WO2009141309A1

WO2009141309A1 - Delivery system for paliperidone

Info

Publication number: WO2009141309A1
Application number: PCT/EP2009/056009
Authority: WO
Inventors: Wouter De Graaff; Armin Szegedi
Original assignee: N.V. Organon
Priority date: 2008-05-20
Filing date: 2009-05-18
Publication date: 2009-11-26

Abstract

This invention relates to an extended release formulation comprising paliperidone, which formulation is a vaginal device having a skin and which device comprises an inner compartment made of a thermoplastic polymer, which polymer is containing solid paliperidone. The formulation is preferably made of ethylene-vinyl acetate copolymer.

Description

DELIVERY SYSTEM FOR PALIPERIDONE

The present invention relates to an extended release formulation comprising solid paliperidone and to a method of manufacture.

Paliperidone (9-hydoxyrisperidone), the principal active metabolite of risperidone, is an atypical antipsychotic agent and is used in psychiatry for the treatment of schizophrenia. Paliperidone belongs to the chemical class of the benzisoxazole derivatives and the chemical designation is 3-[2-[4-(6-fluoro-l,2-benzisoxazol-3-yl)-l-piperidinyl]ethyl]- 6,7,8,9-tetrahydro-9-hydroxy-2-methyl-4H-pyrido[l,2-a]pyrimidin-4-one. US 5,158,952 describes paliperidone and the preparation thereof.

For psychotic disorders chronic use and medication compliance are necessary for obtaining therapeutic results. Medication compliance is a complex and important subject, since insufficient compliance causes reduced personal prospects for patients and also considerable financial costs. All kinds of patients, including the old and mentally infirm, experience difficulties in staying adherent to medication. The reasons for non-compliance are varied and include forgetfulness, over-complex dosing schedules, occurrence of side- effects by peaks in fluctuations of plasma levels of the drug, and inconvenience of administration of the drug caused by pain at the injection site. In particular schizophrenic patients have heightened problems to adhere to medication, and medical practitioners are concerned about compliance in order to improve their patients' well being.

Paliperidone is formulated in extended-release tablets (Invega™) to provide delayed drug delivery over 24 hours and reduction of side effects related to high serum levels that occur with conventional immediate-release dosage forms. With dosage regimes based on prescription of tablets which have to be taken daily, it is very common that tablets are forgotten and that compliance of the patient with the treatment is less than desired. In addition, as the Invega™ extended-release tablets should be swallowed as a whole and not be chewed, divided or crushed, inconvenience in administration is particularly present in elderly and patients with dysphagia. Moreover, there is risk in case of gastrointestinal obstructive symptoms: the extended-release tablet formulation of paliperidone is swallowed whole and the tablet shell may remain intact during gastointestinal transit. Therefore said extended release tablets should not be used in patients with gastrointestinal narrowing or blockage (in oesophagus, stomach, small or large intestine) or other conditions that would restrict or limit transit of these tablets. Furthermore, the patient may be worried if something that looks like a tablet is seen in the stool.

US 2003/0153983 describes implantable medical devices that provide resistance to microbial growth on and in the environment of the device, and resistance to microbial adhesion on the device. In US 4,469,671 a contraceptive device for intravaginal use is described comprising a bioinsoluble, biocompatible polyurethane and an acrosin inhibitor such as salts of alkyl or alkenyl sulfate. An elastomeric vaginal ring comprising a pharmacologically active compound or pharmaceutically acceptable addition salts for the treatment of cancer is described in US 5,558,877. An elastomeric matrix type of system for vaginal delivery of antimicrobial agents is described in WO 02/076426. US 4,016,251 discloses a drug-delivery device comprising of a shaped body of ethylene-vinyl acetate containing a drug and permeable to passage of the drug by diffusion.

