FI76687C - Process for the preparation of a combination of an intrauterine device and a drug releasing portion - Google Patents

Description

1 76687

A method of making a combination of an intrauterine device and a drug release moiety

The invention relates to a method of making an intrauterine device 5 (IUD) and a drug-containing combination. The IUD is then an already known, relatively stable and drug-free structure.

More particularly, the invention relates to a method of making a combination of an intrauterine device and a drug-releasing part 10 comprising a moldable silicone rubber as a carrier and a drug-free, relatively stable body for intrauterine fitting.

U.S. Patent No. 3,913,573 discloses a method of making a combination of an intrauterine device and a system for controlled local and temporal drug delivery. The known solution has a cavity made in the stable body for certain drugs, which may be in a solid or liquid medium and which are gradually released into the uterus over a long period of time. The rate of drug release is controlled by the drug permeable walls of the device. The drug may be incorporated into a portion that is placed in a cavity in the body. The drug can also be fitted to a silicone rubber tube using a room temperature vulcanizable silicone rubber (RTV silicone rubber).

Because RTV silicone rubbers have been found to be too weak for many applications, they have been reinforced with fillers. However, RTV silicone excipients have been found to be unsuitable for drug release formulations because they have been found to inhibit drug release. For this reason, LTV silicone rubbers have been recommended as the base material for drug delivery devices.

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In the present combination, an intrauterine device with a controlled drug release function is attached to a proven IUD structure. In this case, the IUD used is relatively stable and does not contain drug-5. The device according to the invention may be a molded hose which is firmly attached to the shaft part of the IUD.

In a preferred embodiment of the method according to the invention, a drug-permeable cover is placed around the tube, which controls the rate of release of the drug contained in the tube. RTV silicone rubbers can then be used as the basic material for the hose.

When the excipients are removed from the silicone rubber, e.g. by centrifugation, it is then better suited for drug release. When said coating 15 is applied on top of the hose, the silicone rubber without filler is made structurally uniform, so that the device can be handled in the usual manner without damaging it before it is put into its intended use.

The method of the invention is characterized in that the drug released in utero and the carrier to be formulated, which is an excipient-free silicone rubber, are mixed together; the mixture of drug and carrier is formed as an accessory suitable for attachment to the body; the accessory is mounted to the body to release the drug 25 in a controlled manner in the uterus, the installation being performed by expanding the accessory by immersing it in a solvent suitable for swelling the rubber and in which the rubber and drug are substantially insoluble; and that the expanded accessory is shrunk around the arm 30 of the body.

The method of the invention comprises centrifuging a commonly available RTV silicone rubber to remove fillers and attaching a drug-permeable coating, e.g., a silicone rubber tube, over its tubing. Such an outer tube section, which reinforces the filler-free RTV silicone rubber and 3 76687 helps control the dosage of the drug, can also be swollen in the solvent. The combination made according to the invention withstands a normal treatment which would not otherwise be possible in the case of filler-free RTV silicone rubber preparations.

The device of the invention for making drug-containing tubing comprises a multi-cavity mold that makes it easy to cast and easy to remove from the mold, after which they can be attached to the IUD arms. The mold has a pair of plates with parallel recesses. When the plates are pressed together, their recesses together form the actual cavities of the mold. Rods are arranged in the recesses to form through-openings in the middle of the finished hoses. The grooves in the mold plates allow the rods to enter the center of the recesses. The size of the wells can be chosen to provide a dimensioned tubing that provides the required release rate of the drug.

For injecting the viscous silicone rubber and drug mixture 20, a specially designed syringe is used, the injection nozzle of which corresponds to the injection opening in the mold. The syringe and mold plates are structurally strong enough to withstand the pressure required to compress viscous silicone rubber into a mold. Once the silicone-25 rubber has solidified, the mold plates are removed, the multi-part hose assembly is removed from the mold, and the connecting portions formed in the mold channels connecting the hoses are cut off. The tubing can then be inflated and secured to the IUD arms.

