Technical Field

The present invention regards sterile dropper container, especially suitable for ophthalmic prepara tions.

Background Art

Some pharmaceutical applications, in particu lar application of ophthalmic preparations, require a high level of accurate dosing of minimal amounts, i.e. few drops, of a pharmaceutical.

Today, eye drops are sold in dropper bottles, e.g. semi-rigid containers. For accurate dropping the preparations must have low viscosity, since otherwise dropping would be affected by the reduced flow of viscous content towards the applicator.

Also already known are eye ointments sold in tubes. However, such ointments cannot be accurately dosed. Therefore there is a need for a container that allows the accurate dosing also of higher viscosity preparations, especially ophthalmic preparations and that preferably also has good recyclability.

Abbreviations:

PE = polyethylene

LLDPE = linear low density polyethylene 0.915-0.925 g/cm ³ mLLDPE= LLDPE from metallocene based catalyst polymerization route resulting in high density of up to 0.940 g/cm ³ while retaining excellent optical properties such as transparency.

LDPE = low density polyethylene 0.910-

0.940 g/cm ³ HDPE = high density polyethylene >0.941 g/cm ³

MDPE = medium density polyethylene 0.926-

0.940 g/cm ³

PP = polypropylene

EVOH = ethylene vinyl alcohol copolymer WVTR = water vapor transmission rate

OPP = (mono- or biaxial) oriented polypropyl ene

BOPP = biaxial oriented polypropylene

AlOx = aluminum oxide SiOx = silicon oxide

Disclosure of the Invention Hence, it is a general object of the inven tion to provide a dropper container, especially for oph thalmic preparations, that is also suitable for dosing viscous preparations and that preferably also has good recyclability. Now, in order to implement these and still further objects of the invention, which will become more readily apparent as the description proceeds, the dropper container is manifested by the features that it is a com pressible tube comprising a tube body, a shoulder and an applicator, said applicator being suitable for applying a tube content in dosed droplets, said applicator compris ing a sterile venting valve and said tube body having a restoring force sufficient to essentially restore the original volume of the tube body after each of a prede- termined number of applications.

Other subject matter of the present invention are a method for manufacturing such a compressible tube and its use in combination with a pharmaceutical prepara tion / composition for ophthalmic use.

"Essentially" with regard to the restoring force means restoring the original volume to at least 80 %, preferably at least 85 %, more preferred at least 90%, and in particular at least 95%. Such restoring force can be determined by comparing the volume after several ap plications with the original volume, e.g. by filling the tube body up to the shoulder with a liquid such as water, removing the liquid into a means suitable for volume measuring or weighing and comparing the results before and after use.

In a preferred embodiment, the restoring force is achieved with a body wall that does not comprise an aluminum foil. In particular, the tube body is pro duced from at least 85 %, more preferred at least 90 %, most preferred at least 95 % polyolefin comprising lay ers, with other materials optionally present being bar rier layers selected from EVOH in a total thickness of 5 to 30 pm, preferably 5 to 15 pm, and/or metal oxide or ceramic layers, in particular AlOx or SiOx nanometer lay ers in a thickness of <1 pm.

The venting applicator comprises a sterile venting opening, a venting valve that is provided with a sterile filtration means. The respectively equipped vent ing valve ensures that no contaminants can enter into the tube volume, so that preserving agents can be absent or their amount can at least be significantly reduced and/or the time during which the preparation can safely be used is extended. However, due to the sterile filtration means the tube body needs a higher restoring force than needed for a not sterile, filter-free venting means.

For good recyclability it is preferred that the whole tube is made of polyolefins, in particular pol- yethylene and/or polypropylene. In view of the restoring force HDPE and/or PP are preferred, in view of an easy manufacturing process a HDPE rich tube body is preferred. While the tube body can be manufactured by an extrusion or co-extrusion process, presently manufactur ing from a laminate is preferred since the flat laminate can easily be printed in line within the low particles, clean room environment demanded for ophthalmic contain ers. The printed laminates are then formed into a cylin der shaped body and longitudinally seamed. Suitable lami nates can be produced by extrusion, co-extrusion of two or more layers, extrusion lamination and/or by lamination using an adhesive.

In this production process, tube shoulders that may have been manufactured (molded) and packaged at another production site but also in low particles envi ronment are transported into the low particles environ- ment for the tube production. The laminate, optionally also produced and packaged at a different production site and also in low particles environment, is also trans ported into the low particles environment for the tube production . The tube manufacturing process may start with providing the side of the laminate becoming the outside of the tube with an imprint, then forming the laminate into a sleeve and welding the overlapping or abutting ends (blunt welding) of the laminate, thereby generating a longitudinal seam or seal, respectively.

