Improvements relating to the filling and stoppering of containers

Abstract

A method of filling and stoppering a container body (10), comprising the steps of: a) providing a container body (10) that is open at a first end (11); b) filling a fluid (23) into the container body (10) through the first end (11); and c) inserting a stopper (20) into the container body (10) through the first end (11); wherein step c) comprises the steps: i) inserting the stopper (20) into an upper end (43) of an elongate loading member (40), during which insertion an external size of the stopper (20) is reduced by compression of the stopper (20); ii) using a plunger (50) that is inserted into the upper end (43) of the elongate loading member (40) to force the stopper (20) along the elongate loading member (40) towards a lower end (42) of the elongate loading member (40); iii) inserting the elongate loading member (40), the plunger (50), and the stopper (20) into the container body (10) through the first end (11); iv) withdrawing the elongate loading member (40) from the container body (10) while at the same time maintaining the plunger (50) and the stopper (20) within the container body (10) such that the stopper (20) is displaced out of the lower end (42) of the elongate loading member (40) and decompresses to form a seal with an inner face of the container body (10); and v) withdrawing the plunger (50) from the container body (10).

Description

[0001] Improvements relating to the filling and stoppering of containers

[0002] The present disclosure relates to methods of filling and stoppering a container body, containers for fluids and use of such containers in a dispensing apparatus. The container may, for example, be intended for use in a nasal dispensing apparatus.

[0003] Background to the Disclosure

[0004] It is known to provide a metered dose of medicament in a sealed container, such as a vial, to be dispensed from a dispensing apparatus. One example is described in EP 0 827 782 A2 in which a piercing element is provided on a piston that pierces a sealing member in the vial. The sealing member is then displaced into the vial forcing medicament out of the vial through the pierced opening in the sealing member. The medicament then passes through a channel formed in the piston and is expelled from the dispenser. Another example is described in EP 3 820 625 A2 wherein, according to its abstract, a device for dispensing a fluid product comprises a body, a reservoir containing one or two doses of a fluid product, said reservoir comprising a plug which closes off said reservoir in a sealed manner before actuation, a dispensing head provided with a dispensing orifice, and dispensing means for dispensing at least some of said fluid product through said dispensing orifice during an actuation, said device comprising a needle of which the tip is adapted to pierce said plug during the actuation, said reservoir being filled with said fluid product and plugged under vacuum with said plug such that the residual air volume present in said reservoir between said fluid product and said plug is substantially zero.

[0005] While sealed containers for fluids such as medicaments are available there remains a need to provide improved, or at least commercially acceptable, alternative containers and methods for their filling and stoppering.

[0006] Summary of the Disclosure

[0007] A first aspect of the present disclosure provides a method of filling and stoppering a container body, comprising the steps of: a) providing a container body that is open at a first end; b) filling a fluid into the container body through the first end; and c) inserting a stopper into the container body through the first end; wherein step c) comprises the steps: i) inserting the stopper into an upper end of an elongate loading member, during which insertion an external size of the stopper is reduced by compression of the stopper; ii) using a plunger that is inserted into the upper end of the elongate loading member to force the stopper along the elongate loading member towards a lower end of the elongate loading member; ill) inserting the elongate loading member, the plunger, and the stopper into the container body through the first end; iv) withdrawing the elongate loading member from the container body while at the same time maintaining the plunger and the stopper within the container body such that the stopper is displaced out of the lower end of the elongate loading member and decompresses to form a seal with an inner face of the container body; and v) withdrawing the plunger from the container body.

[0008] Beneficially, the method does not require vacuum equipment or a need to provide a seal on or around the container body. Consequently, the method avoids the need to balance pressures between the container and a vacuum pump and avoids any risk of a resultant positive pressure in any headspace, which could drive diffusion / permeation of the fluid from the container. In addition, the method potentially allows a smaller headspace volume to be achieved compared to filling method under vacuum. Further, the method may avoid the risk of stopper movement which may occur with vacuum-filling if a high differential pressure is produced.

[0009] In an embodiment, step iii) comprises inserting the elongate loading member, the plunger, and the stopper into the container body through the first end as a unit.

