HK1162311B - Intravaginal delivery system and process for manufacturing it - Google Patents

Description

Intravaginal delivery system and method of manufacture

It is an object of the present invention to provide an intravaginal delivery system comprising at least one compartment comprising a core and a membrane encapsulating the core, wherein the core and the membrane consist essentially of the same or different polymer composition. In addition, intravaginal delivery systems contain coupling means to form a closed continuous delivery system. It is another object of the present invention to provide a method for manufacturing said intravaginal delivery system. Preferably, the core and/or the membrane are prepared by injection molding or by extrusion.

Background

Intravaginal delivery systems capable of releasing one or more therapeutically active substances at substantially constant rates from each other over an extended period of time are very useful for certain applications, such as contraception and hormone replacement therapy. Many different constructions of delivery systems, in particular vaginal rings, and methods for manufacturing said systems are known from the literature.

US patent 3,920,805 describes the manufacture of a solid pharmaceutical device formed as an intravaginal ring consisting essentially of a central core without incorporated drug and a surrounding finite thickness of a coating with incorporated drug. The manufacturing process involves (1) placing the siloxane and catalyst mixture in two halves of a mould (mould) to provide a so-called centralised polymer core, tightening the mould, and allowing the siloxane mixture to harden (cure); (2) placing the polymer core in its mold halves, filling the outer mold halves with a drug-loaded polymer siloxane mixture containing a catalyst, placing the filled halves over the core of the first step, and curing; (3) after the second mold is cured, the other half of the outer mold is filled with the catalyzed and drug loaded polymeric siloxane mixture, the half is bonded to the cured half of the second mold, and the whole is cured again. This method requires several ring operations because it is formed and is relatively labor intensive. The ring produced by this method requires gating and edging (trimming) of the edge, where the two halves of the outer part of the ring are connected, so that the edge can cause irritation (irritation) after the ring is placed in the body.

US 4,888,074 of DOW CORNING SA provides in one aspect thereof a method for generating a ring enabling a controlled release of a therapeutic agent in a human or animal body. The method comprises extruding a composition comprising a therapeutic agent and an elastomer-forming silicone composition to provide a core, extruding a second elastomer-forming silicone composition to provide an outer sheath (sheath) to encapsulate the core, drawing together (piercing) end portions of the extruded core and outer sheath to form loops, and crosslinking the core and outer sheath.

The sheath may be extruded onto the core after the latter has been extruded, but is preferably extruded simultaneously with the core. Using this co-extrusion (co-extrusion) technique, the positioning of the core inside the sheath can be adequately controlled to remain consistent throughout the manufacturing process. Preferably, the core and sheath remain substantially concentric. The extruded core and sheath have sufficient adhesive strength to retain their shape. The end portions of the extrudate can be closed, for example, by placing a piece (piece) in a mould having a ring shape. For example, the parts are secured together by using a layer of a suitable adhesive compound or unhardened elastomer-forming composition that can crosslink the second, and preferably the first and second elastomer-forming silicone compositions used in the method.

The intravaginal system described in US 4,215,691 of ALZA CORP is manufactured by cutting a tube (tubing) made of a styrene butadiene block copolymer to a suitable length, shaping a segment like a ring, and shaping into a ring. Next, a solid polymer plug having an outer diameter equal to the inner diameter of the tube was wetted with dichloromethane and inserted into the tube to connect the open tube at both ends thereof, thereby forming a closed system. The hollow ring is then filled by injecting the steroid carrier mixture into the reservoir. Finally, the needle puncture was sealed with a little dichloromethane.