Next, the sleeve is cut to tube bodies and one end of the tube body is provided with a shoulder by welding.

The shoulder is formed such that it sealingly engages with the applicator and provides fixing means for the applicator, i.e. the shoulder may be provided with push-on or screw-on means, dependent on the applicator used.

In a next step, the applicator comprising a closure is connected with the shoulder and the final tube packaged for being sent to the filling station. As already indicated above, one of the bene fits of the tubes of the present invention is their usa bility in combination with viscous contents due to their form and compressibility/squeezability. The use of laminates rich in HDPE besides of the good restoring force has the further advantage that HDPE provides low water vapor transmission rate (WVTR) or good barrier properties, respectively. In addition, flex ible or compressible or squeezable, respectively, tubes need less material than rigid bottles due to the lower wall thickness of the body.

While monolayer or two layer laminates (the tie layers are not counted herein) can also be used, presently preferred laminates are three layer laminates composed of an outside layer, a center layer and an in side layer that - for improving certain features - may slightly differ in their composition and/or thickness.

The layers are termed inside and outside with regard to the tube body. In general these three layers are connected with tie layers that may be thin adhesive layers or ex truded layers. Since low molecular weight components are undesired in combination with ophthalmic compositions, it is preferred to laminate the layers by extrusion lamina- tion and not by an adhesive. In an alternative embodiment all layers can be coextruded.

The inside layer and the outside layer pref erably comprise a low amount of LDPE or LLDPE including mLLDPE for improved sealability. In case of blunt weld- ing, the seam is strengthened by means of a sealing band along the seam. This sealing band in general is of LDPE or LLDPE comprising PE material.

The composition of the outside layer is e.g. improved for sealability to the inside layer and/or the shoulder and also for printability. It may also be pro vided with a light barrier such as Ti02 and/or other pig ments for esthetic purposes. The inner layer, in contact with the content, may be of higher quality than the other layers, e.g. at least in part of pharmaceutical grade material, and also improved for sealability to the outside layer and /or the shoulder and/or with itself.

Each of the layers, in particular the center layer and/or the inside layer can further be provided with a barrier layer. The inside layer may preferably be provided with a sandwiched EVOH layer, while a PE center layer/foil may e.g. comprise a metallization and an ori ented PP center film, such as an OPP or a BOPP center (carrier) film may be provided with an SiOx or AlOx layer and/or a metallization. Monoaxial or biaxial oriented foils can also be used as center layer without barrier layer, although their advantage is limited since no oxy gen barrier is needed. In some cases they may add to the desired mechanical properties.

Brief Description of the Drawings

The invention will be better understood and objects other than those set forth above will become ap parent when consideration is given to the following de- tailed description thereof. Such description makes refer ence to the annexed drawings, wherein:

Figure 1 visualizes the restoring force, i.e. a) shows the direction of the compress ing/squeezing force C applied upon withdrawing content by dropping D, b) shows the direction of the restoring force R upon ventilation V.

Figure 2 shows two types of shoulders with different means for attaching the applicator, with a) showing a push-on shoulder and b) showing a screw-on shoulder. Figure 3 schematically shows three kinds of laminates and one co-extruded tube body wall, wherein a) shows a laminate or a laminate based tube body with HDPE center layer with HDPE/LDPE or HDPE/LLDPE outside layer, and a HDPE/LDPE or HDPE/LLDPE inside layer with coextruded EVOH intermediate layer, all layers con nected with tie layers for improved stability, b) shows a laminate as in a) but without co extruded EVOH intermediate layer, c) shows a laminate or a laminate based tube body with a center layer provided with a functional bar rier layer such as an SiOx layer or an AlOx layer (alt hough not shown, the inside layer may also be provided with an intermediate EVOH layer), d) shows an extruded tube body with a co-ex- truded EVOH barrier layer as center layer and two coex truded tie layers for obtaining improved adhesion between EVOH and PE.

Modes for Carrying Out the Invention

Applicators or droppers with a sterile venti lation valve and suitable for dosing single drops of con- stant size upon constant pressure are known and are e.g. obtainable form the firms Silgan, Nemera or Aptar.

In the manufacturing of sterile dropper tubes with a tube body formed from a laminate, the laminate and the tube shoulder can be manufactured in another facil- ity, provided that they are produced and packaged in low particle (clean room) environment.