In the context of psychiatric drug treatment it is highly unusual to contemplate a vaginal delivery system for extended release, although the intravaginal route of administration was mentioned before in a broad list of possibilities for administering antipsychotics (WO 2004041118). WO 03/055424 and WO 2005/004837 describe selected serotonin reuptake inhibitors for use in an extended release formulation in the form of a vaginal delivery system. Rather, the vaginal route of administration appears acceptable for contraceptive regimes or hormone replacement therapies which are exclusively aimed at treatment of the female person. In general, vaginal delivery devices are well-known in the field of gynaecology for the delivery of hydrophobic steroidal drugs for contraceptive uses, such as exemplified in US 4,292,965, WO97/02015, WO2004/103336, WO2005/089723 and EP 0 876 815. A contraceptive vaginal ring is marketed under the trademark Nuvaring^® by

Schering-Plough. Such rings are designed for the purpose of administering high potency steroids, for which drug delivery rates in the order of 0.01 to 0.5 mg/day are usually sufficient to obtain beneficial therapeutic effects. However, for paliperidone therapeutically effective amounts to be delivered systemically are much higher and range in the order of approximately 0.5 to 12 milligrams a day. For improving patient compliance, side-effects as a result of peaks in plasma levels are to be avoided and therefore the delivery of paliperidone from rings requires controlled release rates and a low burst release.

Extended release devices in the form of a vaginal delivery system for selected serotonin reuptake inhibitors as described in WO 03/055424 include, as drug containing compartment, one or more channels in the surface or a pocket molded in the ring or a hollow toroid polydimethylsiloxane tubing for use. WO 2005/004837 describes a device with a reservoir containing dispersed active agent, and a sheath discontinuously surrounding the reservoir. WOO 170154 discloses a siloxane elastomer vaginal ring device with a bore located in the ring comprising an oxybutynin composition, wherein the bore runs from the surface of the ring into the ring. For non-steroidal drugs the choice for polysiloxane polymers relates to their high drug solubility and the well known high permeability of polysiloxane polymers (A.D. Woolfson, R.K. Malcolm, R.J. Gallagher, Journal of Controlled Release 91 (2003) 465-476). In addition, the diffusion coefficient for the same type of molecules in polysiloxanes is typically 100 to 200 times higher than the diffusion coefficient found in polyvinyl acetate copolymers (poly-EVA).

Surprisingly, it has now been found that an extended release formulation in the form of a vaginal delivery device can be prepared for paliperidone with superior drug delivery characteristics in terms of a release almost lacking initial burst, of a substantially constant high release rate in the range of approximately 0.5 to 12 mg/day for a period in the range of one week up to one or two months, in combination with a high efficiency in delivered paliperidone, and which device has optimal mechanical properties, in particular flexibility, by avoiding the use of branched polysiloxane as taught in the prior art. One embodiment of the present invention provides for a vaginal device comprising paliperidone, a skin and an inner compartment, which inner compartment is made of a thermoplastic polymer, which polymer is containing solid paliperidone. In another embodiment the skin is a substantially continuous cover over the inner compartment. In a further embodiment the inner compartment contains 5 - 80 wt% of paliperidone. In yet another embodiment the inner compartment comprises a core, which does not contain solid paliperidone. In yet a further embodiment the inner compartment, and/or the skin, and/or the core or all three of these is or are made of ethylene-vinyl acetate copolymer. In a more specific embodiment an ethylene-vinyl acetate copolymer having a vinyl content in the range of 0.5 to 40 wt% is used.

An extended release formulation according to the invention comprising paliperidone has the advantage of requiring only a single administration for therapeutically effective delivery rates over a period in the range of one week up to one or two months, of providing drug release immediately upon exposure of the formulation to aqueous media, of immediate interruption of drug delivery after removal of the device from the vagina, which is particularly advantageous in case medical practitioners determine a therapeutic need to interrupt or change the treatment, e.g. for reasons related to insufficient therapeutic effect or to serious adverse effects during treatment. In addition, the formulation according to the invention advantageously delivers paliperidone without significant initial burst through the entire surface area of the device and therefore minimizes the risk of high paliperidone concentrations at the vaginal tissue. Moreover, the extended release formulation in the form of a device according to the invention improves compliance with drug treatment in view of the ease with which the formulation can be positioned within and removed from the female vaginal tract by the women in need of treatment.

