method for manufacturing such system and its use in gynecological therapies and contraception

Background of the Invention

[0001] The present invention relates to the subject matter as characterized in the patent claims, in particular to an intravaginal ring system for drug delivery to a female human, wherein one or more drugs are contained i n one or more inserts embedded into a polymer based ring shaped inert carrier material and wherein the insert(s) are enclosed by a cylinder wall made of an inert material impermeable to the drag(s).

[0002] The invention further relates to a delivery systems with an improved release profile and low initial burst-effect.

[0003] The invention further relates to a method for manufacturing intravaginal rings according to the invention. [0004] The invention further relates to the use of the delivery system in contraception and gynecological therapies.

Related Background Art

[0005] Ring-shaped devices (Intra-Vaginal Rings / IVR) for controlled administration of drug substances into the vagina are known in the art for decades. Intravaginal rings are e.g.

described in several patents like EP 0 050 867, US 3,920,805A, US 4,292,965. Some IVR ^' s described in the literature comprise a polymer matrix but no membrane or wall encasing said matrix (monolithic dosage form).

[0006] There are also several products on the market, such as Estring®, Femring®, and Nuvaring®, each of which provide controlled and sustained release of active agent respectively the steroid molecules over several days or weeks. [0007] The IVR can be manufactured in accordance with standard techniques described in the art e.g. US 3,920,805, US 4,888,074, US 4,215,691, WO2010/058070.

[0008] One such type of vaginal ring is the reservoir ring, which comprises a core of a polymeric material loaded with the drug substance, which is completely surrounded by a non-medicated sheath. Accordingly, the release of drug substances from such rings is dependent upon permeation (i.e., molecular dissolution and diffusion) of the core-loaded drag substance through the outer sheath. To date, the polymeric materials used in the construction of commercial vaginal rings have been limited to hydrophobic silicone elastomer and poly(ethylene-co- vinyl acetate) (PEVA) materials.

[0009] Although the products on the market are based on core/membrane design this design has several disadvantages. Thus one important disadvantage of this design is, that at the end of the wearing period a significant amount of unused drug substance remains in the IVR. A reduction of the drug load in the core to an amount which is actually released to the patient during wearing time, is not possible, as a constant drug release over the wearing period can be only achieved, if the drug reservoir (core) contains an excess of the active compound to get a sufficient concentration gradient in the system. Thus in many cases more than 50% of unused substance remains in the IVR.

[0010] This increases not only the cost of goods in the production but could lead also to environmental burdens when the IVR is disposed in the domestic waste or in the toilet. Remaining drug in the ring bears also the risk that others, in particular children, are exposed to the drug, if the device is not properly disposed.

[0011] Therefore, e.g. for Nuvaring®, which contains the hormones etonogestrel and ethinylestradiol, it is recommended to place the used ring in the recloseable foil pouch. This ensures that children could not accidentally get in touch with the drug and creates also a barrier for the substance in the waste before reaching the waste incineration. Alternatively it is suggested to return the used IVR's in the foil pouch to the pharmacy.

[0012] Although disposal of waste is a relevant topic in particular with regard to intravaginal rings which are used only for several weeks and contain the active drug in an larger amount, so far surprisingly only little is described in the literature which deals with this problem. [0013] A further problem all long acting contraceptive methods such as IV 's an intrauterine devices (lUDs) have to deal with, is a constant drug release over the whole wearing period, in particular in the initial phase of the wearing period, where an increased drug release is observed (so called "burst effect"). This leads to an unreasonable burden with the active agent for the patient in the initial phase of the wearing period.

[0014] The initial burst effect is essentially caused by drug which has accumulated during the storage in the membrane. In other words the membrane acts as kind of depot in particular for drugs with a high solubility in the membrane material, as drug diffuses from the core material into the membrane and thus concentrates in the membrane, during storage and transportation period. The "accumulated drug" is emitted from the membrane, in particular during the first 1 to 3 days after insertion, which leads to a higher drug release (so called "initial burst effect"). To counteract this accumulation it is therefore required that Nuvaring® is stored at temperatures from 2-8 °C prior dispending it to the user (see package insert of Nuvaring® under "Storage"). But also for the end user storage in warm climate zones storing in a fridge is advisable.