US 4,292,965 to poloplation countcil describes several methods for making an annular intravaginal device. One such method consists of forming an annular core ring of a suitable inert elastomer in a mold, and dipping the ring into a mixture of an inert volatile solvent containing a mixture of contraceptive steroids and an inert uncured elastomer binder. The solvent is then allowed to evaporate and the ring is dipped into an inert unvulcanized elastomer mixture in an inert volatile solvent which is allowed to evaporate to form the outer layer until the desired thickness of the outer layer is obtained. An alternative method of producing the shell IVR consists of forming the core in a mould and allowing it to harden, cutting it to a suitable length, bringing the rod (rod) to a constant weight, pulling it (pull through) a coating solution containing a mixture of elastomer and mixture of oestradione and progestogen, and polymerizing the coating. The membrane is formed by sliding a length of tubing over a rod. Medical grade adhesive is then applied to the ends of the rod and the surface of the rod near the ends. A second length of swelling tubing of about 4cm was placed over the two ends of the rod to form a loop and the ends of the rod were held together until the adhesive hardened.

To control the release rate of the therapeutic agent from the ring, it is desirable to have the drug in the core of the ring surrounded by an outer sheath of drug-free material. It is most important to control the centralisation (centering) of the core in the ring to ensure the correct release rate. The present invention provides an annular delivery system comprising at least one compartment comprising a core and a membrane, wherein the ends of the core-membrane system are joined together by coupling means in such a way that an impermeable plug is not formed at the point of connection.

Summary of The Invention

The present invention concerns an intravaginal delivery system comprising at least one compartment comprising a core having a first cross-sectional diameter and a membrane encasing the core, wherein the core and the membrane essentially consist of the same or different polymer composition, forming a core-membrane system having a first end and a first cross-sectional surface and a second end and a second cross-sectional surface; and a coupling means having a second cross-sectional diameter and having a length for connecting the first end and the second end of the core-membrane system, wherein the (second) cross-sectional diameter of the coupling means is substantially smaller than the (first) cross-sectional diameter of the core.

According to one embodiment of the invention, an adhesive is applied to the coupling component.

According to a further embodiment of the present invention, an adhesive is applied on the first and/or second cross-sectional end surface of the core-membrane system. It is also possible to apply an adhesive on the coupling means and on at least one cross-sectional end surface of the core-membrane system.

According to one embodiment of the invention, substantially half of the length of the coupling means is located inside the first end of the core-membrane system, while the remaining part of the coupling means is located inside the second end of the core-membrane system.

According to another embodiment of the invention there is an opening substantially in the middle of said core in the first end and/or the second end of the core-membrane system, said coupling means being located in one or more of said openings. The opening may extend through the entire length of the core-membrane system.

According to yet another embodiment of the invention, the coupling member is a polymer rod of biocompatible material.

An intravaginal delivery system according to one embodiment of the invention comprises a coupling member having a length of 5-25mm, preferably 10-20 mm.

Yet another embodiment of the intravaginal delivery system of the invention comprises a core having a cross-sectional diameter of 2-10mm and a coupling member having a cross-sectional diameter of 0.5-4.0 mm.

The intravaginal delivery system according to the invention is suitable for administering various types of therapeutically active substances at a predetermined and controlled release rate over a prolonged period of time. For example, the therapeutically active substance may be a progestogen or a compound having progestogenic activity, or an estrogen or a combination thereof. In addition, the delivery system may comprise at least one other therapeutically active or health-promoting substance.

The present invention also concerns a method for manufacturing an intravaginal delivery system consisting of at least one compartment comprising a core and a membrane encapsulating the core, wherein the core and the membrane consist essentially of the same or different polymer composition, the method comprising the steps of: forming one or more of said cores having a first cross-sectional diameter, encapsulating one or more cores by a membrane, creating a core-membrane system having two ends, and connecting the ends of the core-membrane system by coupling means having a second cross-sectional diameter to form a substantially ring-shaped delivery system, wherein said (second) cross-sectional diameter of said coupling means is substantially smaller than said (first) cross-sectional diameter of said cores.

According to one embodiment of the invention, the core and/or the membrane is prepared by injection molding or by extrusion.

Brief Description of Drawings

Figure 1 shows an illustrative intravaginal delivery system according to the invention.

Figures 2a and 2b show cross-sections of an intravaginal delivery system according to the invention.