Advantageous characteristics of the invention are that the device can easily be manufactured using extrusion techniques, and is flexible in view of the small fibre diameter if manufactured in the form of a ring. In addition to that, the extended release formulation according to the invention has an intrinsically safe design against dose- dumping. By application of a core in the inner compartment, the device allows for an improved drug substance efficiency. Application of a core also allows tuning of the mechanical properties of the device, which are relevant in relation to comfort (foreign body feeling) and retention, without affecting release kinetics significantly. The presence of paliperidone in solid form provides for a sufficient and continuous supply of paliperidone during release, and the solid form prevents crystallisation of the drug on the outside of the device during manufacturing.

With a vaginal device is meant a drug delivery system for insertion into the vagina of a woman. In one embodiment of the invention the delivery system has the form of a ring, such that the system has an elongated shape of which the two ends are joined together.

The ring may comprise one or more loops and those loops may have various shapes, such as oval, ellipsoidal, toroidal, triangular, square, hexagonal, octagonal, etc.

Alternatively, the system according to the invention is helically-shaped, which means the shape of a fibre helix with more than one loop and two ends which are not joined together.

With paliperidone is meant 3-[2-[4-(6-fluoro-l,2-benzisoxazol-3-yl)-l-piperidinyl]ethyl]- 6,7,8,9-tetrahydro-9-hydroxy-2-methyl-4H-pyrido[ 1 ,2-a]pyrimidin-4-one. Paliperidone is a non-ionized drug, having a molecular weight below 500 Dalton and having a solubility of 0.1 wt% in ethylene-vinyl acetate copolymer having a vinyl acetate content of 28 wt%. Solubility is measured as described in Laarhoven, J.A.H., et al. (2002), International Journal of Pharmaceutics 232, page 165. The salts of paliperidone are unsuitable for use in the formulation according to the invention.

In one embodiment of the invention the solid form required to obtain the high load of 5 to 80 wt% of paliperidone in the polymer is crystalline paliperidone. The crystals will effectively be dispersed within the polymer of the inner compartment. Another reason to require the presence of solid paliperidone is to obtain the extended delivery of paliperidone from within the inner compartment as will be explained in more detail herein below. In the delivery devices of the invention all polymer layers comprise paliperidone. When paliperidone in the manufacturing process of the ring is loaded in the intermediate layer, the drug diffuses during the production process and/or during storage of the ring to the skin and the core up to equilibrium concentration.

Cross-sectional presentation of a fibre of a three-layered drug delivery system is presented in Figure 1. The shape of the cross-section is substantially circular or substantially elliptical. In one embodiment of the invention the cross-section of the system has a substantially circular shape.

With continuous skin is meant that the skin continuously surrounds the paliperidone- containing compartment and is devoid of expressly provided parts in the skin for release of the drug. Thus, direct contact between vaginal tissue and the drug compartment is minimised in order to avoid local irritation. The skin is substantially continuous in the sense that only incidental apertures may be present, for example the ends of a helically shaped system or apertures due to shear during manufacturing or due to incomplete closure of ring ends, but such openings are not purposefully introduced into the skin in order to facilitate the passage of paliperidone through the skin.

An inner compartment is the compartment which contains the paliperidone to be delivered to the patient and which is covered by the skin. Therefore, there is no direct contact between the vaginal tissue and the inner compartment. The skin is the barrier protecting the vaginal tissue from undesirable local effects from the concentrated drug in the inner compartment. The inner compartment is formed by a thermoplastic polymer.

A core is an inner structure within the inner compartment and serves to reduce the drug- containing space in the inner compartment. The core does not contain solid paliperidone. It is not excluded, though, that the core material may comprise dissolved paliperidone. When paliperidone is loaded into the inner compartment during the production process, some paliperidone may enter into the core. The core can be made of any suitable material such as the thermoplastic polymer used for the inner compartment. The core can also contribute to the strength or flexibility of the device. In another context the inner compartment is also referred to as an intermediate layer when a core is present in the device.