[0010] In an embodiment, in step iv) during withdrawal of the elongate loading member, the plunger and the stopper are maintained in a fixed position with respect to the container body.

[0011] In an embodiment, in step iii) the elongate loading member, the plunger, and the stopper are inserted into the container body at a speed of less than 10-50 mm / s for venting areas smaller than 1 .47 mm2and / or radial gaps smaller than 0.1 mm. While quicker stoppering times may be achievable with larger venting areas / radial gaps this would mean imposing greater compression to the stopper which may damage the stopper, e.g. potentially wearing off any silicone treatment from the stopper. The use of the specified insertion speeds for the stopper may beneficially limit any pressure build-up within the fluid and / or headspace within the container body by allowing sufficient time for gas to be vented from the headspace.

[0012] In an embodiment, in step iii) a clearance is maintained between an external face of the elongate loading member and the inner face of the container body. For example, the clearance may comprise a radial gap of greater than 0.1 mm. Beneficially, the clearance may provide a means for venting the headspace during step iii).

[0013] In an embodiment, in step ii) the stopper is forced by the plunger along the elongate loading member to a location wherein a lower face of the stopper is within 0.2mm of the lower end of the elongate loading member; optionally wherein the lower face of the stopper is flush with the lower end of the elongate loading member.

[0014] Beneficially, locating the lower face at or close to the lower end of the elongate loading member may permit the lower face of the stopper to be brought very close to the fluid without the elongate loading member contacting the fluid itself. In addition, such a location allows a lower sealing rib of the stopper to be ejected from the elongate loading member and engage against the container body as soon as possible as the elongate loading member starts to be removed, helping to secure the location of the stopper relative to the container body.

[0015] In step iii) the elongate loading member, the plunger, and the stopper may be inserted into the container body such that the stopper is located at a desired final position of the stopper and during step iv) the stopper is maintained in the desired final position. Beneficially this may allow a more controlled and precise positioning of the stopper of the end container, in particular relative to the surface of the fluid.

[0016] In step iii) the elongate loading member, the plunger, and the stopper may be inserted into the container body such that the stopper is located at a distance of up to 1 .5 mm from an upper surface of the fluid. Optionally the headspace volume is minimised.

[0017] The upper end of the elongate loading member may comprise an inwardly-tapered portion for compressing the stopper during step i) as the stopper is forced through the inwardly- tapered portion. In an embodiment, in step i) reducing the external size of the stopper comprises reducing an external diameter of the stopper.

[0018] The container body may be closed at a second end opposite the first end. Typically the container body will be a vial or other tubular member that is open only at one end, with the other end being closed as part of the shaping of a unitary container body. However, the method of the present disclosure may also be used with container bodies that are initially open at both ends and are provided with means for closing the second end, e.g. a second stopper.

[0019] In some embodiments the container body and fluid are subjected to a vacuum or partial vacuum before and / or during step iii).

[0020] In some other embodiments steps i) to v) are carried out at atmospheric pressure.

[0021] Optionally steps i) and / or ii) may be performed before or after step b). Thus, inserting the stopper into the elongate loading member and / or positioning the stopper towards the lower end of the elongate loading member may be carried out at any time before step iii). For example, a pre-prepared sub-unit of the elongate loading member and the stopper may be formed prior to the container body being filled with the fluid.

[0022] Steps a) to c) and steps i) to v) may be performed at one location or at multiple locations. All steps may be performed on a single machine having one or more stations. Alternatively, the steps may be performed using multiple machines. For example, steps a) and b) may be performed using a filling machine and one or more of steps i) to iv) of step c) may be performed using a stoppering machine. Steps i) and ii) may be performed at the same location as steps iii) to v) or at a different location. For example, one machine may be used to pre-load the stopper into the elongate loading member and a different machine may be used to carry out steps iii) to v). However, in an embodiment all of steps i) to v) are carried out at a single location and using a single machine.

[0023] A second aspect of the present disclosure provides a container for fluid that is filled and stoppered using the method of the first aspect as described above.