The actual tube forming method in a low par ticle environment (production in clean room classifica tion ISO 7 or better) starts with in line printing of the laminate. In line printing of the laminate is advanta geous since no rolling of the laminate is needed and therefore no ink transfer to the backside (inside of tube) can occur.

Printing is followed by sleeve forming and welding overlapping regions or abutting edges (blunt welding), optionally provided with a sealing band. Pres ently preferred are overlapping seams.

Then the sleeve is cut into tube bodies 1 of desired length and provided with a tube shoulder 2a, 2b at one end. Fig. 1 and 2 show the tube body 1 with shoul der 2a, 2b but without applicator. The applicator is such that it has a groove into which the shoulder 2a, 2b en gages, i.e. the applicator extends on the interior and the exterior surfaces of the shoulder 2a, 2b. Once the tube body is filled with the con tent, the end of the tube body opposite the shoulder/ap plicator is sealed. This seal 3 is also termed end seal or end seam 3. For stability reasons, it proved advanta geous to position the longitudinal seam extending decen- tralized from the end seam 3 to the shoulder 2a, 2b and not from its center or middle, respectively.

Upon use, compression/squeezing pressure C is applied to the tube body and content drops out D (see Figure la). As soon as the compressing/squeezing pressure is released, the restoring force R sucks in air through the applicator V until the original tube volume is regen erated (see Figure lb).

As shown in Figure 2, the shoulder in addi tion is provided with fixing means for the applicator such as push-on means 2a or screw-on means 2b.

The applicator as bought has a sterile venti lation valve, i.e. an opening provided with a filtering means, and in general is also provided with a cap that can either allow access of air to the venting valve or seals the venting valve.

Presently preferred are caps that do not seal the venting valve. The longtime access of the venting valve allows full restoration of the original volume even if the restoration takes some time. In addition, it al lows the user to mount the cap directly after use, i.e. without waiting for restoration. For viscous contents, the cap should be such that the tube can be placed on the cap to ensure that the content flows towards the applicator between applica tions, thereby ensuring sufficient content in place for the dosed application. Using a compressible tube instead of a bottle for dropping ophthalmic pharmaceuticals has several ad vantages, e.g.

• It can be used to dose low viscosity liquids of about 1 mPas up to viscous liquids of up to 2000 mPas.

• It has better water vapor transmission rate (WVTR) barrier properties.

• Due to the sterile venting valve in the applicator the content needs less or no preservatives and the content can longer be used.

• It needs less material compared with a bottle.

For a reliable dosing of a few drops over the envisaged usable time of the content, a constant and suf ficiently high restoring force R is important. The minimal restoring force required is de pendent on the sterile ventilation valve of the applica tor used and in particular its sterile filtration means. Such sterile filtration means can be a filter material or a suitably shaped access between the outer and inner sur- face of the applicator.

While no oxygen barrier is needed due to the desired ventilation, the WVTR needs to be minimized since constant weight/viscosity is important for accurate dos ing over the whole lifetime. For recyclability it is preferred that the whole tube is made of polyolefin. While polyolefins with the same monomer units are preferred, i.e. polyethylene (PE) or polypropylene (PP), most of the applicators pres ently available are PP based while many tubes are prefer ably made of PE. Presently preferred are laminates with a high content of high density polyethylene (HDPE), option- ally and preferably admixed with minor amounts of low density polyethylene (LDPE) or linear low density poly ethylene (LLDPE) for optimizing specific features such as sealability .

The tube body 1 may be made by extrusion or co-extrusion (Figure 3d), however, presently preferred is manufacturing starting from a laminate 4.

For recyclability, it is preferred that the tubes are free of aluminum foils. While thin film metal lizations are acceptable as long as included into the laminate structure and not being a surface metallization which could lead to NIR (near infrared) sorting issues in mechanical recycling streams, it is preferred that any barrier layer 7a, 9, 10 is either an EVOH layer 7a, 9, or a thin metal and/or metal oxide or ceramic layer 10, such as an AlOx or SiOx layer. While a metallization may be applied on a PE film, for AlOx and SiOx an oriented PP center (Carrier) layer is preferred.

The compressible tube composed of tube body, shoulder and applicator is preferably made of polyolefin materials to at least 90 %, preferably at least 95% more preferred about 98 %, in particular polyolefin materials selected from polyethylene and/or polypropylene.

Where the tube body comprises an EVOH barrier layer, such layer preferably is limited to at most 10% of the body wall thickness.

