Drug-Device Unit Containing Quinagolide

Abstract

The present invention is based on the identification of a cohort of polyurethane block copolymers that are particularly suited for use in pharmaceutical polymeric drug-device units and which offer improved control of drug release. In particular, there is provided a polymeric drug-device unit comprising a polyurethane block copolymer obtainable by reacting together a poly(alkylene oxide); a difunctional compound; a difunctional isocyanate; and optionally a block copolymer comprising poly(alkylene oxide) blocks; and quinagolide as a pharmaceutically active agent. The drug-device units may find application in the treatment and/or prevention of endometriosis.

Claims

1. A polymeric drug-device unit comprising: (i) a polyurethane block copolymer obtainable by reacting together: (a) a poly(alkylene oxide); (b) a difunctional compound; (c) a difunctional isocyanate; and (d) optionally a block copolymer comprising poly(alkylene oxide) blocks; and (ii) quinagolide or a pharmaceutically acceptable salt thereof, as a pharmaceutically active agent.

2. The polymeric drug-device unit of claim 1, wherein the poly(alkylene oxide) is a polyethylene glycol (PEG) or a polypropylene glycol (PPG).

3. The polymeric drug-device unit of claim 2, wherein the polypropylene glycol has a number average molecular weight of 200 to 35,000 g/mol or approximately 2,000 g/mol.

4. The polymeric drug-device unit of claim 2, wherein the polyethylene glycol has a number average molecular weight of 200 to 35,000 g/mol or a molecular weight of approximately 2,000 g/mol.

5. The polymeric drug-device unit of claim 1, wherein the poly(alkylene oxide) block copolymer comprises blocks of polyethylene glycol and polypropylene glycol.

6. The polymeric drug-device unit of claim 1, wherein the difunctional compound is selected from the group consisting of diols; diamines; and amino alcohols; optionally, wherein the diol is a C.sub.3 to C.sub.20 diol or the difunctional compound is selected from the group consisting of: 1,4-butanediol; 1,5-pentanediol; 1,6-hexanediol; 1,10-decanediol; 1,12-dodecanediol; and 1,16-hexadecanediol.

7. The polymeric drug-device unit of claim 1, wherein the difunctional isocyanate is an aromatic diisocyanate or an aliphatic diisocyanate; optionally, wherein the difunctional isocyanate is diphenylmethane-4,4′-diisocyanate, dicyclohexylmethane-4,4′-diisocyanate (DMDI) or hexamethylene diisocyanate (HMDI).

8. The polymeric drug-device unit of claim 1, wherein the molar ratio of the components (a) to (b) to (c) is in the range 0.05-0.75 to 1 to 1.00-2.00.

9. The polymeric drug-device unit of claim 1, wherein the ratio of components (a) to (b) to (c) to (d) is in the range 0.05-0.75 to 1 to 1.00-2.00 to 0.01-0.50.

10. The polymeric drug-device unit of claim 1, wherein the device is obtainable by reacting together components (a), (b), (c) and optionally (d) in the presence of a catalyst; optionally, wherein the catalyst is a ferric chloride and/or bismuth based catalysts.

11. The polymeric drug-device unit of claim 1, wherein the polymeric drug-device unit comprises one or more polyurethane block copolymers, wherein the, or each, polyurethane block copolymer is obtainable by reacting together: (a) a poly(alkylene oxide); (b) a difunctional compound; (c) a difunctional isocyanate; and (d) optionally a block copolymer comprising poly(alkylene oxide) blocks.

12. The polymeric drug-device unit of claim 11, wherein the polymeric drug-device unit comprises a monolithic-type or single matrix-type polymer structure; a reservoir structure; a layered structure, each layer comprising one or more of the polyurethane block copolymers; or an inner core structure or layer and an outer layer, cap, sheath, or coating.

13. The polymeric drug-device unit of claim 12, wherein the inner core structure or layer is loaded with quinagolide.

14. The polymeric drug-device unit of claim 12, wherein quinagolide is absent from the outer layer or coating.

15. The polymeric drug-device unit of claim 1, wherein initial quinagolide release conforms to a release quotient of between 0.05 and 10, the release quotient being calculated as the percentage release over an initial 24 hour period divided by the percentage of quinagolide release over a later period; optionally wherein the percentage of quinagolide release over a later period is the percentage of quinagolide release over the period of 7-14 days after administration.

16. The polymeric drug-device unit of claim 1, wherein the polymeric drug-device unit comprises a resilient, deformable/flexible and/or soft polymer.

17. The polymeric drug-device unit of claim 1, wherein the polymeric drug-device unit takes the form of a ring for insertion and/or location into the vaginal cavity.

18. The polymeric drug-device unit of claim 1, wherein the polymeric drug-device unit has an elastic modulus between about 5 and 100 MPa; optionally wherein the elastic modulus is between about 5 and 30 MPa, between 10 and 20 MPa or between about 10 and 20 MPa when in a hydrated state.

19. The polymeric drug-device unit of claim 1, wherein the polymeric drug-device unit comprises quinagolide or a pharmaceutically acceptable salt thereof at a dose of about 25 to about 15000 micrograms g; optionally wherein the polymeric drug-device unit comprises quinagolide or a pharmaceutically acceptable salt thereof at a dose of about 200 to 5000 μg, about 400-1500 μg, about 200 μg, about 400 μg, about 800 μg, about 1200 μg, about 2400 μg or about 3000 μg quinagolide.

20. The polymeric drug-device unit of claim 1, wherein the polymeric drug-device unit provides a continuous release of quinagolide to the vaginal tissues; optionally, wherein the polymeric drug-device unit continuously releases quinagolide over a period of about 21, 28 or 35 days.

21. The polymeric drug-device unit of claim 1, wherein in use, the polymeric drug-device unit releases between about 1 and about 150 μg or 300 μg or between about 1 and about 50 μg quinagolide/day; optionally, wherein the polymeric drug-device unit releases about 5, about 10, about 15, about 20 or about 30 μg quinagolide/day.

22. The polymeric drug-device unit of claim 1, wherein the quinagolide or a pharmaceutically acceptable salt thereof, is loaded into the polymeric drug-device unit as a granulated formulation, optionally wherein the granulated formulation is a wet granulated formulation.

23. The polymeric drug-device unit of claim 1, wherein the quinagolide or a pharmaceutically acceptable salt thereof is formulated with one or more excipients; optionally, wherein the excipients are selected from the group consisting of cellulose, microcrystalline cellulose, cellulose derivatives, ethyl cellulose, (hydroxypropyl)methyl cellulose (HPMC) and hydroxypropyl cellulose (HPC)), polysaccharides, pre-gelatinised starch and pullulan, Zein and polyvinylpyrrolidone (PVP).

24. The polymeric drug-device unit of claim 1, wherein the quinagolide is selected from the group consisting of quinagolide, a pharmaceutically acceptable quinagolide salt, quinagolide hydrochloride, any active enantiomer, the quinagolide hydrochloride enantiomer with absolute configuration 3 S, 4aS, 10aR, the quinagolide metabolite N-desethyl and the quinagolide metabolite N,N-didesethyl.

