sign in sign up
<<
Home , Alfatradiol, Altrenogest, Clostebol, Clostebol acetate, Cyclofenil, Delmadinone acetate

(19) TZZ¥Z_¥_T

(11) EP 3 501 543 A1

(12) EUROPEAN PATENT APPLICATION

(43) Date of publication: (51) Int Cl.: 26.06.2019 Bulletin 2019/26 A61K 47/34 (2017.01) A61K 31/565 (2006.01) B33Y 10/00 (2015.01) (21) Application number: 17208532.6

(22) Date of filing: 19.12.2017

(84) Designated Contracting States: (72) Inventors: AL AT BE BG CH CY CZ DE DK EE ES FI FR GB • RONCHI, Celestino GR HR HU IE IS IT LI LT LU LV MC MK MT NL NO 20124 MILANO (IT) PL PT RO RS SE SI SK SM TR • RONCHI, Federica Designated Extension States: 20124 MILANO (IT) BA ME • STRUSI, Orazio Luca Designated Validation States: 08207 SABADELL (ES) MA MD TN • ORLANDINI, Milena 08860 CASTELLDEFELS (Barcelona) (ES) (71) Applicants: • Delim Cosmetics & Pharma S.r.l. (74) Representative: Bianchetti Bracco Minoja S.r.l. 20124 Milano (IT) Via Plinio, 63 • Strusi, Orazio Luca 20129 Milano (IT) 08207 Sabadell (ES)

(54) METHOD FOR MANUFACTURING VAGINAL DRUG DELIVERY SYSTEMS USING A THREE DIMENSIONAL PRINTER

(57) The present invention relates to a method for more active pharmaceutical ingredients dissolved or dis- manufacturing a controlled release using a persed in said core, three-dimensional (3D) printer, said vaginal ring compris- b) a membrane, substantially or completely surrounding ing: said core, said membrane consisting of a composition a) a core, said core consisting of a composition compris- comprising one or more thermoplastic polyurethanes. ing one or more thermoplastic polyurethanes and one or EP 3 501 543 A1

Printed by Jouve, 75001 PARIS (FR) EP 3 501 543 A1

Description

[0001] The present invention relates to a method for manufacturing a controlled release vaginal ring by using a three- dimensional (3D) printer and to the product obtained by said method. 5 [0002] Vaginal drug delivery systems that release a drug steadily over a long period such as 21 days, as in the classic contraceptives, may be matrix systems or reservoir systems. [0003] Matrix systems are toroidal rings formed by a that includes the active principle in suspension or in . The release of the active principle is controlled by the ability of the active principle to free itself from the poly mer. [0004] Reservoir systems are toroidal rings consisting of a core, where the active principle is dissolved or suspended, 10 and an outer membrane, covering the core, that controls the release of the active principle. [0005] This of a drug prevents enteric gastrointestinal absorption and enterohepatic passage by increasing the of the drug when compared with . [0006] The contraceptive vaginal ring may contain only one active principle or a combination of active principles. [0007] Examples of contraceptive vaginal ring containing only one active principle are progestin - vaginal ring which 15 may contain , or nestorone. [0008] Vaginal rings containing an - combination are widely used for 3 weeks ’in’ and 1 week ’out’ treatments. NuvaRing® is a vaginal ring in ethylvinyl which releases 120 mcg /die of (active of ) and 15 mcg/die of ethinyl . [0009] Vaginal rings are also used in replacement therapy (TOS) for postmenopausal women. 20 [0010] Currently there are two products on the market: Estring of Pfizer and Femring of Warner Chilcott containing estradiol and respectively. [0011] Vaginal rings can also be used for the administration of active principles for different pathologies, such as glyminox as contraceptive and for the prevention of sexually transmitted diseases, such as terbutaline for dysmenorrhoea and , demegen for the prevention of sexually transmitted diseases, lidocaine for cervical anesthesia, 25 oxybutinin for overactive bladder, tenofovir for the prevention of HIV transmission and antibody III-174 for the prevention and treatment of herpes simplex virus 2. [0012] The used in vaginal rings are silicone polymers and ethylene vinyl acetate polymers. The vaginal ring NuvaRing currently present in the market is made of ethylene vinyl acetate polymers. [0013] In both cases, in order to ensure a constant release over time, which varies from 21 days to 90 days, the rings 30 currently marketed (reservoir systems) have toroidal and coaxial shape, consisting of a core, comprising a polymer and an active principle, and a membrane that covers the core, made up of a polymer that controls the release of the active ingredient continuously over time (zero order release). [0014] The production of said reservoir systems requires high-tech plants and important investments both for devel- opment and for commercial production. 35 [0015] Recently, Welsh at al presented at HIV R4P 2016 a paper entitled "3D printing of microbial vaginal rings: a proof-of-concept study" disclosing a vaginal ring produced using a 3D printer (Fused Deposition Modeling). The vaginal ring is a matrix system (a vaginal ring of toroidal shape without an external membrane controlling the release of the active principle) consisting of a polymer mixture of polylactic acid (PLA) and a thermoplastic polyurethane in a 1: 4 ratio, containing davirapin and / or levonogestrel as active ingredients. 40 [0016] WO2016/025388 discloses a method for manufacturing a bioactive implant comprising the steps of:

