile-butadiene-styrene; polystyrene; and the like. The rate of moisture permeation through the composition used to form the reservoir is reported in the following documents: journal of pharmacy (j.pham.sci.), volume 29, pages 1634-37 (1970); ind, eng, chem, volume 45, page 2292-2306 (1953); materials Engineering, Vol.5, pp.38-45 (1972); book of asttmsstds, vol 8, 2 nd, pages 208-; and industrial and engineering chemistry (Ind. and Eng. chem.), Vol.49, page 1933-. Some Polymers are disclosed in the Handbook of Polymers in general (Handbook of Common Polymers, Scott and Roff, CRC Press, Cleveland rubber co., Cleveland, OH). Metallic materials useful in the present invention include stainless steel, titanium, platinum, tantalum, gold and alloys thereof, as well as gold-plated ferrous alloys, platinum-plated ferrous alloys, cobalt-chromium alloys, and titanium nitride coated stainless steel. Reservoirs made of titanium or titanium alloys containing more than 60%, usually more than 85% titanium are particularly suitable for most critical dimensional conditions, for high load capacity and long-term use and for conditions where components sensitive to body chemistry are used at the implantation site or where the body is sensitive to components. Preferred systems retain at least 70% of the active after 14 months at 37 ℃ and have a storage stability of at least about 9 months, or preferably at least about two years at 2-8 ℃. Most preferably, the system is stored at room temperature. In certain embodiments, for use cases other than the specifically described liquid-imbibing devices in which the labile components are in the chamber 18, particularly protein and/or peptide components, the metal components in contact with these components must be fabricated using titanium or alloys thereof as described above.

The device of the present invention provides a sealed chamber 18 which effectively isolates the active ingredient from the liquid environment. The reservoir 12 is made of a rigid, impermeable and strong material. The water-swellable semipermeable plug 24 is formed of a material of low durometer and is conformable to the shape of the reservoir to form a liquid-tight seal with the inside of the reservoir 12 when wetted. Flow channel 34 separates chamber 18 from back diffusion of ambient liquid. The piston 16 isolates the chamber 18 from ambient fluids that are allowed to enter the chamber 20 by the semipermeable plugs 24 and 26, so that in use under steady-state flow conditions, the active substance is expelled from the outlet conduit 22 at a rate corresponding to the rate of water flow from the environment into the water-swellable material in the chamber 20 through the semipermeable plugs 24 and 26. The plug and the active ingredient are therefore not damaged and their function is not impaired even in the event of deformation of the reservoir. In addition, the use of sealants and adhesives is avoided while the attendant problems of biocompatibility and ease of manufacture are also solved.

The material from which the semipermeable plug is made is semipermeable and is capable of conforming to the shape of the reservoir when wetted and of adhering to a rigid surface of the reservoir. When placed in a fluid environment, the semipermeable plug expands due to its hydration, thereby forming a seal at the interface between the plug and the reservoir. The seal strength between the reservoir 12 and the outlet tube 22 and between the reservoir 12 and the plugs 24 and 26 is designed to withstand the maximum osmotic pressure generated by the device. In another preferred embodiment, the plugs 24 and 26 are designed to withstand at least 10 times the operating pressure of the permeate chamber 20. In yet another alternative, the plugs 24 and 26 may be disengaged from the reservoir at an internal pressure that is lower than the pressure required to disengage the back-diffusion regulating outlet. In this fail-safe embodiment, the water-swellable agent chamber will be opened and depressurized, thereby avoiding extrusion of the diffusion regulating outlet tube and concomitant release of a large amount of active agent. In other cases where the fail-safe system requires the release of an active substance component rather than a water-swellable substance component, the semipermeable plug must be released at a pressure that is greater than the pressure of the outlet tube.