25. The polymeric drug-device unit of claim 1, wherein the quinagolide or a pharmaceutically acceptable salt thereof, is loaded into the device using an antistatic additive; optionally, wherein the antistatic additive is fumed silica.

26. A method of making a polymeric drug-device unit for the intravaginal administration of quinagolide or a pharmaceutically acceptable salt thereof, said method comprising reacting together: (a) a poly(alkylene oxide); (b) a difunctional compound; (c) a difunctional isocyanate; and (d) optionally a block copolymer comprising poly(alkylene oxide) blocks; to provide a polyurethane block copolymer; and loading quinagolide or a pharmaceutically acceptable salt thereof into the polyurethane block copolymer.

27. The method of claim 26, wherein the polyurethane block copolymer is prepared by a reactive extrusion process or a batch process.

28. The method of claim 26, wherein the quinagolide or a pharmaceutically acceptable salt thereof is loaded into the polyurethane block copolymer via a hot melt extrusion process.

29. The method of claim 26, wherein the quinagolide is formulated into granules before loading.

30. (canceled)

31. A method of treating and/or preventing endometriosis, said method comprising administering to a subject in need thereof, a polymeric drug-device unit according to claim 1.

32. (canceled)

33. The method of claim 31, wherein the treatment and/or prevention of endometriosis comprises a method in which the drug device unit is worn intravaginally during all or part of the menstrual cycle.

34-35. (canceled)

36. The method of claim 31, wherein a new drug-device unit is administered at the start of each new menstrual cycle.

37. A kit comprising one or more polymeric drug-device unit(s) according to claim 1; optionally wherein the kit further comprises one or more applicator(s) and/or instructions for use.

38. The kit of claim 37, wherein the applicator facilitates insertion of the polymeric drug-device unit into a vaginal cavity; optionally wherein the polymeric drug-device unit of the kit is pre-loaded into or onto the applicator.

39-40. (canceled)

41. A method of treating or preventing endometriosis, said method comprising the step of administering to a subject in need thereof a therapeutically effective amount of the quinagolide metabolites N-desethyl and/or N,N-didesethyl.

Description

DETAILED DESCRIPTION

[0098] The present invention will now be described in detail with reference to the following Figures which show:

[0099] FIG. 1: General overview of an example manufacturing process for a polymeric drug-device unit according to one embodiment of the invention.

[0100] FIG. 2: In vitro Dissolution profiles showing release of quinagolide from various drug loaded polyurethane block copolymers (1.0% w/w, 4×4 mm Blocks) over a 28 day period.

[0101] FIG. 3: In vitro Dissolution profiles showing release of quinagolide from drug loaded polymers RLST0183 and RLST0157.

[0102] FIG. 4: In vitro Dissolution profiles showing release of quinagolide from drug loaded polymers RLST0072 and RLST0154 (0.5% w/w, 4×4 mm Blocks) over a 28 day period.

[0103] FIG. 5: In vitro Dissolution profiles showing release of quinagolide from further drug loaded polyurethane block copolymers compared to RLST0072 and RLST0154 over a 10 day period.

[0104] FIG. 6: In vitro Dissolution profiles for batches QH12019, QH12020 and QH12022 showing release of quinagolide over a 20 day period.

[0105] FIG. 7: Release of quinagolide in vivo from batches QH12020 and QH12022 over a 28 day period in a first study in sheep.

[0106] FIG. 8: Release of quinagolide in vivo from batches QH13005 and QH13006 over a 28 day period in a second study in sheep.

[0107] FIG. 9: Average daily rate of quinagolide hydrochloride release in vivo from batches QH12020, QH12022, QH13005 and QH13006, as found in the first and second sheep studies over a 28 day period.

[0108] FIG. 10: Plasma concentrations of quinagolide (Q) and active metabolites (M1 and M2) over a 28 day period during the first and second sheep studies.

[0109] FIG. 11: Dissolution profiles of co-extruded batches QH13017-QH13024 showing release of quinagolide over a 28 day period

[0110] FIG. 12: In vivo Release profile of vaginal rings in sheep. Plasma concentrations of quinagolide (Q: 400 ug (panel A): 800 ug (panel B): 1100 ug (panel C)) and active metabolites (M1 and M2) over a 35 day period.

[0111] FIG. 13: Quinagolide metabolites M1 and M2.

[0112] FIG. 14: Time course of quinagolide in sheep with vaginal ring administration.

[0113] Median plasma concentration of quinagolide in sheep treated with a quinagolide vaginal ring over 28 days. Release rates were 5 μg/day (blue), 10 μg/day (red) and 15 μg/day (black).

[0114] FIG. 15: Human data showing mean quinagolide concentrations with extended-release vaginal ring loaded with 400, 800 or 1200 μg.

[0115] FIG. 16: Diagram showing an example/possible drug-device unit based treatment over three menstrual cycles. In this Figure a 1.sup.st drug-device unit according to the invention is inserted early in cycle 1 (which in this example lasts 28 days) and is left in situ until early in cycle 2 when the 1.sup.st device is removed and a 2.sup.nd drug-device unit according to the invention is inserted. This 2.sup.nd drug-device unit is then retained in situ for the remaining period of the 28 day duration of the second cycle. Early in cycle 3 (which also lasts 28 days) the 2.sup.nd drug-device unit is removed and a 3.sup.rd drug-device unit of this invention is inserted. This process may be repeated across or during subsequent cycles. It should be noted that the cycle in this example lasts 28 days, however the length of cycle may vary depending on the subject.

Manufacturing Process Overview

[0116] A general overview of an example manufacturing process for a polymeric drug-device unit according to this invention is shown in FIG. 1.

[0117] The five principal stages of the manufacturing process are shown in boxes 100, 105, 110, 115 and 120.

[0118] The first stage involves preparation of raw materials and catalyst (box 100).

[0119] The polyurethane block copolymer may be manufactured using reactive extrusion, batch processing or any other suitable method (box 105).

[0120] Separately, and optionally in parallel, the active agent may be prepared as a granular formulation (box 110).

[0121] The next stage comprises loading the polymer with the active agent (box 115). The granular drug is uniformly incorporated or compounded with the polymer.

[0122] The fifth stage of the process comprises formation of the ring product. The rings may be formed by any number of suitable methods including, for example, bonding together the ends of extruded cylindrical polymer tubes using a medical-grade adhesive or welding, for example heat welding or laser welding. Alternatively, the ring may be formed via an injection moulding process.

[0123] The ring product is then packaged to allow storage. For example, the ring product may be placed in packaging that protects against moisture and/or gas ingress.

[0124] Each of the stages of the manufacturing process will be further described in the following examples.

Polymer Synthesis

Preparation of Raw Materials for Polymer Manufacture

[0125] The starting polymer compositions (the poly(alkylene oxide), the difunctional compound and (where present) the poly(alkylene oxide) block copolymer) were dried to remove water by heating under vacuum.

[0126] The difunctional isocyanate was stirred and heated under nitrogen prior to use.

Preparation of the Catalyst

[0127] The catalyst may be prepared for use as a dispersion or solution or used neat. Any of the catalysts described herein may be used.

