Process and Equipment Assembly for Aseptic Gravimetric Filling of Solids into a Container

Abstract

A system for and method of gravimetric filling of a solid product in sterile conditions in a pharmaceutical container of small dimensions including syringes, vials, capsules, ampoules, single-dose devices, inhalers, bottles, carpules, well(s) of blister pack(s), sachets or bags with solid substances selected from the group formed by powder, lyophilizate, granules, pellets, nanoparticles or microparticles. More particularly, it relates to a process for the gravimetric filling of pharmaceutical containers with one or more sterile solid pharmaceutical substances or sterile excipients dosed and prepared in an aseptic environment.

Claims

1) A method of gravimetric filling of a solid product in a container (1) comprising the following steps: a) providing a container (1) comprising a generally cylindrical body (2) and which is equipped in its upper part with a ridge (3) of diameter slightly greater than the diameter of the body (2) of the container (1), b) inserting the container (1) in a hollow cylinder (4), the inner cavity (5) of which has a diameter slightly greater than the diameter of the body (2) of the container (1), and which is equipped with a recess (6) in the upper area of the inner cavity (5), so that the ridge (3) of the container (1) rests in the recess (6) of the upper area of the inner cavity (5) of the cylinder, and with the contact area between the ridge (3) of the container (1) and the recess (6) of the upper area of the inner cavity (5) of the cylinder (4) the only area of contact between container (1) and cylinder (4), so that the container (1) is in suspension within the inner cavity (5) of the cylinder (4) and with its upper surface (7) located slightly underneath the upper surface (8) of the cylinder; c) disposing the cylinder (4) and container (1) unit above a gravimetric weighing system (9) which is equipped, on its weighing surface (10), with a mount (11) which has a diameter less than the diameter of the inner cavity (5) of the cylinder (4) and a suitable height to raise the container (1) by the sufficient height (h) so that the ridge (3) of the container is no longer in contact with the recess (6) of the upper area of the inner cavity (5) of the cylinder (4) but without the upper surface (7) of the container (1) exceeding the height of the upper surface (8) of the cylinder (4), so that the container (1) is completely suspended above the mount (11) provided on the surface (10) of the gravimetric weighing system (9) and therefore resting all its weight thereon; d) covering the upper surface (8) of the cylinder (4) hermetically by means of a lid (12) equipped with an orifice (13) wherethrough it is possible to add the solid product by means of a dosing element or nozzle (14); e) weighing with the desired precision the container (1) whilst it is suspended above the mount (11) provided on the surface (10) of the gravimetric weighing system (9) and resting all its weight thereon, and f) filling the container (1) with the solid product through the orifice (13) of the lid (12), gravimetrically controlling the quantity of product added thereto by means of the gravimetric weighing system (9).

2) Method according to claim 1, wherein between container (1) and cylinder (4) is provided at least one sleeve covering the container (1) designed to guarantee the verticality and suspension of the container (1) within the inner cavity (5) of the cylinder (4) so that neither the container (1) nor its covering sleeve touch the inner walls of the cylinder (4).

3) Method according to claim 1 or 2, wherein stages c) to f) are repeated the necessary times in the case that more than one solid product is to be dosed in the container (1).

4) Method according to any of claims 1 to 3, wherein previously, subsequently or simultaneously to any of stages a) to f) an ionization stage of the container (1) and/or of the cylinder (4) is introduced to neutralize its electrostatic charges.

5) Method according to claim 4, wherein the ionization stage is carried out by introducing an ionizing bar, needle or ring in the container (1) and/or in the cylinder (4).

6) Method according to claim 4 or 5, wherein a stream of compressed air or sterile N.sub.2 is introduced in the container (1) and/or the cylinder (4) simultaneously to the ionization to help the dosing and provide the required sterile conditions.

7) Method according to any of the preceding claims, wherein the filling of solid product in the container (1) of stage f) is performed by means of an endless screw, a gravimetric doser by weight loss equipped with a hopper and a high-precision nozzle, a single-thread doser, a double-thread doser, a doser with vibrating channel or with vibrating hopper, a doser equipped with conveyor belt, or a doser equipped with compacting system.

8) Method according to claim 7, wherein the hopper is equipped with a stirrer to guarantee a constant and fluid supply of the solid product in the container (1).

9) Method according to any of the preceding claims, wherein the cylinder (4) is equipped with a multiplicity of inner cavities (5), each one of which is capable of receiving a container (1).

10) Method according to claim 9, wherein the gravimetric weighing system (9) is multiple with the aim of being able to weigh the multiplicity of containers (1) equipped in the multiplicity of inner cavities (5) of the cylinder (4).

11) Method according to any of the preceding claims, wherein the container (1) is a syringe, vial, capsule, ampoule, single-dose device, inhaler, bottle, carpule blister, sachet or bag designed to contain solid substances.

12) Method according to claim 11, wherein the container (1) is a syringe or carpule.

13) Method according to any of the preceding claims, wherein the cylinder (4) is a metal cylinder of titanium, steel, plastic, crystal, glass, stone or resin.

14) Method according to claim 13, wherein the cylinder (4) is equipped with an outer ridge designed so that the cylinder (4) can be supported by means of pliers or clamps, or also so that the cylinder (4) can be displaced by means of rails elevated from some points to others of the filling stations.

15) Method according to any of the preceding claims, wherein the mount (11) provided on the surface (10) of the gravimetric weighing system (9) has generally cylindrical form and its upper surface has substantially flat, conical or truncated cone shape.

16) Method according to any of the preceding claims, wherein the solid product to be filled in the container (1) has the following distribution of particle sizes: no more than 10% of the total volume of particles is less than 20 microns, no more than 10% of the total volume of particles is greater than 230 nor less than 140, a value d0.5 in the range of 60-160 microns, where d0.5 indicates the mean value of the particle size that divides the population exactly in two equal halves, with 50% of the distribution above this value, and 50% below.

17) Method according to any of preceding claims 1 to 15, wherein the solid product to be filled in the container (1) has the following distribution of particle sizes: no more than 10% of the total volume of particles is less than 20 microns, no more than 10% of the total volume of particles is greater than 325 nor less than 245, a value d0.5 in the range of 100-155 microns, where d0.5 indicates the mean value of the particle size that divides the population exactly in two equal halves, with 50% of the distribution above this value, and 50% below.

18) Method according to claim 16 or 17, wherein the solid product to be filled in the container (1) is selected from the group consisting of risperidone, paliperidone, fentanyl, olanzapine, letrozole, aripiprazole, anastrozole, asenapine, brexpiprazole, cariprazine, clozapine, iloperidone, lurasidone, quetiapine, ziprasidone, including any derivative, metabolite or salt thereof, alone or in combination.

19) Method according to any of the preceding claims, which is performed in an aseptic environment in a laminar airflow cabin.

20) Container (1) containing a solid product, wherein the solid product has been filled in the container (1) using the method described in any of preceding claims 1 to 19.

21) Container (1) containing a solid product according to claim 20, wherein the solid product has the following distribution of particle sizes: no more than 10% of the total volume of particles is less than 20 microns, no more than 10% of the total volume of particles is greater than 230 nor less than 140, a value d0.5 in the range of 60-160 microns, where d0.5 indicates the mean value of the particle size that divides the population exactly in two equal halves, with 50% of the distribution above this value, and 50% below.