a. forming a mixture of a bioactive agent with a polymer stock material; b. heating the mixture to an approximate melt flow temperature of the polymer stock material; c. forming the mixture into the shape of the implant 45 wherein the step of forming the mixture into the shape of an implant comprises 3D printing of the mixture. [0017] The polymer stock is a biodegradable polymer such as poly(methyl methacrylate), acrylonitrile butadiene sty- rene, polycarbonate, polylactide, polyglycolide, polycaprolactone, polyanhydride, polyorthocarbonate, polyvinylpyrro- lidone and chitosan. 50 [0018] The bioactive implant has a honeycombed structure having a void content of at least 5%. [0019] WO2017/054433 discloses a polyurethane composition, consisting of two types of polyurethane, having an adjustable elastic modulus. The polyurethane composition is used for preparing medical implants such as implantable devices, implantable prostheses, contact prostheses, stents, interventional catheters and organ auxiliary devices. In particular, the document discloses a degradable scaffold complex comprising a polyurethane composition and a degra- 55 dable metal material. A biodegradable scaffold can be manufactured by using a 3D printer equipped with two feeding devices, one feeding device is added with alloy powder and the other feeding device is added with biode- gradable medical polyurethane solution. [0020] In the state of art, 3D printing, based on FDM technology, was used in the field of implant and topical application

2 EP 3 501 543 A1

for manufacturing devices consisting of one polymer or a combination of more polymers which were extruded from one nozzle to give a matrix object. [0021] The known 3D printing technology, wherein just one material can be extruded per time does not allow manu- facturing in one step vaginal rings with reservoir technology, as the rings actually available on the market. For example, 5 first the core should be manufactured and removed from the printer. The membrane should be manufactured in a second printer and then assembled with the core. Alternatively, half membrane could be printed and two half parts of the membrane could then be assembled with the core. This process is time consuming, expensive and semi-manual, making the 3D printing not competitive compared with the present method of manufacturing. [0022] The most common process of obtaining vaginal rings is hot melt extrusion, where the polymers, alone or mixed 10 with drugs, are melted and forced by extrusion screws to pass through a die. After leaving the die, the obtained coaxial fiber is cooled and cut, the obtained fragments are shaped as rings by gluing both ends with an adequate pharmaceutical adhesive or by molding. [0023] This manufacturing process is time-consuming, it needs tailored equipments for extruding the polymers, cooling down the coaxial fiber that comes out from the twin extruder, a machine for cutting the fiber in short segments which 15 are fitted in a machine for its sealing. [0024] The present invention provides a one step process for manufacturing vaginal rings with reservoir technology by using a 3D printer, which makes the manufacture of the rings cheaper, faster and flexible in terms of formulation. [0025] The process of the present invention uses polyurethanes polymers which allow the vaginal ring to have a perfect shape in comparison to vaginal rings made of other polymers such as EVA which once printed shows imperfections due 20 to draining caused by the low of EVA. [0026] Furthermore, polyurethanes due to their high melting point do not need to be cured once the manufacturing of the ring is over. The use of polyurethanes allows also to avoid the storage of the rings at temperatures below 25°C. [0027] Object of the present invention is a method for manufacturing a controlled release vaginal ring using a three- dimensional (3D) printer, said vaginal ring comprising: 25 (a) a core, said core consisting of a composition comprising one or more thermoplastic polyurethanes and one or more active pharmaceutical ingredients dissolved or dispersed in said core, (b) a membrane, substantially or completely surrounding said core, said membrane consisting of a composition comprising one or more thermoplastic polyurethanes; 30 said method comprising the steps:

i) generating a 3D model of a vaginal ring; ii) preparing a filament or pellets comprising the composition of the core; 35 iii) preparing a filament or pellets comprising the composition of the membrane; iv) feeding the filament or pellets comprising the composition of the core and the filament or pellets comprising the composition of the membrane into a different nozzle of a 3D printer; v) controlling a 3D printer to fabricate the vaginal ring according to the 3D model,

