US3845761A

US3845761A - Intrauterine contraceptive anti-fertility device for the management of reproduction

Info

Publication number: US3845761A
Application number: US00281445A
Authority: US
Inventors: A Zaffaroni
Original assignee: Alza Corp
Current assignee: Alza Corp
Priority date: 1970-06-02
Filing date: 1972-08-17
Publication date: 1974-11-05
Anticipated expiration: 1991-11-05

Abstract

An intrauterine contraceptive delivery device for administering an anti-fertility agent at a controlled rate for a prolonged period of time is comprised of a shaped body having a cross member and a depending member defining a ''''T.'''' The body is comprised of a wall surrounding at least one reservoir containing an anti-fertility agent. The reservoir is formed of a liquid carrier permeable to the passage of the agent and in which the agent has limited solubility. The wall surrounding the reservoir is formed in at least a part of a release rate controlling material permeable to the passage of the agent, but the rate of passage of the agent through the wall is lower than the rate of passage through the carrier so that release by the wall is the release rate controlling step for releasing the anti-fertility agent from the ''''T'''' shaped intrauterine contraceptive antifertility delivery device.

Description

United States Patent [1 1 Zaffaroni [451 Nov. 5, 1974 1 1 INTRAUTERINE CONTRACEPTIVE ANTl-FERTlLllTY DEVICE FOR THE MANAGEMENT OF REPRODUCTION [75] Inventor: Alejandro Zaffaroni,Atherton,

211 Appl. NO.C 281,445

Related US. Application Data [63] ContinuationJn-part of Ser. No. 185,208, Sept. 9, 1971, which is a continuation-in-part of Ser. No. 42,786, June 2, 1970.

OTHER PUBLICATIONS Kinel & Rudel, Sustained Release Hormonal Preparation, ACTA Endocrinologica, The Population Council, Rockerfeller Uni v., 1971.

Chang and Kinel. Sustained Release Hormonal Preparation: Biologic Effectiveness ol Steroid Hormones, Fertility and Sterility, Vol. 21, No. 2, Feb. 1972.

Primary ExaminerRichard A. Gaudet Assistant Examiner-G. F. Dunne Attorney, Agent, or Firm-Paul L. Sabatine; Edward L. Mandell; William H. Benz [57] ABSTRACT Xfiifit'iafiir'ine contraceptive delivery "deviae for administering an anti-fertility agent at a controlled rate for a prolonged period of time is comprised of a shaped body having a cross member and a depending member defining a T. The body is c0m- I prised of a wall surrounding at least one reservoir containing an anti fertility agent. The reservoir is formed of a liquid carrier permeable to the passage of the agent and in which the agent has limited solubility. The wall surrounding the reservoir is formed in at least a part of a release rate controlling material permeable to the passage of the agent, but the rate of passage of the agent through the wall is lower than the rate of passage through the carrier so that release by the wall is the release rate controlling step for releasing the anti-fertility agent from the T shaped intrauterine contraceptive anti-fertility delivery device.

14 Claims, 3 Drawing Figures INTRAUTERINE CONTRACEPTIVE ANTI-FERTILITY DEVICE FOR THE MANAGEMENT OF REPRODUCTION CROSS REFERENCE TO RELATED APPLICATION This application is a continuation-in-part of copending patent application U.S. Ser. No. l85,208 filed on Sept. 9, 197 I which is a contination-in-part of copending US. Pat. application Ser. No. 42,786 filed on June 2, 1970, and assigned to the same assignee of the present patent application.

BACKGROUND OF THE INVENTION l. Field of the Invention This invention relates to both a novel and useful intrauterine contraceptive anti-fertility delivery device for releasing an anti-fertility agent at a controlled rate for a prolonged period of time. The intrauterine device is comprised of a wall substantially in the shape of a T," and a reservoir defined by the inner surface of the wall. The reservoir is comprised of an anti-fertility agent in a liquid carrier permeable to the passage of the agent and in which the agent has limited solubility. The wall of the intrauterine device is comprised in at least a part of a release rate controlling material permeable to the passage of the anti-fertility agent. Both the carrier and the wall are permeable to the passage of the agent, as by diffusion, but the permeability of the wall to the agent is lower that the permeability of the carrier to the agent. Accordingly, the release of anti-fertility agent through the wall is the release rate controlling step for releasing the agent from the intrauterine contraceptive anti-fertility devices of the invention.

2. Description of the Prior Art Intrauterine contraception devices formed ofan integral, solid filamentary body in one of several well known configurations have become an increasingly popular method of birth control. One of the most notable configurations formed in accordance with the prior art practice that is relatively inexpensive to manufacture and seemingly does not require the daily attention of the host is the T" type configuration as described in US. Pat. No. 3,533,406. While it was initially thought that'an intrauterine device of this shape would provide satisfactory uterine retention properties and prevent pregnancy, the recorded medical history of this device has demonstrated that this is not the case. For example, the patent reports a high incident of pregnancy and expulsion of l2.4 and 5.2 percent respectively. Similar statistical results for the T configuration as reported in Am J. ()bstel Gynea, Vol. 109, pages 771 to 774, 1971 show 18.3 pregnancies per 100 users and 5.9 cxpulsions per I users. Thus, the actual medical history of this device with its high incidents of involuntary expulsion and pregnancy has discouraged the use of the T' as an acceptable intrauterine contraceptive device.

The prior art attempted to overcome those disadvantages in similarly designed and constructed devices by using several techniques. One technique used was to design and manufacture a large number of solid, intrauterine devices of varying sizes and assorted configurations for use in all types of uterine cavities. However, this attempt has not been successful because of the large, natural variations in size and contour of the uterine cavity. This makes it virtually impossible to effectively design a device that is satisfactory with a wide range of users for preventing spontaneous involuntary expulsion and a high pregnancy rate. Also, varying the size of the device has been found to be inappropriate because of the lack of reliable techniques for determining the size of the uterine cavity resulting in many instances in the wrong choice of device for insertion into the uterine cavity.

Other attempts by the prior art to avoid the recurrent problems discussed above consist in tying to an intrauterine device a capsule containing a progressional agent, or charging an intrauterine device with a progestional agent that is releasable therefrom for reducing uterine contractility and the accompanying expulsion of the device, and seemingly the incidents of pregnancy and uterine endomet'ritis. However, this approach, as with previous approaches, has been fraught with many problems. One problem associated with this type of device in the past has been the unpredictable and variable release pattern for the progestional agent from the device to the uterus over prolonged'periods of time. This has inherently prevented the prior art from becoming reliable sustained release birth control devices with a continued ability to overcome the mentioned disadvantages.

These, and other unacceptable results can be attributed to the fact that the art has not had available a satisfactory means of carefully administering controlled amounts of an anti-fertility agent, at a constant rate and over a prolonged period of time, for example, periods of a year or more. Exemplary of the unsatisfactory release pattern encountered by the ;art is the use of devices filled with milled crystals or dry powdered progestional agents. With these devices, there is a decrease in the release rate of the progestional agent from thedevice which defeats the critical need for a sustained controlled and constant or zero order release rate, which release rate is critical in order to provide an effective means of contraception. Accordingly, it was reported that this type of device does not lend itself forv use as a sustained hormonal device for intrauterine application.

Fertility and Sterility, Vol. 22, No. 10, pages 671 to 676, l97l. This pattern also can arise in another embodiment wherein a beneficial drug, agent or the like is dispersed in a solid matrix permeable to passage of the drug and surrounded by a membrane, also permea ble to passage of the drum but at a lower rate than through the matrix. The device has proven itself capable of zero order drug release and represents a substantial improvement over previously proposed drug delivery devices. However, in some instances, when zero order release is required for long periods of time, on the order of several months to a year or more, it may not be attained with this type of device. For example, it has been found that as drug is released by that device there is created over time a space in the solid matrix drug carrier which if not occupied by more drug can result in the carrier contracting and moving away from the membrane. The loss of intimate contact between the carrier and the membrane at the carrier/membrane interface tends to decrease the availability of drug at the interface for release by the membrane. Thus, since the amount of drugavailable to the membrane is no longer constant, drug is released from the device at a continually reduced rate and the device does not main tain a constant zero order release rate. For applications in which controlled release is demanded for very long periods, this can be a problem.

One other modification suggested by the prior art is to prepare a plastic intrauterine device into which a contraceptive drug has been incorporated, that is, dispersed in the plastic for subsequent release therefrom. However, it is now known that this type of device has not met with acceptance by the art. Generally, the art has not accepted this type of anti-fertility delivery de- OBJECT OF THE INVENTION Accordingly, it is an immediate object of this invention to provide a shaped intrauterine contraception device for the administration of an anti-fertility agent which device overcomes the aforesaid disadvantages associated with the prior art intrauterine contraceptive devices.

Still another important object of the invention is to provide an intrauterine contraception device for releasing an anti-fertility agent at a controlled and constant rate for a prolonged period of time, for example, for periods of a year-or longer.

Yet still another object of the invention is to provide a reliable and easily used intrauterine contraceptive device suitable for continuously administering controlled quantities of an anti-fertility agent within uteri of various sizes and contours while substantially remaining free of the tribulations of the prior art.

It is also an object of the invention to provide an intrauterine contraceptive device that can be inexpensively fabricated in mass quantities and essentially painlessly and simply inserted through the normal cervical canal.

Another object is to provide an intrauterine device for releasing an anti-fertility agent at a constant rate for a prolonged and predictable period of time.

Still yet another object of the invention is to provide a new and useful intrauterine contraceptive antifertility delivery device that is essentially insoluble in body fluids, is essentially nonbiodegradable and can be used for a prolonged period of time in contact with animal fluids and membranes.

