WO2022013233A1

WO2022013233A1 - Water-free process for preparing a pharmaceutical composition for a more sustained and controlled release of triptorelin or a salt thereof

Info

Publication number: WO2022013233A1
Application number: PCT/EP2021/069491
Authority: WO
Inventors: Paolo Sarmientos; Simona Cerritelli; Carlo Colombo
Original assignee: Xbrane Biopharma Ab; Primm Pharma Srl
Priority date: 2020-07-15
Filing date: 2021-07-13
Publication date: 2022-01-20
Also published as: IT202000017191A1

Abstract

The invention relates to a process and apparatus for preparing a pharmaceutical composition for sustained and controlled release of triptorelin or a salt thereof, said process comprising the steps of: - mixing, in a plurality of reactors, triptorelin or a salt thereof with one or more organic solvents; - adding encapsulation polymer to the resulting suspension; - adding a coacervation agent to the resulting dispersion to form soft microcapsules comprising encapsulation polymer and triptorelin or a salt thereof; - transferring the mixture comprising the soft microcapsules from the plurality of reactors to at least one hardening vessel; - mixing, in the at least one hardening vessel, the mixture comprising the soft microcapsules with a hardening liquid; - filtering and drying, in at least one filtering device, the resulting hard microcapsules; and - adding, to a container, the dried microcapsules as well as one or more dried pharmaceutical excipients.

Description

WATER-FREE PROCESS FOR PREPARING A PHARMACEUTICAL COMPOSITION FOR A MORE SUSTAINED AND CONTROLLED RELEASE OF TRIPTORELIN OR A SALT THEREOF

DESCRIPTION

TECHNICAL FIELD

The present invention relates to a process and apparatus for preparing a pharmaceutical composition for sustained and controlled release of triptorelin or a salt thereof. BACKGROUND OF THE INVENTION

Triptorelin, sold under the brand names such as Decapeptyl, Trelstar, Gonapeptyl among others, is a medication that acts as an agonist analog of Gonadotropin -releasing hormone (GnRH), thus reversibly repressing of luteinizing hormone (LH) and follicle- stimulating hormone (FSH). It is a decapeptide (pGlu-His-Trp-Ser-Tyr-D-Trp-Leu-Arg-Pro-Gly-NH2) and a gonadotropin-releasing hormone agonist (GnRH agonist) used as the acetate or pamoate salts. Primary indications include treatment of endometriosis, uterine fibroids, prostate cancer and precocious puberty. The formulations adopted can take the form of microcapsules in which the triptorelin is incorporated in a biodegradable polymer or copolymer such as poly(lactic-co-glycolic acid) also referred to as PLGA.

Some prior at documents relating to triptorelin are US6217893, US5192741, EP2164467 and WO02058672.

Microparticles comprising an active principle and biodegradable polymer or copolymer can be prepared according to the three different methodologies described below:

1. Solvent Evaporation Method

(a) Single emulsion process: Oil-in-water emulsification processes are examples of single emulsion processes. Polymer in the appropriate amount is first dissolved in a water immiscible, volatile organic solvent (e.g., dichloromethane (DCM)) in order to prepare a single-phase solution. The drug of particle size around 20-30 pm is added to the solution to produce a dispersion in the solution. This polymer dissolved drug dispersed solution is then emulsified in large volume of water in presence of emulsifier (polyvinyl alcohol (PVA) etc.) in appropriate temperature with stirring. The organic solvent is then allowed to evaporate or extracted to harden the oil droplets under applicable conditions. In former case, the emulsion is maintained at reduced or atmospheric pressure with controlling the stir rate as solvent evaporates. In the latter case, the emulsion is transferred to a large quantity of water (with or without surfactant) or other quench medium to diffuse out the solvent associated with the oil droplets. The resultant solid microcapsules (sometimes also referred to as microspheres) are then washed and dried under appropriate conditions to give a final injectable (after reconstitution) microcapsules formulation.

(b) Double (Multiple) emulsion process: Water- in-oil-in- water emulsion methods are best suited to encapsulate water-soluble drugs like peptides, proteins, and vaccines, unlike single emulsion methods which is ideal for water-insoluble drugs like steroids. First, an appropriate amount of drug is dissolved in aqueous phase (deionized water) and then this drug solution is added to organic phase consisting of PLGA and/or PLA (polylactic acid) solution in DCM or chloroform with vigorous stirring to yield a water-in-oil emulsion. Next, the water-in-oil primary emulsion is added to PVA aqueous solution and further emulsified for around a minute at appropriate stress mixing conditions. The organic solvent is then allowed to evaporate or is extracted in the same manner as oil-in-water emulsion techniques. In double emulsion processes, choice of solvents and stirring rate predominantly affects the encapsulation efficiency and final particle size.

2. Phase Separation (Coacervation) — Coacervation is a process focused on preparation of micrometer sized biodegradable polymer encapsulation formulations via liquid-liquid phase separation techniques. The process yields two liquid phases (phase separation) including the polymer containing coacervate phase and the supernatant phase depleted in polymer. The drug which is dispersed/dissolved in the polymer solution is coated by the coacervate. Thus, the coacervation process includes the following three steps: 1. Phase separation of the coating polymer solution, 2. Adsorption of the coacervate around the drug particles, and 3. Hardening of the microcapsules. In the art, the step of hardening the microcapsules is also referred to as quenching of the microspheres. Solutions are prepared by mixing polymer and solvent in appropriate ratios. Hydrophilic drugs like peptides and proteins are dissolved in water and dispersed in polymer solution (water-in-oil emulsion). Hydrophobic drugs like steroids are either solubilized or dispersed in the polymer solution (oil-in-water emulsion). Gradual addition of organic medium to the polymer-drug-solvent phase while stirring, extracts the polymer solvent resulting in phase separation of polymer by forming a soft coacervate of drug containing droplets. The size of these droplets can be controlled by varying stirring rate and temperature of the system. The system is then quickly dipped into a hardening liquid in which it is not soluble (both organic or aqueous) to quench these microdroplets. The soaking time in the hardening bath controls the coarsening and hardness of the droplets. The final form of the microcapsules is collected by washing, sieving, filtration, centrifugation or freeze drying. The processing parameters including polymer concentration, hardening temperature, hardening time and solvent composition affect the morphology and size of the microcapsules.

3. Spray Drying — In this process, drug / protein/peptide loaded microcapsules are prepared by spraying a solid-in-oil dispersion or water-in-oil emulsion in a stream of heated air. The type of drug (hydrophobic or hydrophilic) decides the choice of solvent to be used in the process. The nature of solvent used, temperature of the solvent evaporation and feed rate affects the morphology of the microcapsules. The main disadvantage of this process is the adhesion of the microparticles to the inner walls of the spray-dryer.

All of the above-described techniques provide microcapsules with good properties in terms of drug-loading, dimension, in vitro and in vivo drug release. However, at the end of the microcapsule production it is necessary to mix the microcapsules with excipients before their administration to the patient.

The mix of microcapsules and excipients is usually done by suspending the bulk of microcapsules in a lyophilization medium consisting of excipients (such as mannitol, Tween 80 and sodium carboxymethyl-cellulose) dissolved in water (or more precisely water for injection - WFI). After the lyophilization process the product is dispensed in single vials, ready for use.