30 Since, as already mentioned, the drug tubing can be used in already known drug-free and relatively stable IUD structures, the physician can perform the placement of the IUD as before. As used herein, the term "relatively stable" means that the IUD to which the tubing of the invention is attached does not wear rapidly in the uterus, but forms a long-lasting device comprising 4,768,787 drug tubing. Thus, the closed body portion may be an IUD known for its contraceptive efficacy. Thus, the physician can still use the type of IUD of his choice. Manufacturers do not need to make any changes to their IUD products to incorporate the drug-containing device of the invention. The rate of dosing, i.e. the release of the drug, depends on the dimensioning of the hose and the strength of the outer tube on it, as well as the amount of drug mixed with the silicone rubber mouthpiece used as the base material. Therefore, no change in IUD structure is required to determine or change the dosage.

The above-mentioned and also other advantages of the invention will be described in more detail in the following detailed description of a preferred structure according to the invention, with reference to the accompanying drawings, in which Figure 1 is an enlarged plan view in partial section of a drug delivery device and IUD run; Fig. 3 is an enlarged side view of a combination of mold and syringe 25 for manufacturing drug delivery tubing to be attached to already known IUD bodies; Fig. 4 is a plan view of a multi-cavity plate is part of the mold of Figure 3, and Figure 5 is a partial section of the syringe of Figure 3.

The IUD 11 shown in Figure 1 comprises an arm portion 12 which also supports a drug delivery device 15. The device 15 comprises a hose 16 made of a base material, i.e. silicone rubber, into which the drug is evenly distributed throughout. On top of the hose 16 there is a tube 35 which is firmly attached to it and which allows the drug to pass through.

5 76687

The preferred structure of Figure 1 with a combination of an IUD and a drug delivery device is prepared as shown diagrammatically in Figure 2. First, a suitable, medical-acceptable silicone-5 rubber is selected. RTV silicone rubber, which is easy to use and also commonly available, is processed in a centrifuge until all the filler has been removed from it. For example, Medical Grade 382 Silastic, manufactured by Dow Corning Corporation (Midland, Michigan), has been found to be suitable after centrifugation for several hours (100,000 to 200,000 g).

The drug to be administered to the uterus with device 15 was first mixed with silicone rubber. Levonorgestrel, used as a fine powder, was added to centrifuged 382 Silas-15 tic in small portions at a time, and the mixture was mixed to obtain a soft paste comprising the two components. The mixture was stirred several more times a day for 3-4 days before use. This ensured that the polymer had thoroughly "wetted" the drug-20 substance.

The mixture of polymer and drug was then cast into hose 16 as shown in Figure 1. Prior to this, a suitable catalyst was added to the mixture. The mixture was then sprayed and allowed to solidify until the tubing could be removed from the mold without damage.

A special syringe 20 (Figs. 3 and 5) is used to inject a mixture of polymer and drug viscose into a multi-cavity mold 40 (Figs. 3 and 4). The syringe 20 and the mold 40 will be described in more detail later. In Example 30 using 382 Silastic silicone rubber and levonorgestrel, the catalyst was Dow Corning Catalyst M (tin (II) octoate). It was added and mixed rapidly with the silicone rubber and drug mixture. The syringe was filled with catalyzed viscous paste, which was pressed into a mold with a hydraulic device. The mixture was allowed to solidify for 45-60 minutes, at which time it was already so hard, 6 76687, that the hoses made from it were obtained intact out of the mold. The curing time was determined by observing the curing of the residual batch of the mixture in a Teflon plate on which the catalyst and the material mixture had been mixed.

5 After the hoses solidified, they were removed from the mold and the connections formed by the mold channels were cut off either with a curved knife or with a razor blade. The mold 40 (Figures 3 and 4) has stainless steel bars 41 which act as delimiting portions for the opening 18 in the center of the hoses. Prior to attaching the tubing to the IUD, the rod was carefully removed therefrom without damaging the filler-free silicone and drug structure. To remove the rods, the tubing can be expanded by immersing it for a few minutes in a solvent that does not dissolve or otherwise damage the silicone rubber or the drug mixed with it. Em. the tubes of Example (382 Silastic and levonorgestrel) were swollen in cyclohexane.

Once the hose is expanded in the solvent, it is easy to push the 20 onto the arm 12 of the IUD (11).