40 wherein the steps i), ii) and iii) may be carried out in any time sequence. [0028] The vaginal ring has preferably a toroidal coaxial shape. [0029] The thermoplastic polyurethane of the core composition and the thermoplastic polyurethane of the membrane composition are independently selected from the group consisting of thermoplastic polycarbonate - urethane, thermo- plastic silicone-polycarbonate-urethane, thermoplastic polyether-urethane, thermoplastic silicone-polyether-urethane 45 and a mixture thereof. [0030] Preferably, the thermoplastic polyurethane of the core composition is different from the thermoplastic poly- urethane of the membrane composition. [0031] Most preferably, the thermoplastic polyurethane of the core composition is thermoplastic polyether-urethane and the thermoplastic polyurethane of the membrane composition is thermoplastic silicone-polycarbonate-urethane. 50 [0032] For example, the thermoplastic polyurethane can be Bionate® Thermoplastic Polycarbonate-urethane (PCU), CarboSil® Thermoplastic Silicone-Polycarbonate-urethane (TSPCU), Elasthane™ Thermoplastic Polyether-urethane (TPU, PurSil® Thermoplastic Silicone-Polyether-urethane (TSPU), all commercialized by DSM Biomedical. [0033] In Table the preferred combinations of the polyurethanes used in the core and membrane of the vaginal rings of the invention are shown. 55

3 EP 3 501 543 A1 memb.

5 memb.

10 memb.

15 memb. core core core memb.

20 core core core memb. Combination 25 memb. memb.

30 Table core core core

35 memb.

40 memb. 123456789101112 core corememb. core memb.

45

50 urethane (TSPCU) urethane urethane (TSPU) urethane membrane 55 = Elasthane™ Thermoplastic Polyether- Elasthane™ Thermoplastic (TPU) urethane CarboSil® Thermoplastic Silicone- Thermoplastic CarboSil® Polycarbonate- Memb. Bionate® Thermoplastic Polycarbonate- Thermoplastic Bionate® (PCU) urethane PurSil® Thermoplastic Silicone- Thermoplastic PurSil® Polyether-

4 EP 3 501 543 A1

[0034] The active principle is selected from progestogen, progestergenic, anti-viral agents and a combination of at least two of said agents. [0035] Preferred progestogen or progestergenic agents are selected from the group consisting of , acetophenide, , , , acetate, , undecenoate, 5 acetate, acetate, , citrate, acetate, conjugated oestrogens, , acetate, , , desogestrel, acetate, , , diethyl- dipropionate, , , dienogest, , propionate, , elcometrine, estradiol, , estradiol enantate, estradiol hexahydrobenzoate, estradiol, phenylpropi- onate, estradiol acetate, , , estradiol phenylpropionate, , estradiol cipionate, 10 estradiol, estradiol hemihydrate, norethindrone acetate, , , , , , etonogestrel, acetate, diacetate, , , , , , hydroxyprogesterone caproate, hydroxyestrone diacetate, , , acetate, acetate, acetate, , , , acetate, , norethisterone enantate, , , , , norg- 15 estrienone,, , , progesterone, , , , , , , , testosterone cipionate, ,, testosterone unde- cylate, testosterone phenylpropionate, , , and . [0036] Preferred antiviral agents are selected from the group consisting of abacavir, , emtriacitabine, lami- vudine, zidovudine, emtriacitabine, rilpivirine, tenofovir disoproxil fumarate, emtricitabine, lamivudine, abacavir, lamivu- 20 dine, zidovudine, abacavir, lamivudine, zidovudine, emtricitabine, didanosine, stavudine, rilpivirine, etravirine, delavirdine mesylate, efavirenz, nevirapine, tipranavir, indinavir, atazanavir, cobicistat, saquinavir, lopinavir, ritonavir, fosamprenavir , ritonavir, darunavir, cobicistat, darunavir, atazanavir and nelfinavir. [0037] The active principle is present in an amount from 0.001% to 40% w/w of the total ring weight. Preferably the active principle is present in an amount from 0.001 to 25% w/w. 25 [0038] The vaginal ring preferably has an outer diameter ranging from 20 to 70 mm and a thickness ranging from 2 to 15 mm. [0039] Preferably the core has a thickness ranging from 1.4 mm to 15mm and the membrane has a thickness ranging from 50 to 600 mm. [0040] The vaginal ring has an infill ranging from 15% to 100%. 30 [0041] The infill % is the volume of material used in the internal part of a piece, the higher the infill %, the stronger the produced object with better mechanical properties. [0042] The vaginal ring may comprise one or more compartments, each containing a different active principle. In a particular embodiment, each compartment may be surrounded by a membrane having a different composition and/or a different thickness. 35 [0043] Solid Works, Autodesk Fusion 360°, Rhinoceros or any other computer aided design (CAD) or 3D modelling programs can be used for generating a 3D model of a vaginal ring. [0044] A Fused Deposition Modeling (FDM) printer equipped at least with two nozzles can be used for printing the vaginal rings of the invention such as Delta WASP 2040 Turbo2, Delta type 3D printer with Zen dual extruder system [0045] The nozzles of the printer to be used in this specific case have a diameter ranging from 0.2 to 0.6 mm. 40 [0046] The temperature at which the vaginal rings are printed depends on the materials used but in general temper- atures range from -20°C to +20°C respectively below/above the melting point of the thermoplastic polymers. [0047] The printing temperatures are in general in the range of 180-210°C. [0048] The print speed may be up to 300 mm/s. [0049] The filament or pellets comprising the composition of the core are prepared by well-known extrusion techniques. 45 [0050] The diameter of each filament to be used is 1.75 mm.