[0024] A third aspect of the present disclosure provides for use of the container of the second aspect in a dispensing apparatus. In an embodiment during actuation of the dispensing apparatus, the stopper is pierced by a hollow needle to provide an outlet for fluid, and the stopper is moved further towards the second end of the container body so as to pressurise and dispense the fluid.

[0025] A fourth aspect of the present disclosure provides a dispensing apparatus comprising a container according to the second aspect. The dispensing apparatus may be a nasal dispensing apparatus arranged to dispense a pharmaceutical into a nostril.

[0026] In some examples the dispensing apparatus may be a nasal dispensing apparatus. In some examples, the fluid within the container may consist of a single dose of a nasal medicament.

[0027] The container body of the above aspects may be formed from any suitable material such as glass or a plastic polymer. Examples of suitable glass include Type 1 Borosilicate ‘Fiolax Clear’, & Type 2. Examples of suitable polymers include polypropylene, polyethylene, polystyrene, cyclic olefin copolymer - an example being Topas® COC available from TOPAS Advanced Polymers GmbH, Frankfurt-Hochst, Germany, and liquid crystal polymer - an example being Zenite® LCP available from DuPont, Wilmington, USA.

[0028] The container body may consist of an elongate tube. In an embodiment the elongate tube is closed at one open and open at the other end. The elongate tube may be cylindrical. The container body may comprise an outwardly-turned flange at its open end. Alternatively, the rim at the open end may simply consist of an end surface of a tubular element without an outwardly-turned flange.

[0029] The stopper of the above aspects may be formed from an elastomer or thermoelastomer material such as EPDM, polychloroprene, hydrogenated nitrile, butyl, halo-butyl, dynamically cross-linked EPDM / PP (e.g. Santoprene®), styrenic block copolymers or blends thereof. Other suitable materials include high-density polyethylene and low-density polyethylene.

[0030] An outer surface of the stopper may be provided with one or more sealing features, for example, ribs, rings, etc. to enhance the sealing function of the stopper. In some examples the stopper may have an H-form construction, suitable for puncturing through a thin membrane. The H-form allows pressure within the container to be applied outwards onto the stopper seals, increasing contact pressure and reducing likelihood of dynamic leakage.

[0031] In some examples, one or more sealing ribs may be provided for providing sealing against the container body while maintaining a suitably low friction between the stopper and the container body.

[0032] In some examples the stopper may be coated with a friction-reducing coating, for example a silicone coating, which may be, for example, sprayed or baked onto the stopper. Fluorocarbon film coatings may also be utilised.