To slow the rate of drug release and increase the structural strength of the device, the drug through tube 17 can be pulled over the IUD tubing. The commonly sold silicone rubber tube 25 can first be expanded in a suitable solvent and then easily pushed onto the hose, into which it shrinks tightly. The Silastic Medical Grade Tubing 602-261 used as a tubular material in the example was expanded in cyclohexane.

As can be seen from Figure 3 and as already mentioned, the means for casting the drug and polymer mixture into hoses 16 comprises a specially designed syringe 20 and a suitable mold 48. The syringe of Figure 5 comprises a hollow cylindrical body 21 made of stainless steel. The outer surface of the body 21 has threads at each end, at the other end 33 for an end cap 22 with internal threads and likewise made of stainless steel, with a conical tip 23. There is a channel 24 in the middle of the tip 23, and the outer cone terminates in a shoulder 25 outwardly slightly smaller center tip 26.

At the other end of the syringe body 21 there is also a cap 29 with internal-5 threads, the material of which is, for example, Delrin (a stable-type resin, manufactured by Dupont & Nemours). The piston 30 has an arm 31 which passes through an opening 32 in the cap 29 as a tight fit. In the body 21, the piston terminates in an enlarged end 34. The circumferential groove 35 has a sealed O-ring 36 which rests on the inner surface of the body 21. Opposite the end 34 is a smaller threaded end 37 of the piston 30 to which is attached an internally threaded stainless steel nut 38.

The mold 40 has two plates 43 and 44, which together form the multi-nest mold shown in Figure 4. The plate 44 is shown in detail in Figure 4. The recesses 46 on the surface of the plate 44 join the corresponding recesses 46 of the plate 43 and then form the actual multi-cavity recesses 20 of the mold. The set of grooves 47 forms the connecting channels between the recesses 46 along the corresponding and parallel set of grooves in the plate 43, along which the mixture of polymer and drug is guided from one recess to another during injection. At the side of the plates, parallel halves forming the injection opening are also made at 25 48. The injection port is a conical hole 50, the cone of which corresponds to the conical shape of the syringe nozzle 23. The hole 50 terminates in a shoulder 52 behind which is a channel 53 opening into the first recess 46. The openings 54 passing through the plates in the same direction facilitate the alignment of the plates and the recesses therein when the mold is closed. From the recess 46 farther from the injection opening 48, a final channel 55 begins, leading to the outside of the mold.

At each end of each recess 46 there is a coaxial groove 57 in the same direction, which also leads to the outside of the mold. The second mold plate 43 has a similar structure. The grooves 57 align in place with the rods 41 which form the hoses and, when cast, the openings in the middle thereof. In a preferred construction, the rods are stainless steel parts, but may just as well be rods 5 or other elongate parts made of another suitable material, the width of which is such that they form an opening in the hoses which is tightly connected to the shaft of the IUD.

In Figure 3, the plates 43 and 44 are shown connected to each other by pins 58 passing through alignment holes 54 in the plates. The plates can be pressed together with any suitable device. Figure 3 shows the C-clamps 59, but the plates can be locked together, e.g. with bolts inserted into the openings in the same line. In the preferred construction, the mold plate-15 material is the acetal-type resin Delrin, but other materials can also be used.

When using the device according to the invention, the syringe 20 is filled with a mixture of drug and polymer to which a catalyst has been added. The syringe is closed, the nozzle 20 is inserted into the injection opening 48, and a certain pressure is applied to the nut 38 at the end of the syringe piston 30, e.g. by means of a hydraulic device. Since the cone of the steel nozzle 23 of the syringe corresponds in shape to the injection cone opening 50 of the mold, said parts are completely tightly connected to each other.

In the example above, equal amounts of polymer (Medical Grade 382 Silastic) and steroid levonorgestrel were mixed so that the powdered drug was gradually mixed with the polymer to form a soft paste. Stirring was continued for 30 more days. The mold 40 had recesses 46 and rods 41 dimensioned so that the length of the hose became 18 mm, the outer diameter 3.175 mm and the diameter of the central hole 1.5 mm.

6 grams of the drug-polymer mixture was weighed onto 35 Teflon plates and 15 mg of Dow Corning Catalyst M (tin (II) octoate) was added to the mixture with rapid stirring.