Unfortunately, microcapsules made of PLGA-based polymers and other polymers which are water sensitive (PLGA has ester bonds which are hydrolytically unstable) start degrade as soon as they come into contact with water. As explained in the coacervation process described above, the microparticles are formed in a totally organic environment. However, the last step is the addition of excipients to the microparticles and this is performed in water by mixing the solution of excipients with the microparticles and performing a final lyophilization step. This cause the microparticles to get in contact with water and start the process of degradation. Hence, there is a need for a new process of preparing pharmaceutical composition comprising triptorelin in which said degradation process is hindered. Moreover, other factors such as the medium used in quenching bath (i.e. hardening bath) in the case of the coacervation process, may also affect the stability of the microparticles. Hence, there is a need for a new process for preparing pharmaceutical composition comprising triptorelin in which the pharmaceutical composition comprises as low amounts as possible of impurities such as the hardening liquid and other solvents used in the process of preparing the pharmaceutical composition. Furthermore, the inventors have discovered that the sustained and controlled release pattern of triptorelin in the commercially sold product “Decapeptyl” has a high rate of initial burst, in other words, the rate of the amount (in weight %) of triptorelin cumulatively released in the first 0-24 hours is relatively high. Consequently, the release pattern at the beginning is different than the release pattern in the middle (24-72 hours) and at the near end (72-96 hours) of the therapeutic cycle. Consequently, there is a need for providing pharmaceutical composition comprising triptorelin or a salt with a more controlled release pattern.

OBJECT OF THE INVENTION

The object of the invention is to provide a pharmaceutical composition comprising triptorelin or a salt thereof which is stable.

A further object of the invention is to provide a pharmaceutical composition comprising triptorelin or a salt thereof wherein the pharmaceutical composition comprises low amounts of residual solvents that could affect the total amounts of impurities in the pharmaceutical composition.

A further object of the invention is to provide a pharmaceutical composition comprising triptorelin or a salt thereof which has a decreased rate of initial burst, i.e. has a decreased rate of the amount (in weight %) of triptorelin cumulatively released in the first 24 hours when compared to commercial products such as Decapeptyl.

A further object of the invention is to provide a pharmaceutical composition comprising triptorelin or a salt thereof which has a more controlled release pattern at the beginning, in the middle and at the end of the therapeutic cycle.

A further object of the invention is to provide a pharmaceutical composition which can be stored at ambient temperature and is stable for at least 12 months.

A further object of the invention is to provide a process for preparing pharmaceutical composition comprising triptorelin or a salt thereof wherein the process has dose reproducibility.

A further object of the invention is to provide a water-free process for preparing pharmaceutical composition comprising triptorelin or a salt thereof.

SUMMARY OF THE INVENTION

Other features and advantages of this invention will be apparent from the specification and claims and from the accompanying drawings which illustrate certain embodiments of this invention.

Processes, apparatus and pharmaceutical compositions having the features defined in the independent claims are provided for solving or at least ameliorating one or more of the identified problems as well as achieving the objects of the invention. Preferable embodiments are defined in the dependent claims. A first aspect of the invention relates to a process for preparing a pharmaceutical composition for sustained and controlled release of triptorelin or a salt thereof, said process comprising the steps of: a) mixing, in a plurality of reactors, triptorelin or a salt thereof with one or more organic solvents; b) adding encapsulation polymer to the resulting suspension; c) adding a coacervation agent to the resulting dispersion to form soft microcapsules comprising encapsulation polymer and triptorelin or a salt thereof; d) transferring the mixture comprising the soft microcapsules from the plurality of reactors to at least one hardening vessel; e) mixing, in the at least one hardening vessel, the mixture comprising the soft microcapsules with a hardening liquid; f) filtering and drying, in at least one filtering device, the resulting hard microcapsules; and g) optionally, adding the dried microcapsules to one or more dried pharmaceutical excipients or adding one or more dried pharmaceutical excipients to the dried microcapsules; wherein the number of reactors comprised in the plurality of reactors is greater than the number of vessel(s) comprised in the at least one hardening vessel; and wherein each of the above listed steps a-g of the process is carried out in a water-free environment.

In an embodiment, step (g) is carried out, i.e. it is not an optional step.

In an embodiment, the number of at least one hardening vessel is two or more hardening vessels, wherein the number of reactors comprised in the plurality of reactors is at least two times greater than the number of hardening vessels.

In an embodiment, the number of at least one hardening vessel is two or more hardening vessels, wherein the number of reactors comprised in the plurality of reactors is at least three times greater than the number of hardening vessels.

In an embodiment, the step of transferring the mixture comprising microcapsules from the plurality of reactors to the hardening vessels is carried out by equally dividing the contents of the plurality of reactors between the hardening vessels.

In an embodiment, the ratio between: the volume of hardening liquid in each of the hardening vessels, and the volume of the mixture comprising soft microcapsules transferred from the plurality of reactors to each of the hardening vessels, ranges from 5:1 to 40:1. Alternatively, the ratio may be 4:1 to 30:1; 6:1 to 20:1; or 7:1 to 10:1. In an embodiment, the ratio between: the inner volume of each of the hardening vessels, and the inner volume of each of the plurality of reactors, ranges from 5:1 to 80:1, preferably from 10:1 to 70:1, more preferably from 20:1 to 60:1.

In an embodiment, the one or more organic solvents comprise one or more of esters, halogenated hydrocarbons, ethers and aromatic hydrocarbons, preferably one or more of methylene chloride, trichloromethane, carbon tetrachloride, ethylene dichloride, ethylene chloride, 1,1,2 trichloroethane and 2,2,2-trichloroethane, ethylacetate, methyl acetate, ethyl formate, methyl formate, ethyl ether and isopropyl ether, benzene, toluene and xylene.

In an embodiment, the encapsulation polymer is a biodegradable polymer or copolymer selected from one or more of polyglycolic acid - PGA; polylactic acid - PLA; poly(lactic-co- glycolic acid) - PLGA; poly(p-dioxanone); poly(glycolide-co-triethylene carbonate); a block copolymer of polyglycolide, trimethylene carbonate and polyethylene oxide; poly(alkylene diglycolates); poly(alkylene succinates); poly(alkylene oxalates); poly(caprolactone); poly(alpha-hydroxybutyric acid); poly(ortho esters); poly(anhydrides); poly(amide esters); poly(alkylene tartrate); poly(alkylene fumarate); polystyrene; polymethacrylic acid; copolymers of poly(ethylene glycol) - PEG; triblock copolymers of poly(propylene glycol) flanked by poly (ethylene glycol); methacrylic acid/acrylic acid copolymers; poly amino acids; polyurethanes; polyphosphazenes; maleic anhydride polymers; ethyl cellulose; nitrocellulose; and acetyl cellulose.

In an embodiment, the encapsulation polymer is PLGA produced from 40 to 90 percent of lactic acid and from 10 to 60 percent of glycolic acid, preferably PLGA is ester terminated, more preferably, PLGA is D,L-PLGA produced from 50 to 80 percent of DL-lactic acid and 20 to 50 percent of glycolic acid, more preferably PLGA is D,L-PLGA produced from about 50 percent of DL-lactic acid and about 50 percent of glycolic acid. Percent of lactic acid and glycolic acid in PLGA is mole percent.

In an embodiment, the coacervation agent is selected from one or more of silicone oil, vegetable oil, polyisobutylene, mineral oil and or cyclic polydimethylsiloxane, preferably silicone oil, more preferably dimethicone.