[0015] Different approaches to reduce the initial burst have been described in the literature. Thus WO 2013/110856 (Bayer Oy) proposes to place an intermediate layer, made of an inert material such as e.g. Ti0 ₂ , between the drug containing core and the membrane material. However, aside from a more complicated production process, further improvement of the initial burst is an ongoing problem with a high medical need.

[0016] In connection with the present invention the following prio art should be mentioned. It has to be noted that this prior as explained below addresses completely different object but due to structural similarities a critical appreciation in the context of this applications appears adequate.

[0017] WO 2009/003125 (Warner Chilcott) discloses intravaginal drug delivery devices useful in the administration of pharmaceutically active water-soluble drugs or

macromolecular agents to a female of the human or animal species. Although the structure of the disclosed drug delivery devices looks similar (also here inserts are used), the a.m.

application addresses a completely different object, which is delivery of water-soluble drugs or macromolecular agents which do not permeate (diffuse) through a membrane which is used in the classical drug core / membrane ring systems, as they are used for the delivery of hydrophobic drugs with low molecular weight, such as hormones.

[0018] From, structural point of view the current invention differs not only with regard to the drugs to be delivered and the polymers used as drug carrier material for the inserts, it is further different as no sleeves (impermeable cylinder wall around the insert) are disclosed in the Warner Chilcott application. However, as mentioned below in detail, the sleeve is a key element to address the object of the current invention, in particular for hydrophobic drugs.

[0019] Vaginal rings with insertable drug containing cores are also disclosed in

WO 98/04220 from Population Council. It is one object of this application to avoid initial burst (see e.g. abstract). However, in this application the inserts are not covered with a drug impermeable sleeve and thus it is proposed in this application that the drug containing inserts are separately packed and inserted by the user immediately prior use (see e.g. page 7 lines 29 ff).

[0020] WO 01/13780 (Fei Technologies Inc) discloses an apparatus (vaginal ring) for anesthetizing the cervical region of a female. Here the anesthetic agent is placed in an inert biocompatible material which is placed in a depression of the vaginal ring. The device is intended for an immediate release of the anesthetic. No sleeves are disclosed.

Summary of the Invention

[0021 ] The present invention is directed to an intravaginal rin consisting of an inert carrier material (A) embedding at least one drug containing insert, wherein the insert(s) is (are) made of a biocompatible polymer material (B) (subsequently also called matrix material ) which is enclosed with a cylinder wall (sleeve) made of an inert material impermeable to the drug. The cross sectional diameter of the inserts through which the release into the vaginal environment occurs can be covered by a membrane. Object of invention

[0022] A preferred object of the invention is to provide an intravaginal delivery system with reduced drug load in particular at the end of the wearing period, to reduce manufacturing cost an environmental burdens caused by unspent drug washed-off when littered. [0023] It is a further object of the invention to provide an intravaginal delivery system with an improved release profile, namely with a reduced initial burst effect and an essentially constant drug release over the wearing period.

[0024] Another object of the invention is a process to manufacture such delivery systems, in particular intravaginal rings with an improved release profile. [0025] It is another object of the present invention to provide a delivery system with an improved release profile namely with an essentially constant drug release and a reduced initial burst effect.

[0026] A further object of the invention is the use of such delivery systems and intravaginal rings with an improved release profile in contraception and gynecological therapies in particular in endometriosis.

Detailed Description of invention

[0027] In the context of this invention as inert carrier material (A) ethylene-vinyl acetate copolymer, polyethylene, polypropylene, polyurethane, polyvinylchloride, in general thermoplastic elastomers (TPE's), polydimethylsiloxane elastomers, polyurethane elastomers, polyurea elastomers or polyvinylchloride are used.

