Method for making a reservoir containing an active substance diffused through the reservoir and installation therefor

The invention concerns a method for making a reservoir (5) containing an active substance and adapted to be introduced into a natural cavity of a living being, the reservoir (5) comprising a membrane (9) permeable to the active substance. Said method includes steps which consist in: a) placing at least one tube designed to constitute the membrane (9) in at least one retaining member, the ends of the tube being open; b) injecting through at least one of the tube ends, while expelling any residual air present in the tube, an amount of a product (8) containing an active substance in pasty form, said amount corresponding substantially to an inner free volume of the tube; c) when the tube is full, closing the end of the tube opposite the end from which the injection is performed; d) proceeding with the injection of the product (8) in pasty form into the free volume until achieving the outer desired diameter (D5) for the reservoir (5) by allowing the radial expansion of the tube; e) polymerizing the product (8) when the reservoir (5) reaches the desired outer diameter (D5) while maintaining the reservoir (6) in the retaining member. The method is particularly designed for producing hormonal intrauterine contraceptive devices.

The invention relates to a method of producing a reservoir containing an active substance and suitable for being inserted into a natural cavity of a living being, this reservoir being enveloped by a membrane permeable to the active substance.

Such reservoirs are used as intrauterine contraceptive devices also called hormonal intrauterine devices. This type of reservoir comprises a tubular membrane, usually made of a silicone-based material. A product containing in particular a silicone-based matrix and a contraceptive hormone is enveloped by this membrane. The membrane is permeable to the hormone, the latter diffusing steadily from the inside of the reservoir toward the uterine cavity. Such intrauterine devices also comprise a polymer-based inert support, to which the reservoir is attached in order to hold the device in position in the uterine cavity.

This mode of administering contraceptive products makes it possible to use very low doses of progestative hormones, the latter being delivered directly to the target organ. The effectiveness of these devices is comparable to that of hormone-based contraceptives taken by mouth. Their duration of action is situated between two and five years and, unlike intrauterine devices comprising a copper wire instead of the reservoir, they are nonallergic. These hormonal intrauterine devices are used in particular in cases of hypermenorrhea, which frequently occurs with copper-based intrauterine devices.

The membrane surrounding the reservoir is formed from a silicone tube of small diameter and the thinnest possible wall. The technical constraints, however, do not make it possible to produce silicone tubes with a wall thickness of less than 0.4 millimeter and with a diameter of less than 1.5 millimeters. The diffusion of the hormone through the membrane must be slow, continuous and even, irrespective of the quantity of hormones present in the reservoir. This is possible, in application of Fick's laws on membrane diffusion, only for much thinner membranes.

Because of the maximal dimensions of the reservoir imposed by the morphology, it is known practice, for example from EP-A-0 652 738, to insert a cylinder of a product containing a hormone into a silicone tube. This insertion makes it possible to extend the silicone tube radially and, by stretching, to bring the wall of the tube to the desired thickness by exploiting the elastic properties of the silicone. In this method, a silicone tube is held in place and receives a blank in its opening. This blank comprises a means of injecting pressurized air which dilates the tube. Then, this blank is progressively replaced by a cylinder, made in advance, of product containing the hormone. The final step makes it possible to fixedly attach the membrane around the cylinder by reducing the air pressure inside the tube.

In the same spirit, U.S. Pat. No. 5,400,804 describes a method of making a tubular reservoir containing a contraceptive substance. A tubular reservoir, surrounded by a sheath, covers a needle placed in a mold. The needle injects air to increase the internal diameter of the reservoir. Once the diameter has been increased, a rod forming a support replaces the needle.

Such methods require the availability of a length of tube identical to the length of the cylinder of product. In other words, the latter must be made first and cut to the correct length; the same applies to the silicone tube. Furthermore, the injection of pressurized air may be inadequately controlled and/or the tube incorrectly held during this injection. It is then possible that, on the membrane of the tube, a bulge forms in which an air bubble is housed. Finally, such systems do not make it possible to effectively attach the external membrane to the internal cylinder.

It is these disadvantages that the invention intends more particularly to remedy by proposing a method and an item of equipment for making a reservoir containing an active substance into which a thin membrane is easily placed, while preventing the formation of a bulge on this membrane.