In either case, the semipermeable plug must be long enough to sealingly engage the reservoir wall in an operational situation, i.e., it must have a length to diameter ratio of between 1:10 and 10:1, preferably a length to diameter ratio of at least about 1:2, and typically between 7:10 and 2: 1. The plug must be able to take in between about 0.1% and 200% of its weight in water. The plug has a diameter such that it sealingly fits within the reservoir prior to absorption as a result of the sealing contact of the one or more annular regions, and expands in situ after absorption to form a tighter seal with the reservoir. The polymeric material from which the semipermeable plug is made may vary depending on the pumping rate and the requirements of the device configuration and may include, but is not limited to, plasticized cellulosic materials, reinforced polymethylmethacrylate such as hydroxyethyl methacrylate (HEMA), and elastomeric materials such as polyurethanes and polyamides, polyether-polyamide copolymers, thermoplastic copolyesters, and the like.

The piston 16 isolates the water-swellable agent in the chamber 20 from the active agent in the chamber 18 and is sealingly movable under pressure in the reservoir 12. The piston 16 is preferably made of a material that is less rigid than the reservoir 12 and is deformable to fit within the cavity of the reservoir and form a liquid-tight pressure seal with the reservoir 12. The material from which the piston is made is preferably an elastomeric material that is impermeable, including but not limited to polypropyleneOlefins, rubbers such as EPDM, silicone, butyl, and the like, and thermoplastic elastomers such as plasticized polyvinyl chloride, polyurethane, and the like,TPE (cured Polymer Technologies Inc.), and the like. The piston can be designed to be self-loading or pressure-loaded.

The back-diffusion regulating outlet 22 forms a release channel through which the active substance flows from the chamber 18 to the site of implantation, where it is absorbed. The seal between the outlet tube 22 and the reservoir 12 may be designed to withstand the maximum osmotic pressure generated within the device or to fail-safe as described above. In a preferred embodiment, the pressure required to disengage the back diffusion regulating outlet 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 exit path of the active substance is a channel 34 formed between the junction surface of the back-diffusion regulating outlet 22 and the reservoir 12. The length of the channel, the shape and area of the internal cross-section of the outlet tube path 34 or 36, is selected so that the average linear velocity of the exiting active substance is greater than the linear flux of the substance in the environment of use, which is directed inward by diffusion or osmosis, thereby reducing or reducing back-diffusion and its deleterious effects of contaminating the interior of the pump, destabilizing, diluting or otherwise altering the composition. The release rate of the active substance can be varied by varying the geometry of the outlet channel, the relationship between which is shown below.

The flow of active substance out of the outlet tube 22 is defined by the pumping rate of the system and the concentration of active substance in the chamber 20 and can be expressed mathematically as follows:

Q_ca＝(Q)(C_a) (1)

wherein

Q_caIs substance A transported outwards in mg/day

Q is in cm³Daily total amount of substance transported out and its dilution

C_aIs in mg/cm³The concentration of substance A in the composition in chamber 20

The diffusive flow of substance a through the material in the outlet tube 22 is a function of the substance concentration, the cross-sectional shape of the flow path 34 or 36, the substance diffusing capacity, and the length of the flow path 34 or 36, and can be expressed as follows:

Q_da＝Dπr²ΔC_a/L (2)

wherein

Q_daSubstance A for diffusive transport in mg/day

D is in cm²Diffusion capability of the material in the transit path 34 or 36 on a daily basis

r is the effective inner radius of the flow path in cm

ΔC_aIs in mg/cm³The difference between the concentration of substance A in the meter reservoir and the concentration in the body outside the outlet tube 22

L is the length of the flow path in cm

Typically, the concentration of the substance in the reservoir is much greater than the concentration of the substance in the body outside the orifice, and thus the difference, Δ C_aThe concentration C of the substance in the reservoir can be approximated_aAnd (4) showing.

Q_da＝Dπr²C_a/L (3)

It is generally desirable to maintain the diffusion flux of the substance at less than 10% of the outward flow. This can be represented by the following formula:

Q_da/Q_ca＝Dπr²C_a/QC_aL＝Dπr²/QL 0.1 (4)

equation 4 shows that the relative diffusion flux decreases with increasing volumetric flow rate and path length, increases with increasing diffusion capacity and channel radius, and is independent of drug concentration equation 4 is 2 × 10 for D as a function of length (L) and diameter (D)^-6cm²The second and Q are plotted as 0.36 μ l/day, as shown in fig. 4.