Figure 3 shows the steps of preparation of the intravaginal delivery system of the invention.

Detailed Description

The present invention concerns an intravaginal delivery system (1) comprising at least one compartment (1a, 1b), the compartment (1a, 1b) comprising a first cross-sectional diameter (d)₂) And a membrane (3) encapsulating the core (2), wherein the core (2) and the membrane (3) consist essentially of the same or different polymer composition, forming a core-membrane system (5) having a first end and a second end. The intravaginal delivery system according to the invention further comprises a delivery tube having a second cross-sectional diameter (d)₆) For connecting a first end and a second end of a core-membrane system (5) to form a substantially ring-shaped delivery system (1), in which system the (second) diameter (d) of the coupling means (6)₆) Is substantially larger than the (first) diameter (d) of the core (2)₂) Is small.

The exemplary intravaginal delivery system (1) shown in fig. 1 comprises two compartments (1a and 1b), each comprising a core (2) and a membrane (3) encapsulating the core (2).

In FIG. 2aA cross-sectional view of an intravaginal delivery system (1) according to one embodiment of the invention is shown. The delivery system (1) comprises a core (2), a membrane (3) and an opening (4), which in this particular case extends through the entire length of the core-membrane system. The cross-sectional diameter (d) of the core (2)₂) Typically 2 to 10mm, preferably 3.0 to 5.5mm, and more preferably 4.0 to 5.0 mm.

Figure 2b indicates the diameter of the intravaginal delivery system shown in figure 2a, i.e. the first cross-sectional diameter (d) of the core (2)₂) A second cross-sectional diameter (d) of the coupling member (6)₆) And the cross-sectional diameter (d) of the opening (4)₄). The length (L) of the coupling member (6) is the distance between its ends.

Figure 3 shows the intravaginal delivery system (1) of the invention in an open configuration, i.e. the ends of the core-membrane system are not yet connected. A core-membrane system (5) is manufactured by known methods and cut into suitable lengths, said core-membrane system (5) comprising two compartments (1a and 1b) each having a core (2) encapsulated by a membrane (3). The coupling means (6) is partly introduced into the opening (4) at one end of the core-membrane system (5). To form a closed continuous delivery system (1) as shown in fig. 1, the other end of the core-membrane system (5) is pulled over the coupling means (6). It is of essential significance that no gap remains in the junction, i.e. between the ends of the core-membrane system.

The cross-sectional diameter (d) of the coupling member (6)₆) Is 0.5 to 4.0mm, usually 1.0 to 3.0 mm. The length (L) of the coupling member (6) is generally about 5-25mm, preferably 10-20 mm. On the other hand, if desired and depending on the material used, the coupling means (6) may be as long as the core-membrane system in case the opening (4) extends longitudinally through the entire core-membrane system (5). In order to ensure a tight and permanent connection between the ends of the core-membrane system by means of the coupling means (6), the opening (4) shown in fig. 2b has a cross-sectional diameter (d) corresponding to the coupling means (6)₆) Compatible cross-sectional diameter (d)₄). The opening (4) is usually located in the middle of the core-membrane system as shown in figure 2a to ensure the correct release rate. Section of a coupling part (6)Diameter of face (d)₆) May be the same as the cross-sectional diameter (d4) of the opening (4). The cross-sectional diameter (d) of the opening (4) depends on the material used₄) May be larger than the cross-sectional diameter (d) of the coupling member (6)₆) Slightly larger. Usually, the cross-sectional diameter (d) of the opening (4)₄) Is smaller than the cross-sectional diameter (d) of the coupling member (6)₆) Slightly smaller. In some cases, it is possible that there is no opening in either end of the core-membrane system (5), i.e. the coupling means (6) is pushed into the core material, preferably into the middle of the core material to ensure the correct release rate.