Another object of the invention is to provide an intrauterine contraceptive anti-fertility dispensing device with improved properties for substantially lessening the incident of expulsion and pregnancy.

Yet another object of the invention is to provide an intrauterine contraceptive anti-fertility delivery device that essentially has a constant or zero order rate of release and can be used as a sustained release delivery device.

Still a further object of the invention is to provide an intrauterine contraceptive device that releases antifertility progestational and estrogenic agents.

Other objects, features and advantages of the invention will be apparent to those skilled in the art from the detailed description of the invention which follows, taken in conjunction with the drawings, and the accompanying claims.

SUMMARY OF THE INVENTION This invention concerns, in its broadest aspects, a novel intrauterine contraceptive anti-fertility delivery device comprising a wall enclosing a drug reservoir; The wall is substantially in the shape of a T having a top cross member and a depending member. The wall is comprised ofa flexible, release rate controlling material permeable to the passage of an anti-fertility agent. The reservoir is defined by inner surface of the wall of the cross or depending member or both, and it is comprised of an anti-fertility agent and a liquid core, which core is permeable to the passage of the anti-fertility agent and having limited solubility therefore. Both the wall and the liquid core are permeable to the passage of the agent, as by diffusion, but the permeability of the wall to the passage of the agent is at a lower rate than through the liquid core. Since the permeability of the wall to the passages of the anti-fertility agent is lower than the permeability of the liquid core to the passage of the agent, the passage of the agent through'the wall of the intrauterine T device is the rate determining step for releasing the agent from the intrauterine contraceptive anti-fertility T" shaped dispensing device.

BRIEF DESCRIPTION OF THE DRAWINGS In the drawings, which are not drawn to scale, but

rather are set forth to illustrate various embodiments of the invention, the drawings are as follows:

FIG. 1 is a side, elev ational view of-a T shaped in- DETAILED DESCRIPTION OF THE DRAWINGS Turning now to the drawings in detail, which are examples of various intrauterine contraceptive antifertility devices of the invention, and which examples are not to be construed as limiting the invention, one embodiment of a novel intrauterine contraceptive device is indicated in FIG. 1 by the number 20. Intrauterine contraceptive 20 can be generically defined as a shaped body defining a T. Device 20 is comprised of a cross member 21, also known as cross bar or top cross bar and a depending member 22, also known as the depending leg. Intrauterine device 20 is made ofa biologically acceptable flexible material and it can be temporarily deformed by moving member 21 toward member 22. While device 20 is deformable, it retains its memory and returns to define the T. The devices ability to temporarily deform'conveniently aids in its insertion into a uterus, while the devices memory insures its return to the desired shape in the uterus. Generally, device 20 can be manufactured in different sizes to accommodate all uteri; for example, member 21 can have a length of about 2 cm to 4 cm which length approximates the width of the fundal region of the uterus, and member 22 can have a length of about 2 cm to 4 cm to extend towards the cervical os when member 21 is positioned in the fundal region. Generally, the diameter of either member is the same or different and it is about 0.1 cm to 0.5 cm and the like.

Device is comprised of a wall 23 surrounding a reservoir 24., not shown in FIG. I, but illustrated in FIG. 2 in cross-section through 2-2 of FIG. 1. Wall 23 of FIGS. I and 2 is formed of an anti-fertility release rate controlling material and reservoir 24 is defined by wall 23s inner surface. Reservoir 24 is comprised of an anti-fertility carrier 25 containing an anti-fertility agent 26, or a mixture of anti-fertility agents. Carrier 25 can be a liquid, gel, sol or the like and it is permeable to the passage of anti-fertility agent 26, as by diffusion, or by convection, or by an occurrence of both. The carrier medium confined in the reservoir serves several purposes for effectively releasing drug from the device. First, it is permeable to the passage f0 an anti-fertility agent so that it can migrate to wall 23. Secondly, the carrier contacts and bathes the inner surface of wall 23 for facilitating anti-fertility agent transfer from the carrier to the wall so that molecules can dissolve in and migrate through the wall to the outer surface thereof. Thirdly, the carrier acts as a constant source of antifertility agent as it has a limited, or varying degree of solubility for the anti-fertility agent or a mixture of agents. The carrier is formulated to contain both dissolved and undissolved anti-fertility agent and to act as a constant source of anti-fertility agent, because as dissolved agent transfers from the carrier to the wall, un dissolved agent dissolves in the carrier to insure a constant and uniform supply of agent until essentially all the agent has been released by the device. This mechanism of continually replenishing the agent enables the device to achieve a uniform release rate for the device throughout its use. A detailed description of the carrier is presented later in the disclosure.

Wall 23 of device 20 of FIGS. I and 2 is also permeable to the passage of the anti-fertility agent 26, as by diffusion. but the rate of passage of the anti-fertility agent through wall 23 is lower than the rate of passage of the anti-fertility agent through the carrier 25. In operation, carrier 25 serves as a reservoir by supplying dissolved anti-fertility agent 26 to wall 23 as antifertility molecules move through carrier 25 to bathe the inner surface of wall 23. Anti-fertility agent 26 present at the anti-fertility carrier/wall interface dissolve in and migrate through wall 23, ultimately reaching the outer surface of wall 23 for release in the uterine cavity. As anti-fertility agent 26 leaves carrier 25, undissolved agent present in reservoir 24 dissolve in carrier 25 to maintain a constant supply of dissolved anti-fertility agent in the carrier for continuously supplying it at substantially the same rate to wall 23. Wall 23 operates to effectively control the rate of release of anti-fertility agent throughout the useful period of birth control by the device. Thus, a zero order anti-fertility release rate can be obtained.

Wall 23 is made from a material that can have uniform properties across all its dimensions, or it can be microporous, or it can be a material possessing both of these properties. When wall 23 is made from the former material, that is, a material that is substantially imperforate, molecules of anti-fertility agent 26 dissolve in an diffuse through wall 23 by the process of diffusion. When wall 23 is made from the latter material, that is, a material having microporous properties, mole cules of anti-fertility agent 26 diffuse through a liquid phase. not shown, present in the minute pores, pinholes or cracks, for example, by absorption of uterine fluids by a hydrophilic microporous material, as of uterine fluids by a hydrophilic microporous material, as by diffusion. When wall 23 is made from a material having both of these properties, anti-fertility agent 26 can be released by intrauterine device 20 through wall 23 by a concurrent operation of both of these mechanisms, that is, by diffusion through wall 23 and by'diffusion through liquid in the pores of wall 23. In the specification, the permeation mechanism of drug release through the drug release rate controlling material is generically described as by diffusion for both types of materials used to fabricate wall 23.. The permeability of wall 23 to the diffusion of anti-fertility agent 26 is always lower than the permeability of liquid carrier 25 to the diffusion of anti-fertility agent 26 and accordingly, passage through wall 23 thus acts as the rate limiting step for agent 26 release from intrauterine contraceptive device 20.

In FIG. 3 there is graphically depicted an intrauterine contraceptive anti-fertility delivery device 20 prepared according to the spirit of the invention. Device 20 is of T configuration and it is adapted to be located within a uterine cavity 27, wherein it optionally contacts sides 28 as well as fundus uteri 29 of uterus 27. Deivce 20 is preferably designed with rounded, non-traumatising ends and a thread 30 is attached to trailing end 31, distal from lead or inserting end 32, for manually removing device 20 from uterus 27. Thread 30 can be any suitable material, for example, nylon, surgical thread having a thickness of about 0.002 to 0.020 inches, and the like.

Device 20 of FIG. 3 is formed of a release rate controlling material 23 to continuously meter the flow of an effective amount of an agent from the reservoir, not shown in FIG. 3, within the uterus. Material or wall 23 thus has three functions: first, it has a memory for retaining the shape of the device, secondly, the material forming the wall has a memory for releasing the agent at a controlled rate throughout the devices history, and third, the inner surface of the wall surrounds a reservoir formed of a hollow space defined by the inner surface of wall 23 as described for FIG. 2 through cross-section 2-2 of FIGS. 1 and 2. These operate in unity to form the novel device of the invention. Reservoir 24, not illustrated in FIG. 3, is comprised of top member 21, or depending member 22 or both

members

21 and 22 for housing and releasing antifertility agent 26. Device 20 can be integral or comprised of

members

21 and 22 serving as anintegral unit device 20. Thus, witheither embodiments, wall 23 of device 20 acts as the rate Iimiting barrier for releasing anti-fertility agent 26 from the device to the uterine cavity 27 at a constant and uniform rate for producing the desired result.

DETAILED DESCRIPTION OF THE INVENTION In accordance with the practice of the present invention, it has now been found that the intrauterine contraceptive device 20 of this invention provides many importantadvantages over the prior art. One advantage of device 20 is the ease of construction of the antifertility delivery device by standard manufacturing techniques into devices acceptable to the uterine cavity. A

more important advantage of the claimed intrauterine contraceptive device is to provide devices having a reservoir containing a liquid carrier or a mixture of liquid carriers permeable to the passage of an anti-fertility agent and having limited solubility for an agent or a mixture of agents; and, where the carrier simultaneously releases drug and dissolves replacement drug to maintain a constant supply of drug for release by the intrauterine contraceptive device. Thus, the invention contributes to the art a sustained release intrauterine drug delivery device.