Example 1

Etonogestrel and ethinylestradiol vaginal ring 50 1.a) Preparation of the core filament

[0051] The polymer used was Elastane TPU 75D produced by DSM [0052] The composition of the core filament was the following: 55 Component Weight for each ring Weight for 100 rings Etonogestrel 11.700 mg 1.1700 g

5 EP 3 501 543 A1

(continued)

Component Weight for each ring Weight for 100 rings Ethinylestradiol 2.700 mg 0.2700 g 5 Elastane TPU 75D 1785.600 mg 178.500 g

[0053] The components were carefully weighted. Etonogestrel and ethinylestradiol were mixed and added to the pellets of Elastane TPU75D. The obtained mixture was mixed in a V mixer for 20 minutes at 20 rpm. 10 [0054] The resulting mixture was loaded into the hopper of the extruder Noztek Pro Pellet & Powder Filament Extruder. A filament of 1.75 mm 6 0.04 mm diameter to 2mm was obtained using the following extrusion parameters:

Extrusion speed 2m / min

15 Extrusion temperature: 180°C

[0055] The extruded filament was cooled in a water bath at a temperature lower than 12°C.

1.b) Preparation of the membrane filament 20 [0056] The polymer used was CarboSil TSPU 20 produced by DSM [0057] A membrane filament having the following composition was prepared:

Component Weight for each ring Weight for 100 rings 25 CarboSil TSPU 20 200.000 mg 20.000 g

[0058] The polymer was carefully weighted and loaded into the hopper of the extruder Noztek Pro Pellet & Powder Filament Extruder. A filament of 1.75 mm 6 0.04 mm diameter to 2mm 6 0.04 was obtained using the following extrusion 30 parameters:

Extrusion speed 2m / min

Extrusion temperature: 190°C 35 [0059] The extruded filament was cooled in a water bath at a temperature lower than 12°C.

1.c) 3D Printing of the vaginal ring

40 [0060] FDM ™ printer, WASP 2040 Turbo2, Delta type with double extruder ZEN system, a 50 micron layer resolution and 0.2 and 0.4 mm diameter nozzles were used. [0061] A 3D model of a coaxial toroidal ring with a diameter of 56.0 mm and a section of 4.0 mm was generated by a CAD 3D program and was imported into the printer program. [0062] A Solid Works, Autodesk Fusion 360°, Rhinoceros or any other computer aided design (CAD) or 3D modelling 45 program was used for the manufacture of vaginal rings. [0063] The two nozzles extruded and deposited the melted layers of material in one single step, creating at the same time the core and the membrane of the vaginal ring. [0064] The vaginal rings were printed at 200°C for both the core and the membrane. [0065] Using the same compositions of the filaments and the procedure reported above several prototypes were 50 manufactured using the parameters listed below:

Prototype Membrane layer Core layer Infill Print Extrusion Plate height height speed temperature temperature 55 1 0.1 mm 0.8mm 15% 20 200 40°C 2 0.1 mm 0.8mm 50% 20 200 40°C

6 EP 3 501 543 A1

(continued)

Prototype Membrane layer Core layer Infill Print Extrusion Plate height height speed temperature temperature 5 3 0.1 mm 0.8mm 100% 20 200 40°C

[0066] The printed vaginal rings were packed in / polythene bags.