[0128] For example a bismuth catalyst (BiCat) (e.g. bismuth neodecanoate) (10 g) was dissolved in ethanol. 1,5-pentanediol (100 g) was added to the solution and then the ethanol removed using a rotary evaporator to provide a dispersion of BiCat in 1,5-pentanediol (10 wt %).

Manufacture of Polymer by a Reactive Extrusion Process

[0129] The reactants (the poly(alkylene oxide), the difunctional compound, the difunctional isocyanate and (where present) the poly(alkylene oxide) block copolymer) were dispensed into an extruder using a liquid feed system. The catalyst or the catalyst dispersion was simultaneously dispensed into the extruder from volume calibrated syringes using a syringe pump.

[0130] Using methods that would be known to persons skilled in the art, the rate of flow of each of the individual liquid streams into the extruder was fixed to ensure the final polymer contained the appropriate proportion of each of the starting composition materials.

[0131] The polyurethane block copolymer was discharged from the extruder as a strand. The strand was conveyed through a water bath and cooling coils into a pelletiser. After pelletisation, the polymer pellets were stored at room temperature until required. The pellets may be formed into a drug-device unit of this invention (for example a vaginal ring) by means of an injection moulding process.

Manufacture of Polymer by a Batch Process

[0132] A typical batch reactor comprises a vessel and an agitator which may be jacketed with a heating/cooling system. Once an initial temperature had been reached, the reactor was charged with the reactants and catalyst. Alternatively or additionally, the temperature was adjusted after the reactants had been fed into the reactor vessel. The reaction temperature and torque were monitored throughout the duration of the polymerisation. The polymerisation was considered complete when the torque level reached equilibrium. The polymer was then discharged from the reactor and pelletised.

Preparation of Granular Drug Formulation

[0133] Quinagolide hydrochloride may be prepared as a granular drug formulation using, for example, a wet granulation process, as described below.

[0134] Quinagolide hydrochloride (QH) was blended directly with microcrystalline cellulose (e.g. Avicel PH101). In those cases where lower doses of quinagolide hydrochloride were required, the quinagolide hydrochloride was added as a solution in isopropanol (IPA) to the microcrystalline cellulose. A mixture of ethyl cellulose in IPA was then added to the quinagolide hydrochloride/microcrystalline cellulose blend.

[0135] The wet mixture was passed through a granulator sieve to form granules. The granules were dried in an oven.

[0136] Once dried, the granules were mixed with hydrophilic fumed silica (e.g. Aerosil 200 VV) before being further reduced in size using a finer granulator sieve.

[0137] The final material was then hand sieved.

[0138] Each batch of granules was tested to ensure content uniformity and to monitor the levels of residual water and IPA.

Example Drug-Device Manufacture

[0139] The long chain diols that form the polymer backbone, PPG-2000 and PPG-PEG2000 may be end capped with DMDI and chain extended using 1,5-Pentanediol. The reaction may be catalysed using bismuth neodecanoate. Prior to carrying out the reaction, the water content of the diols may reduced (by for example drying) to less than 1.0%. The starting materials may be dispensed into an extruder where they are reacted in a reactive extrusion process to form a polymer (described above). The polymer may then be extruded, pelletised and gathered. In subsequent steps, a granular drug formulation and the polymer pellets may be loaded into separate feeders. These feeders may be used to accurately dispense their materials into an extruder where there is a hot melt extrusion of granules and polymer. The extruded strand may be cut to length and formed into suitable drug-device units (namely “rings”) using, for example, medical grade adhesive. There are a series of in process controls in all stages of the process.

Calculation of Granule Composition

[0140] As will be appreciated, the exact quantities of the quinagolide salt and other components used during the preparation of the granules will be dependent on the desired dose in the final drug-device unit. To obtain a desired dose of active agent in the final drug-device unit, the skilled person would need to account for the target throughput rate of the extrusion process in the subsequent drug loading step, the concentration of active agent in the granule and also the target drug-device unit weight.

[0141] By way of example only, the following parameters have been adopted: [0142] Target vaginal ring weight: 2.4 g [0143] Target concentration of Quinagolide HCl granule in polymer: 2% [0144] Target throughput rate of drug feeder during extrusion: 40 g/hour [0145] Target throughput rate of polymer feeder during extrusion: 1960 g/hour [0146] Batch size of Quinagolide HCl granule being prepared: 300 g [0147] Target doses of quinagolide HCl in the vaginal ring: 400 mcg, 800 mcg and 1200 mcg

[0148] The quinagolide hydrochloride concentration required for this particular batch size, ring weight and target doses may be calculated as shown in Table 4 below:

TABLE-US-00004 TABLE 4 Calculation of quinagolide hydrochloride concentration for target doses of 400 mcg, 800 mcg and 1200 mcg Quantity of QH QH in Dose in Ring % w/w QH Granule % w/w QH Granule Ring Weight in Ring Concentration in in Granule Batch Batch (g) (mcg) (g) C = A/(B × Polymer (%) E = (C × Size (g) G = (F × A B 10000) D 100)/D F E)/100 400 2.4 0.01667 2 0.8334 300 2.500 800 2.4 0.03333 2 1.6665 300 5.000 1200 2.4 0.05000 2 2.5000 300 7.500

[0149] The concentrations and quantities of the other excipients present in the example granule batches are shown in Tables 5, 6 and 7.

TABLE-US-00005 TABLE 5 Target dose of 400 mcg of quinagolide hydrochloride in vaginal ring Material % w/w in Granule Quantity Required (g) Quinagolide HCl 0.8334 2.500 Avicel PH101 90.667 272.00 Ethyl Cellulose 7.000 21.00 Aerosil 200VV 1.500 4.500 Total Solids 100.00 300.00 Isopropyl Alcohol 53% of solids content 159.00

TABLE-US-00006 TABLE 6 Target dose of 800 mcg of quinagolide hydrochloride in vaginal ring Material % w/w in Granule Quantity Required (g) Quinagolide HCl 1.6665 5.000 Avicel PH102 89.833 269.50 Ethyl Cellulose 7.000 21.00 Aerosil 200VV 1.500 4.500 Total Solids 100.00 300.00 Isopropyl Alcohol 53% of solids content 159.00

TABLE-US-00007 TABLE 7 Target dose of 1200 mcg of quinagolide hydrochloride in vaginal ring Material % w/w in Granule Quantity Required (g) Quinagolide HCl 2.500 7.500 Avicel PH102 89.000 267.00 Ethyl Cellulose 7.000 21.00 Aerosil 200VV 1.500 4.500 Total Solids 100.00 300.00 Isopropyl Alcohol 53% of solids content 159.00
Loading of Active Agent into the Polymer Using Hot Melt Extrusion

[0150] The granules comprising quinagolide hydrochloride were compounded with the pre-prepared polymer pellets using a hot melt extrusion process. Hot melt extrusion is a widely used method of loading active agents into polymers in the pharmaceutical industry.