In an embodiment, the hardening liquid comprises one or more organic compounds and/or a silicone fluids, preferably the hardening liquid comprises an alkane or a siloxane, more preferably one or more of hexane, cyclohexane, heptane, petroleum ether, octamethylcyclotetrasiloxane, decamethylcyclopentasiloxane and hexamethyldisiloxane.

In an embodiment, triptorelin or a salt thereof is selected from the group consisting of triptorelin acetate, triptorelin pamoate, triptorelin tannate and triptorelin stearate, preferably triptorelin or a salt thereof is selected from the group consisting of triptorelin acetate and triptorelin pamoate, more preferably triptorelin or a salt is triptorelin acetate.

In an embodiment, the mixing in step (a) is carried out by stirring the mixture in each of the plurality of reactors at a rotation per minute (RPM) and a time duration which substantially disaggregates powder clumps of triptorelin or salts thereof.

In an embodiment, step (b) is carried out while stirring at a RPM and time duration until substantial dissolution of the encapsulation polymer.

In an embodiment, step (c) is carried out in the plurality of reactors while stirring at a RPM and time duration until substantial coacervation.

In an embodiment, step (e) is carried out in the plurality of reactors while stirring at a RPM and time duration until substantial precipitation and hardening of microcapsules.

In an embodiment, step (e) further comprises a first sub-step (el) comprising the stirring being stopped for letting the microcapsules settle and then decanting the hardening liquid (i.e. decanting the supernatant). The first sub-step (el) is thereafter followed by a second sub-step (e2) comprising adding hardening liquid to the hardening vessel, stirring the hardening liquid with the settled particles, stopping the stirring for letting the hard microcapsules settle and then decanting the hardening liquid (i.e. decanting the supernatant). The second sub-step (e2) is followed with by a third sub-step (e3) comprising the hard microcapsules being resuspended in the hardening tank with the hardening liquid.

In an embodiment, one or more of steps (b), (c) and (e), as well as any sub-steps thereof, are carried out at a temperature lower than ambient temperature, preferably at a temperature interval of 15-18 °C or lower, more preferably at a temperature interval of 15-18 °C.

In an embodiment, step (f) is carried out on resuspended hard microcapsules.

In an embodiment, stirring is carried out by stirring with an impeller.

In an embodiment, the temperature of the inside each of the plurality of reactors and/or the at least one hardening vessel is controlled by carrying out in-thermostating and out- thermo stating. In such an embodiment, preferably, the plurality of reactors and/or the at least one hardening vessel comprise a cooling or heating jacket around each reactor and/or vessel through which a cooling or heating fluid is configured to be circulated, wherein said jacket is a cavity external to the each reactor and/or vessel that is configured to permit the uniform exchange of heat between the fluid circulating in it and the walls of the reactor and/or vessel. In an embodiment, the one or more dried pharmaceutical excipients are selected from one or more of sodium carboxymethyl cellulose, mannitol and Tween 80; preferably the one or more dried pharmaceutical excipients comprise carboxymethylcellulose, mannitol and Tween 80; more preferably the one or more dried pharmaceutical excipients comprise 50-90 weight-% mannitol, 5-45.5 weight-% carboxymethylcellulose and 0.5-5 weight-% Tween 80; most preferably the one or more dried pharmaceutical excipients comprise 65-75 weight-% mannitol, 15-35 weight-% carboxymethylcellulose and 0.1-10 weight-% Tween 80, based on the total weight of the dried pharmaceutical excipients.

In an embodiment, the step of adding the dried microcapsules to one or more dried pharmaceutical excipients comprises the step of sequentially adding the dried microcapsules to one or more dried pharmaceutical excipients or sequentially adding one or more dried pharmaceutical excipients to the dried microcapsules.

In an embodiment, between steps (f) and (g), the dried microcapsules are in one or more intermediary steps subjected to: sieving by using one or more sieves having one or more sieve sizes, preferably sieving by first using a sieve having a 200 micrometer sieve size and then using a sieve having 20 micrometer sieve size; and/or dry-mixing in a blender or another type of mixing equipment.

In an embodiment, step (g) results in a pharmaceutical composition comprising:

0.5 or lower weight-% of the one or more organic solvents;

4.0 or lower weight-% of the hardening liquid; and/or 3.0 or lower weight-% of water.

In an embodiment, step (g) is carried out in one or more containers, preferably the container is a vial, a syringe, a tube, an ampoule or a blister package, more preferably the container is a vial or ampoule, most preferably the container is a vial.

In an embodiment, the process according to the present invention comprises the steps of: a) mixing, in a plurality of six reactors, triptorelin acetate with methylene chloride; b) adding PLGA to the resulting suspension; c) adding dimethicone to the resulting dispersion to form soft microcapsules comprising PLGA and triptorelin acetate; d) transferring the mixture comprising the soft microcapsules from the plurality of reactors to two hardening vessels; e) mixing, in the hardening vessel, the mixture comprising the soft microcapsules with n-heptane; f) filtering and drying, in at least one filtering drier, the resulting hard microcapsules; and g) adding the dried microcapsules to one or more dried pharmaceutical excipients, wherein the one or more dried pharmaceutical excipients comprise sodium carboxymethylcellulose, D-mannitol and Tween 80, wherein each of the above listed steps a-g of the process is carried out in a water-free environment.

In an embodiment, the amount of pharmaceutical composition varies ± 2.5 weight-% between each container.

In an embodiment, the resulting pharmaceutical composition is stable for at least 12 months at 25+/-2 °C.

Stability is measured according to ICH Guidelines Q1A(R2). A second aspect of the invention relates to a pharmaceutical composition obtainable by the process according to the first aspect of the invention and the embodiments thereof described above.

In an embodiment, the pharmaceutical composition comprises:

0.5 or lower weight-% of the one or more organic solvents;

A third aspect of the invention relates to a pharmaceutical composition for sustained and controlled release of triptorelin or a salt thereof, comprising:

10-60 weight-% dried pharmaceutical excipients;

40-90 weight-% dried microcapsules comprising encapsulation polymer and triptorelin or a salt thereof; wherein said pharmaceutical composition comprises:

0.5 or lower weight-% of the one or more organic solvents;

In an embodiment, the pharmaceutical composition comprises:

30-50 weight-% dried pharmaceutical excipients;

50-70 weight-% dried microcapsules comprising encapsulation polymer and triptorelin or a salt thereof; wherein said pharmaceutical composition comprises: 0.5 or lower weight-% of the one or more organic solvents;

In an embodiment, the pharmaceutical composition comprises: about 40 weight-% dried pharmaceutical excipients; about 60 weight-% dried microcapsules comprising encapsulation polymer and triptorelin or a salt thereof; wherein said pharmaceutical composition comprises:

0.5 or lower weight-% of the one or more organic solvents;

Unless otherwise specified, percentages by weight (weight-%) of components of a composition are meant to be based on the total weight of the composition whose content is being defined.

In an embodiment, the dried microcapsules comprise at least 80 weight-% encapsulation polymer and the rest being triptorelin or a salt thereof, on the total weight of the dried microcapsules; preferably the dried microcapsules comprise at least 85 weight-% encapsulation polymer and the rest being triptorelin or a salt thereof; more preferably the dried microcapsules comprise at least 90 weight-% encapsulation polymer and the rest being triptorelin or a salt thereof; and most preferably the dried microcapsules comprise at least 95 weight-% encapsulation polymer and the rest being triptorelin or a salt thereof, on the total weight of the dried microcapsules.