10 Example 2

2.a) Preparation of the core filament

[0067] The polymer used was PurSil TSPU 20 produced by DSM 15 [0068] The composition of the core filament was the following:

Component Weight for each ring Weight for 100 rings Estradiol hemihydrate 2.000 mg 0.200 g

20 PurSil TSPU 20 1,698.000 mg 169.800 g

[0069] The components were carefully weighted. Estradiol hemihydrate was added to the pellets of PurSil TSPU 20. The obtained mixture was mixed in a V mixer for 20 minutes at 20 rpm. [0070] The resulting mixture was loaded into the hopper of the extruder Noztek Pro Pellet & Powder Filament Extruder. 25 A filament of 1.75 mm 6 0.04 mm diameter was obtained using the following extrusion parameters:

Extrusion speed 1.5 m/min Extrusion temperature: 185°C

30 [0071] The extruded filament was cooled in a water bath at a temperature lower than 12°C.

2.b) Preparation of the filament of the membrane:

[0072] The polymer used was Bionate PCU 80 A commercialized by DSM 35 [0073] A membrane filament having the following composition was prepared:

Component Weight for each ring Weight for 100 rings Bionate PCU 80 A 300.000 mg 30.000 g 40

[0074] The polymer was carefully weighted and loaded into the hopper of the extruder Noztek Pro Pellet & Powder Filament Extruder. A filament of 1.75 mm 6 0.04 mm diameter was obtained using the following extrusion parameters:

45 Extrusion speed 1.5 m/min Extrusion temperature: 75°C

[0075] The extruded filament was cooled in a water bath at a temperature lower than 12°C.

50 2.c) 3D Printing of the vaginal ring

[0076] FDM ™ printer, Delta WASP 2040 Turbo2, Delta type with ZEN dual extruder system, a 50 micron layer resolution and 0.2 and 0.4 mm diameter nozzles were used. [0077] A 3D model of a coaxial toroidal ring with a diameter of 56.0 m and a section of 4.0 mm was generated by a

55 CAD 3D program and was imported into the printer program. [0078] A Solid Works, Autodesk Fusion 360° and Rhinoceros computer design program was used for the manufacture of vaginal rings. [0079] The two nozzles extruded and deposited the melted layers of material in one single step, creating at the same

7 EP 3 501 543 A1

time the core and the membrane of the vaginal ring. [0080] The vaginal rings were printed at 200°C for the core and 75°C for the membrane. [0081] Using the same compositions of the filaments and the procedure reported above several prototypes were manufactured using the parameters listed below: 5 Core Membrane Print Coreextrusion Membrane extrusion Plate Prototype layer Infill layer height speed temperature temperature temperature height

10 1 0.1 mm 0.8mm 15% 20 200°C 75°C 40°C 2 0.1 mm 0.8mm 50% 20 200°C 75°C 40°C 3 0.1 mm 0.8mm 100% 20 200°C 75°C 40°C

15 [0082] The printed vaginal rings were packed in aluminium / polythene bags.

Claims

20 1. A method for manufacturing a controlled release vaginal ring using a three-dimensional (3D) printer, said vaginal ring comprising:

a) a core, said core consisting of a composition comprising one or more thermoplastic polyurethanes and one or more active pharmaceutical ingredients dissolved or dispersed in said core, 25 b) a membrane, substantially or completely surrounding said core, said membrane consisting of a composition comprising one or more thermoplastic polyurethanes;

said method comprising the steps:

30 i) generating a 3D model of a vaginal ring; ii) preparing a filament or pellets comprising the composition of the core; iii) preparing a filament or pellets comprising the composition of the membrane; iv) feeding the filament or pellets comprising the composition of the core and the filament or pellets comprising the composition of the membrane into a different nozzle of a 3D printer; 35 v) controlling a 3D printer to fabricate the vaginal ring according to the 3D model,

wherein the steps i), ii) and iii) may be carried out in any time sequence.

2. The method according to claim 1, wherein the thermoplastic polyurethane of the core composition and the thermo- 40 plastic polyurethane of the membrane composition are independently selected from the group consisting of ther- moplastic polycarbonate - urethane, thermoplastic silicone-polycarbonate-urethane, thermoplastic polyether-ure- thane, thermoplastic silicone- polyether-urethane and a mixture thereof.