[0028] As biocompatible polymer (matrix) material (B) for the inserts in principle the same materials as for the inert carrier ring can be used. Preferred are polysiloxane elastomers or etinylvinylacetate (EVA) copolymers. [0029] As an inert and impermeable material suitable for the cylinder wall which covers the inserts (subsequently also called "sleeve"), any biologically compatible and essentially inert material, metal, in particular silver, gold, stainless steel, nitinol (nickel -titanium alloy) or copper can used. Alternatively also a biocompatible polymer, impermeable to the drug, such as polyethylene (PE) or fluorinated polyolefins such as Teflon® can be used.

[0030] The insert can be of cylindrical or of barrel shape, whereby the barrel shape allows for a more stable fit in the punch hole of the surrounding inert carrier material/ring. Thus a firm, fixation of the inserts in the carrier material without utilization of a glue is possible.

[0031] However, also inserts with a cylindrical shape can be firmly fixed without a glue if the cross-sectional diameter of the punch holes in the carrier material/ring is slightly smaller (up to 50 %, depending on insert outer diameter) as the cross sectional diameter of the inserts. The elasticity of the carrier material is of relevance if a tight fixation without the use of additional adhesive or glue is desired. In general materials with a higher elasticity, such as silicones are usually more suitable for the carrier ring than thermoplastic polymers, at least if the use of an adhesive or glue for the fixation of the inserts in the carrier ring should be avoided.

[0032] In dependency from the intended use, the intravaginal ring can contain one or more inserts, dependent on the amount of substance needed. Also the diameter and material of the inserts can be adjusted according to the required amount of the substance and the physico- chemical properties of the drug.

[0033] If more than one insert is included in the carrier ring, the inserts are preferably arranged in a symmetrical order, e.g. in an angle of 180° is preferred if two inserts, respectively an angle of 120° is preferred if three inserts are included.

[0034] The insert design offers also the easy option to combine different drugs, e.g. a progestin and an estradiol, if the ring should be used for contraception, or a combination of a progestin and a therapeutic active substance, such as a nonsteroidal anti-inflammatory agent (NSAID) or an aromatase inhibitor. [0035] When combining different drugs the effective dose differs dependent on the pharmacological activity of the respective compound, thus the drug release for the different compounds has to be adjusted accordingly. The insert design according to the invention allows for an easy adjustment of the release by e.g. using different polymer materials for the inserts. This is a particular advantage of the insert design, as in a standard membrane core ring design, a firm connection of different polymer materials in one intravaginal ring could cause difficulties as the adhesive has to suit for both materials which should be connected. This can cause problems in particular if a thermoplastic should be connected to a silicon based polymer. [0036] Optionally the inserts may be covered with a membrane material. This membrane material can be brought up by a simple dipping process, where the insert (covered by the metal sleeve) is dipped into a liquid solution of the membrane material or a monomer of the membrane material which is subsequently cured. Alternatively only the ends of the insert having the active pharmaceutical ingredient (API) loaded matrix inside can be coated with dipping, spraying, paintbrush or flexoprint means. Another possibility is to dip the insert without sleeve and subsequently insert the half-finished inserts into the sleeve either before or after curing. If different drugs should be included into one carrier ring, the different inserts containing the different drugs can be covered with different or no membrane material, to adjust the drug release. [0037] Alternatively the membrane can be applied to the preassembled IV , by swelling a membrane tube, e.g. in cyclohexane, and slipping the swollen tube over a rod of the inert carrier material (A) which contains already the inserts. After evaporation of the solvent the membrane shrinks to its original diameter and is thus firmly attached to the rod. In the subsequent final step the two ends of the rod are combined to the intravaginal ring. [0038] As membrane material silicones such as poly(disubstituted siloxanes) where the substituents are lower alkyl, preferably alkyl groups of 1 to 6 carbon atoms, or phenyl groups, wherein said alkyl or phenyl can be substituted or unsubstituted, are preferred. A widely used and preferred polymer is curable poly(dimethylsiloxane) (PDMS). Other preferred polymers are siloxane-based polymers comprising either 3,3,3 trifluoropropyl groups attached to the si l icon atoms of the siloxane units (fluoro-modified polysiloxanes) or poly(alkylene oxide) groups, wherein said poly(alkylene oxide) groups are present as alkoxy- terminated grafts or blocks linked to the polysiloxane units by silicon-carbon bonds or as a mixture of these forms. Polysiloxanes and modified polysiloxane polymers are described for example in EP 0652738 B l , WO 00/29464 and WO 00/00550. Among siloxane-based polymers comprising poly(alkylene oxide) groups, polyethylene oxide block- polydimethylsiloxane copolymer (PEO-b-PDMS) is preferred. Such membrane materials are widely used equally in intrauterine and intravaginal systems.