According to the invention, the coupling means (6) is located inside the core-membrane system (5), typically into the opening (4) therein, and it extends a distance therefrom from the end of the core-membrane system (5), such that both structural support and continuity are imparted to the manufactured, closed, annular delivery system. Typically, about half of the length (L) of the coupling means is located inside the first end of the core-membrane system (5), while the remaining part of the coupling means (6) is located inside the second end of the core-membrane system (5). As such, it is possible that the opening (4) shown in fig. 2 extends only a few millimeters, typically 5 to 10mm from the end of the core-membrane system (5), i.e. the length of the opening (4) within each end of the core-membrane system (5) substantially corresponds to the length of the coupling means inserted in said end. In addition, any other compatible opening (4) -coupling means (6) configuration is also possible and within the scope of the present invention, as long as the end connections of the core-membrane system are tight and a seamless connection is performed between the ends. For example, as explained in the description of fig. 2, the opening (4) may extend longitudinally through the entire core-membrane system (5), while about half of the length (L) of the coupling means having a length (L) of 5-25mm is inserted into the first end of the core-membrane system (5), while the remaining part of the coupling means (6) is inserted into the second end of the system (5).

Indeed, for human females, the outer ring diameter is typically 35 to 70mm, preferably 35 to 58mm or 45 to 65mm, and more preferably 50 to 58 mm. Thus, a suitable length of the core-membrane system can be determined.

The intravaginal delivery system (1) according to the invention, i.e. the core (2), the membrane (3) and the coupling means (6), may comprise various materials suitable for its intended use and the manufacturing method for which the delivery system is intended. The applicable materials are biologically compatible and remain unchanged for a sufficient period of time in the conditions prevailing in the vagina. These materials are known to the skilled person. Examples of suitable materials include, but are not limited to, copolymers of dimethylsiloxane and methylvinylsiloxane, ethylene/vinyl acetate copolymers (EVA), polyolefins such as polyethylene and polypropylene, ethylene/propylene copolymers, acrylic polymers, ethylene/ethyl acrylate copolymers, Polytetrafluoroethylene (PTFE), polyurethanes, polyurethane elastomers, polybutadiene, polyisoprene, poly (methacrylate), polydimethylsiloxane, modified polysiloxanes, such as, for example, 3, 3, 3-trifluoropropyl groups comprising silicon atoms attached to siloxane units or polysiloxanes comprising poly (alkylene oxide) groups, which are present as alkoxy-terminated grafts (graft) or blocks linked to the polysiloxane units by silicon-carbon bonds, polymethyl methacrylate, styrene-butadiene-styrene block copolymer, polyvinyl chloride, polyvinyl acetate, polyether, polyacrylonitrile, polyethylene glycol, polymethylpentene, and polybutadiene, or a combination of at least two thereof. Preferred materials are elastomeric compositions comprising poly (alkylene oxide) groups present as alkoxy-terminated grafts or blocks linked to polysiloxane units by silicon-carbon bonds, wherein the amount of polydimethylsiloxane comprising poly (alkylene oxide) groups is from 5 to 80 wt-% of the total amount of polymer.

Preferably, the coupling means comprises a substantially inert material. The term "substantially inert" in this context means that the active agent cannot diffuse or otherwise migrate from the core to the coupling means to any substantial extent. The coupling member may also be made of a material that is somewhat permeable to the therapeutically active substance of the delivery system.

In order to ensure a tight connection between the ends of the core-membrane system and to ensure that no gaps remain in the connection points, in addition, the coupling can be improved or toughened, for example by using solvent bonding, adhesive bonding, thermal fusing, thermal bonding, pressure, etc. When a solvent is used, the ends of the core-membrane system are wetted with an organic solvent that causes the surface to feel tacky, and then the surfaces bond when placed in contact and become bonded in a fluid-tight association with the coupling means. If necessary, the connection between the ends of the core-membrane system can be improved by applying an adhesive or sealant to at least one end of the system, to the cross-sectional surface thereof and/or to the surface of the coupling means, and then contacting the ends.

If the adhesive is applied to one or both of the ends of the core-membrane system (5), on its cross-sectional surface, it is preferred that the adhesive used is permeable to the therapeutically active substance incorporated in the core to ensure that no plugs are formed in the junction.