9 76687 This catalyst mixture was then placed in a special syringe 20 and injected into a sealed mold where it was allowed to solidify for 45-60 minutes. An appropriate degree of solidification could be determined from the curing of the residual material on the Teflon sheet.

When the mold was opened, the result was a Christmas tree structure formed by hoses connected in turn at their ends to the mold channels 47 by short protruding portions of the solidified mixture.

10 The protrusions were then cut off to separate the hoses. The tubing was then expanded in cyclohexane and the rods 41 were removed. The ends of the tubing were rounded so that a flat surface was formed for the uterine mucosa.

The tube was re-expanded in cyclohexane and pushed onto the shaft of the IUD, where it was allowed to shrink, as already mentioned above. Tubes long enough (material Silastic Medical Grade Tubing 602-261) were then cut to cover the tubing. The ul-20 tube had a diameter of 2.41 mm, an inner diameter of 1.98 mm and a wall thickness of 0.22 mm. The tube was then swelled in cyclohexane and inserted over the tubing on the shaft of the IUD, where it was allowed to shrink.

This drug-releasing tubing was tested in an experimental-25 tube (in vitro). The tube then released 20-25 pg of levonorgestrel daily into the surrounding water. In a test performed with another device as an in vivo test in the uterus for 287 days, an average of 10.5 pg of levonorgestrel was released from the tubing into the uterus daily. The same la-30 te was then tested in a test tube to give 20 pg per day. The steroid was extracted and it was found that 94% of the original had remained in the device.

In another in vivo test, a device according to the invention belonging to the same batch as mentioned above was in utero for 503 days. The analysis performed showed that the device had released an average of 30 pg of drug per day.

10 7668 7 The difference in drug extraction in the two in vivo tests corresponded to the differences observed in the separation of levonorgestrel from other types of devices, such as subcutaneous implants. This is assumed to be mainly due to the heterogeneous characteristics of the different 5 individuals and not to the variation in the characteristics of the devices. Variations in the extraction fluids formed in the uterus change the rate of drug extraction. Levonorgestrel has an atrophic effect, i.e. it tends to dry out the lining of the uterus.

In addition, two other hose sizes were tested. The smaller hoses were 13 mm long, 3.34 mm in diameter and 136 mm in total area. They were designed to release 23 pg of levonorgestrel per day. The tubular hose liner was as described above. The average duration of use of the ten IUDs was 281 days (actual duration of use was 98-500 days). Levonorgestrel was released on day-20 at 22 + 7 yug (mean + standard deviation). The larger hoses were again 18 mm long, with a diameter of 2.34 mm and a total area of 189 mm. The hoses were closed in the above pipes, and the results obtained were relatively good. Larger tubing was designed to release 32 μg of levo-25 norgestrel per day. Fourteen devices were studied after an average of 314 days of use (actual operating time 84-482 days). Levonorgestrel was then released at 30 -9 pg per day (mean - standard deviation). Taking into account the average release rates of the drug, the effective service life of the above devices can be assumed to be more than four years.

The dosage of the drug can be controlled in many ways. The diameter or length of the hose, or both, can be changed to change the surface area of the hose. With or without an outer tube, the rate of drug release depends directly on the total area of the tube. If the area 11 76687 is reduced by half, the release rate is also reduced by half if the other parameters do not change. When the outer tube is not used, the rate of drug release was initially very high and resembles the effect of a birth control pill. In contrast, when 5 outer tubes are used, the rate of drug release remains relatively constant. In addition to the surface area of the hose, the speed is also controlled by the wall thickness of the pipe. As the wall thickness of the silicone rubber tube to be inserted over a particular hose is changed in size, the rate of drug release 10 changes, but not directly in proportion to the wall thickness. When the wall thickness is double, the release rate is about 60% and not 50% compared to a half thinner wall.

The effective service life of the hose and its dosing quantity can thus be controlled by changing the dimensioning of the hose and the surrounding pipe. Long-term prevention - up to 7 years - is then entirely possible. As the diameter of the hose is increased, more drug is delivered to the device, and again when a thicker protective tube is used, the release rate 20 decreases. Although the surface area of the hose also increases as the diameter of the hose increases, the thicker protective tube nevertheless reduces the release rate per unit area. Thus, speeds similar to those described above can be achieved. In addition, the effective life of the IUD increases.