[0039] Both methods to bring the membrane up [either (a) individual coating of the insert with or without sleeve or (b) coating of the complete IVK] are suitable. However, if (due to different properties of the drugs A and B) only the inserts containing drag A should be covered with a membrane [and inserts containing drug (B) should remain uncovered], the a.m. "insert dipping process" is preferred.

[0040] The inserts can be prepared in different ways. The easiest way is to mix the compound with the biocompatible, inert polymer material (B) and to inject this mixture into the sleeve. Mixture and injection for thermoplastic polymer materials (B) can occur by heating the polymer up to a temperature which makes the polymer sufficiently

liquid(viscous), if the polymer material is a silicon based material, mixing and injection can be done with the monomer as starting material or a partially polymerized monomer, which is completely cured after mixing with the drug and injection into the sleeve.

[0041] Alternatively it is also possible to prepare drug containing rods of the respective polymer, e.g. by an extrusion process and to press the rods into the sleeve subsequently. If material is overlapping the sleeve, it can be cut-off before the inserts are mounted into the punches of the inert carrier/ring material (A) or before covered with a membrane. [0042] To ensure a stable fixation of the inserts in the inert carrier material (A) an adhesive or glue may be applied to the sleeve or into the punch holes of the inert carrier material before the assembly. Alternatively the cross-sectional diameter of the inserts can be larger as the diameter of the punch holes. The difference of the diameter is dependent on the flexibility of the inert carrier material (A). Usually the diameter of the inserts should be about 10% larger than the diameter of the punch holes.

[0043] As an adhesive or glue the following materials can be used: All medical grade silicone adhesives such as Silastic Adhesive Type A (from Dow Corning), MED3-4213 silicone adhesive (from NuSil ) or P-DERM silicone gel adhesive (from Polymer Science). Selection of a suitable glue is dependent of the selected insert and sleeve material to ensure a stable connection between the insert and the surrounding sleeve.

[0044] I the sleeve of the insert is of barrel shape, an improved fixation in the inert carrier material (A) of the ring is possible. Preferably the holes in the carrier material (A) should be also in barrel shape to ensure a form-lock fixing.

[0045] The sleeve respectively the cylinder material is of utmost importance to fulfill the object of the invention, namely the reduction of the total amount of drug in the intravaginal ring. Thus it is important that the sleeve material is impermeable to the drug, to avoid that the drug diffuses from the drug containing biocompatible polymer material (B) into the surrounding inert carrier material (A) of the ring. This is key as an u tides i red diffusion would reduce the drug concentration/load in the insert (material B) which would negatively impact the release and would at the same time increase the burst phenomena.

[0046] The majority of the drug diffused into the surrounding carrier material could also remain (unused) in the intravaginal ring. Thus a dilution of the drug in the polymer material (B) would occur after manufacturing steps by diffusion into the surrounding carrier material (A). This can be avoided by covering the inserts with a sleeve impermeable to the drug.

[0047] In principle a large number of drags can be used in the context of the current invention. However, boundaries are set by the effective amount needed. It goes without saying that also the administration route impacts the selection of the drug as vaginal rings are naturally only suitable to treat females. Thus pharmaceutical drugs for treatment of female disorders like, endometriosis are preferred in addition to contraceptive acting agents. [0048] The vaginal ring dosage form is furthermore preferred, where a treatment over a longer time period, up to several weeks, is desired and also in cases where bioavailability of the drug (compared e.g. to oral or transdermal dosage forms) should be improved.