Accordingly, the subject of the invention is a method of making a reservoir containing an active substance and suitable for being inserted into a natural cavity of a living being, this reservoir comprising a membrane that is permeable to the active substance, characterized in that it comprises steps consisting in:

a) placing at least one tube designed to form this membrane in at least one retention member, the ends of the tube being open,

b) injecting through one of the ends of the tube, while expelling all the residual air present in this tube, a quantity of a product containing an active substance in paste form, this quantity corresponding substantially to the internal free volume of the tube,

c) when the tube is full, closing the end of the tube opposite to the end from which the injection is performed,

d) continuing the injection of the product in paste form into the free volume of the tube until the desired external diameter for the reservoir is obtained by allowing the tube to expand radially,

e) polymerizing the product when the reservoir has the desired external diameter while keeping the reservoir in the retention member.

Such a method makes it possible, in a single operation, to produce the reservoir and to fill it with active substance. It is no longer necessary to produce a cylinder of product separately. The injection of the product in the absence of air, under pressure, allows the latter to be evenly distributed in the tube while preventing the presence of bulges or air bubbles.

According to advantageous, but not mandatory, aspects of the invention, the method may incorporate one or more of the following features:

After step e), the reservoir is cut to the desired final. Length.

During step a), a rod is inserted into the internal volume of the tube.

During step a), several tubes are simultaneously placed in at least one retention member.

Steps b) to e) are carried out simultaneously on all the tubes placed in at least one retention member.

The invention also relates to an installation making it possible to apply a method as described hereinabove and, more specifically, an installation that comprises:

At least one member for the retention of at least one tube designed to form the membrane,

at least one member for the injection of a product containing the active substance into the tube, at least one member for the closure of at least one end of the tube after it has been filled with the product.

Advantageously, the retention member comprises at least one mold defining a housing for receiving the tube when it is filled and when the product is polymerized.

The closure member comprises a rod and a plate for blanking off one end of the tube and one end of the housing.

The retention member is fitted, on an internal face, with coupling points of the wall of the tube suitable for preventing the retraction and/or the longitudinal extension of the wall when the product is injected and/or polymerized.

The rod is covered with a material not adhering to the rod, particularly a sheath.

The housing comprises at least one zone for receiving at least one member for positioning the ends of the tube.

The housing comprises two reception zones, each being placed in the vicinity of an end of the housing and suitable for receiving a positioning member.

These members are rings furnished with a radial collar.

These rings have an external diameter close to the external diameter desired for the reservoir.

An intrauterine device1comprises a support2made of a polymer-based inert and nonallergic material. This support2is generally T-shaped with branches3curved in the direction of its rod4, so as to be configured generally in the shape of a marine anchor. A reservoir5is positioned on the rod4of the support2. The reservoir is configured as a cylinder with a circular base and provided with a central and longitudinal opening6. The diameter D.sub.6of this opening is suitable for allowing the insertion with reduced clearance of the rod4into the reservoir5. The reservoir5is immobilized in translation on the rod4by two bosses70,71situated respectively in the vicinity of the ends of the rod4. The terminal boss70of the rod4is furnished with an orifice72allowing threads to pass through making it easier to retract the intrauterine device from the uterine cavity.

The cylinder5comprises, in cross section, in addition to the central opening6, an intermediate zone between the external wall of the reservoir and the opening6. This zone, whose thickness lies generally between 1 mm and 2 mm, extends over the whole length of the reservoir5. It is filled by a tube8of solid product. This solid product comprises approximately 20% to 40% of an active principle, particularly a progestative hormone, for example levonorgestrel. The quantity of hormone is sufficient to ensure that the device is effective for two to five years with a hormonal release of between 20 and 25 .mu.g/24 hours which allows an effective contraceptive action. The rest of the product8consists essentially of silicone.

The external wall of the reservoir5is formed by a continuous membrane9, thus producing a protective sleeve around the tube8. Only the terminal sections of the cylinder5have no membrane. This membrane has a base of a silicone or a mixture of silicones. This or these silicones are advantageously of a type different from that entering into the composition of the product8, particularly as concerns the silica filler.

As illustrated inFIGS. 2 and 3, the tubular membrane is formed from a tube10which has an internal diameter D.sub.10approximately two to three times smaller than the external diameter D.sub.8of the product8. The thickness E.sub.10of its wall is greater than the thickness E.sub.5of the final membrane9. The thickness of the wall is inversely proportional to the external diameter of the tube.