The intravaginal delivery system according to the invention is particularly suitable for administering various types of therapeutically active substances at a predetermined and controlled release rate over an extended period of time. The delivery system according to the invention may comprise a progestogen or a compound having progestogenic activity or an estrogen or a combination thereof as the therapeutically active substance. In addition, the delivery system may comprise at least one further therapeutically active substance or health promoting substance, which is capable of conferring and/or enhancing protection against cellular and fungal infections and/or enhancing protection against sexually transmitted diseases.

The intravaginal delivery system according to the invention consists of at least one compartment comprising a core and a membrane encasing the core, wherein at least one core and/or the membrane or the surface of the membrane comprises one or more therapeutically active or health-promoting substances. Thus, the delivery system may for example consist of one compartment comprising a core and a membrane, wherein the core comprises one or more therapeutically active or health-promoting substances.

Alternatively, the delivery system may consist of at least two compartments each comprising a core and a membrane encapsulating said core, wherein at least one core comprises one or more therapeutically active or health-promoting substances. The delivery system may also consist of at least one compartment comprising a core and a membrane encapsulating said core, wherein at least the membrane or the membrane surface comprises one or more therapeutically active or health-promoting substances.

Any suitable design or any structural combination of the delivery system is of course possible and within the scope of the invention.

The present invention also concerns a method for manufacturing an intravaginal delivery system consisting of at least one compartment comprising a core and a membrane encapsulating the core, wherein the core and the membrane consist essentially of the same or different polymer composition, the method comprising the steps of: forming one or more of said cores having a first cross-sectional diameter, encapsulating said one or more cores by a membrane, creating a core-membrane system having two ends, and connecting the ends of said core-membrane system by coupling means having a second cross-sectional diameter to form a substantially annular delivery system, wherein said (second) cross-sectional diameter of said coupling means is substantially smaller than said (first) cross-sectional diameter of said cores.

According to one embodiment of the invention, one or more cores (2) and a membrane (3) are prepared separately, and then the cores (2) are encapsulated by the membrane (3).

According to another embodiment of the invention, one or more cores (2) and/or membranes (3) are prepared simultaneously by using injection molding or coextrusion.

To manufacture the delivery system, the therapeutically active substance is mixed within the polymeric material of the core or membrane and the mixture is processed into the desired shape by using moulding, injection moulding, extrusion such as co-moulding and/or co-extrusion or other suitable methods. The membrane may be assembled by mechanically stretching or extending a prefabricated tubular membrane, for example by using a pressurised gas, for example by air, swelling in a suitable solvent such as cyclohexane, diglyme, propanol, isopropanol or a solvent mixture, and sliding the extended membrane tube over the core, or by using extrusion, moulding, spraying or dipping.

The film or one of the films may be encapsulated, coated or dusted with particles, crystals, microcrystals, powders or suspensions of therapeutically active or health promoting substances. This may be done using known methods, e.g. by spraying the entire delivery system or parts thereof with a suspension of the substance in a suitable solvent or by immersing the delivery system in a suspension.

A method which is particularly suitable for the preparation of the entire delivery system is disclosed in finnish patent FI 97947. This patent discloses an extrusion technique in which a preform containing an active ingredient is coated by an outer film. The therapeutically active agent is mixed within the core matrix polymer composition and processed into the desired shape and size by using known extrusion methods. The film layer may then be applied to a pre-formed core by feeding the core into an extruder followed by another core or a core without any active ingredient, i.e. a placebo compartment, or a space filled with air, which during extrusion will be filled with film material to form a separate film. The drug loaded core and the membrane layer may also be prepared simultaneously by co-extrusion.

The core or compartment so obtained may be cut into segments of the required length and each segment may be assembled in any suitable manner to form a device which is shaped, sized and adapted for placement in the vagina. The device may have many shapes, for example, various continuous, curved shapes, such as circular, annular, oval, helical, elliptical, toroidal (toroidal), and the like. The cross-section of the body may have almost any smooth shape, and it may be, for example, circular, oval, flat, elliptical, star-shaped, etc.