[0049] According to the current invention progestins, such as chlormadinone acetate (CMA), norgestimate (NGM), norelgestromin (NGMN), norethisterone (NET) /

norethisterone acetate (NETA), etonogestrel (3-keto-desogestrel), nomegestrol acetate (NOMAc), demegestone, promegestone, drospirenone (DRSP), medroxyprogesterone acetate (MPA), cyproterone acetate (CPA), trimegestone (TMG), levonorgestrel (LNG), norgestrel (NG), desogestrel (DSG), gestodene (GSD) or dienogest (DNG), of which levonorgestrel (LNG), desogestrel (DSG), gestodene (GSD) and dienogest (DNG) are preferred, whereby levonorgestrel is particularly preferred.

[0050] The inserts can also contain estrogens or therapeutic drugs such as aromatase inhibitors or nonsteroidal anti-inflammatory agents (NSAID) either as mono therapy or in combination with the a.m. progestins. [0051] As estrogens natural and synthetic estrogens, especially estradiol or its esters, for example estradiol valerate or else conjugated estrogens (CEEs = conjugated equine estrogens) are preferred. Particularly preferred are ethinylestradiol and estrogen or their esters such as estradiol valerate or benzoate.

[0052] As aromatase inhibitor selective aromatase inhibitors such as anastrozole

(Arimidex ^® ), exemestane (Aromasin ^® ), fadrozole (Afema ^® ), formestane (Lentaron ^® ), letrozole (Femara ^® ), pentrozole, vorozole (Rivizor ^® ) and pharmaceutical acceptable salts thereof are suitable, whereby anastrozole (ΑΓ) is preferred.

[0053] As NSAID non-selective Cox inhibitors as well as selective Cox 2 inhibitors are equally suitable in the context of this invention. Preferred are meloxicam, piroxicam, naproxen, celecoxib, diclofenac, tenoxicam, nimesulide, lornoxicam and indomethacin, of which indomethacin is particularly preferred. - I I -

[0054] Intravaginal rings according to the invention are useful for contraception and therapy i n particular for the treatment of endometriosis.

[0055] The examples below serve to illustrate the invention.

Examples

Example 1

Preparation of Insert from thermoplastic polymer or elastomer (TPE)

At first the active ingredient (API) was melt blended with ethylenevinyl acetate copolymer in 90 °C 10 minutes in a kneading mixer/extruder (Haake MiniCTW). It is preferred that API has melting temperature above the used TPE. Then the compound was extruded to the desired OD (e.g 1 ,0 mm) extmdate thus containing the API.

In the next step the extmdate was cut to desired length (e.g. 5 mm). This rod was then either; a) Inserted inside an impermeable silver sleeve with tight fitting or b) first coated with a glue and then inserted to the silver sleeve, after which the

overlapping ends were cut off and surplus glue material is removed from the sleeve ends.

Example 2

Preparation of insert from therm oset silicone elastomer

At first the active ingredient (2 and 20 %) was blended with Pt-catalysed silicone polymer in RT for 10 minutes in a kneading mixer/extruder (Haake MiniCTW). This blend was then centrifuged to remove trapped air, and then part of it was transferred to a I ml syringe which was used to inject the uncured compound inside the silver sleeve (Ol ) 3 mm, length 5 mm ) in excess amount. Curing step was carried out in 116 °C for 6 min. The extra material was cut off with surgical knife against silver sleeve ends after curing, thus leading to planar sleeve ends. Some of the samples were additionally dip coated with tin catalysed fluorosilicone in butyl acetate and left in room temperature for moisture induced crossl inkin (tin catalyzed condensation crosslinking). Example 3

Preparation of Insert containing YDS

The inert vaginal carrier ring was prepared through injection molding of heat curable silicone elastomer into a mold containing toroidal cavity with an outer diameter (OD) of 55 mm and an inner diameter (ID) of 43 mm. Thus the cross section of toroid was (55-43)/2 = 6 mm. This toroid was punched with holes (2) that were 2 mm in OD and the inserts (3 mm. in OD, 5 mm in length) were simply pushed inside. Fig. 1 shows photo of such inert carrier ring with 2 punched holes. Fig. 2 shows the carrier ring with empty inserts. Fig. 3 a ring with silicon filled inserts.