Placing the combination device of the invention in the uterus is not more difficult than inserting a standard IUD, but the same technique has been used with good success. A specially formulated IUD is also not required. The NOVA-T type is recommended as the base body of the drug-hose according to the invention. It is easy to handle, the hose stays in it well and it is easy to put in place.

In addition to the dosage factors described above, the diameter of the tubing 16 is selected based on the inside diameter of the push tube used to place the IUD. In the case of the Nova-T 35, its arms turn so that it can easily go into a narrow push tube. Thus, let 12 76687 when the diameter determines the size of the push tube. As can be seen from Figure 1, the diameter of the hose 16 is such that the diameter of the push tube does not need to be increased, at least not much. Also, the placement of the IUD and the related device 5 according to the invention does not cause any difficulties, as already mentioned.

The present combination (IUD + drug delivery device according to the invention) achieves good contraceptive results. It functions as a previously known drug-free contraceptive device and at the same time as a controlled drug delivery device that directly controls the release of the drug. Another benefit is the reduction in blood volume associated with menstruation. Although this can also be achieved with medicated coils 15 already on the market, more ectopic pregnancies have been reported.

With this type of device, the drugs released into the uterus can be any drugs used for various Hoi-20 functions of the uterus and its mucosa, as well as steroids used for contraceptive purposes, either topically or interactively. Although only RTV silicone rubber has so far been used to make hoses, many other polymer and drug blends may be considered. Similarly, only silicone rubber has been used in the manufacture of the protective tube described above, which is intended to control the rate of drug release on the hose and to increase the stability of the structure. The part corresponding to such a tube can equally well be produced from other polymers meeting the same requirements and intended for medical use in many different ways, e.g. by immersion coating, heat sealing, spraying, etc.

Mold 40 was made of Food-Grade Delrin, but the mold material can be selected from carbon steel, stainless steel, brass, aluminum, polycarbonates, 13 76687 polyacetates, Lucite (acrylic resin), Teflon, polyethylene, polypropylene, polysulfone and the like. which are known to be durable and easy to handle. The same applies to the mold rod parts 41 and the syringe 20 parts.

A variety of solvents can be used to expand the silicone rubber and drug tubing as well as the silicone rubber tubing. Cyclohexane was now chosen because it is a very fast blowing agent as well as a powerful and reliable one. However, hexanes, straight-chain paraffins and ordinary hydrocarbons which are fully saturated can be used for this purpose as well. It should be noted, however, that the solvent must not dissolve the steroid or silicone rubber. In this respect, ether, toluene and chloroform are not suitable solvents.

Although the preferred manufacture of an intrauterine device and a drug delivery combination has been described above, various variations may be made therein without departing from the spirit and scope of the invention as set forth in the appended claims.

Claims (9)

A method for preparing a combination (10) of an intrauterine device and a drug releasing portion, said combination comprising a malleable silicone rubber as a carrier and a non-drug-containing, relatively stable body portion (11) for intrauterine placement, characterized in that the drug to be released into the uterus and the moldable carrier which is a non-filler-containing silicone rubber are mixed with each other; the mixture of drug and carrier is formed into an auxiliary device (15) adapted to be attached to the body portion (11); the auxiliary device (15) is mounted on the body portion (11) for controlled release of the drug into the uterus, the assembly being performed by expanding the auxiliary device (15) by immersing it in a solvent suitable for swelling of the rubber and in which the rubber and drug are essentially insoluble; and that the expanded auxiliary device (15) is shrunk around the shaft (12) of the body portion (11). 2. A method according to claim 1, characterized in that a filler is included in the moldable silicone rubber and that the filler is removed from the silicone rubber before the silicone rubber and the drug are mixed with each other, to effect release of drug from the auxiliary device (15). A method according to claim 2, characterized in that the step of removing the filler from the silicone rubber comprises centrifuging the silicone rubber before mixing it with the drug. Method according to Claim 1 or 2, characterized in that, when forming the mixture of drug and carrier substance in auxiliary devices (15), a syringe (20) is filled with an amount of the mixture of drug and carrier substance and that this amount injected into a mold (48) with multiple cavities to