According to the present invention, the ends of the core-membrane system are joined together to form a closed continuous delivery system by using a thin polymer rod as coupling means to ensure a safe and secure bond. The outer diameter of the coupling member is substantially smaller than the diameter of the core. Thus, it does not form an impermeable plug at the point of attachment, but allows diffusion or penetration of the therapeutically active substance. If desired, a biocompatible adhesive may be used to better seal or better adhere one end of the core-membrane system to the other end or the coupling means to the compartment.

The delivery system according to the invention can be manufactured in any size as desired, the exact size depending on the mammal and the specific application. In practice, for human females, the outer diameter of the device (ring) is typically 35 to 70mm, preferably 35 to 58mm or 45 to 65 mm. The core length of the delivery system is chosen to give the desired performance. For example, the length of the drug-containing compartment may be 5mm to 160mm, or up to the total length of the delivery system.

The intravaginal delivery system produced according to the invention may be sterilized by using known methods, for example by using heat, ethylene oxide or radiation.

Examples

Example 1

Universal method for manufacturing intravaginal delivery systems

99.3 parts of commercial poly (dimethylsiloxane-co-vinylmethylsiloxane), 0.4 part of poly (hydrogenmethylsiloxane-co-dimethylsiloxane) crosslinker, 0.05 part of ethynylcyclohexanol inhibitor and 0.2 part of Pt catalyst (of the present reaction kind) in vinyl-methyl-siloxane were mixed in a kneader (kneader mill). The mixture was extruded into a tube-like form having an inner diameter of 1.1mm and an outer diameter of 3.9mm, and solidified by heating at +115 ℃ for 30 minutes, and cooled.

A membrane was prepared by mixing 50 parts of a mixture consisting of 72.3 parts of commercial vinyl-terminated poly (dimethylsiloxane-co-vinylmethylsiloxane), 25.5 parts of silica filler, 0.1 part of ethynylcyclohexanol, 2 parts of poly (hydrogenmethylsiloxane-co-dimethylsiloxane) crosslinker, and 0.05 part of alpha-tocopherol as a co-catalyst, and 50 parts of a mixture consisting of 97.5 parts of commercial vinyl-terminated poly (dimethylsiloxane-co-vinylmethylsiloxane), 0.1 part of ethynylcyclohexanol, 2 parts of poly (hydrogenmethylsiloxane-co-dimethylsiloxane) crosslinker, and 0.3 parts of Pt catalyst (of the present reactive species) in vinyl-methyl-siloxane. The mixture was mixed separately.

The film materials were combined and extrusion coated onto the core prepared above and impact hardened (shock cure) to produce a tubular rod having an outer diameter of 4.4 mm.

Example 2

Manufacture of a delivery system comprising drospirenone (drospirenone) and estradiol

An intravaginal delivery system comprising drospirenone and estradiol valerate is prepared. The first core comprising drospirenone (30 wt-%) consists of PEO-b-PDMS (18 wt-% > based on the total polymer amount) and PDMS and the length of the core is 130 mm. The second core, which contained estradiol valerate (15 wt-%), consisted of PEO-b-PDMS (15 wt-% > based on the total polymer mass) and PDMS, and was 40mm in length. The outer diameter of the core was 3.9 mm. The core was partially encapsulated in a membrane consisting of a 20: 80 ratio of PEO-b-PDMS/PDMS. The film layer is applied to the prefabricated core by using coextrusion. The space left 3mm between the drug-containing cores was filled with the membrane material during this process, thus forming a separate membrane between the cores. The membrane wall thickness is 0.4mm, while the outer diameter of the core-membrane system is 4.7 mm. A10 mm long polyethylene rod having an outer diameter of 1.2mm was used as the coupling member. An adhesive (Nusil Med 1-4213) was spread on the cross-sectional surface of the other end of the core-membrane system and on the other end of the coupling means and then pushed into the core by about 5 mm. Now the cross-sectional surface of the other end of the core-membrane system is glued by using the same adhesive and pushed over the glued polyethylene rod so that the ends of the core-membrane system meet each other. The adhesive was cured at 100 ℃ for 1 hour.