In particular, the tube body is produced from at least 85 % polyolefin comprising layers, preferably polyolefin comprising layers made up of the same monomer units (PE) or with minor amounts of compatible monomer units, like some ethylene units comprised in PP, or the maleic anhydride grafted LLDPE tie layers 6a. Other mate rials optionally present are selected from EVOH barrier layers, in general EVOH layers of a thickness of at most 30 mpi, more preferred at most 20 pm, most preferred about 9 pm and/or metal oxide or ceramic layers, in particular AlOx or SiOx nanometric layers in a thickness of <1 pm. If an EVOH layer is present, also tie layers

(6a) of maleic anhydride grafted LLDPE are present be tween EVOH and PE in a thickness each that is similar to or up to about 50 % smaller than the thickness of the EVOH layer, most preferred about 9 pm Presently preferred is a laminate 4 of three layers or films or foils, referred to as outside 5, cen ter 7 and inside 8 layers, films or foils (for these lay ers/films/foils these terms are used interchangeably, i.e. as synonyms). These foils 5, 7, 7a, 8 are coextruded or connected with each other by means of an extruded tie layer 6, 6a. Instead of the extruded tie layer 6 also an adhesive might be used. However, an adhesive is less pre ferred since low molecular weight ingredients might mi grate into the content. The foils may be PP or rich in HDPE. For foils rich in HDPE, the following preferences exist:

The HDPE content in the HDPE based material should at least be 70%, preferably at least 80%.

The outside foil 5 in general is at least 85 % polyethylene composed of HDPE and LDPE or HDPE and

LLDPE, wherein the HDPE content is at least 70 %, prefer ably about 90 %. In addition, it may comprise up to 15 % additives such as Ti02 for improved light shielding of the content, or it my comprise pigments for esthetic pur- poses.

The center foil 7 might be a monoaxial or bi axial oriented foil because such foils provide higher me chanical strength. However, presently a not oriented HDPE rich laminate is preferred, in particular an at least 90%, preferably 100 % HDPE foil, optionally provided with a barrier coating 10 such as a metallization. In an al ternative embodiment, the center foil can be an oriented polypropylene foil such as an OPP or a BOPP foil, option ally provided with a barrier layer selected from an SiOx or an AlOx layer and/or a metallization.

The inside foil 8 can be a mono foil or a co- extruded foil, e.g. comprising a coextruded EVOH barrier layer 9. In the case of a mono foil, the preferred mate rial is HDPE/LDPE or HDPE/LLDPE foil with a HDPE content of at least 70 % for improved sealability. In case of an EVOH layer, the composition of the polyethylene is the same but an EVOH layer in a thickness of at most 30 pm, more preferred at most 20 pm, most preferred about 9 pm, as well as tie layers (6a) of maleic anhydride grafted LLDPE between EVOH and PE in a thickness each that is similar to or up to about 50 % smaller than the thickness of the EVOH layer are present.

The tie layers 6 between inside, center and outside foil all are preferably >95%, more preferred 100 % HDPE. Their thickness ranges from 10-30 pm.

In case of a coextruded laminate 4 or tube body 1, the center layer may be an EVOH layer 7a sand wiched between two tie layers 6a and inside 8 and outside 5 layers as shown in Figure 3d).

It has been found that the restoring force R is dependent on the laminate thickness, the HDPE content and the laminate structure. Thus, if the restoring force is insufficient, the layer thickness and/or the HDPE con tent may be enhanced and/or the HDPE type and/or the lam inate structure may be adapted.

HDPE is a presently preferred material be- cause it has good water vapor barrier properties, can be processed on usual PE tube manufacturing lines and pro vides good restoring force.

Suitable tube dimensions range from diameters from 16 mm to 30 mm and volumes from 5 ml to 100 ml.

For ophthalmic preparations and available ap plicators presently a volume of 10 ml and a diameter of 22 mm is preferred. For such a tube a minimal restoring force of 63 mbar proved sufficient. Lower restoring forces led to a reduced number of accurate doses. Long lasting restor ing force was e.g. obtained with a laminate with the fol- lowing layers / thicknesses: outside layer 5 / 120 pm, tie layer 6 / 25 pm, center layer 7 / 80 pm, tie layer 6 / 25 pm, inside layer 8 / 100 pm.

With a thinner laminate composed of outside layer 5 / 80 pm, tie layer 6 / 20 pm, center layer 7 / 80 pm, tie layer 6 / 20 pm, inside layer 8 / 100 pm few sam ples did not fully achieve the 63 mbar.