Without undue burden the skilled person is capable to determine whether a polymer can be used for making the drug delivery system according to the present invention by confirming that: the polymer is a thermoplastic polymer suitable for pharmaceutical use; the polymer has a processing temperature for extrusion below the melting point of paliperidone, i.e. below approximately 175 ⁰C; and the polymer has a solubility parameter and a crystallinity close to the solubility parameter and crystallinity of the EVA copolymer, intended to be substituted by said polymer. Solubility parameters for polymers are tabulated in handbooks such as the Polymer Handbook (H. Burrell, Solubility Parameter Values, Polymer Handbook (J. Brandrup, E.H. Immergut, and W. McDowell, Eds), John Wiley, New York, p.IV-337 (1975)).

In one embodiment, ethylene-vinyl acetate copolymer is used due to its excellent mechanical and physical properties. The EVA copolymer may be used for the core, the intermediate compartment (inner compartment) as well as the skin and can be any commercially available ethylene-vinyl acetate copolymer, such as the products available under the trade names: Elvax, Evatane, Lupolen, Movriton, Ultrathene, Ateva, and

Vestypar. These ethylene-vinyl acetate copolymers are available in different grades with respect to the amount of vinyl acetate present in the copolymer, for example, EVA 28 is a copolymer having a vinyl acetate content of 28 wt%.

In one embodiment, at least the inner compartment is made of ethylene-vinyl acetate copolymer. In a further embodiment, the core, the intermediate layer, and the skin or the inner compartment (in a ring without core) and the skin are made of ethylene-vinyl acetate copolymers, which copolymers can each be of the same or different grades.

In another embodiment, the intermediate layer and the core are made of the same grade of ethylene-vinyl acetate copolymer. However, by electing different polymer grades for the intermediate layer and the core, fine-tuning of the flexibility of the ring is possible. The thickness of the skin and the vinyl acetate content of the skin influence the release rate of the active ingredient. The thinner the skin and the higher the vinyl acetate content of the skin, the higher the release rate of the active ingredient.

In one embodiment, EVA copolymers having a vinyl acetate content in the range of 0.5 to 40 wt% are used. In another embodiment, EVA copolymers having a vinyl acetate content in the range of 6 to 40 wt% are used. In yet another embodiment, EVA copolymers having a vinyl acetate content in the range of 6 to 33 wt% are used. In still another embodiment, EVA copolymers having a vinyl acetate content in the range of 9 to 33 wt% are used. In a further embodiment the copolymer of the inner compartment contains 20 to 40 wt% of vinyl acetate. In an even further embodiment the copolymer of the inner compartment contains 26 to 40 wt% of vinyl acetate. In another embodiment the copolymer of the inner compartment contains 26 to 35 wt% of vinyl acetate. In yet another embodiment, the core is made of EVA 9 or 28. In a still further embodiment, the skin is made of EVA copolymers having a vinyl acetate content in the range of 6 to 33wt % or 9 to 33 wt%, for example, EVA 9, EVA 15, EVA 18, EVA 28 or EVA 33. In even a further embodiment, the skin is made of EVA 33. Surprisingly, it has been found that a substantially constant release of paliperidone can be obtained with an extended release formulation according to the present invention having a skin made of EVA 28 or, even more surprising, a skin made of EVA 33. It is known in the art that the lower the vinyl acetate content of the EVA copolymers used, the higher the stiffness of the vaginal ring made therefrom. Moreover, a larger fibre diameter will also result in less flexibility.