The radial extension of the tube10allows it to surround the product8forming the reservoir5of external diameter D.sub.5, with a wall thickness E.sub.5thin enough to form a membrane. The elastic properties of the silicones and their porosity make it possible to satisfy the technical constraints evoked hereinabove. Other inert, nonallergic materials that are elastic, extendable, and permeable to the active substances can be used to produce a reservoir5via a method as described hereinafter.

As shown inFIG. 4, a first type of mold, in two separable parts, is made of a rigid but porous material, so as to allow humid air to pass between the interior and the exterior of the mold. Specifically, certain silicones polymerize in the presence of water; in this case, it is necessary to maintain a high relative humidity inside the mold. Advantageously, the mold is made of aluminum, or of an aluminum alloy, and provided with small orifices, for example of a diameter lying between 0.2 and 0.3 mm, regularly distributed over the mold. As a variant, the mold may be made of a sintered material or of compressed silica. The main portion11of the mold defines a central cylindrical housing12with a circular base and centered on an axis X.sub.12. The internal diameter D.sub.12of the housing12is substantially identical to the final external diameter D.sub.5of the reservoir5.

A rod13, for example a metal rod, is positioned longitudinally in the housing12, along the axis X.sub.12. This rod has an external diameter D.sub.13corresponding substantially to the internal diameter of the finished reservoir5, that is to say to the diameter D.sub.6of the opening6. The rod13is fixedly attached, at one of its ends13A, to a support or plate14, generally in the shape of a disk, with a diameter D.sub.14greater than the diameter D.sub.12. The rod13, over its whole length, passes through the mold11without touching the walls of the housing12. At one end, the housing12communicates through a convergent12A with an orifice15having a smaller diameter than the diameter D.sub.12.

The plate14is placed outside the mold11, on the side of the outlet12B of the housing12opposite the convergent12A.

The orifice15allows the insertion of an end-piece of a first type of injection means represented schematically inFIG. 5. This injection means16, generally syringe-shaped, comprises a main body17in which a piston18moves in a sealed manner. This piston18is hollow, in order to allow the rod13to pass through when the insertion end-piece19of the body17is in place in the orifice15of the mold11. This injection device16is connected, where necessary, to a reserve of product so that it can operate continuously.

As shown inFIG. 6, the first step of the method of making the reservoir5consists in positioning, in the direction of the arrow F.sub.1inFIG. 6and on the rod13, the silicone tube or sleeve10after having inserted the end-piece19, by force, into one end of the tube10. Once the sleeve10covers the rod13, the end-piece19of the injection system16is positioned in the mold as shown inFIG. 7.

A movement of the piston18in the direction of the other end11A of the mold, according to the arrow F.sub.2, moves the product8in paste form toward the annular space20lying between the rod13and the internal face of the tube10. This product8, which comprises the active principle, has a viscosity that varies according to the percentage of active principle. The viscosity of a silicone-based product is not measured directly. It is known practice, for silicones, to indirectly assess this viscosity by measuring the speed of flow of the product under a given pressure. One method used is given by the American standard ASTM-033 in which the speed of flow is expressed in grams per minute. In this instance, the product8has a speed of flow greater than 2 grams per minute and preferably lying between 2.8 and 3 grams per minute. As a variant, the injection is made by an endless screw or a membrane system.

The product8is injected slowly, steadily and continuously for example under the action of an electric, pneumatic or mechanical force exerted on the piston18. The quantity injected is determined in order to substantially fill the annular volume20available in the silicone tube10thus retained in the housing12. This injection takes place without notable radial and/or longitudinal deformation of the tube10, because of the quantity injected and the speed of injection. Furthermore, the mold holds the tube10in place.

As shown inFIGS. 7 and 8, the end21of the tube10, opposite the orifice15remains open throughout the period of injection of the product8. Once the tube10has been filled, the filling being made easier by the opening of the end21, which allows all the residual air to be expelled from the volume20, the piston18is still not abutting against the end-piece19inserted in the end of the mold fitted with the orifice15, because of the quantity of product8initially present in the device16as shown inFIG. 8.

During this step, the tube10is entirely filled by the product8, except for the volume occupied by the rod13. The product is uniformly distributed in the annular space20. It is particularly free of air bubbles in the vicinity of the wall of the tube10.