Example 3

Manufacture of a delivery system comprising drospirenone, ethinyl estradiol and lactobacilli

An intravaginal delivery system comprising drospirenone, ethinyl estradiol and lactobacillus rhamnosus (lactobacillus rhamnosus) was prepared. The first core comprising drospirenone (30 wt-%) consists of PEO-b-PDMS (45 wt-% > based on the total polymer amount) and PDMS and the length of the core is 140 mm. The second core, which contained ethinyl estradiol (10 wt-%), consisted of PEO-b-PDMS (15 wt-% > of the total polymer mass) and PDMS, and the length of the core was 20 mm. A 10mm inert placebo core consisting of PDMS was added between the drug containing cores to separate them. All cores were prepared by extrusion to produce tube-like cores with an outer diameter of 3.8mm and an inner diameter of 1.1 mm.

The core was encapsulated in a membrane consisting of a 20: 80 ratio of PEO-b-PDMS/PDMS. The thickness of the membrane wall is 0.3mm, the inner diameter of the tube is 3.7-3.75mm and the outer diameter is 4.3-4.35 mm. The ends of the delivery system were connected to a closed system by using a 10mm long polyethylene rod with an outer diameter of 1.2mm as coupling means. The adhesive (Nusil Med 1-4213) was spread over the other end of the coupling member and the polyethylene rod was pushed into the core by about 5 mm. The cross-sectional surface of the core-membrane tube and the other end of the coupling means are coated with an adhesive and the other end of the core-membrane system is pushed over the polyethylene rod so that the ends of the core-membrane system meet each other. The adhesive was cured at 100 ℃ for 1 hour. Finally, the delivery system is dipped in stearinIn a lactobacillus rhamnosus suspension to give a thin coating.

Example 4

Manufacture of a delivery system comprising drospirenone

Preparing an intravaginal delivery system comprising drospirenone. The core comprising drospirenone (30 wt-%) consisted of PEO-b-PDMS (45 wt-% > of the total polymer mass) and PDMS, and the length of the core was 167 mm. The core was prepared by extrusion to produce a tube-like core with an outer diameter of 4.1mm and an inner diameter of 1.1 mm.

The core was encapsulated in a membrane consisting of a 20: 80 ratio of PEO-b-PDMS/PDMS. The thickness of the membrane wall was 0.4mm, the inner diameter of the tube was 4.05mm and the outer diameter was 4.85 mm. The ends of the delivery system were connected into a closed system by using a 12mm long polyethylene rod with an outer diameter of 1.1mm as coupling means. The adhesive (Nusil Med 1-4213) was spread over the other end of the coupling member and the polyethylene rod was pushed into the core by about 6 mm. The cross-sectional surface of the core-membrane tube and the other end of the coupling means are coated with the same adhesive and the other end of the core-membrane system is pushed over the polyethylene rod so that the ends of the core-membrane system meet each other. The adhesive was cured (cure) at 100 ℃ for 1 hour.

Claims (12)

1. Intravaginal delivery system (1) comprising

-at least one compartment (1a, 1b) comprising a first cross-sectional diameter (d)₂) And a membrane (3) encapsulating the core (2), wherein the core (2) and the membrane (3) consist essentially of the same or different polymer composition, forming a core-membrane system (5) having a first end and a first cross-sectional surface and a second end and a second cross-sectional surface, and