[0151] The granular drug formulation and the polymer pellets were charged into gravimetric feeders and dispensed into the extruder at a rate to provide the desired dose of active agent in the final ring product. An appropriate set of compounding screws, screw speed and temperature profile were also selected. As will be appreciated, the exact parameters selected may be dependent upon the nature of the polymer compositions, granules and target dose in the final product. The appropriate selection of such parameters would be well within the capabilities of the skilled person.

[0152] After extrusion, the drug loaded polymer strand was passed through a cutting unit and cut to the required length. The length of the strand determines the circumference of the final ring product. Therefore the required length will be dependent upon the target dimensions of the final ring product.

[0153] The cut strand lengths were then sealed in foil bags and stored in a freezer until the subsequent ring formation process.

Ring Formation

[0154] A primer was dispensed onto the cylindrical ends of the polymer strand from a pressurised spray dispenser, before application of a medical grade adhesive to a first end of the strand using a peristaltic pump dispenser. The first end of the strand was then joined to the second end of the strand to form the vaginal ring product.

[0155] As will be appreciated, other methods of joining the ends of the strand may be used to form the vaginal ring product. For example, the ends may be glued (using a medical grade adhesive) or welded together by a heat or laser welding process. Alternatively the ring may be formed via injection moulding. In such cases, the extruded polymer strand can be pelletised, before being transferred to an injection moulder. In such cases, the polymer is formed directly into a ring shape.

[0156] After formation, the ring products were packaged in an individual foil bag.

Polymer Compositions

[0157] The polyurethane block copolymers are obtainable by reacting together components: [0158] (a) a poly(alkylene oxide); [0159] (b) a difunctional compound; [0160] (c) a difunctional isocyanate; and [0161] (d) optionally a block copolymer comprising poly(alkylene oxide) blocks.

[0162] The starting polymer compositions identified in Table 8 have been used to prepare polyurethane block copolymers, which were subsequently investigated for use in drug-device units comprising quinagolide.

[0163] The relative amounts and the nature of these components are indicated in Table 8.

TABLE-US-00008 TABLE 8 Example starting polymer compositions used to prepare polyurethane block copolymers for use as drug-device units comprising quinagolide. Polymer Stoichiometry batch Starting polymer Composition (wt %) (a):(b):(c):(d) RLST0027 PPG2000 26.9%; decanediol 15.6%; 0.15:1:1.3:0.15 DMDI 30.6%; PPG-PEG-PPG2000 26.9%. RLST0047 PPG2000 24.5%; decanediol 17.8%; 0.12:1:1.24:0.12 DMDI 33.2%; PPG-PEG-PPG2000 24.5%. RLST0072 PPG2000 22.5%; decanediol 19.6%; 0.1:1:1.2:0.1 DMDI 35.4%; PPG-PEG-PPG2000 22.5%. RLST0098 PPG2000 27.3%; pentanediol 10.9%; 0.135:1:1.3:0.135 DMDI 34.5%; PPG-PEG-PPG2000 27.3%. RLST0044 PEG2000 10.8%; decanediol 15.6%; 0.06:1:1.3:0.24 DMDI 30.6%; PEG-PPG-PEG2000 43.0%. RLST1015 PPG2000 35.0%; decanediol 12.2%; 0.25:1:1.5:0.25 HMDI 17.7%; PPG-PEG-PPG2000 35.0%. RLST0154 PPG2000 33.1%; pentanediol 11.1%; 0.155:1:1.252:0.097 DMDI 35.1%; PPG-PEG-PPG2000 20.7%. RLST0155 PPG2000 28.0%; pentanediol 13.9%; 0.1048:1:1.169:0.0643 DMDI 41.0%; PPG-PEG-PPG2000 17.1%. RLST0156 PPG2000 34.7%; pentanediol 11.7%; 0.1549:1:1.232:0.0774 DMDI 36.3%; PPG-PEG-PPG2000 17.4%. RLST0157 PPG2000 30.7%; pentanediol 13.9%; 0.1151:1:1.169:0.0539 DMDI 41.0%; PPG-PEG-PPG2000 14.4%. RLST1040 PPG2000 51.9%; decanediol 12.2%; 0.37:1:1.5:0.13 HMDI 17.7%; PPG-PEG-PPG2000 18.2%. RLST1041 PPG2000 55.9%; decanediol 9.4%; HMDI 0.52:1:1.7:0.18 15.4%; PPG-PEG-PPG2000 19.4%. RLST0183 PPG2000 45.1%; pentanediol 13.9%; 0.169:1:1.169 DMDI 41.0% RLST0208 PPG2000 41.5%; pentanediol 10.9%; 0.199:1:1.262:0.0631 DMDI 34.5%; PPG-PEG-PPG2000 13.1%. RLST0207 PPG2000 43.7%; pentanediol 10.2%; 0.2237:1:1.290:0.0667 DMDI 33.1%; PPG-PEG-PPG2000 13.0%. RLST0209 PPG2000 47.0%; pentanediol 9.2%; DMDI 0.2667:1:1.340:0.0730 31.0%; PPG-PEG-PPG2000 12.9%. RLST0210 PPG2000 37.0%; pentanediol 12.3%; 0.156:1:1.211:0.056 DMDI 37.7%; PPG-PEG-PPG2000 13.0%. RLST0211 PPG2000 35.0%; pentanediol 13.0%; 0.1404:1:1.193:0.0523 DMDI 39.0%; PPG-PEG-PPG2000 13.0%. RLST0212 PPG2000 36.0%; pentanediol 12.7%; 0.148:1:1.201:0.054 DMDI 38.3%; PPG-PEG-PPG2000 13.0%. RLST0213 PPG2000 38.0%; pentanediol 12.0%; 0.1646:1:1.221:0.0564 DMDI 37.0%; PPG-PEG-PPG2000 13.0%.
The block co-polymers used in the example compositions were as follows:

[0164] PPG-PEG-PPG2000 comprises approximately 50% by weight of PEG. For example, a block co-polymer having a percentage weight ratio of approximately 25:50:25 of its constituent blocks.

[0165] PEG-PPG-PEG2000 comprised approximately 10% by weight of PEG. For example, a block co-polymer having a percentage weight ratio of approximately 5:90:5 of its constituent blocks.

Evaluation of Polyurethane Block Copolymers

Dissolution Testing

[0166] A dosage form when placed into a vessel containing liquid media will release drug in a defined manner dictated by the formulation. This process, known as dissolution, can be used as an in vitro marker of the mechanism of release in the body. Sampling is carried out at regular intervals and the amount of drug in the samples is analysed by spectrophotometer or HPLC. The data are normally represented as the release of labelled content against time.

Tensile Testing

[0167] Films for each polymer were prepared using a 2 mm mould on a custom made hot-press. The temperature set on the hot-press varied depending on the polymer composition to ensure a linear melt and a suitable film was obtained. The 2 mm polymer films were removed from their moulds and punched with a Ray-Ran hand operated cutting press to make a dog-bone shape of type 2 dimension as outlined in the ISO standard (International Organisation Standardisation) 37:2005(E) or a cylindrical length sample.

[0168] An Instron 3343 mechanical tester was used and the samples were tested to destruction at a rate of 200 mm/min and the stress-strain curves recorded. The capacity of the load cell used for this test was 1000 N.