Another important advantage of the invention resides in the intrauterine contraceptive devices memory to effectively control the rate of release of an antifertility agent from the device by providing a zero order rate of agent release and also this memory ability to act in concert with the device s memory to substantially maintain the devices shape throughout the major portion of the devices medical history. Another important advantage of the intrauterine contraceptive devices of this invention is their improved property for uniformly and continually releasing anti-fertility steroid agents while simultaneously decreasing the incidence of spontaneous expulsion and pregnancy.

The above advantages and objects are achieved by the unique construction and operation of the intrauterine contraceptive device and its ability to transfer antifertility agent to the recipient. in construction, the device can be viewed as asingle unit constructed device comprising two structures acting in combination for effective anti-fertility administration to a host. One structure pertains to a wall comprising the device and formed ofan anti-fertility release rate controlling material permeable to the passage of the agent and the other structure relates to a reservoir comprising a liquid carrier phase formed of a material permeable to the passage of an anti-fertility agent and having limited solubility for the agent. The materials forming the wall and the carrier phase comprising the device are chemically and structurally different within a single device and the rate of anti-fertility release through the wall is lower than the rate of passage in the carrier phase.

These two structures, comprising the unit intrauterine contraceptive device 20, operate to effectively transfer anti-fertility agent from the device by first transferring the agent from the carrier to the wall, and secondly, by transferring the agent through the wall to a uterus. The transfer of agent through the wall can occur by two different processes or transfer mechanisms. These transfer processes are the diffusion of an agent through a uniform material, and by diffusion of an agent through the media present in the micropores ofa material, as hereinafter described. Thus, for example, an agent can be transferred from the carrier to the wall and then through the wall by diffusion to the recipient, or the agent can be transferred from the carrier to the wall and then through the media in micropores of the wall by diffusion to the recipient. With the contraceptive devices of this invention, an anti-fertility agent can be transferred by using a combination of these mechanisms for transferring the agent through the wall. Thus, by fabricating devices having different kinds of walls made from different materials, the device can provide for transfer of an agent through the wall by either diffusion in a substantially homogenous material or by diffusion through the media in a microporous wall. The wall ofthe delivery device is made from a material that has a lower agent release rate than the rate of passage of the agent through the carrier phase to ensure that release kinetics of the device are controlled by the release rate of agent through the wall. Thus, by choosing the wall, a zero order release of an antifertility agent or a time release pattern of an agent to the body site can be achieved.

In the diffusion process, wall 23 is formed of an antifertility agent release rate controlling material that is permeable to the agent to permit passage of the agent by diffusion through the material at predetermined rates. In this process, the agent dissolves and equilibrates in the wall surface, and then diffuses in the direction of lower chemical potential. At the second boundary equilibrium is again established. When the boundary conditions on both sides of the wall are maintained constant, a steady state flux of the agent will be established which can be described by Ficks First Law of Diffusion. The rate of passage of the agent through the wall is generally dependent, in the case of diffusion, on the solubility of the agent therein, as well as on the thickness of the material. This means that selection of appropriate materialsfor fabricating the wall will be dependent on the particular agent to be used. By varying the composition and thickness of the wall, the dosage rates per area of the device can be controlled for this material acts to meter the diffusion of the agent from the reservoir. in the devices of this invention, the materials comprising the wall are chemically and/or structurally different than the material comprising the carrier of the reservoir. The carrier of the reservoir is permeable to the passage of the agent, but the rate of diffusion or passage through the wall is lower than the rate of diffusion or passage through the carrier, so that the rate of passage of the agent through the wall is the rate release controlling step for the device. Thus, through this invention, devices of the same surface area, functioning by diffusion, can give different dosages of the agent by varying the characteristics of wall to give controlled administration of the agent.

in the devices of the invention, when the wall is formed from a release rate controlling microporous material that is permeable to the agent, the agent transfer mechanism is by diffusion through a medium contained in the micropores of the material at a controlled and predetermined rate. That is, in this material, the rate of passage or the rate of agent release through the wall is governed by diffusion of the agent through a diffusive medium present in the pores, microholes and cracks of the material forming the wall. The diffusive medium, in one embodiment, is a liquid phase comprised of a solution, a colloidal solution, a suspension, or a sol, and the solution can be polar, semi-polar or non-polar. In these diffusive mediums, the agent can have different degrees of solubility, such as fully soluble, partially soluble and the like, to act in cooperation with the material for achieving a-eontrolled release rate.

The diffusive medium can be added to'the microporous material by methods well known to the art, for example, by immersion of the material in a bath containing the medium to let'the medium partially fill or fully saturate the micropores of the material. Another method for charging the micropores with a diffusive medium is to first add to the reservoir a diffusive medium, or a mixture of diffusive media so that the medium can flow from within the reservoir into the pores.

and remain therein to permit diffusion of later added agent, but not its solubilizing limited carrier, to pass therethrough. The media suitable for the immersion purpose are those well known to the art such as water, glycerin, ethylene glycol, propylene glycol, castor oil, olive oil, alcohols of two to l carbon atoms, halogentated hydrocarbons having two to 20 carbon atoms, aldehydes, and ketones having four to carbon atoms, syrups and the like. Additionally, the medium can be emulsifying and suspending agents such as methyl cellulose mixed with water, mixtures of propylene glycol monostearate and oils, gum tragacanth and water, assorted waxes and the like. Representative mediums are set forth in Remington s Pharmaceutical Science, pages 246 to 269 and 1,338 to 1,380, 1970, published by Mack Publishing Company, Easton, Pa.

In another embodiment, the medium can be added to the pores and cracks of the material forming the wall by locating the wall in a fluid environment, for example, by contacting the device with a body tissue, for example, the mucous membranes of the uterus, that can make available its intracellular and/or extra-cellular fluid for subsequent transfer into the micropores of the wall for functioning as a medium for the drug. In another embodiment, the pores can be filled with plasticizer by immersing the wall in a plasticizer solvent composition, and removing the solvent in vacuo after the filling of the pores. Exemplary plasticizers suitable for employment of the present purpose are the commercially available plasticizers conventionally used for the manufacture of polymeric materials such as diethyl adipate, di-isobutyl adipate, di-n-hexyl adipate, di-isooctyl adipate, di-n-hexyl azelate, di-2-ethylhexylazelate, ethylene glycol dibenzoate, acetyl tri-n-butyl citrate, epoxidized soy bean oil, glycerol monoacetate, diethylene glycol dipelargonate, propylene glycol diluarate, isooctyl palmitate, tripehnyl phosphate and the like.

The materials comprising the wall are chemically and/or structurally different than the materials comprising the carrier. Both of the materials are permeable to the passage of the anti-fertility agent but the rate of flow through the wall is lower than the rate through the carrier. Thus, the rate of passage of the agent through the wall is the rate release controlling step for the device. Generally, for the practice of this invention, the ratio of the agent release rate through the carrier ofthe reservoir to the agent release rate through the wall should be from l00:l to 2:1 and preferably from 10:1 to 2:l. Of course, the invention is not limited to these release rates as the invention comprises lower or higher release rates from the carrier and lower and higher rates through the wall with the release rate of the wall lower than the release rate of the carrier. Thus, the invention provides that devices of the same surface area, activated by diffusion, can give different dosages of a drug by varying the characteristics ofthe wall material to give controlled administration of an anti-fertility agent; Encyclopedia of Polynwr Science and Technology, Vol. 9, pages 794 to 807,1968.

For either of the above discussed mechanisms, diffusion through a homogenous material, or diffusion through a medium present in the micropores and cracks of a material, the transfer or rate of release of the anti-fertility agent through the wall is at a lower rate than the rate of release of the agent from the carrier of the reservoir for administration to the receptor site. Thus, the passage of the agent through the wall is the release rate controlling step for the agent delivery sys tem. In addition, because the reservoir serves to transfer anti-fertility molecules to all areas of the wall, the wall of the delivery device housing the reservoir remains substantially at the thermodynamic activity corresponding to that of the agent until substantially all of the agent has been released from the reservoir. Ordinarily, one would expect migration of anti-fertility agent from the reservoir to cease when sufficient agent has entered the wall to establish an equilibrium; however, when the delivery device is in situ, molecules are continuously removed from the outer surface of the wall. For optimum results, the rate of release of the agent through the wall should be less than the rate of clearance of migrated agent from the external surface of the device. This ensures that the agent administration rate is dependent on the rate of release of the agent through the wall which can be controlled, rather than upon clearance of the agent from the device in vivo, which can vary. Thus, in contrast to previously proposed intrauterine contraceptive delivery devices, the rate of release of the agent from the device of the invention can remain essentially constant until the intrauterine contraceptive device has substantially completed its useful function.

The term reservoir as used in the specification and the accompanying claims generally refers to a carrier" or to a medium containing the anti-fertility agent, that constantly bathes the inner surface of the release rate controlling wall and supplies agent thereto. That is, the reservoir is comprised of a carrier material containing dissolved agent, and/or undissolved agent, and/or a mixture of both, and it is a material that is permeable to the passage of the agent as by diffusion or convection. The carrier medium used for the purpose of the invention is a liquid, and it can be inorganic or organic, and of naturally occurring or synthetic origin; Examples of carries comprised within the terms liquid are, r

for example, solutions, immiscible liquids, suspensions, dispersions, liquid pre-cured polymers, liquid polymers, liquid plasticizers, liquid thixotropic agents, polar solvents, semipolar solvents, nonpolar solvents, liquidlike mediums, mixturs thereof, and the like. Further, for the purpose of this invention, the terms liquid and the examples thereof are deemed as functional equivalents and they can be generically termed liquid carriers."