In the nozzle opening into the chamber 18, the diffused flow of water can be expressed approximately as:

Q_wd(res)＝C₀Qe^(-QL/DwA) (5)

wherein

C₀Is in mg/cm³Water concentration distribution of meter

Q is the mass flow rate in mg/day

L is the length of the flow path in cm

Dw is in cm²Water diffusion capacity through material in flow path

A is in cm²Cross-sectional area of flow path of meter

The reduction in hydrodynamic pressure through the orifice can be calculated by:

ΔP＝8QLμ/πr⁴ (6)

the results obtained by simultaneously solving formulae (4), (5) and (6) are shown in Table 1, in which:

q is 0.38. mu.l/day

C_a＝0.4mg/μl

L＝5cm

D_a＝2.00E-06cm²Second/second

μ＝5.00E+02cp

C_w0＝0mg/μl

D_w＝6.00E+06cm²Second/second

TABLE 1

Calculations show that nozzle diameters between about 3 and 10 mils and lengths of 2 to 7cm are optimal for an apparatus having the above-described operating conditions. In a preferred embodiment, the pressure drop across the orifice is less than 10% of the pressure required to disengage the back-diffusion regulating outlet 22.

The back-diffusion regulating outlet 22 preferably forms a spiral path 34 or 36 comprising a long flow path through a means for mechanically connecting the outlet to the reservoir without the use of adhesives or other sealants. The back-diffusion regulating outlet is made of an inert and biocompatible material selected from, but not limited to, metals including but not limited to titanium, stainless steel, platinum and alloys thereof, cobalt-chromium alloys, and the like; polymers include, but are not limited to, polyethylene, polypropylene, polycarbonate, and polymethylmethacrylate, and the like. The flow path is typically between about 0.5 and 20cm in length, preferably between about 1 and 10cm in length, and between about 0.001 and 0.020 inches in diameter, preferably between about 0.003 and 0.015 inches, so that the flow is between about 0.02 and 50 μ l/day, typically 0.2 to 10 μ l/day and often 0.2 to 2.0 μ l/day. Alternatively, a catheter or other system may be attached to the end of the back-diffusion regulating outlet tube to provide a location for the released active agent formulation to be removed from the implant. Such systems are well known in the art and are described, for example, in U.S. Pat. Nos. 3,732,865 and 4,340,054, which are incorporated herein by reference. Additionally, the design of the flow path may also be useful for systems other than the liquid-imbibing devices specifically described herein.

The above-described configuration of the apparatus of the present invention is also applicable to the case of a minimum lag period from start-up to steady-state flow rate. This is accomplished, in part, by the construction of the semipermeable plug 24 or 26. When water is imbibed by the semipermeable plug, the plug expands. Its radial expansion is limited by the rigid reservoir 12 so that expansion must occur in a straight line, pushing the water-swellable agent in chamber 18 which in turn pushes the piston 16. This will allow pumping to begin before the water reaches the water-swelling substance, which would otherwise be required to reach the swelling medium before pumping is initiated. To facilitate reliable activation, the flow path 34 may be pre-filled with an active substance in the chamber 18. In addition, the geometry of the outlet tube 22 provides for initial release, which is influenced by the concentration gradient of the drug along the length of the outlet tube. The start-up period is less than about 25% of the predetermined release time, often less than about 10%, and typically less than about 5% of the predetermined release time. In a preferred embodiment of a one year system, at least 70% of the time to steady-state flow rate is 14 days.