[0169] Tensile testing was also carried out on formed rings in the dry, hydrated, blank and drug loaded state.

Dynamic Mechanical Analysis (DMA)

[0170] A dynamic mechanical analyser was used to record storage and loss modulus (G′ and G″, respectively) and loss tangent (G′/G″) as a function of temperature. The samples were cooled below the glass transition temperature before being heated at a rate of 2° C./min. Samples (1 mm) were prepared in accordance with the method outlined above under “Tensile Testing”).

Gel Permeation Chromatography (GPC)

[0171] Molecular weight analysis (Mw, Mn and polydispersity index (PDI)) of the polymers was carried out by Gel Permeation Chromatography (GPC.) Each sample was dissolved in tetrahydrofuran (THF.) The system eluent was converted to THF at least 24 hours prior to samples being run. The equipment was calibrated using the polystyrene narrow and broad standards and set up with a 2×PLgel MIXED-C, 5 μm, 300×7.5 mm column (including a guard column) before use. The samples were run at a flow rate of 1 ml min.sup.−1.

Release of Quinagolide

[0172] To provide an initial analysis of the suitability of the polyurethane block copolymers for the delivery of quinagolide, various polymers were loaded with quinagolide and their release profiles assessed.

[0173] Exemplary drug loaded polyurethane block copolymers were prepared by compounding quinagolide and pellitised polyurethane block copolymer in a batch compounder. The resultant 1.0% w/w drug loaded polymers were processed into sample blocks (4×4 mm) and dissolution testing was carried out.

[0174] The results are shown in Table 9 and FIG. 2.

TABLE-US-00009 TABLE 9 Release of quinagolide from various drug loaded polymer compositions (1.0% w/w, 4 × 4 mm Blocks) over a 28 day period. Quotient of drug released drug released 24 h release/ Polymer in first 24 h between 7 and 7-14 day batch (%) 14 day (%) release QH12001 RLST0027 28.2 11.6 2.4 QH12002 RLST0047 20.4 15.2 1.3 QH12003 RLST0072 8.6 9.9 0.9 QH12004 RLST1015 50.0 5.7 8.8 QH12005 RLST0098 41.8 8.9 4.7 QH12006 RLST0044 13.6 20.7 0.7

[0175] The quotient (of 24 h release/7-14 day release) provides a measurement of the “burst release” of an active agent relative to a steady state release. In Table 9, the quotient has been calculated by division of the percentage of drug released in the initial 24 hour period by the percentage of drug released between 7 and 14 days (representing the steady state for a 1 month product)

[0176] Polymers RLST0072 and RLST0044 gave lower quotient values indicating that such polymers would be suitable for a release profile with minimal burst release. The other polymers, RLST0027, RLST0047, RLST1015 and RLST0098, gave higher quotient values and so would be useful when a higher initial rate of quinagolide delivery is required.

[0177] The release of quinagolide from polymers RLST0183 and RLST0157 is also shown in FIG. 3.

[0178] As a consequence, polymer batch RLST0154 was developed and its release profile was compared with that of RLST0072. Both polymers were compounded with quinagolide in a batch compounder to produce 0.5% w/w drug loaded polymers and processed into blocks and dissolution tested (as shown in Table 10 and FIG. 4).

TABLE-US-00010 TABLE 10 Release of quinagolide from two drug loaded polymers (0.5% w/w, 4 × 4 mm Blocks) over a 28 day period. drug released in rug released Quotient Polymer first 24 h d between 7 24 h release/7-14 batch (%) and 14 day (%) day release QH12012 RLST0072 18.6 5.4 3.5 QH12013 RLST0154 22.5 10.8 2.1

[0179] The results demonstrated that polymer RLST0154 provides a slightly reduced comparative burst release (lower quotient value) and similar release profile when compared to polymer RLST0072.

[0180] The dosage of the active agent in the polymer also has an effect on the relative burst release compared to the steady state release of the agent from the polymer. This is exemplified in the different quotient values observed for polymer RLST0072 when loaded with 1.0% w/w and 0.5% w/w of quinagolide (0.9 and 3.5 respectively).

[0181] To develop a polymer that provided a slower release rate than RLST0154 and RLST0072, a number of polymers were manufactured by modulating the starting polymer compositions used to prepare polymer RLST0154. The relative performance of these new polymer batches against RLST0072 and RLST0154 was assessed and the results are presented in Table 11 and FIG. 5.

TABLE-US-00011 TABLE 11 Release of quinagolide from further drug loaded polymers compared to RLST0072 and RLST0154, including dosage form and loading details. drug drug released in released Quotient Polymer Dosage form & first 24 h after 7 days 24 h release/ batch Loading details (%) (%) 7 day release.sup.3 QH12013 RLST0154 Melt mix blocks 22.5 48.2 0.47 0.05% w/w 48 μg/unit QH12024 RLST0156 Melt mix blocks 13.3 32.6 0.41 0.05% w/w 51 μg/unit QH12025 RLST0155.sup.1 Melt mix blocks 12.9 29.5 0.44 0.05% w/w 60 μg/unit QH13003 RLST0157.sup.2 Extruded rods 5.8 15.6 0.37 0.05% w/w 1824 μg/unit .sup.1,2Manufactured by a reactive extrusion process. .sup.3Dissolution was stopped after 7 days for QU12023, 024 & 025. Therefore the final column shows the quotient of the 24 hour release over the 7 day release.

Sheep Study Trial

[0182] Polymer batches were loaded with quinagolide and manufactured into rings for a sheep study.

[0183] Table 12 provides details of the polyurethane block copolymers manufactured and Table 13 provides details of the mechanical properties. It should be noted that hot melt extrusion was used to compound the drug with the polymer and therefore quinagolide was dry blended with Avicel to enable the powder feeder dispensing the drug into the extruder to meet the low doses being targeted with good content uniformity. The hot melt extruded material was manufactured into rings using the process of heat sealing.

TABLE-US-00012 TABLE 12 Polymer batches used for the first sheep study. Ring dimensions drug released drug released Quotient Polymer & Loading in first 24 h between 7 and 24 h release/7-14 batch details (%) 14 day (%) day release QH12019 RLST0044 5 mm Ring Units 10.1 10.3 1.0 0.05% w/w 1840 μg/unit QH12020 RLST0072 4 mm Ring Units 6.9 7.3 0.9 0.05% w/w 2223 μg/unit QH12022 RLST0072 5 mm Ring Units 6.7 7.6 0.9 0.1% w/w 3430 μg/unit

TABLE-US-00013 TABLE 13 Dry blend formulation details and mechanical properties of formulations used in the first sheep study. Mechanical Properties Load at Tensile Stress Batch Formulation Detail Elastic Break at Max Load Tensile Stress at number (Dry Blend) Modulus (MPa) (N) (MPa) 500% (%) RLST0072 N/A 10.91 334.35 17.90 786.17 QH12020 Quinagolide HCl 10.23 272.64 13.67 707.45 3.5% w/w Avicel PH101 96.5% w/w QH12022 Quinagolide HCl 12.72 293.84 13.86 760.43 3.5% w/w Avicel PH101 96.5% w/w

[0184] Dissolution profiles for QH12019, QH12020 and QH12022 are shown in FIG. 6.