As already indicated above, for good seala- bility the inside and the outside foils comprise LDPE and/or LLDPE. Presently preferred materials are:

Outside layer/film/foil 5: 90/10 HDPE/LDPE or

HDPE/LLDPE

Center layer/film/foil 7: 100 HDPE

Inside layer/film/foil 8: 80/20 HDPE/LDPE or HDPE/LLDPE, or a foil with HDPE/LLDPE 80/20 inside/out side plus 9 pm EVOH and 2x7 pm tie layer 6a (maleic anhy dride grafted LLDPE)

Tie layer 6: 100 HDPE Experimental part:

Tubes with diameter of 22 mm and volume of 10 ml were produced as indicated above. The tube body was either made of a laminate composed of

A) outside layer / 80 pm, tie layer / 20 pm, center layer / 80 pm, tie layer / 20 pm, inside layer /

100 pm, or

B) outside layer / 120 pm, tie layer / 25 pm, center layer / 80 pm, tie layer / 25 pm, inside layer / 100 pm. Both laminates were made with foils/layers of the following composition:

Outside foil 5: 90/10 HDPE/LDPE Center foil 7: 100 HDPE

Inside foil 8: barrier foil composed of HDPE/LLDPE 80/20 inside/outside plus 9 pm EVOH layer 9 and 2x7 pm tie layer 6a (maleic anhydride grafted LLDPE) Tie layer 6: 100 HDPE

The applicator used was a push-on applicator obtainable from Aptar.

While usually oxygen transmission is relevant for tubes, this measure is irrelevant for the present, vented tubes.

The above described tubes were tested for their initial restoring force, for the conservation of the restoring force over multiple applications, the WVTR barrier effect and the weight loss upon storing. The restoring force was tested as indicated in Figure 1 with a) showing the compression, the squeez ing situation, b) the restoring situation.

In this test, the open end/applicator end of a squeezed tube is sealingly placed on a vacuum measuring device to detect the vacuum (sucking force) of the tube. The results obtained are shown in Table 1.

Table 1:

The letters m and s before the wall thickness indicate whether the longitudinal seam extended from the middle of the end seam (m) or decentralized to a side (s).

The minor results obtained with tubes with a seam extending from the middle of the end seam were due to bending of the tube. Such bending could be eliminated by positioning the longitudinal seam at one of the sides.

Table 2 shows the squeezing and restoring forces over a multitude of applications. From each tube 3 times a day 4 drops were dosed and the squeezing force / restoring force indicated.

The following kinds of tubes were tested and the mean value per dosing indicated.

BB (laminate B, vented cap, content physio- logical NaCl solution)

BK (laminate B, sealing cap, content physio logical NaCl solution) FB (laminate B, vented cap, content adjusted to 1000 mPas)

GB (laminate B, vented cap, content adjusted to 1000 mPas)(produced in a second facillity) HB (laminate B, vented cap, physiological

NaCl solution)(produced in a second facility)

JB (laminate B, vented cap, content adjusted to 1000 mPas)(produced in a third facility)

KB (laminate B, vented cap, content adjusted to 1000 mPas)(produced in a third facility

In the following table the number of samples is indicated after the sample designation.

0 = no deformation 1 = slight remaining deformation 2 = stronger deformation, force had to be slightly enhanced e = tube fully emptied

Table 2: As can be seen from the above table, all vented tube samples with laminate B) provided good re sults even with viscous content until the tube was fully emptied .

5 A further important feature for reliable dos ing is the WVTR barrier effect or the weight conserva tion, respectively.

WVTR barrier measurements after 24 h at 40°C and 75 %rh are shown in Table 3 below:

Table 3:

The applicator used in the above measurements was supplied by Aptar. 5

Also weight loss experiments have already been performed at 40°C (Table 4) and at room temperature (RT) (Table 5)

Table 4 (40°C at 20%rh):

X = mean value of 10 samples

S = standard deviation * produced on a new production line ** Reference bottle: HDPE-bottle with diame ter 22 mm, height 45 mm and a wall-thickness of 0.8 mm

Table 5 (RT at 35%rh):

X = mean value of 10 samples S = standard deviation * produced on a new production line ** Reference bottle: HDPE-bottle with diame ter 22 mm, height 45 mm and a wall-thickness of 0.8 mm

The WVTR measurements as well as the weight loss measurements show improved properties of the in ventive tubes over a standard bottle.

While there are shown and described presently preferred embodiments of the invention, it is to be dis tinctly understood that the invention is not limited thereto but may be otherwise variously embodied and prac ticed within the scope of the following claims.