The delivery system according to the present invention has superior drug delivery characteristics in terms of a substantially constant high release rate during its duration of use and is almost lacking initial burst release. The reduced burst release is defined by the burst-factor, which is defined as with Dl and D2 the in vitro release rate m measured on day 1 and day 2, respectively. In one embodiment of the invention the burst-factor is in the range of- 1.0 to + 3.0, in another embodiment in the range of - 0.5 to + 1.5 and in a further embodiment in the range of - 0.5 to + 0.5. The substantially constant release is defined by the constant release factor, which is calculated by dividing the average in vitro release rate of the first half of the release curve (AVGl) in mg/day excluding day 1, by the average release rate of the second half of the release curve (AVG2) in mg/day (e.g. for an in vitro release curve measured for 24 days the average release from day 2 to day 12 is divided by the average release from day 14 to day 24). In one embodiment of the present invention the constant release factor is in the range of 0.80 to 1.20, in another embodiment in the range of 0.85 to 1.15. for a period of use in the range of one week up to 1 or 2 months.

A further embodiment of the vaginal delivery system according to the present invention provides a release rate of paliperidone in the range of 0.5 to 12 mg/day for a period of use in the range of one week up to 1 or 2 months, another embodiment in the range of 2 to 8 mg/day for a period of use in the range of one week up to 1 or 2 months.

The delivery system of the invention comprising paliperidone is useful in treating female mammals suffering from diseases which are susceptible to treatment by said agent. Such diseases include mental disorders, such as schizophrenia and bipolar disorders. Thus further object of the invention is the use of the system according to the invention for treating mental disorders in female mammals.

The characteristic of the invention may be understood and influenced by the following explanation and use thereof: Fick's law of diffusion governs the release of compounds. Vaginal rings are cylindrical reservoir/membrane designs of which the release rate can be described by the equation below. Suitable rings can therefore be made by an appropriate choice of the parameters that affect the release rate. The release rate of a cylindrical reservoir/membrane design is:

dM ₌ 2πL D_P K_{P/ S}ΔC dt Ln (r₀ 1 X\ ) L = the length of the cylinder

D_p = the diffusion co-efficient of the compound in the skin polymer

K_p/S = partition coefficient of the compound between the skin and inner compartment

ΔC = the difference in concentration of dissolved paliperidone between the inner compartment near the skin and the in vitro release medium (under sink conditions) r₀ = is the overall radius, i.e. half the of the fibre diameter ri = is the radius of the inner compartment

V₂ = is the radius of the core

The in vitro release testing is conducted under sink conditions, i.e. the concentration of paliperidone in the release medium never reaches more than 10 to 15% of its maximum solubility.

The equation shows that zero order release is obtained when the term on the right-hand side of the equation is constant, i.e. not a function of time.

Substantially constant release rates of paliperidone of approximately 0.5 to 12 mg/day are provided with the devices according to the invention having a skin substantially continuously covering the inner compartment.

Apparently, the solubility of paliperidone in ethylene-vinyl acetate (EVA) of the inner compartment is such that the ΔC for paliperidone is high enough to provide for fast release kinetics. The limiting factor in maintaining a substantially constant ΔC in a quasi steady state with a high release rate of paliperidone, i.e. maintaining a substantially constant drug delivery from the device in the presence of a relatively thin skin with low barrier properties, is the supply of dissolved paliperidone to the interface between the inner compartment and the skin. The supply (or referred to as release rate) is the result of a complex mass transport process determined by factors including the dissolution rate of paliperidone into the polymer of the inner compartment, which in turn is determined by the solubility of paliperidone in said polymer and the surface area of the drug exposed to said polymer. The latter is determined by particle size, shape and paliperidone content. Also the diffusion rate of paliperidone through the polymer is an important factor for dissolution and release rate. Devices having paliperidone in the inner compartment in the range of 30 to 70 wt% not only provide for fast release rates but also provide for substantially constant release kinetics.