[0033] The fluid contained within the container of the above aspects may consist of a single dose of fluid or may comprise multiple doses of fluid. The fluid may contain a pharmaceutical. The term pharmaceutical, as used herein, is intended to encompass any pharmaceutical, compound, composition, medicament, agent or product which can be delivered or administered to a human being or animal, for example pharmaceuticals, drugs, biological and medicinal products. Examples include antiallergics, analgesics, bronchodilators, antihistamines, therapeutic proteins and peptides, antitussives, anginal preparations, antibiotics, anti-inflammatory preparations, hormones, or sulfonamides, such as, for example, a vasoconstrictive amine, an enzyme, an alkaloid, or a steroid, including combinations of two or more thereof. In particular, examples include isoproterenol [alpha- (isopropylaminomethyl) protocatechuyl alcohol], phenylephrine, phenylpropanolamine, glucagon, adrenochrome, trypsin, epinephrine, ephedrine, narcotine, codeine, atropine, heparin, morphine, dihydromorphinone, ergotamine, scopolamine, methapyrilene, cyanocobalamin, terbutaline, rimiterol, salbutamol, ipratropium bromide and salbutamol, flunisolide, colchicine, pirbuterol, beclomethasone, orciprenaline, fentanyl, and diamorphine, streptomycin, penicillin, procaine penicillin, tetracycline, chlorotetracycline and hydroxytetracycline, adrenocorticotropic hormone and adrenocortical hormones, such as cortisone, hydrocortisone, hydrocortisone acetate and prednisolone, insulin, cromolyn sodium, and mometasone, including combinations of two or more thereof. The pharmaceutical may be used as either the free base or as one or more salts conventional in the art, such as, for example, acetate, benzenesulphonate, benzoate, bicarbonate, bitartrate, bromide, calcium edetate, camsylate, carbonate, chloride, citrate, dihydrochloride, edetate, edisylate, estolate, esylate, fumarate, fluceptate, gluconate, glutamate, glycollylarsanilate, hexylresorcinate, hydrobromide, hydrochloride, hydroxynaphthoate, iodide, isethionate, lactate, lactobionate, malate, maleate, mandelate, mesylate, methylbromide, methylnitrate, methylsulphate, mucate, napsylate, nitrate, pamoate, (embonate), pantothenate, phosphate, diphosphate, polygalacturonate, salicylate, stearate, subacetate, succinate, sulphate, tannate, tartrate, and triethiodide, including combinations of two or more thereof. Cationic salts may also be used, for example the alkali metals, e.g. Na and K, and ammonium salts and salts of amines known in the art to be pharmaceutically acceptable, for example glycine, ethylene diamine, choline, diethanolamine, triethanolamine, octadecylamine, diethylamine, triethylamine, 1 - amino-2-propanol-amino-2-(hydroxymethyl)propane-1 ,3-diol, and 1-(3,4-dihydroxyphenyl)-2 isopropylaminoethanol. The pharmaceutical will typically be one which is suitable for nasal inhalation and may be provided in any suitable fluid form for this purpose, for example as a solution or powder suspension in a solvent or carrier liquid, for example ethanol, or isopropyl alcohol. The pharmaceutical may alternatively be one suitable for sub-lingual or ophthalmic delivery. The pharmaceutical may, for example, be one which is suitable for the treatment of asthma. Examples include salbutamol, beclomethasone, salmeterol, fluticasone, formoterol, terbutaline, sodium chromoglycate, budesonide and flunisolide, and physiologically acceptable salts (for example salbutamol sulphate, salmeterol xinafoate, fluticasone propionate, beclomethasone dipropionate, and terbutaline sulphate), solvates and esters, including combinations of two or more thereof. Individual isomers such as, for example, R-salbutamol, may also be used. The pharmaceutical may, for example, be one which is suitable for the treatment of migraine. An example is sumatriptan. As will be appreciated, the pharmaceutical may comprise of one or more active ingredients, an example of which is flutiform. One or more surfactants may be included if desired.

[0034] Brief Description of the Drawings

[0035] One or more embodiments of the disclosure will now be described, by way of example only, with reference to the accompanying drawings in which:

[0036] Figures 1 to 6 illustrate the steps of filling a container body with a fluid and stoppering the container body with a stopper to form a container.

[0037] Detailed Description

[0038] Unless defined otherwise, all technical and scientific terms used in this specification have the same meaning as is commonly understood by the reader skilled in the art to which the claimed subject matter belongs. It is to be understood that the foregoing summary of the disclosure and the following examples are exemplary and explanatory only and are not restrictive of any subject matter claimed.

[0039] The following description is directed to embodiments of the disclosure. The description of the embodiments is not meant to include all the possible embodiments of the disclosure that are claimed in the appended claims. Many modifications, improvements and equivalents which are not explicitly recited in the following embodiments may fall within the scope of the appended claims. Features described as part of one embodiment may be combined with features of one or more other embodiments unless the context clearly requires otherwise.

[0040] Figures 1 to 6 illustrate the steps of filling a container body 10 with a fluid 23 and stoppering the container body 10 with a stopper 20 to form a container 1 . In the following example the method will be described as carried out at atmospheric pressure and without the application of any vacuum step. However, it will be appreciated that one or more steps of the method may be performed under a vacuum or partial vacuum if desired.

[0041] Figure 1 shows the container body 10 containing a fluid 23. The container body 10 is open at a first end 11 and closed at a second end 12. The container body 10 may be cylindrical having a circular cross-section. The fluid 23 may be filled into the container body 10 by any suitable means. In an embodiment a known and pre-determined volume of fluid 23 is filled into the container body 10 so that an upper surface 24 of the fluid 23 will be at a known height within the container body 10. A headspace 30, containing gas, within the container body 10 may be defined as the volume above the upper surface 24 of the fluid 23.