22) Container (1) containing a solid product according to claim 20, wherein the solid product has the following distribution of particle sizes: no more than 10% of the total volume of particles is less than 20 microns, no more than 10% of the total volume of particles is greater than 325 nor less than 245, a value d0.5 in the range of 100-155 microns, where d0.5 indicates the mean value of the particle size that divides the population exactly in two equal halves, with 50% of the distribution above this value, and 50% below.

23) Container (1) containing a solid product according to any of claims 20 to 22, wherein the solid product is a drug.

24) Container (1) containing a solid product according to any of claims 20 to 23, wherein the drug is selected from the group consisting of risperidone, paliperidone, fentanyl, olanzapine, letrozole, aripiprazole, anastrozole, asenapine, brexpiprazole, cariprazine, clozapine, iloperidone, lurasidone, quetiapine, ziprasidone, including any derivative, metabolite or salt thereof, alone or in combination.

25) Container (1) containing a solid product according to any of claims 20 to 24, wherein the container is a syringe or carpule.

26) A gravimetric filling process for charging one or more materials into one or more containers, said method comprising: providing a gravimetric filling apparatus comprising at least one lid (comprising at least one charging port), at least one receiver (for receiving container(s)), and at least one gravimetric system (comprising at least one weighing element and at least one non-weighing surface); placing at least one container in said receiver and assembling said at least one lid, said at least one receiver, and said at least one gravimetric system, thereby defining a contained (confined) space within which said at least one container is disposed, whereby said at least one container rests on said at least one weighing element (disposed within said contained space) but does not rest on a horizontal surface of said at least one receiver; charging an amount of at least one material through said at least one charging port and into said at least one container; and determining the combined weight of said at least one material and a respective container.

27) The process of claim 26, wherein said at least one container comprises at least one flange, and a respective one of said at least one receiver comprises at least one receptacle for said flange, wherein the diameter and height of said receptacle is larger than the diameter and height of said flange.

28) The process of claim 26 or 27, wherein the process further comprises at least one of the following steps: a) neutralizing the electrostatic charge of at least one of the container, receiver, lid, gravimetric system, and material; b) purging the contained space with gas or air prior to or after charging of material; c) placing under vacuum the contained space prior to, during, or after charging of material; d) taring the container resting upon the weighing element prior to charging material into the container; e) sterilizing the container and material in the container; f) charging (dosing) a predetermined amount of material into the container; g) providing at least one sleeve (spacer) between the container and a respective receiver; h) transferring the receiver to the weighing surface (system, element); i) charging a predetermined amount of material into each of plural containers; j) charging more than one material into a container; k) charging a mixture of two or more materials into a container; l) placing a plunger within the container after charging material into the container; m) vibrating the container; n) exposing the exterior of said at least one lid and said at least one receiver to laminar air (gas) flow before, during, and/or after said charging step, whereby said laminar air (gas) does not enter said contained space; o) purging the contained space with gas or air prior to or after weighing of said container(s); p) conducting said process as an aseptic gravimetric filling process; q) transferring said container(s) having said material(s) to a sealing operations area; r) transferring said receiver(s) with respective ones of said container(s) having said material(s) to a sealing operations area (sealing station(s)); and/or s) sealing said container(s) containing said material(s).

29) The process of any one of claims 26-28, wherein at least two materials are charged into said one or more containers, and said materials are charged simultaneously or sequentially.

30) The process of any one of claims 26-29, wherein the process excludes a heat and steam-based terminal sterilization step conducted after filling and sealing of said at least one container.

31) The process of any one of claims 26-30, wherein said at least one material comprises solid material.

32) A gravimetric filling apparatus (equipment assembly) for use in gravimetric filling of one or more containers, said apparatus comprising: a) at least one receiver for said one or more containers, said receiver(s) comprising a respective receptacle adjoining a respective chamber (for receiving said one or more containers), a first end, and a second end; b) at least one lid for respective ones of said one or more receivers, said lid(s) comprising at least one charging port and said lid(s) being disposed at said first end; and c) at least one gravimetric system comprising a non-weighing surface and at least one abutment (mount, projection, cup, stand, platform) directed into said respective chamber(s) and adapted to raise said one or more containers when said container(s) is/are disposed within said chamber(s), and disposed at said second end, thereby forming contained space(s) defined by said at least one receiver, said at least one lid, and said non-weighing surface, said contained space(s) adapted for receiving said one or more containers, and said contained space(s) being accessible through said charging port(s) for charging material therethrough into said one or more containers.

33) The apparatus of claim 32, wherein the gravimetric filling apparatus is further defined by at least one of the following: a) said receptacle has a larger diameter than said chamber; b) the length of said container combined with the height of said abutment is less than the length of said contained space; c) the apparatus is adapted for gravimetric filling of containers comprising one or more flanges (ridges), wherein the spatial volume of said receptacle is greater than the spatial volume of said flange; d) the spatial volume defined by the outer surfaces of said container is less than the spatial volume defined by the inner surfaces of said contained space; and/or e) the apparatus is adapted for gravimetric filling of containers comprising one or more flanges (ridges), wherein the height and inner diameter of said receptacle is greater than the height and outer diameter of said flange.

34) An apparatus (equipment assembly) adapted for use in (optionally aseptic) gravimetric filling of containers, said apparatus comprising: a hollow receiver having a height (4H) and comprising: a) an inner cavity (4A) having a first length (4L) and a first inner diameter (4ID), said receiver having a first outer diameter (4OD); and b) a receptacle disposed at an upper end of said inner cavity, said receptacle having a first height (6H) and a second inner diameter (6ID), and said receptacle being defined by a lower surface (6A) and a circumferential surface (6B), wherein 4OD>6ID>4ID; a container comprising: a) a body having a length (16H) and an outer diameter (16OD) and an inner cavity; and b) a flange disposed adjacent to or at an upper end of said body, said flange (or ring or ridge) having a second height (3H) and a second outer diameter (3OD), and said flange being defined by a lower surface (3A) and a circumferential surface (3B), wherein 3OD>16 OD and 16H>3H; and a lid having a charging port therethrough, said lid having an outer diameter (12OD), whereby the smallest outer diameter of said lid is sufficient to cover the receptacle; wherein
6ID>3OD>4ID; and
4H>16H and 6H>3H.

35) The apparatus of claim 34, further comprising a gravimetric weighing system comprising a non-weighing surface and a mount (projection, abutment, weighing element, cup, platform) associated with said surface.

36) The apparatus of claim 35, wherein said mount has a height (11H) and an outer diameter (11OD), wherein: a) 4H>(16H+11H); and b) 4ID>11OD.

37) The apparatus of any one of claims 34-36, wherein said mount comprises at least one weighing element that can weigh the container with and/or without material charged into the container.

38) The apparatus of any one of claims 34-37, wherein when said hollow receiver, said container, said lid, and said gravimetric weighing system are assembled, the lower surface of said flange is spaced away from said non-weighing surface (6A), the upper surface of said flange is spaced away from the lower surface of said lid, and said circumferential surface (3B) is spaced away from said circumferential surface (6B).