[0185] The intravaginal rings were placed in sheep and the amount of quinagolide released in vivo was monitored over a 28 day period. The results of this first sheep study are shown in Table 14 below and illustrated in FIG. 7.

TABLE-US-00014 TABLE 14 Release of quinagolide in vivo over a 28 day period in the first sheep study. Batch Dose Quinagolide Average Daily Release Number (mcg) released (mcg) over 28 days (mcg) QH12020 2000 1065.5 38.1 QH12022 3100 1461.6 52.2

[0186] For the purposes of comparison, the in vitro release of quinagolide from QH12020 and QH12022 is also shown on FIG. 7.

[0187] A second study in sheep was conducted using polymer batches based on RLST0157. This polymer had been shown to have a slower release profile than RLST0072. Tables 15 and 16 below show the formulation details and mechanical data for the polymers tested.

TABLE-US-00015 TABLE 15 Polymer batches used for second sheep study. drug drug released Quotient Polymer Ring dimensions released in between 7 and 24 h release/7- batch & Loading details first 24 h (%) 14 day (%) 14 day release QH13005 RLST0157 6 mm Ring Units 5.8 5.2 1.1 0.03% w/w 1500 μg/unit QH13006 RLST0157 5 mm Ring Units 6.4 5.9 1.1 0.03% w/w 1200 μg/unit

TABLE-US-00016 TABLE 16 Dry blend formulation details and mechanical properties of formulations used in the second sheep study. Mechanical Properties Tensile Formulation Stress at Batch Detail (Dry Elastic Modulus Load at Max Load Tensile stress at number Blend) (MPa) Break (N) (MPa) 500% (%) RLST0157 N/A 32.32 337.41 16.51 1115.92 QH13005 Quinagolide 32.94 411.44 14.69 1143.55 HCl 2.4% w/w Avicel PH101 97.6% w/w QH13006 Quinagolide 34.37 306.08 15.10 1065.77 HCl 2.4% w/w Avicel PH101 97.6% w/w

[0188] The intravaginal rings were placed in sheep and the amount of quinagolide released in vivo was monitored over a 28 day period. The results of this sheep study are shown in Table 17 below and illustrated in FIG. 8.

TABLE-US-00017 TABLE 17 Release of quinagolide in vivo over a 28 day period in the second sheep study. Batch Dose Quinagolide Average Daily Release Number (mcg) released (mcg) over 28 days (mcg) QH13005 1500 580.8 20.7 QH13006 1100 464.9 16.6

[0189] For the purposes of comparison, the in vitro release of quinagolide from QH13005 and QH13006 is also shown on FIG. 8.

[0190] The average daily rate of quinagolide hydrochloride release from batches QH12020, QH12022, QH13005 and QH13006, as found in the first and second sheep studies, is further illustrated in FIG. 9 (see Tables 14 and 17 for quinagolide dose).

[0191] During the first and second sheep trials, the plasma concentration of quinagolide (Q) was monitored over the 28 day period. The plasma concentrations of active metabolites (M1 and M2: see FIG. 13) were also monitored in the sheep. The results are illustrated in FIG. 10 (see Tables 14 and 17 for quinagolide dose).

[0192] It was found that the use of intravaginal rings made from batches QH12022, QH12020 and QH13006 provided substantially constant levels of quinagolide in the plasma over the 28 day period. Further, the quinagolide concentration in the plasma did not exceed 50 μg/ml at any point during the study. The levels of the active metabolites M1 and M2 were present in the plasma at approximately 10-fold lower molar concentrations than the quinagolide.

[0193] A further study was carried out in sheep to determine the in vivo release over the period of 35 days for polymer rings with a quinagolide load targeted at delivering 5, 10 and 15 μg/day. Table 18 below shows the actual release rates achieved were almost identical to the target and that the initial release on day one has been reduced.

TABLE-US-00018 TABLE 18 In vivo Release profile of vaginal rings in sheep. Average Average Target release release release Day 1 from Day 2 from Day 2 Dose rate release to Day 28 to Day 35 (μg) (μg/day) (μg) (μg/day) ((μg/day) 400 5 15 4.1 5.4 (QH13067) 800 10 29 10.9 10.4 (QH13068) 1100  15 35 14.8 13.9 (QH13069)

[0194] By way of comparison to the data shown in Table 18, Table 19 (below) shows the in-vivo release profile of vaginal rings in clinical study 000155 (A placebo-controlled, double-blind, parallel, randomised study. In this study, three dose strengths of 400, 800, and 1200 μg quinagolide with anticipated release rates of 5, 10 and 15 μg/day and placebo vaginal ring administered for the following durations: 7 days: 12 subjects (active) 14 days: 12 subjects (active) 28 days: 32 subjects (24 active+8 placebo) 35 days: 12 subjects (active); 68 healthy women, 18-40 years of age with a BMI of 18-30 kg/m2, with a regular menstrual cycle)

TABLE-US-00019 TABLE 19 Average Average Average Dose Target release release release load release 7 days 28 days 35 Days (μg) (μg/day) (μg/day) (μg/day) (μg/day) 400 5 10.4 8.8 9.4 800 10 24.1 12.6 16.8 1200 15 43.4 29.7 21.3

Reservoir Type Drug-Device Units

[0195] Reservoir type quinagolide vaginal rings were manufactured using an excipient blend of quinagolide HCl with Avicel at a drug concentration of 3.5% compounded with RLST072 as a core and co-extruded with RLST072 or RLST0047 or RLST0046 as a sheath or cap (which did not contain quinagolide HCl) surrounding the core to form coextruded tubes that were cut to length and formed into rings.

[0196] The dissolution data for the reservoir-type rings is shown in FIG. 11 and Table 20 below.

TABLE-US-00020 TABLE 20 Composition and release details for the reservoir-type rings. drug released Quotient 24 h Polymer batch Ring dimensions drug released in between 7 and release/7- Composition & Loading details first 24 h (%) 14 day (%) 14 day release QH13017 RLST0072 3.5 mm ring 1.9 11.4 0.35 core/RLST0072 0.1% w/w/ cap 2817 μg/unit QH13018 RLST0072 3.5 mm ring 2.5 8.6 0.20 core/RLST0047 0.1% w/w/ cap 2616 μg/unit QH13019 RLST0072 3.5 mm ring 2.6 7.5 0.22 core/RLST0046 0.1% w/w/ cap 2641 μg/unit QH13020 RLST0072 3.5 mm ring 1.2 6.9 0.16 core/RLST0046 0.1% w/w/ cap 2269 μg/unit QH13021 RLST0072 3.5 mm ring 0.2 3.8 0.09 core/RLST0046 0.1% w/w/ cap 3822 μg/unit QH13022 RLST0072 3.5 mm ring 0.7 6.1 0.13 core/RLST0047 0.1% w/w/ cap 3664 μg/unit QH13023 RLST0072 3.5 mm ring 1.2 7.3 0.14 core/RLST0072 0.1% w/w/ cap 3115 μg/unit QH13024 RLST0072 3.5 mm ring 5.6 8.2 0.31 core/No cap 0.1% w/w/ Control 4546 μg/unit

[0197] It was observed that these reservoir type vaginal rings were able to provide substantially zero order release with little or no burst release and low steady state release. The quotient of the %24 hour release divided by the % drug released between 7 and 14 days for the reservoir-type rings were all extremely low (0.09 to 0.35).