In an embodiment, the pharmaceutical composition comprises microcapsules having a diameter between 20 and 200 micrometer.

A fourth aspect of the invention relates to a kit of parts comprising a container and a pharmaceutical composition according to the second or third aspects of the invention (and embodiments thereof) comprised in said container, preferably the container is a vial, a syringe, a tube, an ampoule or a blister package, more preferably the container is a vial or ampoule, most preferably the container is a vial.

A fifth aspect of the invention relates to an apparatus suitable for preparing a pharmaceutical composition for sustained and controlled release of triptorelin or a salt thereof, said apparatus comprising: a plurality of reactors (10, 11, 12, 13, 14, 15), configured for S mixing, triptorelin or a salt thereof with one or more organic solvents; S adding encapsulation polymer to the resulting suspension; S adding a coacervation agent to the resulting dispersion to form soft microcapsules comprising encapsulation polymer and triptorelin or a salt thereof; at least one hardening vessel (20, 21); transfer tubes configured for transferring the mixture comprising the soft microcapsules from the plurality of reactors (10, 11, 12, 13, 14, 15) to the at least one hardening vessel (20, 21), and wherein the at least one hardening vessel (20, 21) is configured for mixing the mixture comprising the soft microcapsules with a hardening liquid; and at least one filtering device, configured for filtering and drying the resulting hard microcapsules; wherein the number of reactors comprised in the plurality of reactors is greater than the number of vessel(s) comprised in the at least one hardening vessel.

In an embodiment, the number of at least one hardening vessel is two or more hardening vessels, wherein the number of reactors comprised in the plurality of reactors is at least two to three times greater than the number of hardening vessels.

In an embodiment, the apparatus comprises one hardening vessel and a plurality of three reactors.

In an embodiment, the ratio between: the inner volume of each of the at least one hardening vessel, and the inner volume of each of the plurality of reactors, ranges from 5:1 to 80:1, preferably from 10:1 to 70:1, more preferably from 20:1 to 60:1.

In an embodiment, the plurality of reactors and/or the at least one hardening vessel are made of glass material.

In an embodiment, the plurality of reactors and/or the at least one hardening vessel comprise one or more of a relief valve, temperature probe, a pressure gauge and a rupture disc.

In an embodiment, the plurality of reactors and/or the at least one hardening vessel comprise an impeller configured for stirring.

In an embodiment, the plurality of reactors and/or the at least one hardening vessel comprise a cooling or heating jacket around each reactor and/or vessel through which a cooling or heating fluid is configured to be circulated, wherein said jacket is a cavity external to the each reactor and/or vessel that is configured to permit the uniform exchange of heat between the fluid circulating in it and the walls of the vessel. In an embodiment, the at least one filtering device is a filter drier.

BRIEF DESCRIPTION OF DRAWINGS

Figure 1 illustrates a front view of an exemplary apparatus of this invention, with a cross sectional view of a plurality of six reactors and two hardening vessels.

Figure 2 shows a graph in which the trends of the cumulative release of triptorelin in the pharmaceutical compositions according to the present invention (Samples 1-4) is compared to that of commercially sold product “Decapeptyl”.

DETAIFED DESCRIPTION

The present invention relates to a process and apparatus for preparing a pharmaceutical composition for sustained and controlled release of triptorelin or a salt thereof. Preferred salts of triptorelin are the acetate, pamoate, tannate and stearate salts of t iptorclirh The process according to the present invention comprises the step of: a) mixing, in a plurality of reactors 10, 11, 12, 13, 14, 15, triptorelin or a salt thereof with one or more organic solvent; b) adding encapsulation polymer to the resulting suspension; c) adding a coacervation agent to the resulting dispersion to form soft microcapsules comprising encapsulation polymer and triptorelin or a salt thereof; d) transferring the mixture comprising the soft microcapsules from the plurality of reactors 10, 11, 12, 13, 14, 15 to at least one hardening vessel 20, 21; e) mixing, in the at least one hardening vessel 20, 21, the mixture comprising the soft microcapsules with a hardening liquid; f) filtering and drying, in at least one filtering device, the resulting hard microcapsules; and g) adding (for example in a container) the dried microcapsules to one or more dried pharmaceutical excipients; wherein the number of reactors comprised in the plurality of reactors is greater than the number of vessel(s) comprised in the at least one hardening vessel; and wherein all of the above listed steps in the process are carried out in a water-free environment. In an embodiment of the invention, step (g) may be an optional step.

The term “water-free environment” means that each of steps a-g of the above described process is carried out without substantial amounts of water (i.e. water in liquid phase) being present in each of steps a-g. Preferably, “water-free environment” is less than or equal to 5.0 weight-% water in liquid phase being present in each of steps a-g (i.e. less than or equal to 5.0 weight-% water in liquid being present in/inside a reactor, a hardening vessel, a transfer tube, a filter device or a container). More preferably, “water-free environment” is less than or equal to 3.0 weight-% water in liquid phase being present in each of steps a-g.

An example of an apparatus according to the present invention which may be used for carrying out the above-described process is illustrated in figure 1. The reactors and hardening vessel(s) are preferably made of glass material that is approved for preparing pharmaceutical compositions to be administered to a human subject. An example of such type of glass is borosilicate glass. The reactors and hardening vessels may have one or more sidearms offering easy access without interrupting the reactions taking place therein. Moreover, as illustrated in figure 1, the plurality of reactors may each comprise a relief valve (RV), temperature probe (TP) and a pressure gauge (PG) to control pressure. Furthermore each of the hardening vessels may also comprise a temperature probe (TP) and a pressure gauge (PG) as well as a rupture disc (RD).

The organic solvent may be transferred to the plurality of reactors 10, 11, 12, 13, 14, 15 from at least one solvent tank before the step (a) of mixing with triptorelin or a salt thereof. The mixing in step (a) is carried out by stirring the mixture in each of the plurality of reactors at a rotation per minute (RPM) and a time duration which substantially disaggregates powder clumps of triptorelin or salts thereof. The stirring may be achieved by various means such as each reactor being equipped with an impeller 51 as illustrated in figure 1. Such an impeller ensures optimal stirring.

The organic solvent which is mixed with triptorelin or a salt thereof may comprise one or more of esters, halogenated hydrocarbons, ethers and aromatic hydrocarbons. Some examples of halogenated hydrocarbons which may be used are methylene chloride, trichloromethane, carbon tetrachloride, ethylene dichloride, ethylene chloride, 1,1,2 trichloroethane and 2,2,2- trichloroethane. Some examples of non-halogenated hydrocarbons which may be used are ethylacetate, methyl acetate, ethyl formate, methyl formate, ethyl ether and isopropyl ether. Some examples of aromatic hydrocarbons which may be used are benzene, toluene and xylene.

Although a plurality of six reactors 10, 11, 12, 13, 14, 15 are illustrated in figure 1, the invention may be carried out with any number of reactors ranging from two to more reactors. Preferably, the number of reactors in the plurality of reactors is multiple times greater than the number of hardening vessels. In other words, the number of reactors in the plurality of reactors is at least two times, three times, four times, five times, six times, seven times, eight times, nine times or ten times greater than the number of hardening vessels. As an example, the invention may be carried with only one hardening vessel 20 and a plurality of three reactors 10, 11, 12. As a further example, the invention may be carried with multiple set-ups of the embodiment illustrated in figure 1, in other words, the invention could be carried out with: 12 reactors and 4 hardening vessels; 24 reactors and 8 hardening vessels; 36 reactors and 12 hardening vessels etc. The invention may also be carried out with uneven number of reactors and/or hardening vessels.