39) The apparatus of any one of claims 34-37, wherein when said hollow receiver, said container, said lid, and said gravimetric weighing system are assembled, the lower surface of said flange is spaced away from said non-weighing surface (6A) by the distance (S1), the upper surface of said flange is space away from the lower surface of said lid by the distance (S2), and said circumferential surface (3B) is spaced away from said circumferential surface (6B) by the distance (S3).

40) The apparatus of any one of claims 34-39, wherein 12OD>6ID or wherein 12OD>4OD>6ID.

41) The apparatus of any one of claims 32-40 further comprising one or more sleeves (spacers) disposed between the outer surface of the container and the inner surface of the cavity of the receiver.

42) The apparatus of any one of claims 32-41, wherein the hollow receiver contacts (or engages) said non-weighing surface and the lower surface of said lid, thereby forming a contained space within the receiver, said contained space having the container therein.

43) The apparatus of any one of claims 32-42 further comprising at least one of the following: a) at least one control system that controls the amount of material charged into one or more containers; b) at least one material charging system for charging material into one or more containers; c) at least one laminar airflow system; d) at least one deionizer; e) at least one transfer system for transferring the material-containing container, with or without its respective receiver, to another operational area; or f) a combination of any two or more thereof.

44) A gravimetric filling system comprising one or more receivers adapted to provide respective one or more contained (enclosed) non-laminar airflow spaces within which respective one or more containers (to be charged with material and to be weighed) can be placed, whereby when said gravimetric filling system is exposed to laminar air (gas) flow, said laminar air (gas) flow cannot enter said one or more contained spaces nor said one or more containers during charging (filling) and weighing of said one or more containers.

45) An operational station in an equipment assembly, said operational station comprising a gravimetric filling system under laminar airflow, said gravimetric filling system comprising one or more receivers adapted to provide respective one or more contained (enclosed) non-laminar airflow spaces within which respective one or more containers (to be charged with material and to be weighed) can be placed, whereby said laminar airflow does not enter said one or more contained non-laminar airflow spaces nor said one or more containers during the operational steps of charging (filling) and weighing of said one or more containers.

46) A method for gravimetric filling of one or more containers, said method comprising the following steps: a) providing one or more receivers adapted to provide respective one or more contained (enclosed) spaces within which respective one or more containers (to be charged with material and to be weighed) are disposed; b) charging one or more materials into said one or more containers; and c) weighing said one or more containers with said one or more materials; wherein the exterior of said one or more receivers is exposed to laminar air (gas) flow during said charging and weighing steps, whereby said laminar airflow does not enter said one or more contained spaces nor said one or more containers during said charging and weighing steps.

47) A method of preparing a pharmaceutical kit comprising at least the following: a) a first container comprising solvent(s); and b) a second container comprising particulate drug(s) and particulate polymeric carrier(s); said method comprising at least the following step(s): aseptically filling and weighing said particulate drug(s) and said particulate polymeric carrier(s) into a container by employing an aseptic gravimetric filling system (apparatus or equipment assembly) and/or method according to any one of the claims herein; sealing said container, thereby providing said second container; providing said first container; and packaging said first container and said second container, thereby providing said pharmaceutical kit.

48) An equipment assembly as described and/or depicted herein.

49) A gravimetric filling system as described and/or depicted herein.

50) An apparatus as described and/or depicted herein.

51) A gravimetric filling apparatus as described and/or depicted herein.

52) A method for gravimetric filling of one or more containers as described and/or depicted herein.

Description

BRIEF DESCRIPTION OF THE FIGURES

[0085] The accompanying figures, which are incorporated herein and form a part of the specification, illustrate one or more embodiments of the present invention and, together with the description, further serve to explain the principles of the present invention and to enable a person skill in the pertinent art to make and use the invention. The following drawings are given by way of illustration only, and thus are not intended to limit the complete scope of the present invention.

[0086] FIG. 1 depicts a front perspective view of the container (1) used in the present invention. The container comprises a hollow body (2) (e.g. cylinder or tube) and a ridge (3, flange) disposed adjacent to or at one end of said hollow body.

[0087] FIG. 2 depicts a front perspective view of the hollow receiving-cylinder (4, receiver) used also in the present invention, showing its inner cavity (5) and the recess (6, receptacle) disposed adjacent to or at the upper end of said inner cavity (5).

[0088] FIG. 3 depicts a partial front perspective of the container (1) inserted in the receiving-cylinder (4), so that the flange (3) of the container (1) rests on/in the lower surface defining the receptacle (6) of the cylinder (4), so that the only area of contact between container (1) and cylinder (4) is a lower surface of the flange and the lower surface defining the receptacle.

[0089] FIG. 4 depicts a front perspective view of the cylinder (4) and container (1) unit inserted therein, when both parts are about to be located above the gravimetric weighing system (9) which is equipped, on its non-weighing surface (10), with a mount (11). When the cylinder (4, receiver) and container (1) unit are lowered, the projection contacts the container (1) thereby slightly raising it from its resting-position in the recess (6) of the cylinder (4) so that it is totally in suspension above the mount (11), resting all its weight on the projection, whereby the gravimetric weighing system (9) can accurately measure the weight of the container (1). FIG. 4 also depicts the lid (12) adapted to cover the unit (adapted to seal the open end of the cylinder (4)) so that it is hermetically isolated from the outside.

[0090] FIG. 5 depicts an illustrative diagram of the different stages which may be present in the filling process according to the invention and which may comprise, according to the illustrative example shown in the figure, the following: (A1): neutralization of electrostatic charges of the container by means of an ionizing bar; (A2): neutralization of electrostatic charges of the container by means of an ionizing needle; (A3) neutralization of electrostatic charges of product A to be dosed, and dosing thereof; (A4): neutralization of electrostatic charges of the container after the dosing of product A; (A5) neutralization of electrostatic charges of product B to be dosed, and dosing thereof; (A6): neutralization of electrostatic charges of the container after the dosing of product B; (A7): capping of the container.

[0091] FIG. 6 depicts a partial sectional front elevation view of an equipment assembly (15) of the invention.