The carrier medium comprising the reservoir, also has in addition to the properties described supra, limited solubility for thecontained anti-fertility agent or for a mixture of agents. By limited solubility is meant that the agent is soluble in given amounts in the carrier, that is, it comprises varying concentration of the agent dissolved in the carrier. Essentially, there is also an excess amount of undissolved drug present in the carrier. These varying limited solubility concentrations include solubilities such as, soluble, sparingly soluble, slightly soluble, very slightly soluble, and almost practically insoluble. Generally, on a weight basis at 25C, the amount of the agent dissolved in a carrier that is termed a soluble carrier is about l part of agent to about 10 to 25 parts of carrier, the amount of agent dissolved in a carrier that is sparingly soluble for the agent is 1 part of agent to about 25 to parts of carrier, from 100 to 1,000 parts of carrier for 1 part: of agent when the agent is slightly soluble in the carrier, from 1,000 to 10,000 parts of carrier for l part of agent when the agent is very slightly soluble in the carrier, and from 10,000 to 15,000. parts of carrier for I part of agent in a carrier that is almost practically insoluble for the drug. Hence, the term limited solubility comprises a range of solubility of the agent in a carrier of l part of agent to about to 15,000 parts of carrier on a weight basis at 25C. The above ranges are set forth to aid in defining the invention, and they should not be considered as limiting as other ranges at higher or lower temperatures are embraced within the above presentation are also included herein. The amount of undissolved antifertility agent incorporated in the reservoir will vary depending on the type of materials and design of the device, the particular agent, the length of time the device is used, and the rate of release of desired agent from the reservoir. That is, there is no critical upper limit on the amount of undissolved agent incorporated in the reservoir, since, it serves as a reserve source of agent for replacing released agent by dissolving in the carrier to make the agent continually available from the carrier to the wall during the history of the device, or until the device is no longer used. The lower limit will depend on the activity of the particular agent and the time span of its release from the device. Generally, the amount of undissolved drug initially present in the reservoir will range from about 90 percent by weight to about 99.9 percent by weight, of the total amount of agent present in the reservoir.

The materials suitable for fabricating the wall of the intrauterine device are generally those materials capable of forming walls, with or without micropores,

through which the agent can pass at a controlled rate of release by diffusion. Such materials are referred to in this specification and the appended claims as release rate controlling materials." Suitable materials for forming the wall are naturally occurring or synthetic materials, preferably materials that are biologically compatible with body fluids. and uterine tissues, and essentially insoluble in body fluids with which the device will come in contact. The use of rapidly dissolving materials or materials highly soluble in natural body fluids'is to be avoided since dissolution of the wall of the device would affect the constancy of the drug release, as well as the capability of the system to remain in place for certain uses for prolonged periods of time.

Exemplary naturally occurring or synthetic materials suitable for fabricating the wall are release rate controlling materials such as poly(methylmethracrylate), poly(butylmethacrylate), plasticized poly(vinylchloride), plasticized nylon, plasticized soft nylon, plasticized poly(ethylene terephthalate), natural rubber, poly(isoprene), poly(isobutylene), poly(butadiene), poly(ethylene), poly(tetrafluoroethylene), poly(vinylidene chloride), poly(acrylonitrile), cross-linked poly(- vinylpyrrolidone), poly(trifluorochloroethylene), blends of poly(ethylene) and ethylene vinyl acetate copolymer, poly(4,4-isopropylidene diphenylene carbonate), and the like. Also, by way of non-limiting example, copolymers such as ethylene-vinylacetate, vinylidene chloride acrylonitrile, vinyl chloride diethyl fumarate and the like. Examples of other materials include silicone rubbers, expecially the medical grade poly(dimethylsiloxanes), and siliconecarbonate copolymers; modified insoluble collagen, cross-linked insoluble poly(vinylalcohol), cross-linked partially hydrolyzed insoluble poly(vinylacetate), and surface treated silicone rubbers as described in U.S. Pat. No. 3,350,216. Other polymeric membranes that are biologically compatible and do not adversely affect the drugs can be used.

Additionally, other materials permeable to the passage of the anti-fertility agent that are suitable for the present purpose include copolymers such as acrylonitrile dithioglycidol, acrylonitrile ethylene oxide, poly(- vinyl butyral) comprised of 11 to 45 percent free hydroxyls, anisotropic permeable microporous membranes of ionically associated polyelectrolytes, the microporous polymers formed by the coprecipitation of a polycation and a polyanion as described in U.S. Pat. Nos. 3,276,589; 3,541,005; 3,541,006; 3,546,142; and the like; treated aliphatic polyamide membranes as in U.S. Pat. Nos. 2,071,253; 2,966,700; 2,999,296; and the like; vinylidene chloride vinyl chloride copolymer 40/60 and 10/90; vinyl chloride acrylonitrile copolymer /20, 75/25, 50/50 and the like; vinylidene chloride acrylonitrile copolymer 60/40 and 12/88; water insoluble natural gums, and the like. Also, materials such as regenerated cellulose diacetate, cellulose triacetate, poly(urethanes), poly(arylenes), poly(carbonates) and the like. Materials having a pore size of several hundredth microns or larger, or down to several angstroms or smaller. For example, the wall can comprise regenerated insoluble, nonerodible cellulose, poly(electrolytes) with a pore size of 7 to 50A, epoxy resins, poly(olefins), poly(vinylchlorides) with a pore size of about 50A or less to microns or larger as conventionally made by leaching out incorporated salts, soap micelles, starch or the like materials to give a microporous membrane. Also, the materials that can be used include these materials having homogenous properties and microporous properties, such as crosslinked gelatinous membranes; and the like.

The carrier used to form the reservoir containing the anti-fertility agent is comprised of materials of natrually occurring or synthetic origin, of the inorganic or organic types that do not adversely affect the agent, or the mixture of agents contained therein and which are permeable to the passage of the agent. Generally, the carrier used does not substantially diffuse from the reservoir, but if the carrier does diffuse from the reservoir, for example if the carrier is an aqueous medium, it would be replaced by a corresponding amount of medium diffusing inward from the exterior of the device when the device is positioned in an aqueous type environment. Representative liquid carriers include ethylene glycol, diethylene glycol, triethylene glycol, propylene glycol, dipropylene glycol, thiodiethylene glycol, ethylene glycol monomethyl ether, ethylene glycol mono-n-butyl ether, ethylene glycol diethyl ether, propylene glycol mono-propyl ether, liquid polyethylene glycols having a molecular weight of 200, 300, 400 and 600, 1,3-butylene glycol; solvent system like ethyl acetate-ethyl alcohol-water l0:83:7; isobutyl acetateisobutyl alcohol-water 24:46:30; mixed binary liquid systems such as methanokwater, ethyl alcoholzwater, n-amyl alcohol:ethyl acetate; mixed tertiary liquid systems such as n-butyl acetate-butyl alcohol-water 27:27:46; esters such as liquid methyl propionate, methyl isobutyrate, butyl stearate, dibutyl fumerate; fats and oils of plant, animal and marine origin such as almond oil, babassu oil, corn oil, eucalyptus oil, cottonseed oil, olive oil, palm oil, peanut oil, rapeseed oil, soybean oil, tung oil, whale oil, herring oil; saturated,

unsaturated, straight and branched chain liquid fatty acids such as caproic, lauric, arachidic, oleic, linoleic,

etc.; emulsions of the single phase and two phase types such as oil in water; water in oil, lipophilic-liquid-inhydrophilic-liquid emulsions with or without suspending ingredients; emulsions of castor oil in aqueous solution of pigskin gelatin, emulsion of gum arabic, water and ethyl cellulose, halogenated hydrocarbons having two to carton atoms, aldehydes and ketones having four to 10 carbon atoms, syrups, and the like. Other carries include silicone oil, medical oil, sterile water; saline, dextrose; dextrose in water or saline; condensation products of castor oil and ethylene oxide combining about 30 to about 35 moles of ethylene oxide per mole of castor oil; liquid glyceryl triester ofa lower molecular weight fatty acid; oils with emulsifiers such as monoor di-glyceride of a fatty acid, or a phosphatide, e.g., lecithin, and the like; aqueous media in the presence of a suspending agent for example, sodium carboxymethylcellulose; sodium alginate; poly (vinylpyrrolidone); and the like, alone, or with suitable dispensing agents such as lecithin; polyoxyethylene stearate; and the like, carriers such as acetamide; N,N-dimethyl acetamide, N-(Z-hydroxyethyl) acetamide, and the like. The carrier can also contain adjuvants such as preserving, stabilizing, or wetting agents, and the like.

The rate of release of an agent through various materials can easily be determined by those skilled in the art by standard procedures. ln this manner, particular materials used as the device wall as the drug release rate controlling barrier for release of drug from the reservoirs can be selected. Various techniques, such as the transmission method, the sorption desorption method, and the like, can be used as measurers of permeability. One technique that hasbeen found to be eminently well suited is to cast or hot press a film of the material to a thickness in the range of 2 to 60 mils. The film is used as a barrier between a rapidly stirred (e.g., 150 r.p.m.) saturated solution of the drug and a rapidly stirred solvent bath, both maintained at constant temperature (typically 37C). Samples are periodically withdrawn from the solvent bath and analyzed for drug concentration. By plotting the agents concentration in the solvent bath versus time, the permeability constant P of the material isdetermined by the Ficks First Law of Diffusion.

1 i and solving the equation using the known or measured values of A C, and h, the permeability P constant in cm /time of the material'for a given drug is readily determined.