It is believed that with paliperidone contents in the polymer above approximately 30 wt% drug particles can be close to each other within the polymer of the inner compartment. The structure formed by the dispersed solid particles in the polymer depends on paliperidone content and additionally on particle size and shape. During paliperidone release, the properties of the inner compartment itself change in time by the slow dissolution of the drug particles, apparently facilitating drug dissolution and transport rate resulting in substantially constant high release rates. Probably the formation of improved diffusion pathways in the polymer by the progressively dissolving particles leaving voids in the polymer and the simultaneous flow of aqueous liquids through the skin into the inner compartment filling the voids with water are important factors in achieving substantially constant release at high levels of paliperidone content.

Three-layered fibres have an efficient design for obtaining devices with a low initial load of paliperidone. Moreover, in three-layered fibres the thickness of the skin and intermediate layer can be varied as well as the skin material of the devices. In this way the time period in which a therapeutically effective release rate is sustained can be modified in such a way that low residual contents of paliperidone in the device can be obtained at the end of that period by exhaustion of the intermediate layer. Additionally, in three-layered fibres where paliperidone present in the intermediate layer is sufficient to obtain the required delivery kinetics, efficient use of the drug can be advantageously further increased by using in the core polymer grades with very low solubility properties for paliperidone, such as EVA 6 or EVA 9. The high efficiency in delivered drug, i.e. high total amount of paliperidone released by the device at the end of the treatment time period in percentage of the initial drug load of the device, is advantageous not only from an economical but also from an ecological point of view. One embodiment of the device according to the invention has an efficiency in delivered paliperidone of at least 55%, another embodiment at least 70%.

A vaginal ring of the present invention can be manufactured by the known process of extrusion, such as co-extrusion and blend extrusion. To obtain the material for the inner compartment comprising the drug, paliperidone is mixed with an EVA copolymer. The major step in the mixing process is blend extrusion. Subsequently, the drug/EVA copolymer mixture is co-extruded with the core and skin materials into a three-layered (core comprising) fibre. Alternatively, the drug/EVA copolymer mixture is co-extruded with the skin material into a two-layered fibre (ring without core). After this step, the drug will partly be dissolved in the EVA copolymer. The solubility of the drug in the copolymer is determined by the vinyl acetate content of the EVA copolymer used. Any drug material that is not dissolved will be present as a solid phase in the inner compartment. The solid phase will be in equilibrium with the dissolved phase of the drug, such providing a constant concentration of dissolved active substance close to the rate controlling skin layer. The three-layered or two-layered fibre thus obtained is cut into pieces of a desired length and each piece is assembled to a ring-shaped device in any suitable manner known to the person skilled in this art. The rings are then packed, for example in a suitable sachet, optionally after being sterilized or disinfected.

A person skilled in the art of extrusion will have no difficulty in finding the optimal processing conditions, such as determining the extrusion temperature, extrusion speed, and air gap, for making a three-layered or two-layered fibre containing drug on the basis of methods and procedures known in the art and the description and examples given in this application. A suitable temperature for blend extrusion of the drug/EVA copolymer mixture lies in the range of 80 to 130 ⁰C, e.g. approx. 90 ⁰C. Suitable temperatures for co-extrusion of the three-layered or two-layered fibre lie in the range of 80 to 150 ⁰C. A preferred temperature for extrusion of paliperidone/EVA copolymer mixtures is below the melting point of the drug, i.e. below approximately 175 ⁰C. Melting the drug during extrusion may lead to phenomena like delayed crystallization of the drug. In the manufacture of the extended release formulation according to the invention crystalline paliperidone is preferred.

In this way, vaginal rings with constant release rates of paliperidone, for example releasing in the range of 0.5 to 12 mg/day of the drug, can be manufactured.

The vaginal ring according to the present invention can be manufactured in any practical size. In one embodiment, the ring has an outer diameter in the range of about 50 to 60 mm and in another embodiment about 52 to 56 mm. In a further embodiment, the fibre diameter is in the range of about 2.0 to 6.0 mm, in a still further embodiment about 2.5 to 5.0 mm, in another embodiment about 3.0 to 4.0 mm, and in yet another embodiment it is about 4.0 mm. In one embodiment, the amount of paliperidone contained in the inner compartment is in the range of 5 to 80 wt%, in another embodiment 10 to 70 wt %, in still another embodiment 30 to 70 wt%, and in a further embodiment 40 to 65 wt%.