[0042] The container body 10 once sealed using a stopper 20 forms the container 1 as shown in Figure 6. In an embodiment the container 1 consists only of the two components of the container body 10 and the stopper 20.

[0043] Figure 2 shows the container body 10 and fluid 23 together with an elongate loading member 40 and the stopper 20 ready to be loaded into the elongate loading member 40.

[0044] The elongate loading member 40 comprises a hollow, tubular body 41 that extends from a lower end 42 towards an upper end 43. An enlarged head portion 44 is provided at the upper end 43. In an embodiment the bore 41a of the tubular body 41 is constant but the bore 44a of the enlarged head portion 44 is flared by the provision of an inwardly-tapered portion 45. The inwardly-tapered portion 45 may, for example, have a conical face.

[0045] The stopper 20 as shown in Figure 2 may be configured as a slidable stopper that can move along a length of the container body 10 in use. The stopper 20 may comprise a plug form. The stopper 20 may comprise, for example, a tubular portion 26 and a transverse portion 27 arranged part-way along the tubular portion 26. One or more ribs 22 may be provided on an outer face of the tubular portion 26 of the stopper 20. Three ribs 22 may be provided. The ribs 22 may be annular. The ribs 22 may function to enhance the sealing function of the stopper 20 and or may enable the stopper 20 to function as a sliding seal.

[0046] An external size of the stopper 20 (in an uncompressed, rest state) is greater than the internal diameter of the bore 41a of the tubular body 41 . The external size may be considered, for example, as the external diameter of the stopper 22. Where the stopper 20 is provided with ribs 22 or other equivalent features the external diameter may be considered the largest external diameter of the ribs 22.

[0047] Figure 3 shows the stopper 20 once it has been inserted via the upper end 43 of the elongate loading member 40 and forced along the elongate loading member 40 towards the lower end 42. In the illustrated example, a lower face of the stopper 20 is positioned flush with the lower end 42 of the elongate loading member 40.

[0048] A plunger 50 is used to insert the stopper 20 into and along the elongate loading member 40. The plunger 50 comprises a cylindrical portion 51 and an enlarged head 52 provided at an upper end of the cylindrical portion 51 . An external diameter of the cylindrical portion 51 is slightly smaller than an internal diameter of the tubular body 41 so that the cylindrical portion 51 may move freely with respect to the tubular portion 41 .

[0049] An end face 53 of the cylindrical portion 51 is sized to be able to contact and impose force onto an upper face of the stopper 20.

[0050] The initial stage of inserting the stopper 20 compresses the stopper 20 as the stopper 20 is forced, by the plunger 50, through the inwardly-tapered portion 45. In particular, the compression reduces the external size, e.g. external diameter, of the stopper 20 so that it can be fitted within the tubular portion 41 . Thereafter, the plunger 50 acts to force the now compressed stopper 20 along the tubular portion 41 until the lower face of the stopper 20 is positioned flush with the lower end 42 of the elongate loading member 40 as shown in Figure 3. Allowing for tolerances, the lower face may be positioned within, for example, 0.20mm of the lower end 42.

[0051] Next, as shown in Figure 4, the elongate loading member 40, the plunger 50, and the stopper 20 are inserted into the container body 10 through its first end 11 , in an embodiment as a unit. The elongate loading member 40, the plunger 50, and the stopper 20 may be inserted into the container body 10 at a speed of less than 50 mm / sec, optionally at a speed of 10-50 mm / sec to aid venting of gas from the headspace 30 through a clearance provided between the external face of the elongate loading member 40 and the inner face of the container body 10.

[0052] The elongate loading member 40, the plunger 50, and the stopper 20 may be inserted into the container body 10 so that the stopper 20 is located at a desired final position of the stopper 20. For example, this may be such that a lower face of the stopper 20 is located at a distance of up to 1 .5 mm from the upper surface 24 of the fluid 23.