Using the above technique, the permeability constant P of the anti-fertility progesterone from isotonic solution through different materials into isotonic solution at 37C was found to be:-

Permeability (onstant Membrane (enfVhr) Polytdimethylsiloxanel X 10" Poly(ethylene) 4.7 X 10 Ethylene vinyl acetate copolymer 9% vinyl acetate 3.8 X 10" Siliconepolycarhonate copolymer,

General Electric Mem 213 12.6 X 10" Using the above technique and data to design a device of the invention to release the anti-fertility agent progesterone, one would employ poly(ethylene) as the release rate controlling material as the wall if a slow rate of release is desired, and the cured poly(dimethylsiloxane) membrane as the wall if a faster rate of release is desired. lf a faster rate of release than the rate of release through poly(ethylene) but slower than the rate of release through poly-(dimethylsiloxane) is preferred for progesterone, either the copolymer ethylene vinyl acetate or the silicone polycarbonate can be used as the release rate controlling material. The po1y( ethylene), the poly(dimethylsiloxane), the ethylene vinyl acetate copolymer and the siliconepolycarbonate copolymer are commercially available products. The poly(dimethylsiloxane) used above is commercially available Silastic 340 of the Dow Corning Co., and the poly(ethylene) is low density with a metl index of 0.85. These examples and like examples can be used to determine the rate of drug releasethrough different drug release controlling materials by easily ascertained stan dard techniques known to the art as recorded in J. Pharm. Sci, Vol. 52, pages 1,145 to 1,149, 1963; ibid. Vol. 53, pages 798 to 802, 1964; ibid. Vol. 54, pages 1,459 to 1,464, 1965; ibid. Vol. 55, pages 840 to 843, and 1,224 to 1,239, 1966; Encyl. Polymer Sci. TechnoL, Vol. 5 and 9, pages 65 to 82 and 794 to 807, 1968; the references cited therein, and the like.

The rate of solubilitzation, or the rate at which the anti-fertility agent will go into solution is quantitatively governed by physico-chemical principles. For an example, a particle of an agent dispersed in a solvent is surrounded by a thin layer of solvent having a finite thickness 1 in cm. This layer is considered as an integral part of the agent and it is characteristically referred to as the stagnant layer. The stagnant layer remains apart of the surface of the agent, moving wherever the agent moves. Using Ficks First Law of Diffusion, the rate of movement of the agent through the stagnant layer is the difference in concentration of the agent, C,, in the stagnant layer at the surface of the agent and the concentration C on the farthest side of the stagnant layer. The difference in concentration C, C determines the rate at which agent is solubilized in the carrier. Hence, if the carrier on the farthest side contains its optimum concentration because of a low release by the agent release rate controlling wall, the rate of solubilization of new agent will be low. Correspondingly, as agent leaves the carrier, new agent is solubilized to establish a steady state within the carrier.

The rate of diffusion of the anti-fertility agent in a her through a sintered glass filter of known pore size and thickness into another chamber at atmospheric pressure and room temperature about C, or body temperature 375C, and calculating from the obtained data the agents transfer rate. The method is carried out by adding to a first conical flask equipped with a ground glass stopper and a stirring bar, a measured amount of carrier and simultaneously, the agent in the same carrier is added to a second conical flask similarly equipped while keeping the level of the carrier in the two flasks the same. Next, the flasks are stirred, and samples drawn at various time intervals for analysis. The measured rate of agent transport through the sintered glass filter, and the concentration difference of the agent in the two flasks is then calculated. These procedures are known to the art in Proc. Roy. Sci. London, Ser. A, Vol. 148, page 1,935; J. Pharm. Sci., Vol. 55, pages 1,224 to 1,229, 1966; and references cited therein. The diffusion coefficient of an agent can also be experimentally determined by using the above apparatus and references, or similar apparatus and procedures as described in Diffusion in Solids, Liquids and Gases, by W. Jost, Chapter Xl, pages 436 to 488, 1960, Revised Edition, Academic Press lnc., New York.

Also, according to Ficks Law, the rate of an agents solution is directly proportional to the area of the agent, A in cm as exposed to carrier and inversely proportional to the length of the path through which the dissolved agent molecule must diffuse. Then, the rate of solution of the agent is given by wherein R is the rate of solution, D is a proportionality constnat called diffusion coefficient in cm /sec, and C,,

Q, and l are as previously defined. See Remington Pharmaceutical Science, l4th Ed., pages 246 to 269, 1970, Mack Publishing Company.

The solubility ofthe anti-fertility agent in the release rate controlling material comprising the wall of a device broadly is determined by preparing a saturated solution ofa given anti-fertility agent and ascertaining, by analysis, the amount present in a definite area of the material. For example, the solubility ofthe agent in the wall is determined by first equilibrating the wall material with a measured saturated solution of the agent at a known temperature and pressure, for example 37C and one atmosphere. Next, agent is desorbed from the saturated wall material with a suitable solvent for the agent. The resultant solution for the agent then is analyzed by standard techniques such as ultraviolet, visible spectrophotometry, refractive index, polarography, electrical conductivity and the like, and calculating from the data the. concentration, or solubility of the agent in the material.

The solubility of an anti-fertility agent in a liquid carrier can be determined by various, conventional known techniques. One technique consists in preparing a solution, for example, a carrier plus agent and ascertaining by analysis the amount of agent present in a definite quantity ofthe carrier. A simple apparatus for this purpose consists ofa test tube of medium size fastened upright in a water bath maintained at constant temperature and pressure, for example, 375C and l atmosphere. The carrier and agent are placed in the tube and stirred by means of a motor driven rotating glass spiral. After a given period ofstirring, a definite weight of the carrier is analyzed and the stirring continued for an additional period of time. lf the analysis shows no increase of dissolved substanceafter the second period of stirring, the results are taken as the degree of solubility of the agent in the carrier. Numerous other methods are available for the determination of the degree of solubility of an agent in a liquid carrier. Typical methods used for the measurement of solubility are chemical analysis, measurement of density, refractive index, electrical conductivity, and the like. Details of various methods for determining solubilities are described in United States Public Health Service Bulletin No. 67 of the Hygienic Laboratory; Encyclopedia of Science and Technology, Vol. 12, pages 542 to 556, l97l McGraw- Hill, Inc.; Encyclopaedic Dictionary of Physics, Vol. 6; pages 545 to 557, 1962, Pergamon Press, Inc.; and the like.

Using the procedures and formulas above described, one skilled in the art can design an intrauterine contraceptive anti-fertility dispensing device according to the invention by ascertaining the properties of the wall and carrier forming material and then fabricating the intrauterine contraceptive device by selecting a carrier in which the agent has limited solubility and which is permeable to the agent but at a higher rate than the permeability of the wall. For example, by using the permeability coefficient, which is determined by using the above procedures and formulas, and which permeability coefficient is defined as the product of the diffusion coefficient, D,,., of the agent in the wall and a distribution coefficient, K, which is a ratio of the solubility of the agent in the wall to the solubility of the agent in the saturated solution, the selection of materials for forming the wall and the carrier can be made for making a device according to the invention. For purposes of comparing the permeability of the wall to that of the liquid carrier, it is convenient to define the permeability as follows: P,,.= PC= D,,.S,,. wherein P, C and D have the meaning as above described and S is the solubility of the agent in the wall. The permeability of the carrier to the agent can similarly be defined as P,. D S, wherein D and S,. are the diffusion coefficient and the solubility ofthe agent in the liquid core carrier. The solubility, S can be determined by cited methods. The diffusion coefficients ofthe anti-fertility agent in liquid carriers will be in the range of 10" to 10* cm /sec. The diffusion coefficient of the antifertility agent in the wall will be in the range of 10 to 10 cm /sec. Thus, a selection of carrier materials such that P than P preferably P 5 P,,., is ascertained for preparting an intrauterine contraceptive anti-fertility delivery device. The symbols used herein have then conventional meaning, for example, the symbol means greater than and the symbol means greater than or equal to.

In the specification and the accompanying claims, the phrase anti-fertility agent" and the term agent are used interchangeably and they broadly include progestational substances that have anti-fertility properties and estrogenic substances that have anti-fertility properties. These substances can be of naturally occurring or synthetic origin and they generally possess a cyclopentanophenanthrene nucleus. The term progestational substance as used herein embraces progestogen which term is used in the pharmaceutically acceptable steroid art to generically describe steroids possessing progestational activity, and the former also includes progestins," a term widely used for synthetic steroids that have progestational effects. The active anti-fertility progestational agents that can be used to produce the desired effects in mammals, including humans, and primates, include without limitations: pregn- 4 ene-3,20-dione, also known are progesterone; l9- nor-pregn-4-ene-3,ZO-dione; l7-hydroxyl 9-norl 711- pregn-5( lO)-3n3-20-yn-3-one; dl-l la-ethyl-l7- ethinyl-l 7-0z-hydroxygon-4-ene-3'one; l7ethinyl l 7- hydroxy-5( l0)-estren-3-one; l7a-ethyinyl-19- norestosterone; 6-chloro-l 7-hydroxypregna-4,6-diene- 3,20-dione; l7ahydroxy6or-methyll 7(- l -propynyl- )androst-4-ene-3-one; 9a,lOa-pregna-4,6-diene-3,20- dione; l7-hydroxy-l7a-pregn-4-en-20-yne-3-one; 19- nor- 1 7a-preg-4-3n-20-yen-3a, l 7-dial; l7-hydroxypregn-4ene-3,20-dione; l7a-hydroxyprogesterone; l- 7-hydroxy-6a-methylpregn-4-ene-3,ZO'dione; mixtures thereof, and the like.