Although each of the reactors and hardening vessels shown in the small-scale prototype illustrated in figure 1 have an inner volume of 2 liters and 40 liters, respectively, the reactors and hardening vessels in full scale chemical plants may have inner volumes ranging from several hundred liters to several tons.

Step (b) is preferably carried out in the plurality of reactors 10, 11, 12, 13, 14, 15 while stirring at a RPM and time duration until substantial dissolution of the encapsulation polymer is achieved. In some embodiments of the invention, step (b) may be carried out at a temperature lower than ambient temperature such as at a temperature interval of 15-18 °C or lower. The temperature of the inside each of the plurality of reactors may be controlled by carrying out in-thermostating 60 and out-thermostating 61 as illustrated in figure 1. Although, thermostating is a preferred method of maintaining the temperature near a desired setpoint, other methods of sensing temperature and performing temperature control may also be used. The encapsulation polymer may be a biodegradable polymer or copolymer selected from one or more of polyglycolic acid - PGA (i.e. polyglycolide); polylactic acid - PLA (i.e. polylactide); poly(lactic-co-glycolic acid) - PLGA (i.e. poly(glycolide-co-lactide)); poly(p- dioxanone); poly(glycolide-co-triethylene carbonate); a block copolymer of polyglycolide, trimethylene carbonate and polyethylene oxide; poly(alkylene diglycolates); poly(alkylene succinates); poly(alkylene oxalates); poly(caprolactone); poly(alpha-hydroxybutyric acid); poly(ortho esters); poly(anhydrides); poly(amide esters); poly(alkylene tartrate); poly(alkylene fumarate); polystyrene; polymethacrylic acid; copolymers of poly(ethylene glycol) - PEG; triblock copolymers of poly(propylene glycol) flanked by poly(ethylene glycol); methacrylic acid/acrylic acid copolymers; poly amino acids; polyurethanes; polyphosphazenes; maleic anhydride polymers; ethyl cellulose; nitrocellulose; and acetyl cellulose.

In a preferred embodiment of the invention, the encapsulation polymer is PLGA. The PLGA polymers may range in molecular weight from about 20,000 to about 100,000. The PLGA may comprise from 40 to 90 percent of lactic acid (lactide) residues and from 10 to 60 percent of glycolic acid (glycolide) residues. It will be preferable to use D,L-PLGA and more preferable to use a D,L-PLGA produced from 50 to 80 percent of DL-lactic acid and 50 to 20 percent of glycolic acid. Preferably, a PLGA synthesized from about 50 percent of DL-lactic acid and about 50 percent of glycolic acid will be particularly suitable for the invention. Percent of lactic acid and glycolic acid in PLGA is mole percent.

Moreover, D,L-PLGA may either be acid terminated or ester terminated. Interestingly, the inventors unexpectedly discovered that the ester terminated D,L-PLGA may provide the formation of microcapsules comprising low amount of methylene chloride (i.e. the organic solvent) without using secondary drying steps.

The coacervation agent which is used in step (c) may be one or more of silicone oil, plant/vegetable oil, polyisobutylene, mineral oil and or cyclic polydimethylsiloxane. Examples of vegetable oils which may be used as coacervation agent are one or more of peanut oil, soybean oil, com oil, cotton seed oil, coconut oil and linseed oil. A silicone oil is in the present invention defined as any liquid polymerized siloxane with organic side chains wherein a siloxane is a functional group in organosilicon chemistry with the Si-O-Si linkage. In preferred embodiments of the invention, the silicone oil is dimethicone (also known as polydimethylsiloxane and dimethylpoly siloxane).

Step (c) is preferably carried out in the plurality of reactors 10, 11, 12, 13, 14, 15 while stirring at a RPM and time duration until substantial coacervation is achieved. As in step (b), step (c) may also be carried out at a temperature lower than ambient temperature such as at a temperature interval of 15-18 °C or lower.

In step (d), the mixture comprising the soft microcapsules is transferred from the plurality of reactors 10, 11, 12, 13, 14, 15 to at least one hardening vessel 20, 21. Such a transfer may for example be carried out by a pump coupled to the transfer tubes connecting the plurality of reactors 10, 11, 12, 13, 14, 15 to the at least one hardening vessel 20, 21. In the embodiment of the invention illustrated in figure 1, the number of at least one hardening vessel 20, 21 is two or more hardening vessels, and the step of transferring the mixture comprising soft microcapsules from the plurality of six reactors 10, 11, 12, 13, 14, 15 to the hardening vessels is carried out by equally dividing the contents of the plurality of reactors 10, 11, 12, 13, 14, 15 between the hardening vessel 20, 21.

The ratio between (i) the inner volume of each of the hardening vessels 20, 21, and the inner volume of each of the plurality of reactors 10, 11, 12, 13, 14, 15 may range from 5:1 to 80:1, preferably from 10:1 to 70:1, more preferably from 20:1 to 60:1. In the embodiment of the invention illustrated in figure 1, the inner volume of each of the hardening vessels is 40 liters while the inner volume of each of the plurality of reactors is 2 liters, i.e. the ratio between the inner volume of each of the hardening vessels and the inner volume of each of the plurality of reactors is 20:1.

In step (e), the soft microcapsules which are formed in step (c) are precipitated into hard microcapsules when the soft microcapsules come into contact with the hardening liquid; this step is in the art referred to as hardening (and sometimes also as quenching). The temperature of the inside the at least one hardening vessel 20, 21 may be controlled by carrying out in- thermostating 62, 64 and out-thermo stating 63, 65 as illustrated in figure 1. As in steps (b) and step (c), step (e) may also be carried out at a temperature lower than ambient temperature such as at a temperature interval of 15-18 °C or lower. Furthermore, the inventors have discovered that hardening at temperature interval of 15-18 °C increases the yields of the hard microcapsules.

It should be noted that the above-described soft microcapsules and hard microcapsules are sometimes in the art also referred to as microdroplets and microparticles, respectively.

The thermostating of the plurality of reactors and the at least one vessel may be carried out by using jacketed vessels for controlling temperature of its contents, by using a cooling or heating "jacket" around the vessel through which a cooling or heating fluid is circulated. A jacket is a cavity external to the vessel that permits the uniform exchange of heat between the fluid circulating in it and the walls of the vessel.

The ratio between (i) the volume of hardening liquid in each of the hardening vessels 20, 21, and (ii) the volume of the mixture comprising the soft microcapsules transferred from the plurality of reactors 10, 11, 12, 13, 14, 15 to each of the hardening vessels 20, 21, may range from 5:1 to 40:1. Other alternatives are from 6:1 to 30:1, from 7:1 to 20:1 or from 8:1 to 10:1. The hardening liquid used in step (e) may comprise one or more organic compounds and/or a silicone fluids. Preferably, the hardening liquid comprises an alkane or a siloxane (such as a cyclosiloxane or polyalkylsiloxane). Some preferred examples of hardening liquids comprise one or more of hexane, cyclohexane, heptane, petroleum ether, octamethylcyclotetrasiloxane, decamethylcyclopentasiloxane and hexamethyldisiloxane.