DETAILED DESCRIPTION OF THE INVENTION

[0092] The invention provides a method of gravimetric filling of a solid product in a container, the method comprising the following steps, which are illustrated in attached FIGS. 1 to 4:

a) providing a container (1) comprising a generally cylindrical body (2) and which is equipped in its upper part with a ridge (3, flange) of diameter slightly greater than the diameter of the body (2) of the container (1);
b) inserting the container (1) in a hollow cylinder (4), the inner cavity (5) of which has a diameter slightly greater than the diameter of the body (2) of the container (1), and which is equipped with a recess (6, receptable) in the upper area of the inner cavity (5), so that the ridge (3) of the container (1) rests in the recess (6) of the upper area of the inner cavity (5) of the cylinder, and with the contact area between the ridge (3) of the container (1) and the recess (6) of the upper area of the inner cavity (5) of the cylinder being the only area of contact between container (1) and cylinder (4), so that the container (1) is in suspension within the inner cavity (5) of the cylinder (4) and with its upper surface (7) located slightly underneath the upper surface (8) of the cylinder;
c) placing the cylinder (4) and container (1) unit above a gravimetric weighing system (9) which is provided on its non-weighing surface (10) with a mount (11, weighing element) which has a diameter less than the diameter of the inner cavity (5) of the cylinder (4) and a suitable height to raise the container (1) by the sufficient height (h) so that the ridge (3) of the container is no longer in contact with the recess (6) of the upper area of the inner cavity (5) of the cylinder (4) but without the upper surface (7) of the container (1) exceeding the height of the upper surface (8) of the cylinder (4), so that the container (1) is disposed above and rests upon the mount (11) provided on the non-weighing surface (10) of the gravimetric weighing system (9) and therefore resting all its weight thereon;
d) covering the upper surface (8) of the cylinder (4) hermetically by means of a lid (12) equipped with an orifice (13) wherethrough it is possible to add the solid product by means of a dosing element (14) or nozzle;
e) weighing with the desired precision the container (1) while it is disposed above and rest its weight upon the mount (11), and
f) filling the container (1) with the solid product through the orifice (13) of the lid (12), gravimetrically controlling the quantity of product added thereto by means of the gravimetric weighing system (9).

[0093] The lid of step d) must be understood in general terms as any element which may hermetically cover the cylinder (4), so that, for example, said lid may be implemented in the practice in the form of the lower walls or of a flexible hopper which incorporates a dosing element or nozzle, provided that this hopper is adapted to the cylinder so that it does not allow the access of airflow therein but still allows charging of material into the container.

[0094] Steps e) and f) are preferably performed in the same dosing station with the object that the precision of the weighing is optimum, although nothing would prevent it from being performed in different dosing stations.

[0095] Through the steps of the method described, the vertically elevated position of the container (1) is achieved so that the container (1) does not touch the inner walls of the cylinder (4), so that the weighing device may precisely guarantee the pre-set weight of added solid product. Furthermore, said vertically elevated position renders is possible for the dosing element (14, solids charging device) or nozzle to enter the container (1) and facilitate the dosing (charging). All of this may occur even in the presence of vibration provided by an external vibrating element, which in embodiments of the invention may help correctly dose the product in the container (1).

[0096] The invention also provides an apparatus (equipment assembly) adapted for use in aseptic gravimetric filling of containers. In some embodiments, the invention provides an apparatus (15) comprising: [0097] a hollow receiver (4) having a height (4H) and comprising: a) an inner cavity (4A) having a first length (4L) and a first inner diameter (4ID), said receiver having a first outer diameter (4OD); and b) a receptacle (6) disposed at an upper end of said inner cavity, said receptacle having a first height (6H) and a second inner diameter (6ID), and said receptacle being defined by a lower surface (6A) and a circumferential surface (6B), wherein 4OD>6ID>4ID; [0098] a container (16) comprising: a) a body having a length (16H) and an outer diameter (16OD) and an inner cavity; and b) a flange (3) disposed adjacent to or at an upper end of said body, said flange (or ring or ridge) having a second height (3H) and a second outer diameter (3OD), and said flange being defined by a lower surface (3A) and a circumferential surface (3B), wherein 3OD>16 OD and 16H>3H; and [0099] a lid (12) having a charging port therethrough, said lid having an outer diameter (12OD), whereby the smallest outer diameter of said lid is sufficient large so that lids covers the receptacle entirely; [0100] wherein: 6ID>3OD>4ID; and 4H>16H and 6H>3H.

[0101] In the exemplary embodiment of FIG. 6, the container can be a carpule, ampoule, bottle, vial, syringe or other such container having a flange or ring. In this exemplary embodiment, the apparatus further comprises a gravimetric weighing system (9) comprising an upper surface (10) and a mount (11, projection, weighing element, load cell). The mount has a height (11H) and an outer diameter (11OD), wherein: a) 4H>(16H+11H); and b) 4ID>11OD. When said hollow receiver, said container, said lid, and said gravimetric weighing system are assembled, the lower surface of said flange (3) is spaced away from said upper surface (6A), the upper surface of said flange is spaced away from the lower surface of said lid, and said circumferential surface (3B) is spaced away from said circumferential surface (6B). In particular embodiments, when said hollow receiver, said container, said lid, and said gravimetric weighing system are assembled, the lower surface of said flange (3) is spaced away from said upper surface (6A) by the distance (S1), the upper surface of said flange is space away from the lower surface of said lid by the distance (S2), and said circumferential surface (3B) is spaced away from said circumferential surface (6B) by the distance (S3). The inner dimensions and shape of the inner cavity (4A) of the hollow receiver (4) and the outer dimensions and shape of the outer surface of the container (16) are adapted to ensure the container remains vertical and spaced away from the hollow receiver yet enclosed within the inner cavity (4A) during the weighing operation.

[0102] In some embodiments, the apparatus of the invention further comprises one or more sleeves (spacers, as described further herein) disposed between the outer surface of the container (1, 16) and the inner surface of the cavity of the receiver (4).

[0103] In some embodiments, the apparatus further comprises a vibrating element or system, external to the receiver.

[0104] In some embodiments, 12OD>6ID. In some embodiments, 12OD>4OD>6ID. The hollow receiver (4) contacts (or engages) said upper surface (10) and the lower surface of said lid (12). The purpose of the lid is to temporarily seal (except for the existence of the materials charging port in the lid) the receptable and cavity of the receiver after the container has been placed within the receiver, whereby laminar airflow cannot enter the contained spaced during the charging and weighing steps.

[0105] In a preferred embodiment, the process is carried out in an isolator, meaning the equipment assembly or apparatus is placed in an isolator. In another preferred embodiment, the process is carried out in a sterile open room (meaning the equipment assembly or apparatus is placed in said room), e.g. a cleanroom or restricted area barrier system (RABS), complying with in both cases Grade A according to the classification of clean air rooms and devices commonly accepted by standard EN ISO 14644-1.

[0106] In the case of isolators, and according to a preferred embodiment, before the dosing operation stated in the present invention, it requires a sterilization with nebulized or vaporized hydrogen peroxide or a mixture of hydrogen peroxide with peracetic acid. In some embodiments, the process of the invention further comprises sterilizing at least one of said isolator, said container, and said receiver prior to charging of material into said container. Said sterilizing can be carried as described herein or using a method accepted for use in the pharmaceutical industry.

[0107] In some embodiments, the pharmaceutical substance is a particulate solid, which can be selected from the group consisting of powder(s), lyophilizate(s), granule(s), bead(s), particle(s), pellet(s), nanoparticle(s), nanosphere(s), microsphere(s), and microparticle(s). In some embodiments, the container is selected from the group consisting of one or more syringe(s), one or more vial(s), one or more capsule(s), one or more ampoule(s), one or more single-dose device(s), one or more inhaler(s), one or more bottle(s), one or more carpule(s), one or more well(s) of blister pack(s), one or more sachet(s), and one or more bag(s).