TABLE-US-00021 TABLE 21 Summary of PK variables for quinagolide administered by an intravaginal ring in clinical study 000155. CMAX TMAX AUC Day 0- Mean (SD) (pg/mL) (day){circumflex over ( )} 28 (Hpg/mL T½ (h) 400 μg 3.4 (1.8) 2 738 (236) 14 (5) 800 μg 5.3 (2.4) 2 1497 (379)  1200 μg  10.9 (4.5)  1.5 3297 (1040) {circumflex over ( )}median Note: numbers outside the parenthesis represent the mean value; numbers inside the parenthesis represent the standard deviation.

[0198] Following intravaginal administration the plasma concentration of quinagolide increased to reach a maximum at approximately 37-39 hours with a subsequent slow decline until the ring was removed (see FIG. 15). The mean time for reaching a maximum serum concentration was similar between all three dose groups but with substantial inter-individual variation. C.sub.max increased with increasing dose while the mean terminal half-life estimations were appropriately the same in all three doses (Table 21: above).

Modulation of Mechanical Properties

[0199] Further development work centred round modulation of the mechanical properties of the polymer. It had been found that RLST0157 (having a Young's modulus of approximately 52 MPa) provided a relatively stiff ring polymeric drug-device. There was interest in developing further compositions with decreased stiffness which could prove more comfortable to an end user.

[0200] Table 22 below provides the details of the further polymers that were manufactured.

TABLE-US-00022 TABLE 22 Polymers manufactured during the investigation of mechanical properties Polymer Hard Segment batch Starting polymer composition (wt %) Content (wt %).sup.1 RLST0157 DMDI 41.0% - pentanediol 13.9% - 55 PPG2000 30.7% - PPG-PEG- PPG2000 14.4%. RLST0208 DMDI 34.5% - pentanediol 10.9% - 45 PPG2000 41.5% - PPG-PEG- PPG2000 13.1%. RLST 0210 DMDI 37.7% - pentanediol 12.3% - 50 PPG2000 37.0% - PPG-PEG- PPG2000 13.0%. RLST0211 DMDI 39.0% - pentanediol 13.0% - 52 PPG2000 35.0% - PPG-PEG- PPG2000 13.0%. RLST0212 DMDI 38.3% - pentanediol 12.7% - 51 PPG2000 36.0% - PPG-PEG- PPG2000 13.0%. RLST0213 DMDI 37.0% - pentanediol 12.0% - 49 PPG2000 38.0% - PPG-PEG- PPG2000 13.0%. .sup.1Hard Segment Content is the combined % by weight of the diol and diisocyanate components.

[0201] The mechanical properties of these polymers were tested and the results compared to RLST0157 as shown in Table 23 below.

TABLE-US-00023 TABLE 23 Mechanical properties of various polymers. Hard Elastic Tensile stress at Tensile segment Modulus 500% strain Strain at max Elastomer (%) (MPa) (MPa) (%) RLST0157 57 52 N/A 844 RLST0211 52 25.6 9.3 1267 RLST0213 51 10.8 5.7 1523 RLST0210 50 13.6 6.0 1831 RLST0208 46 7.8 4.7 1880

[0202] As can be seen from the table above, all the tested polymers exhibited lower elastic modulus values than RLST0157. Based on the mechanical data, RLST0210 was selected for further investigation as a lead polymer for clinical trial manufacture.

Dynamic Mechanical Analysis

[0203] Dynamic thermal mechanical analysis of samples was performed in tension mode (Table 24).

TABLE-US-00024 TABLE 24 Thermal transitions of example polymers as determined by DMA Polymer batch Hard Segment Content (%) Tg (° C.) Tm1 (° C.) RLST0208 46 −41 21 RLST0213 49 −43 28 RLST0210 50 −43 26 RLST0212 51 −41 32 RLST0211 52 −42 33 RLST0157 57 −40 40

[0204] A glass transition (T.sub.g) and low melts (T.sub.m1, T.sub.m2) were observed in all the example polymers. The polymers all demonstrate a Tg around −40° C. corresponding to the amorphous soft segment. A gradual increase in Tm1 was observed as the amount of hard segment was increased.

[0205] It was observed that the melting peak was particularly broad for polymer RLST0208 (46% hard segment). The polyurethane block copolymers rarely fully phase separate but rather undergo liquid-liquid demixing. This phenomenon can make it difficult to clearly assign melting peaks other than attribute them to crystalline segments of telechelic diols and carbamate containing segments (hard segment).

Gel Permeation Chromatography (GPC) Analysis

[0206] Molecular weight analysis of the example polymers was carried out by GPC (see Table 25).

TABLE-US-00025 TABLE 25 Molecular weights as determined by GPC sample Mw (Da) Mn (Da) PDI RLST0208-003 REX A 57000 35400 1.60 RLST0208-003 REX B 57400 35600 1.61 Mean 57232 35537 1.61 RLST0210-001 REX A 78200 48900 1.60 RLST0210-001 REX B 77900 48100 1.62 Mean 78000 48000 1.61 RLST211-001 A 60500 41000 1.45 RLST211-001 B 62000 41900 1.48 Mean 61300 41800 1.47 RLST212-001 A N/A N/A N/A RLST212-001 B N/A N/A N/A RLST0213-001 REX A 67300 42600 1.58 RLST0213-001 REX B 66500 42200 1.60 Mean 66900 42400 1.58

[0207] There were no significant differences in the polydispersity index (PDI) of the example polymers and the observed variation was within the expected 20% error margin. The GPC of elastomer RLST0212-001 was not run due to insufficient amount of sample.

Wet Granulation Formulations

[0208] To improve the content uniformity of the quinagolide in the linear polymer and to facilitate further control over the initial burst release, a wet granulation formulation was developed (using RLST0210 as the base polymer). The formulation used excipients which bind with the drug and impede its release. Initially different binders such Zein, PVP K10 and ethyl cellulose were tested for their suitability. Due to their water soluble nature, Zein and PVP K 10 were discarded. However an ethyl cellulose based wet granulated formulation was found to be effective in minimising the burst release. Different ethyl cellulose concentrations were tested and an optimised level of 7% w/w was selected for future batches.

[0209] Although wet granulation significantly improved content uniformity it was found that due to electrostatic charges in the powder, the powder flow from these formulations was erratic. In order to rectify this problem fumed silica (Commercial name Aerosil®) was incorporated at 1.5% w/w. This improved flowability as well as the content uniformity of the final product.

[0210] The formulation details and mechanical data for all of the RLST0210 development batches tested are shown in Table 26 below and their release properties can be found in Table 27. It was found that a combination of the polymer and the quinagolide wet granulation formulation significantly reduces the quotient of the %24 hour release divided by the % drug released between 7 and 14 days for these formulations (0.24-0.33).