The term estrogenic and estrogenic anti-fertility gents as used herein also includes the compounds known as estrogens, and the metabolic products thereof that possess anti-fertility properties or are converted to active anti-fertility agents in the preselected biological environment. Exemplary estrogenic compounds include a-estradiol, a-estradiol 3-benzoate, l7-cx-cyclopentanepropionate estradiol, 1,3,5(l0)- estratricne3, l 7a-diol dipropionate, estral ,3,5(

triene 3,l7-a-diol valerate, estrone, ethinyl estradiol, l7-ethinyl estradiol-3-methyl ether, l7-ethinyl estradiol-3-cyelopentoether, estriol, mixtures thereof, and the like.

Additionally, the above progestational and estrogenic agents can be in the form of their pharmacologically accepted derivatives, such as their hydroxy or keto groups can be in a derivative form for the present purpose. The progestational or estrogenic derivative used should easily convert to the parent agent upon its release from the device by biological activities such as enzymatic transformation, pH assisted hydrolysis in uteri, tissue and metabolism and the like. The derivative can also be used to control the solubility of the agent in the liquid core and to assist in metering the agent from the device. Suitable derivatives include without limitation, esters with pharmaceutically acceptable acids such as acetate, glucuronate, benzoate, propionate, butyrate, valeroate, hexanoate, heptanoate, maleate, citrate, succinate, tartrate, fumarate, malate, ascorbate, sulphate, phosphate and the like; ethers such as lower alkoxy-tetrahydropyran-yl, unsubstituted tetrahydropyran-yl, silyl moieties, trifluoromethyloxy, cyclopentyl enol ethers and other functional groups such as ureido, and the like.

The degree of solubility ofvarious progestational and anti-fertility agents in various liquid cores, is ascertained by using the above techniques. Typical examples of solubilites are as follows: 6-chloro-l7- hydroxypregna-4,6-diene-3,ZO-dione acetate practically insoluble in water; l7a-hydroxy-6a-methyll 7-( lpropynyl)androst-4-en3-3-one slightly soluble in acetone; 9a,l0a-pregna-4,6-diene-3,20 dione slightly soluble in distilled water; l7-hydroxy-l7ot-pregn-4-en-20- yn-3-one slightly soluble in alcohol and slightly soluble in vegetable oil, l9-nor-l7a-pregn-4-en-20-yne 3a-l7- dioldiacetate sparingly soluble in fixed oils, l7- hydroxy-oa-methylpregn-4-ene-3,20-dione acetate sparingly soluble in methanol, l7-hydroxy-l9-nor-l7apregn-4-en-20-yn-3-one sparingly soluble in vegetable oil, l7-0z-estradiol sparingly soluble in vegetable oil,

18 ethinyl estradiol soluble in various vegetable oils, and the like.

The amount of anti-fertility agent present in the reservoir, whether dissolved, partially dissolved or undissolved is generally non-limited and it is an amount equal to or larger than the amount of an agent that on its release from the device is effective for being about the agnets anti-fertility effect. For example, the amount of agent present in the reservoir of an intrauterine device when the device is used for a predetermined period of time to achieve an anti-fertility effect in a potential child-bearing woman is for A-pregene- 3,20-dione, progesterone, for a year supply wherein a year is 400 days, and the rate of release from the device is 25p.g/day is 10 mg in the reservoir, at the same rate of release for 2 years a reservoir supply of 20 mg and for 3 years 30 mg. If the rate of release for the same progestational agent is 100 ,ug/day and the length of the year is as before, the reservoir concentration for 1 year is 40 mg, for 2 years mg and for .3 years 120 mg. The amount of progestational agent present in the reservoir for 1 year, 2 year and 3 year device is 80 mg, I60 mg and 240 mg respectively when the rate of release is 200 ,ug/day. The amount of estrogenic .agent present in the reservoir will also vary dependingon the size of the de vice and the capacity of its reservoir. Generally, the reservoir will contain from 50 mg to 250 mg of estogenie agent for release for! to 3 years or longer. For these devices, the estrogenic anti-fertility agent is released from the device at a rate of release of about 1 microgram to micrograms per day, and the like. Of course, for shorter periods or longer periods smaller amounts or larger amounts will be present in the reservoir, and the amount will also vary relative to the degree of activity of the progestational agent or the estrogenic agent, or mixtures thereof, Generally the intrauterine contraceptive device will contain from about 0.1 mg to 10 g of a progestational or estrogenic agent for releasing it at a controlled rate of from about 1 microgram to 300 micrograms of agent, or larger amounts per day. Of course, devices containing differentamounts of agent for use for different time periods such as week, month, and the like, are also readily made by the invention.

The reservoir comprising the liquid core and the agent is fabricated by standard techniques. For example, in one embodiment the liquid can be mixed with the anti-fertility agent in solid, semi-solid or liquid forms at the time of mixing, and then distributed therethrough by conventional methods, such as ballmilling, calendering, stirring, shaking, rollmilling, and the like. The liquid core anti-fertility agent composition is then charged into the lumen of the device formed from release rate controlling material and sealed therein. In another embodiment the liquid core and the agent are mixed and then charged into a highly permeable tube that is positioned within a drug release rate controlling material. The wall material forming the anti-fertility dispensing device and having the reservoir contained therein can be formed to a given intrauterine contraceptive devices design by molding, casting, pressing, extruding, drawing, rotational molding, compression and transfer molding, or like standard processes of manufacture. Also, depending on the material used to form the wall, a monomers may be cured at this stage of manufacture. The ability to design and shape the wall into devices of highly reproducible shapes of controlled composition, readily results in fabrication of intrauterine contraceptive device with controlled characteristics and thus overcome a significant disadvantage of previously described devices,

The intrauterine device can be fabricated as an integral unit device by using the above, art known techniques. For example, the device can be fabricated by blow molding into a parison whose shaped cavity is the predesigned device, by extrusion molding, casting, vacuum forming and the like. The device can also be manufactured from two members suitably joined into a unit article of manufacture by conventional techniques. For example, two members positioned in assembly relation can be joined by dielectric heating, radiant heating, or

- hot iron pressed heating and the like. Also, two members can be joined by solvent welding employing a mixture of solvent and polymer that is painted onto the joinable areas and then the solvent evaporated, such as using a sealing composition of methylene chloride containing 10 to l percent ethylene vinyl acetate copolymers for joining like copolymer parts. Additionally, members can be united by friction welding, ultrasonic welding, insert injection molding, radiant heat and the like. Other standard procedures, as described in Madern Plastics Encyclopedia, Vol. 46, pages 62 to 70, 1969, well known to those skilled in the art can be used to fabricate the drug delivery device of the invention.

The following examples are merely illustrative of the present invention and they should not be considered as limiting the scope of the invention in any way, as these examples and other equivalents thereof will become apparent tho those versed in the art in the light of the present disclosure. drawings and the accompanying claims.

EXAMPLE l barium sulfate in a mixture of 3 parts by weight of Dow- Corning Silastic 382 elastomer resin liquid silicone oil and 1 part by weight of Dow-Corning 360 medical grade fluid silicone oil is thoroughly mixed in a standard laboratory v-blender to yield a liquid core. The progesterone is sparingly soluble in the liquid core. Next, an aliquot of the liquid core is injected into a section of medical grade polyethylene tubing having an outside diameter of 0.! inches and an inside diameter of 0.070 inches and the ends of the tubing heat sealed with a standard, hand heater. The filled polyethylene tubing, about 3.6 cm in length is placed into the lower halfof a two piece T shaped mold in the depending position of the molds T. The top cross position of the molds T is previously charged with a 3.2 cm section of unfilled polyethylene tubing having its ends previously heat sealed as described above. Next, the upper half of the mold is placed threon and the mold electrically heated to yield a T shaped anti-fertility device. The device will release micrograms of progesterone per day for controlling fertility in an adult woman.

EXAMPLE 2 An intrauterine contraceptive anti-fertility administrating device having the shape of a T with the wall of the T formed of a release rate controlling material permeable to the passage of the agent and surrounding a reservoir comprised of a liquid core containing the agent is fabricated as follows: first, a section of medical grade polyethylene tubing is washed with methanol for at least 72 hours, rinsed with water, and then air dried. Next, a core material is prepared as a homogenous mixture consisting of 11 percent by weight of progesterone, N.F., 10 percent by weight of barium sulfate, U.S.P., 19 percent by weight of Dow-Corning 360 Medical Fluid, a water white polydimethylsiloxane fluid, and 59.25 percent by weight of Dow-Corning Silastic 382 Medical Grade Elastomer, a fluid polysiloxane polymer by thoroughly blending the ingredients for about 10 to 12 hours. Next, the bore material is injected into two precut lengths of the washed polyethylene and the devices formed by placing the filled polyethylene length in a T molh having a female portion containing a cavity which corresponds to the shape of the device. When the mold is closed, the male portion of the mold forms the top of the device. The clearance between the male member and the female member is sufficiently small, so that closing the molds and applying heat thereto forms the predetermined device by heat joining the two sections at their point of contact. The device contains 20 mg of progesterone for releasing it at a rate of 25 ug/day for 2 years.

EXAMPLE 3 An intrauterine contraceptive anti-fertility device comprised of a release rate controlling wall permeable to the passage of a therapeutically acceptable antifertility agent and surrounding a reservoir comprised of an agent and a liquid core for releasing the agent is manufactured as follows: a liquid carrier is prepared by intimately contacting and blending in a rotating mill 25 percent by weight of progesterone and 10 percent by weight of barium sulfate with percent by weight of Dow-Corning 360 medical fluid silicone oil to yield a liquid carrier. The liquid carrier is permeable to the progesterone and the progesterone is sparingly soluble therein. Next, the liquid carrier is injected into a length of ethylene vinyl acetate copolymer tubing comprised of 9 percent by weight of vinyl acetate having an inside diameter of 0.090 inches and an outside diameter of 0.110 inches. The ends of tubing are heat sealed and the tubing is then formed into a T device by joiningit to a like length of ethylene vinyl acetate copolymer tubing in a heated mold. The device releases 65 to micrograms of progesterone per day.