-a coupling member (6) having a second cross-sectional diameter (d)₆) And has means for connecting saidA length (L) of the first end and the second end of the core-membrane system (5),

characterized in that wherein there is an opening (4) essentially in the middle of the core (2) in the first end and/or the second end of the core-membrane system (5), the coupling means (6) being located in the one or more openings (4) and wherein the second cross-sectional diameter (d) of the coupling means (6)₆) Is substantially larger than the first cross-sectional diameter (d) of the core (2)₂) Small, and wherein the cross-sectional diameter (d) of the core (2)₂) Is 3.0-5.5mm, and the cross-sectional diameter (d) of the coupling member (6)₆) Is 1.0-3.0mm, wherein the intravaginal delivery system consists of an elastomeric composition comprising poly (alkylene oxide) groups present as alkoxy-terminated grafts or blocks linked to polysiloxane units by silicon-carbon bonds, wherein the amount of polydimethylsiloxane comprising poly (alkylene oxide) groups is 5-80% by weight of the total polymer.

2. Intravaginal delivery system (1) according to claim 1, wherein an adhesive is applied on the coupling means (6).

3. Intravaginal delivery system (1) according to claim 1 or 2, wherein an adhesive is applied on the first and/or the second cross-sectional end surface of the core-membrane system (5).

4. Intravaginal delivery system (1) according to claim 1, wherein substantially half of the length (L) of the coupling means is located inside the first end of the delivery system and the remaining part of the coupling means is located inside the second end of the delivery system.

5. Intravaginal delivery system (1) according to claim 4, wherein there is an opening (4) essentially in the middle of the core (2), the opening (4) extending through the entire length of the core-membrane system (5), and the coupling means (6) is located in the opening (4).

6. Intravaginal delivery system (1) according to claim 1, wherein the coupling means (6) is a polymer rod of a biocompatible material.

7. Intravaginal delivery system (1) according to claim 4, wherein the length (L) of the coupling means (6) is 5-25 mm.

8. Intravaginal delivery system (1) according to claim 7, wherein the length (L) of the coupling means (6) is 10-20 mm.

9. Intravaginal delivery system (1) according to claim 1, suitable for administering various types of therapeutically active substances at a predetermined and controlled release rate over a prolonged period of time.

10. Intravaginal delivery system (1) according to claim 9, wherein the therapeutically active substance is a progestogen or a compound having progestogenic activity, or an estrogen or a combination thereof.

11. Intravaginal delivery system (1) according to claim 10, wherein at least one further therapeutically active or health-promoting substance is present.

12. Method for manufacturing an intravaginal delivery system (1), the intravaginal delivery system (1) consisting of at least one compartment (1a, 1b), the compartment (1a, 1b) comprising a core (2) and a membrane (3) encapsulating the core (2), wherein the core (2) and the membrane (3) essentially consist of the same or different polymer composition, the method comprising the steps of:

-forming a tube having a first cross-sectional diameter (d)₂) Of one or more of said cores (2),

-encapsulating one or more of said cores (2) by means of a membrane (3), resulting in a core-membrane system (5) having two ends, and

by having a second cross-sectional diameter (d)₆) Connecting the ends of the core-membrane system (5) to form a substantially ring-shaped delivery system (1),

characterized in that wherein there is an opening (4) essentially in the middle of the core (2) in the first end and/or the second end of the core-membrane system (5), the coupling means (6) being located in the one or more openings (4) and wherein the second cross-sectional diameter (d) of the coupling means (6)₆) Substantially larger than said first cross-sectional diameter (d) of one or more of said cores (2)₂) Small, and wherein the cross-sectional diameter (d) of the core (2)₂) Is 3.0-5.5mm, and the cross-sectional diameter (d) of the coupling member (6)₆) Is 1.0-3.0mm, wherein the intravaginal delivery system consists of an elastomeric composition comprising poly (alkylene oxide) groups present as alkoxy-terminated grafts or blocks linked to polysiloxane units by silicon-carbon bonds, wherein the amount of polydimethylsiloxane comprising poly (alkylene oxide) groups is 5-80% by weight of the total polymer.

13. Method for manufacturing an intravaginal delivery system according to claim 12, wherein the one or more of the cores (2) and/or the membrane (3) are prepared by injection molding or by extrusion.