[0108] The method (aseptic gravimetric filling and weighing process) and apparatus (equipment assembly) of the invention provide numerous advantages over other methods for filling containers, esp. small pharmaceutical containers, with sterile solid(s). [0109] The cylinder (receiver), possessing the herein described characteristics, and retaining the container and which is temporarily hermetically closed before the weighing, achieves hermetic isolation of the container from the laminar airflow in the measurement cabin and, therefore weighing, of both the full and empty container, is no longer be affected by the existence of laminar flow. [0110] Likewise, the product to be filled in the container, in addition to its access channel (the charging port in the lid) thereto, is also isolated from the outside hermetically, so that the laminar flow in the measurement cabin cannot affect the falling of the solid product in the container either. [0111] The empty container is weighed under essentially the same conditions and normally only with seconds of difference before it starts being filled with the solid product, thereby avoiding or minimizing potential errors that might occur when the weighing is performed at different moments and/or circumstances of the process. [0112] With the container and receiver designed as described herein, it is possible to very precisely dose solids that have certain characteristics such as apparent density, intrinsic viscosity, specific distribution of particle size of the solid, etc. aseptically under laminar flow conditions.

[0113] For the person skilled in the art, it will be clear that the process indicated may be implemented in different embodiments of the invention, all of which are hereby included within the scope of the invention and according to the content of the attached claims. For example, and without limiting character, the present invention includes the particular embodiments, all independent from one another but they may be combined together without limitation.

[0114] In some embodiments, one or more sleeves is/are disposed between the container and cylinder (receiver) provided said sleeves do not interfere with the process of the invention. The one or more sleeves may provide additional advantages such as a better balance of the container within the cylinder cavity. Illustratively, a sleeve of this type between container and cylinder may have a height of between 0.5 mm and 10 mm, and preferably between 0.5 and 5 mm in height. This sleeve provides suitable verticality or suspension of the container in the receiver, so that the container remains in a suitable position when the dispenser needle (nozzle, solids dispenser) enters through the lid and the top of the container facilitating the dosing. In addition, the container remains suspended vertically (without touching the walls of the vibration buffer part), so that the weighing device (weighing system/element) can provide an accurate weight of the pre-set (predetermined) dose charged into the container.

[0115] In another embodiment, the cylinder (receiver) may be equipped with additional external surface features, such as an outer ridge of a certain thickness, adapted to allow the cylinder to rest without the risk of the cylinder sliding or falling and/or adapted to allow the cylinder, with said ridge, to be transferred from one place to another within the different points of the filling stations, such as by means of a series of elevated rails.

[0116] In a further embodiment, the projection (abutment, mount, load cell, weighing cell, cup) provided on the weighing (gravimetric) surface may have a generally cylindrical form but may also adopt any other form such as square, hexagonal or others, when viewed from a top plan view or side elevation view. The projection can be symmetric or asymmetric. Its upper surface may also be flat or may end in other geometric forms, such as conical or truncated cone shaped. All these variations may be possible as long as the projection continues to fulfil its function of raising (elevating) the container, optionally covered by one or more sleeves, sufficiently so that the ridge (flange) of the container is separated from the recess of the upper surface of the cylinder so that all the weight of the container, with or without product, rests on the projection and therefore on the balance (weighing system), thereby essentially guaranteeing correct weighing thereof (before and after charging of solid therein). It is also important that the height of the projection not be too high to ensure that the upper surface of the container (mounted on the projection) does not rise above the upper surface of the cylinder (receiver, receptacle of the receiver), because if the upper surface of the container is above the upper surface of the cylinder, hermetic sealing of the cylinder by means of the indicated lid would be prevented.

[0117] Referring to FIG. 6, 4H must be greater than the sum of 11H+16H, and 6H must be greater than 3H. The inner diameter 6ID of the receptacle (6) of the receiver must be greater than the outer diameter 3OD of the flange (3) of the container (carpule, syringe, bottle, vial, etc.) (16) (see FIG. 6). Likewise, the inner diameter 4ID of the cavity in the retainer (4) must be greater than the outer diameter (16OD) of the hollow body of the container (16).

[0118] In some embodiments, the invention provides a method and apparatus for aseptic gravimetric filling of at least one container. The invention also provides a method and apparatus for aseptic gravimetric filling of two or more containers, i.e. of plural containers. The filling can be done sequentially, simultaneously or in an overlapping manner.

[0119] The product filling stage may be repeated as many times as necessary, for example if more than one different product is filled in the container, the different products can be filled in the container in different filling stages. Alternatively, if there were no reasons to keep the different solid products in different or separate stages, it would also be possible to previously mix the different products and charge the solids mixture into one or more containers in a single filling stage and weighing in a single weight measurement.

[0120] In some embodiments, the invention provides an aseptic gravimetric filling method further comprising the step of ionizing and/or neutralizing the electrostatic charge of one or more containers. The apparatus (equipment assembly) of the invention can further comprise one or more ionizers that neutralize (or discharge or dissipate) the electrostatic charge, if present, of one or more containers.

[0121] For example, one or more filling steps may be accompanied, previously, subsequently and/or simultaneously, with one or more ionization steps of the container to neutralize its electrostatic charges. Ionization (electrostatic charge neutralization) can be achieved by employing one or more ionizers. Exemplary ionizers can comprise devices selected from the group consisting of bar, needle, curtain, filter, ring, and etc. This ionization step allows the solid product to falls in the form of powder into the container, particularly when the container is made of plastic material, whereby the particles of the solid (e.g. powder) should not adhere to the inner or outer walls of the container and instead fall to the bottom thereof.

[0122] In some embodiments, the method of the invention further comprises the step of filling solid into one or more containers under a stream of sterile inert gas (e.g. nitrogen, or air). In some embodiments, the apparatus (equipment assembly) of the invention further comprises a source of sterile inert gas, a source of sterile air, or a combination of the two. In some embodiments, the inert gas is filtered through a high efficiency particulate (HEPA) air filter. In some embodiments, the equipment assembly further comprises a nitrogen generator and/or a source of compressed nitrogen gas.

[0123] As used herein, the term airflow or air flow is considered to encompass gas flow, e.g. inert gas flow, whereby laminar airflow is taken to also include laminar gas flow. Accordingly, the term laminar flow is taken to include laminar airflow and laminar gas flow.

[0124] For example, the filling of the product(s) into one or more containers may be simultaneously accompanied with a gaseous stream, which is preferably sterile N.sub.2 gas or sterile compressed air, to facilitate dosing and provide the necessary sterility conditions required by the process. Furthermore, when the airstream is N.sub.2 it displaces some, most, or all of the oxygen present inside the container, thereby preventing or minimizing oxidation of the product and its subsequent oxidative degradation. The flowing gas can flow outside the exterior of the receiver but will preferably not flow within the sealed receiver during the charging and weighing operations, thereby essentially maintaining aseptic conditions during such operations without having the laminar airflow interfere with the charging and weighing operations.

[0125] In some embodiments, the method of the invention further provides the step of charging solid(s) into the container by way of one or more dosing devices independently selected at each occurrence from the group consisting of a) endless screw, b) a weight loss based gravimetric doser further equipped with a hopper and a high-precision nozzle, c) single-thread doser, d) double-threaded doser, e) vibrating channel based doser, f) vibrating hopper, g) doser with equipped with conveyor belt, h) doser equipped with a solids compacting system, and i) other such solids charging devices.