EXAMPLE 4 Following the procedure set forth in Example 1, except that the members of the T are joined at their perpendicular point of contact by heating with a heating iron, a device having a reservoir comprised of a liquid core containing aqueous poly( vinyl pyrrolidone) and progesterone housed within a poly(ethylene) barrier is prepared by generally following the example. The progesterone is sparingly soluble in the aqueous poly- (vinyl pyrrolidone) and both the poly(vinyl pyrrolidone) and the poly(ethylene) are permeable to the passage of the steroid, but the rate of passage is lower for the polytethylene). The poly(ethylene) barrier has a thickness of 50 microns, and it releases about 33 micrograms per square centimeter per day of progesterone to a progesterone receptor site.

EXAMPLE An intrauterine contraceptive anti-fertility drug delivery device shaped like a T and comprised of a liquid carrier of aqueous carboxymethylcellulose containing progesterone laminated between two sections of poly- (ethylene) half tubes, hermetically heat sealed at their end and contacting surfaces and where the cross member and the depending member meet in T fashion, is generally prepared according to the procedure of Example l. The poly(ethylene) had a thickness of 50 microns. The steroid is sparingly soluble in the carrier, and both the carrier and the poly(ethylene) are permeable to the passage of the steroid, with the rate of passage for the former higher than the rate of passage of the latter. The use of this device results in a controlled rate of release of progesterone over a prolonged period of about 1 year at the rate of 33 micrograms per sq. cm. per day.

EXAMPLE 6 EXAMPLE 7 Repeating the general procedures as described in Examples 1 through 6, an intrauterine contraceptive device is made of a permeable, release rate controlling wall of a biologically acceptable material and surrounds a reservoir comprised ofan estrogenic agent admixed in a liquid core. The device is substantially in the shape of a T and will release the agent at a controlled 4 rate for a prolonged period of time.

ln Table 1, immediately below, the rate of release obtained with an intrauterine contraceptive device shaped like a T and having a wall of ethylene vinyl acetate copolymer with 9 percent vinyl acetate and a reservoir comprising liquid core of silicone oil and progesterone is measured and compared with the rate of release obtained for an intrauterine device shaped like a T with the upright of the T made of cured silicone tubing filled within its lumen with dry, powdered progesterone. The release rates for these delivery devices is determined by agitating each device in separate isotonic saline baths at 37C, and determining the optical absorbance of the test saline solution at 248 nm using 10 cm cells in a double-beam ultraviolet spectrophotometer with isotonic saline in the reference cell. The concentration of progesterone in the test solution is determined by comparing the absorbance value at 248 nm with the values obtained at 248 nm for various known progesterone concentrations in isotonic saline. The results are expressed in micrograms per day for devices of like surfaces. In the table, the release rate for the liquid core T is the measured rate for 10 devices. Two identical sets of 10 devices are presented in the table.

TABLE 1 Release Rates of Intrauterine Devices Release Rate p-g/day Release Rate tg/day It will be understood to those versed in the art in the light of the present specification, drawings and accompanying claims that the invention makes available to the art both a novel and useful intrauterine contraceptive anti-fertility delivery device for administering an anti-fertility agent to produce the desired effect; and, that the rate of release from the device can be controlled to produce these effects, while simultaneously lessening or overcoming the undesirable effects frequently associated with the prior art methods. lt will be further understood to those versed in the art that different embodiments of this invention can be made without departing from the spirit and the scope of the invention. Accordingly, it is to be understood that the invention is not to be construed as limited, but it embraces all equivalents inherent herein.

I claim:

1. A method of interfering with the reproductive process of a female mammal by continuously administering a contraceptive agent within the uterine cavity of said female over a prolonged period of time by the steps of: (a) inserting into the uterine cavity an intrauterine device comprising a reservoir containing dissolved agent and undissolved replacement agent in a liquid core material permeable to the passage of the agent, the undissolved replacement agent being present in an amount in excess of its solubility in the core and sufficient to maintain the dissolved agent during the prolonged period substantially equal to the amount of dissolved agent originally present in the core, the reservoir confined within an enveloping shape membrane substantially in the shape of a T comprised of a biologically acceptable material insoluble in mammalian body fluid, and formed at least in part of a material permeable by diffusion to passage of said agent at a rate which is lower than the rate of permeability of said agent through said core, (b) releasing said agent from said reservoir into the uterine cavity at a controlled, continuous, contraceptively effective rate by diffusional passage through said shaped membrane, and (c) continuously replacing the dissolved agent released from the reservoir by continuously dissolving said undissolved replacement agent in the core so as to substantially maintain the amount of dissolved drug at its originally present amount.

2. An intrauterine device for the administration of an anti-fertility agent at a controlled and continuous rate over a prolonged period of time to effect contraception, said device comprising: (a) a reservoir comprising both dissolved anti-fertility agent and undissolved replacement anti-fertility agent in a liquid core material permeable to the passage of the agent, with antifertility agent having limited solubility in the liquid core, the undissolved replacement anti-fertility agent being present in an amount in excess of its solubility in the core and in amounts sufficient to maintain the dissolved drug in an amount substantially equal to the amount of dissolved drug originally present in the core material during the prolonged period of time, said reservoir surrounded by, (b) a wall of a configuration which is substantially in the shape ofa T, the wall made of a material insoluble in body fluid, and formed in at least a part of a release rate controlling material permeable to the passage of the anti-fertility agent, with the permeability of the wall to anti-fertility agent lower than the permeability of the liquid core material to anti-fertility agent, and (c) wherein the device when placed in the uterus continuously releases anti-fertility agent from the reservoir in a contraceptively effective amount by metered passage through the wall, with released anti-fertility agent being continuously replaced in the liquid core by replacement anti-fertility agent to substantially maintain the amount of dissolved antifertility agent at its initial present amount in the liquid core.

3. An intrauterine contraceptive device for the administration of an anti-fertility agent at a controlled and continuous rate over a prolonged period of time, said device comprising: (a) a reservoir comprising both dissolved anti-fertility agent and undissolved replacement anti-fertility agent in a liquid core permeable to the passage of the agent. with the anti-fertility agent having limited solubiltiy in the liquid core, the undissolved replacement anti-fertility agent contained in the liquid core in an excess amount to continuously replenish and maintain dissolved anti-fertility agent substantially at its original amount in the liquid core during the prolonged period of time, said reservoir surrounded by (b) a wall of a configuration which is substantially in the shape of a T, the wall made of a material insoluble in body fluid, and formed in at least a part of a release rate controlling material permeable to the passage of the anti-fertility agent, with the permeability of the wall to anti-fertility agent lower than the permeability of the liquid core to anti-fertility agent, and (c) wherein the intrauterine device when placed in the uterus releases dissolved anti-fertility agent from the reservoir in an effective amount for contraception by metered passage through the release rate controlling wall, with released anti-fertility agent continously replaced in the liquid core by replacement anti-fertility agent simultaneously dissolving to substantially maintain the amount of dissolved anti-fertility agent in the liquid core for release at a controlled and continuous rate over a prolonged period of time.

4. An intrauterine contraceptive device for the administration of an anti-fertility agent at a controlled and continuous rate for a prolonged period of time according to claim 3 wherein the release rate controlling material is a substantially homogenous material permeable to anti-fertility agent, the liquid core is a liquid medium containing anti-fertility agent that constantly bathes the inner surface of the release rate controlling material and is permeable to the passage of anti-fertility agent, and the anti-fertility agent is a progestogen.

5. An intrauterine contraceptive device for the administration of an effective amount of an anti-fertility agent at a controlled and continuous rate over a prolonged time according to claim 3 wherein the release rate controlling material is ethylene vinyl acetate copolymer, the liquid core is silicone oil and the antifertility agent is progesterone.

6. An intrauterine contraceptive device for the administration of an effective amount of an anti-fertility agent at a controlled and continuous rate over a prolonged period of time according Jo claim 3 wherein the liquid core is a mixture permeable to the passage of anti-fertility agent comprised of an oil, a liquid prepolymer and an'anti-fertiltiy agent which is a progestational agent.

7. An intrauterine contraceptive device for administration of an antifertility agent at a controlled and continuous rate for a prolonged period of time according to claim 3 wherein the anti-fertility agent is a progestational agent.

8. An intrauterine contraceptive device for the administration of an anti-fertility agent at a controlled and continuous rate over a prolonged period of time according to claim 3 wherein said agent release rate controlling material is permeable to passage of dissolved anti-fertility agent by diffusion.

9. An intrauterine contraceptive device for the administration of an anti-fertility agent at a controlled and continuous rate over a prolonged period of time according to claim 3 wherein said release rate controlling material is a microporous material having its pores filled with a liquid medium permeable to passage of the anti-fertility agent by diffusion.

10. An intrauterine contraceptive device for the administration of an anti-fertility agent at a controlled and continuous rate over a prolonged period of time according to claim 3 wherein the liquid core is permeable to the passage of dissolved anti-fertility agent by diffusion.

11. An intrauterine contraceptive device for the administration of an anti-fertility agent at a controlled and continuous rate over a prolonged period of time according to claim 3 wherein the liquid core is an oil and the anti-fertility agent is a diffusible estrogenic agent.