In the next step, illustrated inFIG. 9, the end21of the tube10is blanked off by the plate14because of its movement in the direction of the arrow F.sub.3by sliding along the rod13. The plate14then closes the outlet12B and the end21of the tube10. Only a passage for the rod13: is preserved in the closure system. The rod13is immobilized, for example, by a jaw device, a guillotine valve device. As a variant, not shown, the end21and the outlet12B are closed by a guillotine or pincer system. This blanking off of the end21being carried out, the product8can no longer be expelled through this end of the tube10opposite to the syringe16. The injection of the product8into the tube10in the direction of the arrow F.sub.4continues. This second injection takes place under a greater pressure than the first. Because of the elastic properties of the wall9of the silicone tube10, the latter dilates radially in the direction of the arrows F.sub.5and F′.sub.5until coming into contact with the internal face11A of the mold11which defines the housing12. Because the pressure exerted by the product8on the wall9is constant and uniformly distributed on this wall9, the tube10is dilated while preventing any bulge and while producing a wall9whose final thickness is even at all points of the wall. This forms a membrane whose porosity and diffusion coefficient are optimal and even. The quantity of product8injected during this step is particularly a function of the final diameter D.sub.5of the reservoir5, that is to say, in practice, a function of the internal diameter D.sub.12of the housing12.

The injection is terminated when the external face of the wall9of the tube10and the internal face11A of the mold11are in contact over the whole of their respective surface.

It is then appropriate to await the polymerization of the product in the tube10. The polymerization of a silicone-based product on an element itself made of silicone allows an effective connection between the components, in a manner similar to a weld. The porosity, at the same time of the wall9and of the material forming the mold11, makes it possible to maintain in the mold enough relative humidity to ensure a rapid and complete polymerization of the product B. This produces a reservoir5in which the product8is effectively retained and evenly distributed in the membrane9, which improves the hormonal diffusion.

In order to prevent any retraction and/or longitudinal extension during the injection of the product8, the internal face11A is not smooth but has asperities, not shown, sufficiently large to form coupling points of the wall9of the tube10thus preventing its retraction and/or its longitudinal extension during the injection of the product8and/or the polymerization.

If necessary, a pause in the injection is made to leave time for the tube10to resume its initial longitudinal dimensions.

In this way, the production of the product8and its insertion into the reservoir5are achieved in a single operation.

In a final step, not shown, the rod13is withdrawn from the mold11in the direction of the arrow F.sub.6inFIG. 10, which allows the reservoir5to be extracted from the housing12. The rod may then be extracted from the reservoir.

At the time of polymerization, an adhesion of the product8on the rod13may compromise an easy retraction of the latter from the mold11.

To prevent this adhesion, the rod13is covered with a material that does not adhere to the rod13. Advantageously, it is a sheath130. This thin sheath130is made of a material that is biocompatible and inert relative to the other components of the intrauterine device1.

This sheath130is positioned on the rod13prior to the latter being installed in the mold11.

In addition to an easy retraction of the rod13, this sheath130helps the seal between the ends of the rod13with the piston18and the plate14.

As a variant, the sheath130is replaced by a surface coating of the rod13that does not adhere to the product8. In another embodiment, the material forming the rod13itself does not adhere to the product8.

According to one aspect, not shown, of the invention, the mold11may be formed of two matching half-shells together defining the housing12. In this case, after the polymerization, the mold is opened to allow the retraction of the reservoir5.

When the rod13has been withdrawn, the aforementioned assembly is cut to the desired length as a function of the length of the rod4that is then inserted into the opening6. In practice, the length of the housing12may make it possible to produce several reservoirs5end-to-end.

In a variant, not shown, the mold11comprises several grooves12placed in parallel and/or in a star shape, thus allowing the simultaneous and parallel production of several reservoirs. The injection device16is adapted accordingly.

As a variant, the injection device16is fitted with a means of continuously supplying the main body17with the product8.

In another embodiment, the mold11has no rod similar to the rod13. The reservoir obtained is a full cylinder. It is then necessary to produce a support different from that previously described. This may be, for example, a support fitted with open ring type coupling means.

As a variant, the installation comprises a mold11whereof the length of the housing12is shorter than that described. These molds are suitable for receiving, instead of the central rod13, the rod4of a support2. In this case, the hormonal intrauterine device is produced, in a single operation ready for use, by overmolding the reservoir5onto the rod4. In this case, the length of the housing12corresponds substantially to the length of the intrauterine device1, the cutting step being no longer necessary.

FIG. 11illustrates another type of mold and another means of injecting the product according to the invention. This other mold22comprises a bottom half-mold23and a top half-mold24. The mold22is made of a material similar to that of the mold11in order to allow the retention of a high relative humidity in the mold.