TABLE-US-00026 TABLE 26 Formulation details and mechanical data for the RLST0210 development batches. Mechanical Properties Elastic Tensile Stress Batch Formulation detail (wet Modulus Load at at Max Load Tensile Stress number granulation composition) (MPa) Break (N) (MPa) at 500% (%) QH13058 *Quinagolide HCl 0.05% 29.77 148.68 14.59 7.46 w/w, Ethyl cellulose (EC) 7% w/w, Avicel 92.95% w/w QH13059 *Quinagolide HCl 0.12% 27.33 171.54 15.02 7.32 w/w, Ethyl cellulose (EC) 7% w/w, Avicel 92.88% w/w QH13060 *Quinagolide HCl 0.5% 31.06 153.56 13.33 6.96 w/w, Ethylcellulose (EC) 7% w/w, Avicel 92.50% w/w QH13061 *Quinagolide HCl 0.66% 28.31 182.53 15.67 7.68 w/w, Ethyl cellulose (EC) 7% w/w, Avicel 92.34% w/w QH13062 *Quinagolide HCl 6.0% 27.54 170.43 15.03 7.71 w/w, Ethyl cellulose (EC) 7% w/w, Avicel 87% w/w QH13063 *Quinagolide HCl 25.01 164.54 14.78 7.54 33.33% w/w, Ethyl cellulose (EC) 7% w/w, Avicel 59.67% w/w QH13067R *Quinagolide HCl 1.65% 27.00 168.70 16.72 8.26 w/w, Ethyl cellulose (EC) 7% w/w, Avicel 91.35% w/w QH13068R *Quinagolide HCl 3.3% 23.10 192.18 14.82 7.29 w/w, Ethyl cellulose (EC) 7% w/w, Avicel 89.70% w/w QH13069R *Quinagolide HCl 6.6% 27.90 202.31 14.84 7.29 w/w, Ethyl cellulose (EC) 7% w/w, Avicel 86.40% w/w QH14021R *Quinagolide HCl 0.9% 24.01 193.21 14.72 6.08 w/w, Ethylcellulose (EC) 7% w/w, Aerosil 1.5% w/w, Avicel 90.60% w/w QH14022R *Quinagolide HCl 1.8% 25.03 209.41 15.74 5.97 w/w, Ethyl cellulose (EC) 7% w/w, Aerosil 1.5% w/w, Avicel 89.70% w/w QH14023R *Quinagolide HCl 2.7% 23.34 192.09 13.98 6.27 w/w, Ethyl cellulose (EC) 7% w/w, Aerosil 1.5% w/w, Avicel 88.80% w/w QH14024R *Quinagolide HCl 24.92 179.37 15.65 5.93 0.833% w/w, Ethyl cellulose (EC) 7% w/w, Aerosil 1.5% w/w, Avicel 90.667% w/w QH14025R *Quinagolide HCl 24.46 180.78 15.80 6.18 1.667% w/w, Ethyl cellulose (EC) 7% w/w, Aerosil 1.5% w/w, Avicel 89.833% w/w QH14028R *Quinagolide HCl 2.5% 24.65 237.28 17.95 5.97 w/w, Ethyl cellulose (EC) 7% w/w, Aerosil 1.5% w/w, Avicel 89.00% w/w *In all batches IPA is used as a granulating solvent which was evaporated during the manufacturing process.

TABLE-US-00027 TABLE 27 Release data for the various RLST02010 formulations described in Table 24. drug drug released Quotient Formulation released between 7 24 h release/ & Loading in first and 14 7-14 day details 24 h (%) day (%) release QH13058 4 mm Ring Units 15.9 * * 0.02% w/w, 137 μg/unit QH13059 4 mm Ring Units 3.6 * * 0.10% w/w, 1008 μg/unit QH13060 4 mm Ring Units 2.3 * * 0.50% w/w, 4197 μg/unit QH13061 4 mm Ring Units 27.4 19.5 0.33 (minipig) 0.02% w/w, 218 μg/unit QH13062 4 mm Ring Units 6.2 10.9 0.28 (minipig) 0.18% w/w, 1689 μg/unit QH13063 4 mm Ring Units 1.5 2.6 0.28 (minipig) 1.00% w/w, 11362 μg/unit QH13067R 4 mm Ring Units 14.3 25.0 0.24 (Sheep) 0.02% w/w, 400 μg/unit QH13068R 4 mm Ring Units 14.4 27.1 0.24 (Sheep) 0.03% w/w, 800 μg/unit QH13069R 4 mm Ring Units 15.6 27.1 0.26 (Sheep) 0.05% w/w, 1200 μg/unit QH13070R 4 mm Ring Units 12.1 18.7 0.29 0.07% w/w, 1550 μg/unit QH13071R 4 mm Ring Units 5.3 10.3 0.26 0.10% w/w, 2450 μg/unit QH13072R 4 mm Ring Units 4.9 8.9 0.27 0.10% w/w, 2500 μg/unit QH13073X Extruded Rods 8.5 * * (REX) 0.01% w/w, 200 μg/unit QH13074M Melt Mix Blocks 3.6 3.0 0.33 0.03% w/w, 400 μg/unit QH14021R 4 mm Ring Units 5.8 9.1 0.29 (CTA) 0.02% w/w, 400 μg/unit QH14022R 4 mm Ring Units 4.5 7.4 0.24 (CTA) 0.03% w/w, 800 μg/unit QH14023R 4 mm Ring Units 4.3 8.6 0.26 (CTA) 0.04% w/w, 1200 μg/unit QH14024R 4 mm Ring Units 5.3 7.5 0.29 (Phase I) 0.02% w/w, 400 μg/unit QH14025R 4 mm Ring Units 4.4 8.7 0.25 (Phase I) 0.03% w/w, 800 μg/unit QH14028R 4 mm Ring Units 4.6 8.5 0.26 (Phase I) 0.04% w/w, 1200 μg/unit

[0211] To provide an indication of the mechanical properties of the rings in vivo, batches QH13067R, QH13068R and QH13069R were also assessed after being hydrated for a period of 48 hours. The results are illustrated in Table 28 below.

TABLE-US-00028 TABLE 28 Mechanical properties after 48 hrs hydration. Mechanical Properties Elastic Load at Tensile Stress Tensile Batch Formulation detail (wet Modulus Break at Max Load Stress at number granulation composition) (MPa) (N) (MPa) 500% (%) QH13067R *Quinagolide HCl 1.65% w/w 13.73 143.37 11.99 5.57 Ethyl cellulose (EC) 7% w/w Avicel 91.35% w/w QH13068R *Quinagolide HCl 3.3% w/w 14.26 118.03 11.43 5.49 Ethylcellulose (EC) 7% w/w Avicel 89.70% w/w QH13069R *Quinagolide HCl 6.6% w/w 16.29 136.91 11.09 5.46 Ethyl cellulose (EC) 7% w/w Avicel 86.40% w/w

[0212] It was observed that after hydration, the elastic modulus of RLST0210 is reduced to around 13-16 MPa. Therefore, after hydration this polymer has an elastic modulus comparable to the elastic modulus of the commercially available Nuvaring® product.