12. An improved process of contraception wherein an intrauterine contraceptive device for the administration of an anti-fertility agent at a controlled and continuous rate over a prolonged period of time is placed within a fertile uterus, the improvement comprised of using an intrauterine contraceptive device having (a) a reservoir comprising a liquid core, liquid core containing, (b) both diffusible anti-fertility agent dissolved in the liquid core and undissolved replacement antifertility agent in the liquid core, the liquid core permeable to the passage of anti-fertility agent with the antifertility agent having limited solubility in the liquid core, the undissolved replacement anti-fertility agent contained in an amount sufficient to continuously dissolve to replenish and substantially maintain dissolved anti-fertility agent in the core for continuous availability at substantially the same rate to the wall during the prolonged period of time, the reservoir surrounded by (c) a wall of a configuration substantially in the shape of a T, the wall made of a material insoluble in body fluid, and formed of a release rate controlling material permeable to the passage of a diffusible anti-fertility agent with the permeability of the wall to the antifertility agent lower than the-permeability of the liquid core to the anti-fertility agent, and (d) wherein during the process of contraception when the intrauterine device is placed in the uterus, the intrauterine device releases dissolved anti-fertility agent from the reservoir in an effective amount for contraception by metered passage through the release rate controlling wall, with released anti-fertility agent continuously replaced in the liquid core by replacement anti-fertility agent simultaneously dissolving to substantially maintain dissolved anti-fertility agent in the liquid core for release at a controlled and continuous rate over a prolonged period of time to produce contraception.

13. A process of contraception according to claim 12 for the controlled and continuous rate of release over a prolonged time wherein the reservoir consists of an oil and the antifertility agent is a diffusible estrogenic anti-fertility agent, or a diffusible progestational antifertility agent.

14. An intrauterine contraceptive device for administering a member selected from the group of antifertility agents consisting of progestational, estrogenic and mixtures thereof at a controlled and constant rate over a prolonged period of time up to three years com prising: (a) a wall substantially in the shape of a T comthe anti-fertility agent by diffusion, the material insoluble in body fluid, and capable of substantially maintaining the devices shape throughout the prolonged period of time, said wall surrounding (b) at least one reservoir defined by the walls inner surface with the reservoir comprising a liquid core, containing up to 10 grams of both dissolved anti-fertility agent and undissolved replacement anti-fertility agent with the liquid core permeable to the passage of the anti-fertility agent and having limited solubility for the anti-fertility agent, the undissolved replacement anti-fertility agent in the liquid core present in an excess amount to continuously replenish and maintain a substantially constant supply of dissolved anti-fertility agent in the liquid core during the prolonged period of time, with the permeability of the wall to the anti-fertility agent lower than the permeability of the core to the agent, (c) and wherein antifertility agent administered from the intrauterine device is effected by releasing dissolved anti-fertility agent with such released agent being replaced by undissolved replacement agent to continuously maintain dissolved anti-fertility agent in the liquid core for supplying the anti-fertility agent at substantially the same rate to the wall so that anti-fertility agent is metered at a controlled and substantially constant rate from the res ervoir by passage through the wall over the prolonged period of time.

Claims

2. An intrauterine device for the administration of an anti-fertility agent at a controlled and continuous rate over a prolonged period of time to effect contraception, said device comprising: (a) a reservoir comprising both dissolved anti-fertility agent and undissolved replacement anti-fertility agent in a liquid core material permeable to the passage of the agent, with anti-fertility agent having limited solubility in the liquid core, the undissolved replacement anti-fertility agent being present in an amount in excess of its solubility in the core and in amounts sufficient to maintain the dissolved drug in an amount substantially equal to the amount of dissolved drug originally present in the core material during the prolonged period of time, said reservoir surrounded by, (b) a wall of a configuration which is substantially in the shape of a T, the wall made of a material insoluble in body fluid, and formed in at least a part of a release rate controlling material permeable to the passage of the anti-fertility agent, with the permeability of the wall to anti-fertility agent lower than the permeability of the liquid core material to anti-fertility agent, and (c) wherein the device when placed in the uterus continuously releases anti-fertility agent from the reservoir in a contraceptively effective amount by metered passage through the wall, with released anti-fertility agent being continuously replaced in the liquid core by replacement anti-fertility agent to substantially maintain the amount of dissolved anti-fertility agent at its initial present amount in the liquid core.

3. An intrauterine contraceptive device for the administration of an anti-fertility agent at a controlled and continuous rate over a prolonged period of time, said device comprising: (a) a reservoir comprising both dissolved anti-fertility agent and undissolved replacement anti-fertility agent in a liquid core permeable to the passage of the agent, with the anti-fertility agent having limited solubiltiy in the liquid core, the undissolved replacement anti-fertility agent contained in the liquid core in an excess amount to continuously replenish and maintain dissolved anti-fertility agent substantially at its original amount in the liquid core during the prolonged period of time, said reservoir surrounded by (b) a wall of a configuration which is substantially in the shape of a T, the wall made of a material insoluble in body fluid, and formed in at least a part of a release rate controlling material permeable to the passage of the anti-fertility agent, with the permeability of the wall to anti-fertiliTy agent lower than the permeability of the liquid core to anti-fertility agent, and (c) wherein the intrauterine device when placed in the uterus releases dissolved anti-fertility agent from the reservoir in an effective amount for contraception by metered passage through the release rate controlling wall, with released anti-fertility agent continously replaced in the liquid core by replacement anti-fertility agent simultaneously dissolving to substantially maintain the amount of dissolved anti-fertility agent in the liquid core for release at a controlled and continuous rate over a prolonged period of time.

5. An intrauterine contraceptive device for the administration of an effective amount of an anti-fertility agent at a controlled and continuous rate over a prolonged time according to claim 3 wherein the release rate controlling material is ethylene vinyl acetate copolymer, the liquid core is silicone oil and the anti-fertility agent is progesterone.

6. An intrauterine contraceptive device for the administration of an effective amount of an anti-fertility agent at a controlled and continuous rate over a prolonged period of time according Jo claim 3 wherein the liquid core is a mixture permeable to the passage of anti-fertility agent comprised of an oil, a liquid prepolymer and an anti-fertiltiy agent which is a progestational agent.

7. An intrauterine contraceptive device for administration of an anti-fertility agent at a controlled and continuous rate for a prolonged period of time according to claim 3 wherein the anti-fertility agent is a progestational agent.

12. An improved process of contraception wherein an intrauterine contraceptive device for the administration of an anti-fertility agent at a controlled and continuous rate over a prolonged period of time is placed within a fertile uterus, the improvement comprised of using an intrauterine contraceptive device having (a) a reservoir comprising a liquid core, liquid core containing, (b) both diffusible anti-fertility agent dissolved in the liquid core and undissolved replacement anti-fertility agent in the liquid core, the liquid core permeable to the passage of anti-fertility agent with the anti-fertility agent having limited solubility in the liqUid core, the undissolved replacement anti-fertility agent contained in an amount sufficient to continuously dissolve to replenish and substantially maintain dissolved anti-fertility agent in the core for continuous availability at substantially the same rate to the wall during the prolonged period of time, the reservoir surrounded by (c) a wall of a configuration substantially in the shape of a T, the wall made of a material insoluble in body fluid, and formed of a release rate controlling material permeable to the passage of a diffusible anti-fertility agent with the permeability of the wall to the anti-fertility agent lower than the permeability of the liquid core to the anti-fertility agent, and (d) wherein during the process of contraception when the intrauterine device is placed in the uterus, the intrauterine device releases dissolved anti-fertility agent from the reservoir in an effective amount for contraception by metered passage through the release rate controlling wall, with released anti-fertility agent continuously replaced in the liquid core by replacement anti-fertility agent simultaneously dissolving to substantially maintain dissolved anti-fertility agent in the liquid core for release at a controlled and continuous rate over a prolonged period of time to produce contraception.

13. A process of contraception according to claim 12 for the controlled and continuous rate of release over a prolonged time wherein the reservoir consists of an oil and the anti-fertility agent is a diffusible estrogenic anti-fertility agent, or a diffusible progestational anti-fertility agent.

14. An intrauterine contraceptive device for administering a member selected from the group of anti-fertility agents consisting of progestational, estrogenic and mixtures thereof at a controlled and constant rate over a prolonged period of time up to three years comprising: (a) a wall substantially in the shape of a T comprising the anti-fertility device and formed of a release rate controlling material permeable to the passage of the anti-fertility agent by diffusion, the material insoluble in body fluid, and capable of substantially maintaining the device''s shape throughout the prolonged period of time, said wall surrounding (b) at least one reservoir defined by the wall''s inner surface with the reservoir comprising a liquid core, containing up to 10 grams of both dissolved anti-fertility agent and undissolved replacement anti-fertility agent with the liquid core permeable to the passage of the anti-fertility agent and having limited solubility for the anti-fertility agent, the undissolved replacement anti-fertility agent in the liquid core present in an excess amount to continuously replenish and maintain a substantially constant supply of dissolved anti-fertility agent in the liquid core during the prolonged period of time, with the permeability of the wall to the anti-fertility agent lower than the permeability of the core to the agent, (c) and wherein anti-fertility agent administered from the intrauterine device is effected by releasing dissolved anti-fertility agent with such released agent being replaced by undissolved replacement agent to continuously maintain dissolved anti-fertility agent in the liquid core for supplying the anti-fertility agent at substantially the same rate to the wall so that anti-fertility agent is metered at a controlled and substantially constant rate from the reservoir by passage through the wall over the prolonged period of time.