The water-swellable agent component in chamber 20 is preferably a tissue-resistant component that has a high osmotic pressure and a high solubility that propels the active agent over a longer period of time while remaining in a saturated solution in the water allowed by the semi-permeable membrane. The water-swellable agent is preferably selected to be tolerated by the subcutaneous tissue, at least at a pumping rate and presumed concentration that will allow for accidental delivery from an implanted device that remains in the patient's body for a longer period of time than the marking time. In a preferred embodiment, the water-swellable agent does not cause any significant percolation or permeation (e.g., less than 8%) through the semipermeable plug 24 or 26 under normal operating conditions. Osmotic agents, such as NaCl with appropriate amounts of tableting agent (lubricant and binder) and viscosity modifier, such as sodium carboxymethylcellulose or sodium polyacrylate, are preferred water-swellable agents. Other osmotic agents useful as water-swellable agents include osmophilic polymers and osmophilic agents and are described, for example, in U.S. Pat. No. 5,413,572, which is incorporated herein by reference. The water-swellable agent component may be a slurry, tablet, molded or extruded material or other form known in the art. A liquid or gel additive or filler may be added to the chamber 20 to exclude the surrounding osmotic engineThe air of the space. Purging air from the device is intended to reduce calibrated external pressure changes (e.g., + -7 pounds/inch)²(+ 5 atm)) on release rate.

The device of the present invention is suitable for use with a wide variety of active substances. These substances include, but are not limited to, pharmacologically active peptides and proteins, genes and gene preparations, other gene therapy substances, and other small molecules. Polypeptides include, but are not limited to, growth hormone analogs, somatomedin-C, gonadotropin releasing hormone, follicle stimulating hormone, luteinizing hormone, LHRH analogs (e.g., leuprolide, nafarelin, and goserelin), LHRH agonists and antagonists, growth hormone releasing factor, calcitonin, colchicine, gonadotropins (e.g., chorionic gonadotropin), oxytocin, octreotide, growth hormone plus amino acids, vasopressin, corticotropin, epidermal growth factor, prolactin, somatostatin, growth hormone plus protein, alpha 1-24 adrenocorticotropic hormone (osyntropin), lysine vasopressin; polypeptides such as thyroid stimulating hormone releasing hormone, thyroid stimulating hormone, secretin, enkephalin, glucagon, endocrine and endocrine substances distributed in the bloodstream, and the like. Other releasable substances include alpha₁Antitrypsin, factor VIII, factor IX and other clotting factors, insulin and other peptide hormones, corticotropin, thyroid stimulating hormone and other pituitary hormones, interferon alpha, beta, and delta, erythropoietin, growth factors such as GCSF, GMCSF, insulin-like growth factor 1, tissue plasminogen activator, CD4, dDAVP, interleukin-1 receptor antagonist, tumor necrosis factor, pancreatin, lactase, cytokinin, interleukin-1 receptor antagonist, interleukin-2, tumor necrosis factor receptor, tumor suppressor protein, cytotoxic proteins, and recombinant antibodies and antibody fragments, and the like.

The above substances are useful for the treatment of a variety of indications including, but not limited to hemophilia and other hematological disorders, growth disorders, diabetes, leukemia, hepatitis, renal failure, HIV infection, genetic disorders (e.g., cerebrosidase deficiency and adenosine deaminase deficiency), hypertension, septic shock, autoimmune diseases (e.g., multiple sclerosis, graves 'disease, systemic lupus erythematosus, and rheumatoid arthritis), shock and wasting disorders, cystic fibrosis, lactose intolerance, crohn's disease, inflammatory bowel disease, gastrointestinal and other cancers.

The active substance may be an anhydrous or aqueous solution, suspension or complex with pharmaceutically acceptable excipients or carriers to form a flowable formulation which may be stored on shelf or under refrigeration for extended periods of time and in an implantable delivery system. The composition may include a pharmaceutically acceptable carrier and other inert ingredients. The active substance may be in various forms, such as uncharged molecules, molecular complex components or pharmaceutically acceptable salts. Likewise, simple derivatives of substances that are readily hydrolyzed at body pH, enzymes, etc. (e.g., prodrugs, ethers, esters, amides, etc.) may also be used.