The bottom half-mold23comprises a central housing25A of dimensions and shape adapted to the desired dimensions of the reservoir5. In this instance, the housing25A is semicylindtical with a circular base. In the vicinity of the ends of this housing25A, cut-outs26are made.

The end sections of the half-mold23are fitted, in the top portion, with a groove27. These grooves27have a shape and dimensions suitable for receiving the rod13.

The top half-mold24is similar to the half-mold23. It comprises a semicylindrical central housing25B with a circular base. This housing25B, similar to the housing25A, has dimensions and a shape adapted to the desired dimensions of the reservoir5. In particular, the half-mold24is fitted with grooves27and cut-outs26of shapes and dimensions similar to those of the half-mold23. The cut-outs26and the grooves27of each half-mold23,24are advantageously placed facing one another when the mold22is closed. In this configuration, the mold22comprises a central housing25formed by the housings25A and258of the half-molds23and24.

The half-mold24is provided with two orifices28,29placed in the vicinity of its ends. These orifices28,29are perpendicular to a longitudinal axis X.sub.25of the housing25B when the mold is closed. They allow a communication between the outside of the mold22and the housing25when the mold is closed.

The orifice28is a through-orifice and opens into the housing25B, between a cut-out26and the end wall25C of the housing25B. The external outlet of this orifice has an internal diameter close to the external diameter of the end-piece19of a syringe16.

The orifice29made on the other end of the half-mold24forms a blind compartment. This orifice is traversed, in the vicinity of its closed end, by a channel30. This channel is oriented in a direction generally parallel to the axis X.sub.25when the mold is closed. The channel30connects the outside and the housing25. This channel30receives a stopping member31, for example a pin made of rigid polymer. This pin31can be moved in the channel30in order to stop the latter and prevent, any communication, via the channel30or the orifice29, between the housing25and the outside.

The orifice28is also traversed by a channel32in which a stopping member33in the form of a pin moves. This channel32is blind, its closed end being situated in the wall of the half-mold24. It is placed in the vicinity of the outlet of the orifice28. The channel32is oriented parallel to the axis X.sub.25when the mold is closed.

These stopping members31,33have a length and a diameter that are sufficient to stop the corresponding channels30,32in a sealed manner.

When it is desired to produce an intrauterine device1, the user inserts, at each end of a tube10, for example by means of a spreader-type plier, a positioning member34. This member is formed by a ring34made of a rigid, inert and biocompatible material. This ring34is fitted with a radial collar35extending outward. The internal diameter D.sub.34of the ring34is close to the desired external diameter D.sub.5of the reservoir5. Thus the ends of the tube10covering the rings34have a diameter close to their final diameter when the reservoir5is produced. The rod13, also covered by a sheath130similar to that mentioned hereinabove, is then inserted into the opening of the tube10. The assembly is then positioned in the bottom half-mold23, so that the ends of the rod13rest in the grooves27. The tube10is positioned in the half-mold23so that the collars35of the end rings34are inserted, with reduced clearance, into the corresponding cut-outs26.

The mold22is closed by folding down the top half-mold24. Thus, the grooves27and the cut-outs26of the half-mold24cover the free portions of the rod13and of the collars35. Thus the tube10and the rod13are retained and positioned exactly in the mold22.

In a first step, similar to that previously described, the product8in paste form is injected through the orifice28after the end-piece19of a syringe has been inserted into the outlet of the latter. The pin33is in the retracted position in order to allow the product to pass into the housings25A and25B. The product8enters the tube10. The air contained in the tube10is expelled from the mold22and exits via the orifice29whose passage is free, the pin31being in the retracted position.

When the paste product8occupies all the available space between the concentric tube10and sheath130, the orifice29is stopped by pushing the pin31in the direction of the housing25B. The injection of the product8is then continued until the desired diameter of the reservoir5is obtained. During the injection, the tube10is held in place by the rings34. There may therefore be no longitudinal expansion of the tube10; only radial expansion is permitted. At the end of the operation, the injection orifice28is stopped by pushing the pin33to the end of the channel32.

The polymerization takes place in a humid environment in a manner similar to that previously described. At the end of the method, the mold is opened and the rod13which slides freely inside the sheath130is easily withdrawn. The reservoir is cut to the desired length. This cut is made particularly at the rings34.

As a variant, the user places several molds,22in parallel, supplied by a syringe-type device with multiple end-pieces in order to produce several reservoirs5in parallel.