[0126] In some embodiments, the apparatus (equipment assembly) of the invention further provides one or more solids charging devices (dosing devices), for charging solid into the container, independently selected at each occurrence from the group consisting of a) endless screw, b) a weight loss based gravimetric doser further equipped with a hopper and a high-precision nozzle, c) single-thread doser, d) double-threaded doser, e) vibrating channel based doser, f) vibrating hopper, g) doser with equipped with conveyor belt, h) doser equipped with a solids compacting system, and i) other such solids charging devices.

[0127] In yet another additional embodiment, the doser (dosing device, solids charging device) may be equipped with a mixer.

[0128] In some embodiments, the method of the invention comprises the step of filling plural containers with one or more solid(s). In some embodiments, the apparatus (equipment assembly) of the invention comprises two or more receivers as described herein. In some embodiments, the apparatus (equipment assembly) of the invention comprises a receiver comprising two or more inner cavities and two or more respective receptacles as described herein.

[0129] For example, the cylinder (receiver) of the present invention may be equipped with plural inner cavities each of which has a diameter slightly greater than the diameter of the body of the container it is adapted to receive. Each cavity is adjacent a respective receptacle in the upper area so that the respective ridges (flanges) of the containers rest in the respective receptacles, and the contact area between the ridge of each container and of each recess of the upper area of the cavity of the cylinder being the only area of contact between container and cylinder, whereby, prior to weighing, each container is in within each cavity of the cylinder, and the upper surface of each container is vertically disposed slightly below the upper surface of its respective receptacle.

[0130] In some embodiments, the weighing system comprises one or more weighing cells (load cells). In some embodiments, the weighing system comprises plural weighing cells, whereby plural containers can be filled and weighed. In another embodiment, the weighing cell is a high-precision cell, preferably impermeable to water, environmental dust, vapors, disinfecting agents, etc.

[0131] The pharmaceutical container is preferably charged (filled) while the container is in a vertical position. If a container has a wider end and a narrower end, solids can be charged preferably through the wider end; however, solids can also be charged through the narrower, provided that the inner diameter of the narrower end allows access of the filling needle or nozzle inside the container.

[0132] In some embodiments, the equipment assembly further comprises one or more deionizers adapted to eliminate the electrostatic charge of the container and/or receiver so that adherence of powder to the wall of the container and/or receiver during the loading and weighing operations is minimized or eliminated. The use of deionizer(s) minimizes the risk of adherence of powder to the closure surface of the container, such that no powder is on said surface when a cap is placed thereon downstream in the process.

[0133] An exemplary overall diagram, included as an illustrative purpose or by way of example, of the part of the process incorporating plural deionizers is depicted in FIG. 5, which depicts a generalized filling-line with various stations (A1-A7). The stations (A1-A7) employs various types of deionizers. The exemplary stations are defined as follows: Station A1pucks charging station; Station A2pre-filling station; Station A3filling station; Stations A4 and A6prefilling station; Station A5second filling station; and Station A7stoppering station.

[0134] Station A1 employs a bar deionizer that eliminates the electrostatic charge on the surface of the receiver(s). Stations A2, A4, A6 and A7 employ needle-type (needles) deionizer(s) that eliminates the electrostatic charge on the surface of the container(s). Stations A3 and A5 employ pointing deionizer(s). The transport of ions generated by the electrode of an ionizer, at each of the stations, can be facilitated by use of flowing nitrogen gas or air, either of which can act as a conduit for the ions. The use of such flowing gases is optional.

[0135] Each container is independently selected at each occurrence from the group consisting of syringe(s), vial(s), capsule(s), ampoule(s), single-dose device(s), inhaler(s), bottle(s), carpule(s), well(s) of blister pack(s), sachet(s), and bag(s). In some preferred embodiments, the container is a syringe or a carpule. In such cases, the ridge (flange) described above is the ridge that the syringes or the carpules usually have in their upper end, i.e. at the end whereby the plunger or plug of the carpule, respectively, is introduced.

[0136] The flange of a container can be permanently or removably attached to the hollow body of the container. The flange can have a height and outer diameter smaller than the height and inner diameter of a respective receptacle in which the container is placed.

[0137] The invention also includes embodiments wherein the container (syringe or carpule) is filled by the opposite end, i.e. by the end with the smaller diameter wherethrough the needle would normally be coupled.

[0138] A container can be made of any pharmaceutically acceptable material. Exemplary materials include one or more metals, one or more polymers, one or more composites, one or more glasses, crystal, combinations thereof, or any inert (with respect to the solid to be charged into the container) material. Exemplary polymers include polyolefins and cyclic polyolefins, polypropylene, polybutadiene, polyethylene, polystyrene, vinyl polychloride, polyacrylonitrile, polyamides etc., polyesters (containing the ester functional group in its main chain: poly(ethylene terephthalate), polycarbonate), acrylic polymers (poly(methyl methacrylate), polyacrylonitrile), thermoplastic resins (polyacetals and polyhaloethylenes), polyurethanes, formaldehyde resins (phenol resin, urea resin), phenoplasts, aminoplasts, thioplasts, duroplastic resins (unsaturated polyester, polyurethanes), silicones, polyvinylidenes, cellulose derivatives, polycarbonates, and mixtures of two or more thereof, etc. Alternatively, the receptacle may also be metal, e.g. of steel or titanium suitable for the administration of drugs.

[0139] The cylinder (receiver) is preferably composed of a metal material such as steel or titanium, although the invention contemplates the possibility that it can be made from various materials, such as different polymer(s), glass, stone, resin, crystal, etc. A preferred material may be a coating that minimizes the formation of electrostatic charge.

[0140] Both the materials used for the container and the cylinder materials are preferably gas impermeable, water impermeable, inert, solvent impermeable, and do not absorb and/or adsorb the solid(s) within the container.

[0141] Preferably, the container of the present invention is a syringe or carpule. The nozzle (tip, end) thereof preferably comprises a threaded narrow end (male or female) or non-threaded narrow end (cone, tip). The end can be adapted to engage a needle. In some embodiments, the end is sealed with a rubber (or silicone) stopper (diaphragm, septum) and a cap securing the stopper to the end.

[0142] In some embodiments, the invention further comprises the step of placing a plunger within the syringe or carpule after material has been charged. In some embodiments, the container further comprises a plunger disposed within the container containing material.

[0143] The invention described herein is useful for aseptic gravimetric filling and weighing of any solid small enough to fit within a respective container, such as within a pharmaceutical container. Exemplary solids include pulverulent solid compounds of any type or composition.

[0144] In some embodiments, the solid possesses a particle size distribution defined as follows: [0145] no more than 10% of the total volume of particles is less than 20 microns, [0146] no more than 10% of the total volume of particles is greater than 230 nor less than 140, [0147] a value d0.5 in the range of 60-160 microns, [0148] where d0.5 indicates the mean value of the particle size that divides the population exactly in two equal halves, with 50% of the distribution above this value, and 50% below. In general, throughout the present specification, a value called d0.X represents the fraction in mass of the drug with particle sizes below the specified value, having a range of 0.0 to 1.0.