It will be appreciated that more than one active substance may be incorporated into the active substance component of the device of the present invention and the use of the term "substance" does not exclude the use of two or more such active substances. The drug delivery device of the present invention may be applied to, for example, humans or other animals. The environment in which the application takes place is a liquid environment and may include any subcutaneous site or body cavity, such as the peritoneum or uterus, but this may or may not be equivalent to the point of ultimate release of the active substance ingredient. A single administration device or a plurality of administration devices may be used to administer the drug to the subject during a single treatment session. The device is designed to remain implanted for a predetermined administration period. If the device is not removed after administration, it may be designed to withstand the maximum osmotic pressure of the water-swellable agent or may be designed with a shunt path to relieve the pressure generated within the device.

The device of the invention should preferably be sterile before use, especially when the application is implantation. This can be done by sterilizing each component separately, for example with gamma radiation, steam sterilization or sterile filtration, and then assembling the final system. Or the device is assembled and then finally sterilized using suitable methods.

Manufacture of the inventive device

The reservoir 12 is preferably manufactured by machining a metal rod or die casting or injection molding a polymer. The top of the reservoir may be open as shown in fig. 1 or with a cavity as shown in fig. 2.

When the reservoir 12 is open as shown in fig. 1, a water-swellable semipermeable plug 24 is mechanically inserted from outside the reservoir, and no adhesive is used either before or after the piston and water-swellable agent formulation are placed. Reservoir 12 may be provided with grooves or threads that engage ribs or threads on plug 24.

Where the reservoir 12 is provided with a cavity as shown in figure 2, the cavity may be cylindrical in shape as shown in figure 5; may be stepped as shown in fig. 6; may be helical, as shown in fig. 7; or may be a shape that leaves a space, as shown in fig. 8. The semipermeable plug 26 is then injected, inserted, or otherwise assembled into the cavity to form a seal with the reservoir wall.

After inserting the plug 26, either mechanically or by welding or injection, the water-swellable agent is loaded into the reservoir, followed by insertion of the piston, taking appropriate steps to expel entrapped air. The active substance is filled into the device with a syringe or a precision drug delivery pump. The diffusion reducers are typically inserted into the device by a rotational or helical action, or by axial compression.

The following examples are provided to illustrate the invention. These examples are not to be construed as limiting the scope of the invention. Variations and equivalents of these examples will be apparent to those of ordinary skill in the art in light of this disclosure, the drawings and the claims herein.

Detailed Description

Examples

EXAMPLE 1 fabrication of devices with HDPE reservoirs

A system comprising leuprolide acetate for the treatment of prostate cancer is assembled from:

accumulator (HDPE) (external diameter 5mm, internal diameter 3mm)

Piston

Lubricant (Silicone medicinal liquid)

Compressed osmotic starting parts (60% NaCl, 40% sodium carboxymethylcellulose)

Membrane plug (Hytrel polyether-ester block copolymer, injection molded into the desired shape)

Back diffusion regulating outlet pipe (polycarbonate)

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

Assembly

The piston and reservoir inner diameter are slightly lubricated with a silicone medical fluid. The piston 16 is inserted into the open end of the chamber 20. Two osmotic engine tablets (40mg per tablet) were then inserted on top of the piston 16. After implantation, the osmotic engine is flush with the end of the reservoir. The membrane plug 24 is implanted by aligning it with the reservoir and gently pushing until the plug is fully engaged in the reservoir. The active substance is loaded into a syringe and the chamber 18 is filled by injecting the material into the open tube through the open end until the formulation ingredients are about 3mm from the end. The filled reservoir is centrifuged (outlet tube end "up") to expel the air bubbles trapped in the formulation during filling. The outlet tube 22 is screwed into the open end of the reservoir until it is fully engaged. When the outlet tube is screwed in, excess formulation component escapes through the nozzle to ensure a standard fill.

Example 2 insertion of the device of example 1

Insertion of the device in example 1Is used for implantation under aseptic conditionA similar trocar as used in contraceptive implants places the device subcutaneously. The site of insertion is typically 8 to 10cm medial of the upper arm, above the elbow.