In another embodiment, the skin is made of EVA copolymers having a vinyl acetate content in the range of 9 to 33 wt% and the inner compartment contains paliperidone in the range of 30 to 65 wt%. In yet another embodiment, the skin has a thickness in the range of 20 to 200 μm and is made of EVA copolymers having a vinyl acetate content in the range of 15 to 33 wt%, the inner compartment is made of EVA copolymers having a vinyl acetate content in the range of 28 to 33 wt% and contains paliperidone in the range of 40 to 65 wt%.

In one embodiment the drug delivery system according to the invention is a cylindrical fibre, consisting of a cylindrical inner compartment and a skin covering this compartment. In another embodiment the diameter of such a cylindrical fibre is in the range of 2.5 to 6 mm, in a further embodiment 3.0 to 5.5 mm, and in still a further embodiment 3.5 to 4.5 mm and in yet another embodiment 4.0 to 5.0 mm. In one embodiment, the surface of the fibre is more than 800 mm², and in another embodiment more than 1000 mm² and in a further embodiment in the range of 1700 to 2200 mm². Significantly larger surfaces are possible, provided that the design (physical dimensions) of a drug delivery system intended for vaginal use prevents inconvenience for the subject.

In one embodiment said skin has a thickness in the range of 20 to 200 μm and in another 20 to 100 μm. In a still further embodiment said skin has a thickness in the range of 20 to 70 μm.

The subject invention provides for a method of manufacturing the three-layered delivery system with paliperidone in the intermediate layer, comprising: (i) producing a medicated homogenous polymer intermediate layer granulate;

(ii) co-extruding a polymer core granulate and the intermediate layer granulate with a polymer skin granulate to form the three-layered fibre

(iii) collecting the fibre on a reel and forming the extended release system according to the invention.

The production of the medicated homogeneous polymer intermediate layer granulate comprises: a. grinding the polymer; b. dry powder mixing the grounded polymer with paliperidone to be loaded in the intermediate layer; c. blend extruding the resulting powder mixture; d. cutting the resulting medicated polymer strands into granules, thereby obtaining an intermediate layer granulate; e. lubricating the intermediate granulate with a lubricant.

REFERENCES

A.D. Woolfson, et al, Journal of Controlled Release (2003), 19: 465-476. J.A.H. van Laarhoven, et al. International Journal of Pharmaceutics (2002), 232: 165. H. Burrell, Solubility Parameter Values Polymer Handbook (J. Brandrup, E.H. Immergut, and W. McDowell, Eds), John Wiley, New York, p.IV-337 (1975).

FIGURE LEGENDS

Figure 1 shows a cross-sectional presentation of a fibre of a three-layered drug (core comprising) delivery system in accordance with the present invention (r₀ = is the overall radius, i.e. half the fibre diameter; Xγ = is the radius of the inner compartment; r₂ = is the radius of the core).

The present invention is illustrated by the following Examples.

EXAMPLE 1 Preparation of three-layered vaginal rings containing paliperidone

Preparation of three-layered vaginal rings consists of several steps. First of all, an inner compartment granulate containing paliperidone and EVA 33 copolymer is manufactured in a conventional way by pre-mixing, blend extrusion and lubrication with magnesium stearate. Secondly, a core material of EVA 28 is prepared by lubricating the as-supplied material. Subsequently, the inner compartment granulate, the core granulate and the skin material are co-extruded into a three-layered fibre. The fibre is cut to fibre ends of a specific length, as described below, after which the fibre ends are welded to a ring.