[0149] In a first preferred embodiment of the invention, the particle size distribution of the solid is defined as follows: [0150] no more than 10% of the total volume of particles is less than 20 microns, [0151] no more than 10% of the total volume of particles is greater than 230 nor less than 140, [0152] a value d0.5 in the range of 60-130 microns.

[0153] In a second preferred embodiment of the invention, the particle size distribution of the solid is defined as follows: [0154] no more than 10% of the total volume of particles is less than 20 microns, [0155] no more than 10% of the total volume of particles is greater than 325 nor less than 245, [0156] a value d0.5 in the range of 100-155 microns.

[0157] The method and apparatus (equipment assembly) of the invention need not be limited to pharmaceutical ingredients. In some embodiments, the solid(s) charged into the container is/are a pharmaceutical excipient(s) (or combination thereof), drug (medicament, active agent, pharmaceutically active ingredient, or combination thereof), or a combination thereof.

[0158] Suitable drugs include, by way of example and without limitation, risperidone, paliperidone, fentanyl, olanzapine, letrozole, aripiprazole, anastrozole, asenapine, brexpiprazole, cariprazine, clozapine, iloperidone, lurasidone, quetiapine, ziprasidone, etc. A derivative, metabolite or salt of drug can be used. Exemplary drug salt(s) (such as pamoate or palmitate) can be used. Said materials can be used alone or in combination.

[0159] The invention described here is applicable to pulverulent solid compounds of any nature.

[0160] A particular embodiment of the invention concerns the preparation of containers for use in preparing injectable depot compositions such as those described in U.S. Ser. No. 10/085,936, U.S. Ser. No. 10/182,982, U.S. Ser. No. 10/058,504, U.S. Ser. No. 10/195,138, Pub. US 2015/0147398A1, Pub. US 2015/0150791A1, U.S. Ser. No. 10/285,936B1 and related patents and applications, the entire disclosures of which are hereby incorporated by reference. In said patent documents, the injectable depot composition can be prepared from a kit of two or three different containers. According to one embodiment, a first container comprises organic solvent, a second container comprises drug, and a third container comprises polymeric pharmaceutical excipient. According to another embodiment, a first container comprises organic solvent, and a second container comprises drug and polymeric pharmaceutical excipient.

[0161] A particular embodiment of the invention provides a kit comprising a sealed pharmaceutical container comprising drug and polymeric excipient or a kit comprising a sealed container comprising drug and a sealed container comprising polymeric excipient. The sealed container can be independently selected upon each occurrence from a carpule, syringe, vial, bottle, etc. The drug and polymeric excipient can be provided in solid form or liquid form.

[0162] According to a particular embodiment, the polymeric excipient is a solid. Any pharmaceutically acceptable polymer can be employed in the invention. Exemplary polymeric excipients include lactic acid homopolymer (PLA), glycolic acid homopolymer (PLG), and poly(lactic acid)-co-poly(glycolic acid) copolymer (PLGA). Preferred exemplary PLGA copolymer include those with a ratio of lactic/glycolic monomer ratio in the range of 40:60 to 70:30, preferably in the range of 45:55 to 75:25.

[0163] Other exemplary polymeric excipients include polydioxanone, polytrimethylene-carbonate in the form of copolymers and homopolymers, poly(e-caprolactone) copolymers, polyanhydrides and polyorthoesters, which have been accepted as materials of biomedical use. The polymers may be of synthetic, semi-synthetic and/or natural origin. Combinations thereof are contemplated. They also include cellulose derivatives (for example, cellulose acetate, ethylcellulose, cellulose acetate phthalate, cellulose ethers such as, for example, hydroxypropyl methylcellulose), acrylate derivatives (for example Eudragit, poly(methyl methacrylate), cyanoacrylates) and biocompatible and biodegradable polymers such as polyanhydrides, polyesters, polyorthoesters, polyurethanes, polycarbonates, polyphosphazenes, polyacetals, polyoxyethylene-polyoxypropylenes. Polyesters such as polylactic, polyglycolide, polycaprolactone, polyhydroxybutirate or polyhydroxyvalerate are important. Furthermore, polysaccharides such as sodium alginate, chitosan or chitin or proteins may also be used. Other pharmaceutically acceptable, cosmetically acceptable, or GRAS materials are suitable for use according to the invention.

[0164] The preferred polymeric excipients in this invention are selected from copolymers with an intrinsic inherent viscosity preferably in the range of 0.16-0.60 dl/g, and more preferably between 0.25-0.55 dl/g, measured in chloroform at 25 C. and a concentration of 0.1%. The concentration of the polymeric component in the compositions of the invention is preferably included in the range of 25-50%, (expressed as the percentage of polymer weight based on the total polymer solution component) and more preferably between 30-40%.

[0165] For the purpose of the present invention, throughout this specification, the term intrinsic or inherent viscosity (.sub.inh) of the polymer is defined as the ratio of the natural logarithm of relative viscosity, (.sub.r), with respect to the polymer mass concentration, c, i.e.: .sub.inh=(ln .sub.r)/c [0166] considering that the relative viscosity (.sub.r) is the ratio of the viscosity of the solution with respect to the viscosity of the solvent .sub.s, i.e.:

.sub.r=/.sub.s

[0167] Furthermore, it shall be understood that the values of intrinsic viscosity throughout the present specification are measured at 25 C. in a chloroform solution with a concentration of 0.1%. The term of the intrinsic viscosity is commonly considered an indirect indicator of the polymer's molecular weight. In this way, a reduction in the intrinsic viscosity of a polymer, measured at a given concentration in a certain solvent, with the same composition of monomer and terminal groups, is an indicator of the reduction in molecular weight of the polymer (IUPAC. Basic definitions of terms relating to polymers 1974. Pure Appl. Chem. 40, 477-491 (1974).

[0168] The following examples illustrate the invention and should not be considered as defining the full scope thereof.

EXAMPLES

[0169] Several examples of container filling by means of the process of the present invention are shown below, which must be considered as solely illustrative purposes and not limiting of the scope of the invention. To explain said examples, it should be mentioned that syringes (or carpules) are used as pharmaceutical containers with a female or male connection system indifferently, and PLGA and PLA as polymeric excipients, and Risperidone and Letrozole, respectively, as pharmaceutically active compounds.

Example 1

Sterile Filling of Letrozole into a Syringe

[0170] The compound to be charged into the syringe is Letrozole (50 mg dose) to provide a prefilled syringe. The filling process takes place within a TESLTAR AZBIL rigid-walled aseptic isolator. Before starting with the filling process, all equipment is cleaned and sterilized. Sterilization is performed with nebulized or vaporized hydrogen peroxide or a mixture of hydrogen peroxide with peracetic acid.

[0171] Provide sterile syringes and caps (at capping station). Each syringe is placed beneath an ionized nitrogen stream, preferably, although a compressed airstream can be used, to achieve its ionization and elimination of the electrostatic charge. Then, the syringe is moved to the filling station and placed within the cylinder (4). The syringe is placed above the weighing cell, which tares the weight of the empty syringe and records the data in the weight tracker of the control system. After this, the syringe is filled with a quantity of 50 mg30% of letrozole by means of a nozzle. The syringe is weighed as it is filled during the filling, so that the system can control filling and stop the filling when the desired weight is reached, in this case 50 mg30% of letrozole.