The site is anesthetized and an incision is made through the skin. The incision was about 4mm long. The trocar is inserted into the incision until the tip of the trocar is located at a distance of 4 to 6cm from the incision. The obturator is then removed from the trocar and the device of example 1 is inserted into the trocar. The device is then advanced to the open end of the trocar with the obturator. The obturator is then secured in place, thereby immobilizing the device of example 1 while the trocar is pulled from the device and obturator. The plug is removed leaving the implant in a well controlled position. The edges of the opening are secured with a skin closure. The area was covered and kept dry for 2 to 3 days.

Example 3 removal of the device in example 1

The apparatus of example 1 was taken out as follows: the position of the device is ascertained by touching the upper arm part. Anesthesia was applied to the site at one end of the implant and a vertical incision of approximately 4mm was made through the skin and all fibrous capsule tissue surrounding the implant area. The opposite end of the device from the incision is pushed to push the device out of the incision proximally relative to the incision. Other fibrous tissues were cut with a scalpel. After removal, a new device can be implanted following the procedure of example 2.

Example 4 Release Rate of the device in example 1

A few glass test tubes were filled with 35ml of distilled water and then placed in a water bath at 37 ℃. A single device as described in example 1 is placed in each test tube, which is periodically changed. The release rate profile from the system is shown in figure 9. The system does not have any start-up time because the system exhibits an initial high release period followed by a lower steady state release for a period of about 200 days.

Example 5 Release Rate profiles

A few glass test tubes were filled with 35ml of distilled water and then placed in a water bath at 37 ℃. After the tubes had reached temperature, a single device as shown in FIG. 1, with membrane material as described below and containing 1% FD, was placed into each tube&C blue dye water solution is used as a medicine component. The permeation of water from the tube through the membrane causes the system to pump the ingredients (blue dye) into the surrounding water in the tube. At regular intervals, the system is switched to a new test tube. The amount of dye released was determined by measuring the concentration of blue dye in each tube using a spectrophotometer. The pumping rate can be calculated from the total dye delivery, the volume of water in the tube, the initial concentration of dye and the time interval the system is in the tube. The results of two different sets of experiments are shown in figures 10 and 11. FIG. 10 shows 3 different plug materials: (2. 3 and 12 month systems), fig. 11 shows 4 systems with different plug materials. These materials are:

film Material

1 month Pebax 25 (Polyamide)

Pebax 22 (Polyamide) for 2 months

3 months old Polyimidyl ester (HP60D)

12 months Pebax 24 (Polyamide)

The release period for these systems may be from 2 to 12 months, depending on the membrane applied.

EXAMPLE 6 production of a Release device with a titanium reservoir

A leuprolide acetate-containing system for treating prostate cancer is assembled from:

accumulator (titanium, Ti6A14V alloy) (outer diameter 4mm, inner diameter 3mm)

Piston

Lubricant (Silicone medicinal liquid)

Compressed osmotic starting components (76.4% NaCl, 15.5% sodium carboxymethylcellulose, 6% polyvinylpyrrolidone, 0.5% magnesium stearate, 1.6% water)

PEG400(8mg, added to an osmotic engine to fill air space)

Membrane cartridge (polyurethane polymer, injection molded into desired shape)

Back diffusion regulating outlet pipe (polyethylene)

Pharmaceutical composition (0.150g of 60% water and 40% leuprorelin acetate)

Assembly

The piston and reservoir inner diameter are slightly lubricated. The piston was inserted into the reservoir at the end of the membrane by about 0.5 cm. PEG400 was added to the reservoir. Two osmotic engine tablets (40mg each) were then inserted into the reservoir from the end of the membrane. After insertion, the osmotic engine is flush with the end of the reservoir. The membrane plug is inserted into the reservoir by aligning it with the reservoir and gently advancing it until the retaining shape of the plug is fully engaged in the reservoir. The dosage form ingredients were loaded into the syringe and then used to fill the reservoir from the end of the outlet tube by injecting the dosage form ingredients into the open tube until the ingredients were about 3mm from the end. The filled reservoir was centrifuged (outlet tube end "up") to expel air bubbles trapped in the formulation during filling. The outlet tube is screwed into the open end of the reservoir until fully engaged. When screwed into the outlet tube, excess formulation components will escape from the nozzle to ensure a standard filling.