Stirring is preferably also used in the hardening vessel 20, 21 to mix the hardening liquid with the microcapsules; however, the stirring is stopped for letting the microcapsules (i.e. the particles) settle. This is then followed up with decanting the supernatant. As in the plurality of reactors, the stirring may be achieved by with an impeller 52 as illustrated in figure 1.

In an embodiment of the invention, further hardening liquid may be added to the hardening vessel and then stirred with the settled particles. The stirring is thereafter stopped for letting the hard microcapsules settle. This embodiment removes impurities, i.e. it is a washing step, and may be repeated one or more times.

Before step (f), the hard microcapsules are resuspended in the hardening tank with the hardening liquid and the resulting suspension is thereafter transferred to a filtering device and in step (f) the hard microcapsules are dried. The filtering device is preferably a filter drier which filters and dries the microcapsules. The filtration and drying process of the filter drier may be performed under pressure using nitrogen purge (e.g. for at least 5 minutes) and then followed by applying vacuum (e.g. for at least 30 minutes). However, other types of filtering and/or drying devices (either combined filtering and drying devices or separate filtering and drying devices) which are coupled to the apparatus system illustrated in figure 1 may also be used.

The dried microcapsules may be transferred to storing packages made wholly or partially of plastics, cellulosic-materials and/or glass future use. However, in preferred embodiments of the invention, the dried microcapsules are after the drying process subjected to sieving by using one or more sieves having one or more sieve sizes. In the art, sieve size is also referred to as opening dimension as well as mesh dimension.

The sieving step separates wanted microcapsules from unwanted material as well as for selecting microcapsules with a specific particle size distribution. As an example, the dried microcapsules resulting from step may first be subjected to sieving with a big mesh size in order to eliminate unwanted material and then in the next step be subjected to sieving with a smaller mesh size in order to collect microcapsules having particle size distribution.

Moreover, either as an alternative to sieving, or after conducting sieving, the microcapsules may be subjected to dry-mixing in a device such as a blender or another type of mixing equipment. The resulting microcapsules may be transferred to storing packages for future use after the sieving and/or dry mixing step.

In order to prepare a pharmaceutical composition, the microcapsules may be mixed with any excipient composition which is suitable for administering to a mammal such as a human subject. Triptorelin and salt thereof which are to be injected into a human subject are in the art typically mixed with excipients such as carboxymethylcellulose, mannitol and/or Tween 80 (polysorbate 80).

In an embodiment of the present invention, sodium carboxymethylcellulose, mannitol and polysorbate 80 are mixed with water and then dried e.g. by lyophilization. Thereafter, the resulting dried excipient composition is sequentially added to the dried microcapsules (or vice versa) in a container suitable for storing pharmaceutical compositions. Some examples of such a container is a vial, a syringe (or a barrel thereof), a tube, an ampoule or a blister package.

The sequential addition of the dried excipient composition to the dried microcapsules (or vice versa) provides a much better dose control of the final pharmaceutical composition. As a contrast, some triptorelin compositions such as the one described in WO02058672 (Example 1) are prepared by suspending microcapsules in a lyophilization medium comprising water and excipients, and thereafter, the resulting suspension is dosed into the single containers and then dried. Not only does the process of preparing the final drug product possibly lead to poor dose control in each vial (due to mixing of a dried component with a “wet” component), but also, the resulting suspension needs to be lyophilized right away. In the present invention, the dried microcapsules are quite stable and can be added to an excipient composition (or vice versa) later point in time. Moreover, in the present invention, the resulting pharmaceutical composition will have better dose control due to the adding of two dried components (i.e. the microcapsules and excipient composition) which can be done with 100% weight control.

The excipient composition may comprise 50-90 weight-% mannitol, 5-45.5 weight-% sodium carboxymethylcellulose and 0.5-5 weight-% Tween 80, on the total weight of the excipient composition. Preferably, the excipient composition has been prepared by lyophilizing in water of extra high quality wherein the water is without significant contamination. This type of water is in the art often referred to as “water for injection” - WFI

The resulting pharmaceutical composition may be stored at room temperature. Optionally, the pharmaceutical composition may be subjected to gamma sterilization prior to storage.

In preferred embodiments of the invention, the resulting pharmaceutical composition comprises:

0.5 or lower weight-% of the one or more organic solvents (used in step (a) of the process according to the present invention);

4.0 or lower weight-% of the hardening liquid; and/or

3.0 or lower weight-% of water.

Although the above process and apparatus has been described for triptorelin or a salt thereof, the process and apparatus may also be used for other GnRH analogue peptides. Moreover, it should be understood that the invention is not limited to the particular embodiments illustrated and described herein, but that various changes and modifications may be made without departing from the spirit and scope of the novel and inventive embodiments as defined by the claims.

EXAMPLES The example described below and illustrated in figure 1 describes a preferred embodiment of the invention; however, is not intended to limit the claims in any manner whatsoever.

Example 1

700 ml methylene chloride (i.e. the organic solvent) is transferred from a solvent tank to each of the six reactors 10, 11, 12, 13, 14, 15. While stirring the methylene chloride content in each of the six reactors at about 5000 RPM, about 1.6 gram triptorelin acetate is added to each of said reactors. The stirring speed is increased to 18000 RPM for a duration of about 10 minutes in order to disaggregates triptorelin acetate clumps. Subsequently, the stirring speed is decreased back to about 5000 RPM and the temperature of the six reactors 10, 11, 12, 13, 14, 15 is set to about 16 °C. In the next step, about 60 grams of PLGA (i.e. the encapsulation polymer) is added to the resulting mixture in each the six reactors while continued stirring at about 5000 RPM until complete dissolution of PLGA is achieved. Subsequently, about 133 ml dimethicone oil (i.e. coacervation agent) is added to the dispersion in each the six reactors by using a peristaltic pump at a flow rate of about 10 milliliters per minute (ml/min). The stirring speed and temperature are maintained at 5000 RPM and 16 °C, respectively.

Each of the hardening vessels 20, 21 are filled with 30 liters of n-heptane (i.e. hardening liquid) and the temperature is set to about 16 °C while stirring. The stirring speed of each of the six reactors is set to 14000 RPM for about 1-2 minutes. The contents of three of the reactors 10, 11, 12 are transferred to one of the hardening vessels 20 while the contents of the other three reactors 13, 14, 15 are transferred to the other hardening vessels 21 as shown by the arrows 70 in figure 1. The contents of each of the hardening vessels 20, 21 are stirred at about 16 °C for 65 minutes. Thereafter, the stirring of hardening vessels 20, 21 is stopped, and once the microcapsules (i.e. particles) have settled, then the supernatant (i.e. n-heptane) is decanted out of the hardening vessels 20, 21 without removing microcapsules. Subsequently, each of the hardening vessels 20, 21 are filled with 5 liters of n-heptane and the contents of the vessels are stirred for about 5 minutes. Next, the stirring of hardening vessels 20, 21 is stopped, and once the microcapsules have settled, then the supernatant is decanted out of the hardening vessels 20, 21 without removing microcapsules. Then, each of the hardening vessels 20, 21 are filled with 3 liters of n-heptane and the contents of the vessels are stirred for about 5 minutes to resuspend the microcapsules.