[0172] Subsequently, if a second substance, such as an excipient, is to be charged into the cylinder (4), the syringe filled with letrozole is transported to a second filling station, and the same steps described above are repeated, replacing the letrozole with the excipient.

[0173] After filling is complete, the cylinder (4) together with the syringe is passed through an ionization station and then transferred to the capping or sealing station. The sealed syringed is placed on a tray with the other filled and sealed syringes.

[0174] This example has been performed for doses of 50, 75, 100, 200, 300, 400 and 500 mg of letrozole, operating suitably and precisely dosing.

Example 2

Sterile Filling of Risperidone into a Syringe

[0175] The compound to be charged into the syringe is risperidone (100 mg dose) to provide a prefilled syringe. The filling process takes place within a TESLTAR AZBIL rigid-walled aseptic isolator. Before starting with the filling process, all equipment is cleaned and sterilized. Sterilization is performed with nebulized or vaporized hydrogen peroxide or a mixture of hydrogen peroxide with peracetic acid.

[0176] Provide sterile syringes and caps (at capping station). Each syringe is placed beneath an ionized nitrogen stream, preferably, although a compressed airstream can be used, to achieve its ionization and elimination of the electrostatic charge. Then, the syringe is moved to the filling station and placed within the cylinder (4). The syringe is placed above the weighing cell, which tares the weight of the empty syringe and records the data in the weight tracker of the control system. After this, the syringe is filled with a quantity of 100 mg30% of risperidone by means of a nozzle. The syringe is weighed as it is filled during the filling, so that the system can control filling and stop the filling when the desired weight is reached, in this case 100 mg30% of risperidone.

[0177] Subsequently, if a second substance, such as an excipient, is to be charged into the cylinder (4), the syringe filled with risperidone is transported to a second filling station, and the same steps described above are repeated, replacing the risperidone with the excipient. See Example 4 for preparation of syringes charged with risperidone and PLGA copolymer.

[0178] After filling is complete, the cylinder (4) together with the syringe is passed through an ionization station and then transferred to the capping or sealing station. The sealed syringed is placed on a tray with the other filled and sealed syringes.

[0179] This example has been performed for doses of 50, 75, 100, 200, 300, 400 and 500 mg of risperidone, operating suitably and precisely dosing.

Example 3

Sterile Filling of Poly(Lactic Acid) (PLA) into a Syringe

[0180] The compound to be charged into the syringe is PLA (90 mg dose) to provide a prefilled syringe. The filling process takes place within a TESLTAR AZBIL rigid-walled aseptic isolator. Before starting with the filling process, all equipment is cleaned and sterilized. Sterilization is performed with nebulized or vaporized hydrogen peroxide or a mixture of hydrogen peroxide with peracetic acid.

[0181] Provide sterile syringes and caps (at capping station). Each syringe is placed beneath an ionized nitrogen stream, preferably, although a compressed airstream can be used, to achieve its ionization and elimination of the electrostatic charge. Then, the syringe is moved to the filling station and placed within the cylinder (4). The syringe is placed above the weighing cell, which tares the weight of the empty syringe and records the data in the weight tracker of the control system. After this, the syringe is filled with a quantity of 90 mg30% of PLA by means of a nozzle. The syringe is weighed as it is filled during the filling, so that the system can control filling and stop the filling when the desired weight is reached, in this case 90 mg30% of PLA.

[0182] Subsequently, if a second substance, such as an excipient, is to be charged into the cylinder (4), the syringe filled with PLA is transported to a second filling station, and the same steps described above are repeated, replacing the PLA with the excipient.

[0183] After filling is complete, the cylinder (4) together with the syringe is passed through an ionization station and then transferred to the capping or sealing station. The sealed syringed is placed on a tray with the other filled and sealed syringes.

[0184] This example has been performed for doses between 90 and 1000 mg of PLA, operating suitably and precisely dosing.

Example 4

Sterile Filling of Poly(Lactic Acid)-Co-Poly(Glycolic Acid) Copolymer (PLGA) into a Syringe Containing Risperidone

[0185] After charging risperidone into syringes according to Example 2 and prior to sealing said syringes, the syringe is passed to a second filling station within the cylinder (4). The syringe is placed above the weighing cell, which tares the weight of the syringe containing risperidone, recording the data in the weight tracker of the control system. After this, the syringe is charged with quantity of 100 mg30% of PLGA (Resomer 503) by means of a nozzle. The syringe is weighed as it is filled during the filling, so that the system can be controlled to stop the filling when the desired weight is reached, in this case 100 mg30% of Resomer 503.

[0186] Subsequently, if a third substance, such as an excipient or another active compound, is to be charged into the cylinder (4), the previously filled syringe is transported to the next filling station, performing the same steps described above as many times as necessary.

[0187] After being filled with PLGA, the cylinder (4) together with the syringe is passed through an ionization station and then transferred to the capping or sealing station. Once the syringe is filled and sealed, it is placed on a tray with the other filled and sealed syringes.

[0188] This example has been performed for doses of 100 to 500 mg of PLGA, and 50, 75, 100, 200, 300, 400 and 500 mg of risperidone operating suitably and precisely dosing.

[0189] The phrase pharmaceutically acceptable is employed herein to refer to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with tissues of human beings and animals and without excessive toxicity, irritation, allergic response, or any other problem or complication, commensurate with a reasonable benefit/risk ratio.

[0190] As used herein, the term about or approximately is taken to mean10%, 5% or 1% of a specified value. As used herein, the term substantially is taken to mean to a large degree or at least a majority of or more than 50% of. Moreover, all ranges specified herein are inclusive of the range limits and all integer and fractional values therein especially as defined by the definition of the term about.

[0191] As used herein, the term prodrug is taken to mean a compound that is administered in an inactive (or less than fully active) form, and is subsequently converted to an active pharmacological agent through normal metabolic processes. A prodrug serves as a type of precursor to the intended drug, e.g. risperidone. Exemplary prodrugs include the fatty acid esters of paliperidone (9-hydroxyrisperidone) as disclosed in U.S. Pat. No. 6,555,544, the entire disclosure of which is hereby incorporated by reference. Preferred prodrugs and salts of paliperidone include those having a water solubility of less than or about 2 mg/ml.

[0192] As used herein, the term derivative is taken to mean a compound that is obtained by chemical modification of a parent compound such that the derivative includes within it almost all or all of the chemical structure of the parent (or base) compound. A derivative is a compound that is formed from a similar compound or a compound that can be imagined to arise from another compound, if one atom is replaced with another atom or group of atoms. A derivative is a compound derived or obtained from another and containing essential elements of the parent substance. A derivative is a chemical compound that may be produced from another compound of similar structure in one or more steps.

[0193] In view of the above description and the examples below, one of ordinary skill in the art will be able to practice the invention as claimed without undue experimentation. The foregoing will be better understood with reference to the following examples that detail certain procedures for the preparation of embodiments of the present invention. All references made to these examples are for the purposes of illustration. The following examples should not be considered exhaustive, but merely illustrative of only a few of the many embodiments contemplated by the present invention.