EXAMPLE 7 manufacture of leuprolide acetate Release devices with titanium reservoirs

A system containing leuprolide acetate for the treatment of prostate cancer is assembled from:

reservoir (titanium Ti6A14V alloy) (4 mm outer diameter, 3mm inner diameter, 4.5cm long) piston: (TPE elastomers available from Consolidated Polymer technologies, Inc

Lubricant (Silicone fluid 360)

Compressed osmotic starter tablet (76.4% NaCl, 15.5% sodium carboxymethylcellulose, 6% polyvinylpyrrolidone, 0.5% magnesium stearate, 1.5% water, 50mg total)

PEG400(8mg, added to the osmotic engine to fill the air space)

Membrane plug (polyurethane polymer 20% water, injection molding into the desired shape 3mm diameter x 4mm length)

Back diffusion regulating outlet (polyethylene, with 6mil by 5cm channel)

Pharmaceutical composition (leuprorelin acetate dissolved in DMSO until the measured leuprorelin content is 65mg)

Assembly

The gamma-irradiated component assembly system was assembled using aseptic technique and filled aseptically with sterile filtered leuprolide DMSO formulation ingredients as shown in example 6.

Release rate

The systemic release of leuprolide was about 0.35 μ l/day with an average total daily release of 150 μ g leuprolide. The device can release leuprolide at this rate for at least one year. The system achieved approximately 70% of the steady state release over 14 days.

Implantation and extraction

Implantation of the system will be performed under local anesthesia using an incision and trocar on patients with advanced prostate cancer as in example 2.

One year later, the system will be removed under local anesthesia as described in example 3.

EXAMPLE 8 treatment of prostate cancer

Leuprolide acetate, an LHRH stimulant, acts as an effective inhibitor of gonadotropin secretion when administered continuously and in therapeutic doses. Animal and human studies have shown that long-term release of leuprolide acetate after an initial stimulus results in inhibition of testosterone production. This effect can be reversed after discontinuation of drug treatment. Administration of leuprolide acetate results in inhibition of the growth of certain hormone-dependent tumors (prostate tumors in Noble and Dunning males and DMBA-initiated breast tumors in females) and atrophy of reproductive organs. In humans, administration of leuprolide acetate results in an increase in the initial circulating levels of Luteinizing Hormone (LH) and Follicle Stimulating Hormone (FSH), leading to a transient increase in the levels of gonadal steroids (testosterone and dihydrotestosterone in men). However, continuous administration of leuprolide acetate results in decreased levels of LH and FSH. In men, testosterone is reduced to castration levels. This reduction occurs within two to six weeks after initiation of treatment, and castration levels of testosterone in prostate cancer patients have been shown for years. Leuprolide acetate is inactive when taken orally.

The system was fabricated as described in example 7 and then implanted as described. Continuous delivery of leuprolide for one year using this system will reduce testosterone to castration levels.

The above description is made for ease of understanding only. No unnecessary limitations are to be understood therefrom, as modifications will be obvious to those having ordinary skill in the art.

Claims (5)

1. A fluid-imbibing device for the delivery of an active agent into a fluid environment of use, said device comprising a water-swellable semipermeable material in the form of a plug sealingly disposed on an interior surface of an impermeable reservoir at one end thereof, and an active agent released from the device upon swelling of the water-swellable material.

2. The device of claim 1, wherein the plug has a length to diameter ratio of 1:10 to 10: 1.

3. The device of claim 1, wherein the semipermeable material is fitted into one open end of the reservoir.

4. The device of claim 1 wherein the semipermeable material is disposed within a chamber of said reservoir.

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