The suspension in hardening vessel 20 is transferred to a filter dryer (i.e. filtering device) and the microcapsules are filtered out of the suspension under vacuum. The suspension in hardening vessel 21 is thereafter also transferred to a filter dryer and the microcapsules are filtered out of the suspension under vacuum. The contents in the filter dryer (i.e. the hardened microcapsules from derived from hardening vessels 20, 21) are then flushed with nitrogen for about 10-20 minutes with an open valve. The valve is in the next step closed and the contents of the filter dryer are dried under vacuum for about 15-20 hours at 26 °C. In an alternative embodiment of Example 1, if the inner volume and/or capacity of the filtering device allows, then the suspensions in both hardening vessels 20, 21 may be transferred to the filter dryer and then filtered together according to the filtering procedure described in this paragraph.

The dried microcapsules are transferred to sieving equipment and subjected to sieving by first using a sieve having a 200 micrometer sieve size and then using a sieves having 20 micrometer sieve size. The sieved microcapsules are thereafter homogenized in a double cone blender in which the microcapsules are subjected to dry-mixing.

The resulting sieved and blended microcapsules are sequentially filled into glass vials together with a lyophilized excipient composition comprising D-mannitol, sodium carboxymethyl cellulose and polysorbate 80 (Tween 80). The resulting pharmaceutical composition in the vials comprises the composition disclosed in Table 1.

Table 1 - Pharmaceutical composition according to the present invention

Each vial comprises 288 mg ± 7.2 mg (± 2.5 weight-%) of the pharmaceutical composition of which 117 mg is lyophilized excipients. Hence, the present invention provides a high degree of dose control (i.e. dose reproducibility) wherein the amount of the pharmaceutical composition only varies ± 2.5 weight-% between each vial.

Various other characteristics of a sample obtained by the above described process of Example 1 (referred to as Sample) was compared with a commercial product sold as “Decapeptyl 3,75” as illustrated in Table 2. The results clearly show that the level of water and n-heptane is lower in the pharmaceutic composition according to the present invention.

Moreover, the level of methylene chloride is almost the same in the pharmaceutic composition according to the present invention and commercial product “Decapeptyl 3.75”. Hence, the pharmaceutical composition according to the present invention comprises lower amounts of residual solvents that could affect the total amounts of impurities in the pharmaceutical composition and increase the stability of the microcapsules at room temperature conditions - no refrigeration is needed to store the microcapsules overtime.

It appears as if the novel and inventive features of the present invention, such as: - the number of reactors comprised in the plurality of reactors being greater than the number of vessels, ratio between the inner volume of each of the hardening vessels and the inner volume of each of the plurality of reactors ranging from 5:1 to 80:1; and/or the ratio between the volume of hardening liquid in each of the hardening vessels and the volume of the mixture comprising soft microcapsules transferred from the plurality of reactors to each of the hardening vessels ranging from 5:1 to 40:1; results in the lower amounts of residual solvents such as n-heptane in the Sample.

Table 2:

Moreover, due to the absence of water during the microcapsules manufacturing, the microcapsules are stable for storage overtime at room temperature conditions without need of refrigeration.

Indeed, samples stored in qualified storage chambers in storage condition of 25°C ± 2°C/60% RH ± 5% (12 months, long-term storage), and in storage conditions of 40°C ± 2°C/75% RH ± 5% RH (6 months accelerated storage), were stable as for all the measured parameters (see Table 3), evaluated according to ICH Guidelines Q1A(R2). Table 3:

Furthermore, as illustrated in the graph in figure 2, other unexpected feature of the present invention (Samples 1-4 prepared according to Example 1) when compared with “Decapeptyl 3,75” are: decreased rate of initial burst of triptorelin in Samples 1-4, i.e. decreased rate of the amount of triptorelin released in the first 24 hours; a more controlled release pattern of triptorelin in Samples 1-4 at the beginning (0-24 hours), in the middle (24-72 hours) as well as at the near-end (72-96 hours) of the therapeutic cycle.

Moreover, as clearly illustrated by the graph in figure 2, triptorelin is no longer released from “Decapeptyl 3,75” after 72 hours, i.e. the cumulative release of triptorelin reaches a plateau at about 71 weight-% of triptorelin being released from “Decapeptyl 3,75”. As a contrast, the pharmaceutical compositions of the present invention (i.e. Samples 1-4) release triptorelin in a sustained and controlled manner after 72 hours, as well as after 96 hours, and does not reach any plateau whatsoever within the 0-96 hours therapeutic cycle.

Consequently, the present invention avoids uneven releases of triptorelin and thereby provides a more sustained and controlled release of triptorelin. Furthermore, it can also be derived from figure 2 that the process according to the present invention provides reproducible rates of triptorelin being released within the 0-96 hours therapeutic cycle, i.e. all four of Samples 1-4 show similar rates of triptorelin release. Additionally, stability data conducted on the samples prepared according to Example 1 show that the final pharmaceutical composition is stable for at least 12 months at 25+/-2 °C (i.e. 25 °C plus or minus 2 °C). Furthermore, projections from collected data show that the final pharmaceutical composition is stable for at least 36 months at 25+/-2 °C.

Claims

1. A process for preparing a pharmaceutical composition for sustained and controlled release of triptorelin or a salt thereof, said process comprising the steps of: a) mixing, in a plurality of reactors (10, 11, 12, 13, 14, 15), triptorelin or a salt thereof with one or more organic solvents; b) adding encapsulation polymer to the resulting mixture; c) adding a coacervation agent to the resulting dispersion to form microcapsules comprising encapsulation polymer and triptorelin or a salt thereof; d) transferring the mixture comprising microcapsules from the plurality of reactors (10, 11, 12, 13, 14, 15) to at least one hardening vessel (20, 21); e) mixing, in the at least one hardening vessel (20, 21), the mixture comprising microcapsules with a hardening liquid; and f) filtering and drying, in at least one filtering device, the hardened microcapsules; wherein the number of reactors comprised in the plurality of reactors is greater than the number of vessel(s) comprised in the at least one hardening vessel; and wherein each of the above listed steps a-f of the process is carried out in a water-free environment.

2. A process according to claim 1, further comprising the step of: g) adding the dried microcapsules to one or more dried pharmaceutical excipients or adding one or more dried pharmaceutical excipients to the dried microcapsules; wherein each of the above listed steps a-g of the process is carried out in a water-free environment.

3. A process according to any one of the previous claims, wherein the number of at least one hardening vessel (20, 21) is two or more hardening vessels, wherein the number of reactors comprised in the plurality of reactors is at least two to three times greater than the number of hardening vessels.

4. A process according to any one of the previous claims, wherein the step of transferring the mixture comprising microcapsules from the plurality of reactors (10, 11, 12, 13, 14, 15) to the hardening vessels is carried out by equally dividing the contents of the plurality of reactors (10, 11, 12, 13, 14, 15) between the hardening vessels (20, 21).

5. A process according to any one of the previous claims, wherein the ratio between: the volume of hardening liquid in each of the hardening vessels, and the volume of the mixture comprising soft microcapsules transferred from the plurality of reactors to each of the hardening vessels, ranges from 5:1 to 40:1.

6. A process according to any one of the previous claims, wherein the ratio between: the inner volume of each of the hardening vessels, and the inner volume of each of the plurality of reactors, ranges from 5:1 to 80:1, preferably from 10:1 to 70:1, more preferably from 20:1 to 60:1.

7. A process according to any one of the previous claims, wherein the one or more organic solvents comprise one or more of esters, halogenated hydrocarbons, ethers and aromatic hydrocarbons, preferably one or more of methylene chloride, trichloromethane, carbon tetrachloride, ethylene dichloride, ethylene chloride, 1,1,2 trichloroethane and 2,2,2- trichloroethane, ethylacetate, methyl acetate, ethyl formate, methyl formate, ethyl ether and isopropyl ether, benzene, toluene and xylene.