3. The method according to claim 1 or 2, wherein the thermoplastic polyurethane of the core composition is different 45 from the thermoplastic polyurethane of the membrane composition.

4. The method according to claim 3, wherein the thermoplastic polyurethane of the core composition is thermoplastic polyether-urethane and the thermoplastic polyurethane of the membrane composition is thermoplastic silicone- polycarbonate-urethane. 50 5. The method according any one of the preceding claims, wherein the active principle is selected from progestogen, progestergenic and anti-viral agents or a combination thereof.

6. The method according to claim 5, wherein progestogen or progestergenic agents are selected from the group 55 consisting of alfatradiol, , allylestrenol, altrenogest, androstenedione, bazedoxifene acetate, Buserelin, boldenone undecenoate, cetrorelix acetate, , chlorotrianisene, clomifene citrate, , conjugated oestrogens, cyclofenil, , danazol, degarelix, desogestrel, delmadi-

8 EP 3 501 543 A1

none acetate, deslorelin, dienestrol, diethylstilbestrol dipropionate, dienogest, diethylstilbestrol, dienogest, dros- pirenone, , dydrogesterone, elcometrine, estradiol, estradiol dipropionate, estradiol enan- tate, estradiol hexahydrobenzoate, estradiol, phenylpropionate, estradiol acetate, equilin, estradiol benzoate, es- tradiol phenylpropionate, estradiol valerate, estradiol cipionate, estradiol, estradiol hemihydrate, norethindrone ac- 5 etate, estrapronicate, ethinylestradiol, estriol, estrone, ethylestrenol, etonogestrel, , etynodiol diacetate, fluoxymesterone, gestodene, gestonorone caproate, gestrinone, hexestrol, hydroxyprogesterone caproate, hydroxyestrone diacetate, lynestrenol, medrogestone, medroxyprogesterone acetate, , , methyltestosterone, norethandrolone, norethisterone, , norethisterone acetate, norethisterone enantate, noretynodrel, norgestrel, norgestimate, norgestomet, , normeth- 10 androne, oxandrolone, prasterone, progesterone, promegestone, promestriene, proligestone, quinestradol, quinestrol, stanozolol, testosterone, testosterone cipionate, testosterone decanoate, testosterone undecylate, tes- tosterone phenylpropionate, testosterone propionate, tetrahydrogestrinone, tibolone and trimegestone.

7. The method according to any one of the preceding claims, wherein the active principle is present in an amount from 15 0.001% to 40%.

8. The method according to any one of the preceding claims, wherein the vaginal ring has an outer diameter ranging from 20 to 70 mm and a thickness ranging from 2 to 15 mm.

20 9. The method according to any one of the preceding claims, wherein the core has a thickness ranging from 1.4 mm to 14.950 mm.

10. The method according to any one of the preceding claims, wherein the membrane has a thickness ranging from 50 to 600 mm. 25 11. The method according to any one of the preceding claims, wherein the vaginal ring has been manufactured with an infill ranging from 15% to 100%.

12. The methodaccording anyoneof thepreceding claims, whereinthe vaginal ringcomprises one or more compartments 30 each containing a different active principle.

13. The method according to claim 5, wherein the vaginal ring comprises more compartments each one surrounded by a membrane having a different composition and/or a different thickness.

35 14. The method according to any one of the preceding claims, wherein the 3D printer is a Fused Deposition Modeling (FDM) printer equipped at least with two nozzles.

15. The method according to any one of the preceding claims, wherein the printing temperature of the core ranges from -20°C to +20°C respectively below/above the melting point of the thermoplastic polymers. 40 16. The method according to any one of the preceding claims, wherein the printing temperature of the membrane ranges from -20°C to +20°C respectively below/above the melting point of the thermoplastic polymers.

17. A controlled release vaginal ring obtained through the method of claim 1. 45

50

55

9 EP 3 501 543 A1

5

10

15

20

25

30

35

40

45

50

55

10 EP 3 501 543 A1

5

10

15

20

25

30

35

40

45

50

55

11 EP 3 501 543 A1

5

10

15

20

25

30

35

40

45

50

55

12 EP 3 501 543 A1

REFERENCES CITED IN THE DESCRIPTION

This list of references cited by the applicant is for the reader’s convenience only. It does not form part of the European patent document. Even though great care has been taken in compiling the references, errors or omissions cannot be excluded and the EPO disclaims all liability in this regard.

Patent documents cited in the description

• WO 2016025388 A [0016] • WO 2017054433 A [0019]

13