The inner compartment material is prepared by adding the desired amount of ingredients to a stainless steel drum after which the powder mixture is pre-mixed by rotating the drum on a Rhόnrad at 47 rpm for 60 minutes. The powder mixture is subsequently fed to a Berstorff ZE25 co-rotating twin screw extruder and blend extruded at an extrusion temperature of 80 ⁰C. Blend extrusion results in strands in which paliperidone is homogeneously dispersed in the EVA 33 copolymer. The strands are subsequently granulated to inner compartment granulate. Prior to co-extrusion, the intermediate layer granulate is lubricated with 0.1 wt% magnesium stearate and homogenized in a stainless steel drum on a Rhόnrad (barrel-hoop principle) with a fixed rotation speed of 47 rpm for 60 minutes.

The core granulate EVA 28 is also lubricated with 0.1 wt% magnesium stearate and homogenized in stainless steel drum on a Rhόnrad (barrel-hoop principle) with a fixed rotation speed of 47 rpm for 60 minutes. The co-extrusion set-up consists of a 15 mm skin extruder that processes the skin material, a 18 mm core extruder that processes the core material and an 18 mm inner compartment extruder that processes the inner compartment granulate as delivered by the blend extruder. The melt flows are combined in a spinneret resulting in a three- layered skin-inner compartment-core fibre. The volume flow rate of all three melt flows is controlled by a set of separate spinning pumps. An extrusion temperature of approx. 90 ⁰C is used. Extrusion results in a three-layered fibre with a diameter of approx. 4 mm. The fibre is cooled down to room temperature in a water bath and wound on a reel. The fibre is cut into 157 mm fibre ends and subsequently the fibre ends are welded into a ring at 110 0C.

Table 1. Examples of three-layered paliperidone rings comprising an EVA 28 core

In vitro release of three-layered vaginal rings containing paliperidone

The in vitro release of three-layered vaginal rings containing paliperidone is measured in water (buffered at pH 4.4) at 37 ⁰C for at least 24 days. The dimensions of examples of paliperidone rings comprising a core are reflected in Table 1.

EXAMPLE 2 Test of the risk of dose-dumping

In an in vitro release study in water (buffered at pH 4.4) at 37 ⁰C the paliperidone release rate of a vaginal ring according to the invention is compared with a ring, cut into a rod with two open "ring-ends".

Claims

1. An extended release formulation comprising paliperidone, characterised in that the formulation is a vaginal device having a skin and which device comprises an inner compartment made of a thermoplastic polymer, which polymer contains solid paliperidone.

2. The formulation according to claim 1, characterised in that the polymer contains paliperidone in the range of 5 to 80 wt%.

3. The formulation according to claim 2, characterised in that the polymer contains paliperidone in the range of 30 to 70 wt%.

4. The formulation according to any one of claims 1-3, characterised in that the skin is substantially continuous.

5. The formulation according to any one of claims 1-4, characterised in that the device is a ring.

6. The formulation according to any one of claims 1-5, characterised in that the inner compartment is made of ethylene-vinyl acetate copolymer.

7. The formulation according to any one of claims 1-6, characterised in that the inner compartment comprises a core, which does not contain solid paliperidone.

8. The formulation according to any one of claims 1-7, characterised in that the skin is made of ethylene-vinyl acetate copolymer.

9. The formulation according to claim 7 or 8, characterised in that an ethylene-vinyl acetate copolymer having a vinyl acetate content in the range of 0.5 to 40 wt% is used.

10. The formulation according to any one of claims 1 to 9 for treating mental disorders in a female mammal.

11. A method of treating mental disorders, comprising (i) positioning a formulation according to any one of claims 1 to 9 within the female vaginal tract and (ii) retaining the formulation within the vaginal tract for a period in the range of one week up to one or two months.

12. A method of manufacturing a formulation according to any one of claims 1 to 9, comprising the steps of: (i) producing a medicated homogenous ethylene-vinyl acetate copolymer inner compartment granulate comprising paliperidone; (ii) co-extruding the inner compartment granulate with an ethylene-vinyl acetate copolymer skin granulate, resulting in a copolymer fibre comprising an inner compartment covered by a skin; (iii) forming the extended release formulation according to the invention.