8. A process according to any one of the previous claims, wherein the encapsulation polymer is a biodegradable polymer or copolymer selected from one or more of polyglycolic acid - PGA; polylactic acid - PLA; poly(lactic-co-glycolic acid) - PLGA; poly(p-dioxanone); poly(glycolide-co-triethylene carbonate); a block copolymer of polyglycolide, trimethylene carbonate and polyethylene oxide; poly(alkylene diglycolates); poly(alkylene succinates); poly(alkylene oxalates); poly(caprolactone); poly(alpha-hydroxybutyric acid); poly (ortho esters); poly (anhydrides); poly (amide esters); poly (alky lene tartrate); poly(alkylene fumarate); polystyrene; polymethacrylic acid; copolymers of poly(ethylene glycol) - PEG; triblock copolymers of poly(propylene glycol) flanked by poly(ethylene glycol); methacrylic acid/acrylic acid copolymers; poly amino acids; polyurethanes; polyphosphazenes; maleic anhydride polymers; ethyl cellulose; nitrocellulose; and acetyl cellulose.

9. A process according to any one of the previous claims, wherein the encapsulation polymer is PLGA produced from 40 to 90 percent of lactic acid and from 10 to 60 percent of glycolic acid, preferably PLGA is ester terminated, more preferably, PLGA is D,L-PLGA produced from 50 to 80 percent of DL-lactic acid and 20 to 50 percent of glycolic acid, more preferably PLGA is D,L-PLGA produced from about 50 percent of DL-lactic acid and about 50 percent of glycolic acid.

10. A process according to any one of the previous claims, wherein the coacervation agent is selected from one or more of silicone oil, vegetable oil, polyisobutylene, mineral oil and or cyclic polydimethylsiloxane, preferably silicone oil, more preferably dimethicone.

11. A process according to any one of the previous claims, wherein the hardening liquid comprises one or more organic compounds and/or a silicone fluids, preferably the hardening liquid comprises an alkane or a siloxane, more preferably one or more of hexane, cyclohexane, heptane, petroleum ether, octamethylcyclotetrasiloxane, decamethylcyclopentasiloxane and hexamethyldisiloxane.

12. A process according to any one of the previous claims, wherein triptorelin or a salt thereof is selected from the group consisting of triptorelin acetate, triptorelin pamoate, triptorelin tannate and triptorelin stearate, preferably triptorelin or a salt thereof is selected from the group consisting of triptorelin acetate and triptorelin pamoate, more preferably triptorelin or a salt is triptorelin acetate.

13. A process according to any one of the previous claims 2-12, wherein the one or more dried pharmaceutical excipients are selected from one or more of sodium carboxymethyl cellulose, mannitol and Tween 80; preferably the one or more dried pharmaceutical excipients comprise carboxymethylcellulose, mannitol and Tween 80; more preferably the one or more dried pharmaceutical excipients comprise 50-90 weight-% mannitol, 5-45.5 weight-% carboxymethylcellulose and 0.5-5 weight-% Tween 80; most preferably the one or more dried pharmaceutical excipients comprise 65-75 weight-% mannitol, 15-35 weight-% carboxymethylcellulose and 0.1-10 weight-% Tween 80, on the total weight of the dried pharmaceutical excipients.

14. A process according to any one of the previous claims 2-13, wherein the step of adding the dried microcapsules to one or more dried pharmaceutical excipients comprises the step of sequentially adding the dried microcapsules to one or more dried pharmaceutical excipients or sequentially adding one or more dried pharmaceutical excipients to the dried microcapsules.

15. A process according to any one of the previous claims 2-14, wherein step (g) results in a pharmaceutical composition comprising:

0.5 or lower weight-% of the one or more organic solvents;

4.0 or lower weight-% of the hardening liquid; and 3.0 or lower weight-% of water, and wherein the resulting pharmaceutical composition is preferably stable for at least 12 months at 25+/-2 °C, more preferably for at least 36 months at 25+/-2 °C.

16. A process according to any one of the previous claims, said process comprising the steps of: h) mixing, in a plurality of six reactors (10, 11, 12, 13, 14, 15), triptorelin acetate with methylene chloride; i) adding PLGA to the resulting suspension; j) adding dimethicone to the resulting dispersion to form soft microcapsules comprising PLGA and triptorelin acetate; k) transferring the mixture comprising the soft microcapsules from the plurality of reactors (10, 11, 12, 13, 14, 15) to two hardening vessels (20, 21); l) mixing, in the hardening vessel (20, 21), the mixture comprising the soft microcapsules with n-heptane; m) filtering and drying, in at least one filtering drier, the resulting hard microcapsules; and n) adding the dried microcapsules to one or more dried pharmaceutical excipients, wherein the one or more dried pharmaceutical excipients comprise sodium carboxymethylcellulose, D-mannitol and Tween 80, wherein each of the above listed steps a-g of the process is carried out in a water-free environment.

17. A process according to any one of the previous claims, wherein said pharmaceutical composition comprises:

0.5 or lower weight-% of the one or more organic solvents;

4.0 or lower weight-% of the hardening liquid; and 3.0 or lower weight-% of water.

18. A process according to any one of the previous claims, wherein said pharmaceutical composition comprises:

10-60 weight-% dried pharmaceutical excipients;

40-90 weight-% dried microcapsules comprising encapsulation polymer and triptorelin or a salt thereof;

0.5 or lower weight-% of the one or more organic solvents;

19. A pharmaceutical composition obtainable by the process according to any one of the previous claims.

20. A pharmaceutical composition for sustained and controlled release of triptorelin or a salt thereof, obtainable by the process according to any one of the previous claims 1-18, comprising:

0.5 or lower weight-% of the one or more organic solvents;

21. A pharmaceutical composition for sustained and controlled release of triptorelin or a salt thereof, obtainable by the process according to any one of the previous claims 1-17, comprising:

10-60 weight-% dried pharmaceutical excipients;

0.5 or lower weight-% of the one or more organic solvents;

22. A kit of parts comprising a container and a pharmaceutical composition according to any of claims 19-21 comprised in said container, preferably the container is a vial, a syringe, a tube, an ampoule or a blister package, more preferably the container is a vial or ampoule, most preferably the container is a vial.

23. An apparatus suitable for preparing a pharmaceutical composition for sustained and controlled release of triptorelin or a salt thereof, said apparatus comprising: a plurality of reactors (10, 11, 12, 13, 14, 15), configured for S mixing, triptorelin or a salt thereof with one or more organic solvents; S adding encapsulation polymer to the resulting suspension; S adding a coacervation agent to the resulting dispersion to form soft microcapsules comprising encapsulation polymer and triptorelin or a salt thereof; at least one hardening vessel (20, 21); transfer tubes configured for transferring the mixture comprising the soft microcapsules from the plurality of reactors (10, 11, 12, 13, 14, 15) to the at least one hardening vessel (20, 21), and wherein the at least one hardening vessel (20, 21) is configured for mixing the mixture comprising the soft microcapsules with a hardening liquid; and at least one filtering device, configured for filtering and drying the resulting hard microcapsules; wherein the number of reactors comprised in the plurality of reactors is greater than the number of vessel(s) comprised in the at least one hardening vessel.