[0053] Next, as shown in Figure 5, the elongate loading member 40 is withdrawn from the container body 10 while at the same time maintaining the plunger 50 and the stopper 20 within the container body 10 such that the stopper 20 is displaced out of the lower end 42 of the elongate loading member 40 and decompresses, e.g. expands, to form a seal with the inner face of the container body 10. In an embodiment the plunger 50 remains stationary during this step and as a result the stopper 20 is maintained at the desired final position due to the engagement of the end face 53 of the plunger 50 against the stopper 20.

[0054] Finally, as shown in Figure 6, the plunger 50 is fully withdrawn from the container body 10 and the stoppering of the container 1 is completed.

[0055] It is to be understood that at least some of the figures and descriptions of the disclosure have been simplified to focus on elements that are relevant for a clear understanding of the disclosure, while eliminating, for purposes of clarity, other elements that the reader skilled in the art will appreciate may also be required. Because such elements are well known to the reader skilled in the art, and because they do not necessarily facilitate a better understanding of the disclosure, a description of such elements is not provided herein.

Claims

Claims:1 . A method of filling and stoppering a container body, comprising the steps of: a) providing a container body that is open at a first end; b) filling a fluid into the container body through the first end; and c) inserting a stopper into the container body through the first end; wherein step c) comprises the steps: i) inserting the stopper into an upper end of an elongate loading member, during which insertion an external size of the stopper is reduced by compression of the stopper; ii) using a plunger that is inserted into the upper end of the elongate loading member to force the stopper along the elongate loading member towards a lower end of the elongate loading member; ill) inserting the elongate loading member, the plunger, and the stopper into the container body through the first end; iv) withdrawing the elongate loading member from the container body while at the same time maintaining the plunger and the stopper within the container body such that the stopper is displaced out of the lower end of the elongate loading member and decompresses to form a seal with an inner face of the container body; and v) withdrawing the plunger from the container body.

2. The method of claim 1 , wherein step iii) comprises inserting the elongate loading member, the plunger, and the stopper into the container body through the first end as a unit.

3. The method of claim 1 or claim 2, wherein in step iv) during withdrawal of the elongate loading member, the plunger and the stopper are maintained in a fixed position with respect to the container body.

4. The method of any preceding claim, wherein in step iii) the elongate loading member, the plunger, and the stopper are inserted into the container body at a speed of less than 50 mm / sec.

5. The method of any preceding claim, wherein in step iii) a clearance is maintained between an external face of the elongate loading member and the inner face of the container body.

6. The method of claim 5, wherein the clearance comprises a radial gap of greater than 0.1 mm.

7. The method of any preceding claim, wherein in step ii) the stopper is forced by the plunger along the elongate loading member to a location wherein a lower face of the stopper is within 0.2mm of the lower end of the elongate loading member; optionally wherein the lower face of the stopper is flush with the lower end of the elongate loading member.

8. The method of any preceding claim, wherein in step iii) the elongate loading member, the plunger, and the stopper are inserted into the container body such that the stopper is located at a desired final position of the stopper and during step iv) the stopper is maintained in the desired final position.

9. The method of any preceding claim, wherein in step iii) the elongate loading member, the plunger, and the stopper are inserted into the container body such that the stopper is located at a distance of up to 1 .5 mm from an upper surface of the fluid.

10. The method of any preceding claim, wherein the upper end of the elongate loading member comprises an inwardly-tapered portion for compressing the stopper during step i) as the stopper is forced through the inwardly-tapered portion.11 . The method of any preceding claim, wherein in step i) reducing the external size of the stopper comprises reducing an external diameter of the stopper.

12. The method of any preceding claim, wherein the container body is closed at a second end opposite the first end.

13. The method of any preceding claim, wherein the container body and fluid are subjected to a vacuum or partial vacuum before and / or during step iii).

14. The method of any one of claims 1 to 12, wherein steps i) to v) are carried out at atmospheric pressure.

15. The method of any preceding claim, wherein steps i) and / or ii) are performed before or after step b).

16. A nasal dispensing apparatus comprising a container body filled and stoppered by the method of any of claims 1 to 15.

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