KR20070107028A - Sealing of plastic containers - Google Patents

Abstract

An ampoule (4) of plastics material contains a solution of an inhalation or injectable pharmaceutical, and an outer surface of the ampoule is coated with a metal or metal compound or with a polymer deposited by vapour deposition so as to reduce moisture egress from the ampoule and reduce contamination of ampoule contents from external sources. Labels are easily applied to the coating.

Description

Sealing of plastic containers

The present invention relates to the sealing of containers and to the coating of containers made of plastic materials which can be used for cosmetic and / or pharmaceutical preparations, and more particularly to the coating of ampoules for achieving a sealing effect. The invention also relates to a sealed or coated container, in particular a sealed or coated ampoule.

Pharmaceutical and cosmetic formulations are present in a variety of different packaging including packaging made of glass, metal, plastic and natural materials. For liquid preparations, for example solutions or suspensions, the package must be sealed and kept sealed to prevent leakage. However, there are numerous technical and practical difficulties in all such containers.

Some formulations may contain very relatively volatile materials or other relatively small molecules that can diffuse out of the container material. This is, so to speak, a special problem with perfume. Since the product may lose efficacy, aroma or flavor, shelf life is therefore limited. As a result, containers for such products are made of impermeable containers, for example glass, which materials are generally expensive. Therefore, it is not possible to use cheaper materials, such as plastic, resulting in high packaging costs.

The pharmaceutical formulation in the container may have to be sterilized under high temperature or pressure conditions, or should be robust enough to maintain its sterility when filled under sterile conditions. This also leads to higher manufacturing costs.

In order to enable the patient to take the drug while breathing normally, it is known to use a nebulizer to administer the drug to the patient's lungs. Such drugs are provided in unit dosage ampoules (UDAs), which contain a relatively small amount of solution, typically 1 ml to 5 ml, and are typically made of plastic material. The method of making the ampoule is blow-fill-sealed (BFS) in which the ampoule is formed by extrusion under sterility and filled into solution in a multi-part but essentially one-step process. By law If necessary, also under the assumption that the contents are not heat labile, heat sterilization can be used, for example the ampoule can be sterilized, for example, by terminal sterilization after the ampoule has been filled and sealed. This method is well established and well approved by regulators worldwide.

A known problem with existing ampoules is that they allow air, other gases and other volatile compounds into the ampoule and allow water (moisture) to be released. Testing of the contents indicated that during storage, contaminants could penetrate the plastic ampoule wall and be absorbed into the formulation. As one specific example, an unacceptable amount of vanillin has been found inside the ampoule, which results in the regulator's refusal to authorize the ampoule without failing the product and safeguarding against external contaminants.

As an example of a particular problem, the US FDA recently required that ampoules be overwrap in a sealed pouch to prevent contamination of the ampoule contents. Pouch materials are typically triple laminates of paper and / or polymers, aluminum and low density polyethylene (LDP). This pouch is considered an acceptable solution.

Ampoules are typically prepared in strips of a plurality of single unit dosages, for example five, ten, thirty. Thus, one problem with the pouch is that if several ampoules are contained in one pouch, as soon as the pouch is opened and the first ampoule is used, the remaining ampoules may be exposed to the outside and contaminated.

In addition, the permeability of the LDP limits the labeling of the ampoule, which must be carefully checked to ensure that the ink used to print directly onto the ampoule and the adhesive used to attach the paper label do not pass through the ampoule and contaminate the contents. Because.

Some ampoules are filled with an inert gas such as nitrogen. Even inside the pouch, there is an equilibrium of nitrogen and gas outside the ampoule or inside the pouch. As soon as the pouch is opened, more nitrogen will be lost from the ampoule.

LDP ampoules are translucent and some light sensitive materials will be damaged after prolonged storage and exposure to light if stored in them. The pouch presents a partial solution, but again, if the pouch is opened, the internal ampoule is exposed to light for an indefinite period of time before being used.

Individually, LDP tubes are quite commonly used for cosmetics. However, if there are liposomes or other oxygen sensitive contents, for example, it is necessary to avoid oxygen from entering the specific tube contents. As a result, LDP and other such materials are generally unacceptable for the production of such cosmetic tubes.

It is an object of the present invention to solve or at least mitigate the above identified problems. It is an object of a preferred embodiment of the present invention to provide an alternative, more preferably improved method of sealing and / or coating a container and a container, in particular an ampoule sealed and / or coated by said method.

The present invention is based on the use of a metal containing or polymer containing sealing layer to provide a coating on a container made of plastic material.

In a first aspect, the present invention provides an ampoule comprising a coating of (a) a metal or metal compound, or (b) a polymer deposited by vapor deposition.

In general, the present invention provides a container for containing a liquid, which is made of a plastic material and comprises a coating of a metal or metal compound or polymer.

In a second aspect, the present invention provides a method of reducing water leakage from a container made of plastic material, comprising applying a coating comprising a metal or metal compound or a coating of a polymer to an outer surface of the container. .

In a third aspect, the present invention provides a method of sealing a container made of plastic material, comprising applying a coating comprising a metal or metal compound or a coating of a polymer to an outer surface of the container.

In a fourth aspect, the present invention provides a method of applying a label to an ampoule comprising applying a coating of a metal or metal compound or of a polymer to the ampoule and applying the label to the coating.

The coating may be applied by first providing a plastic layer and then applying a coating over the layer, or by making a plastic layer applied with the coating, for example by extrusion or other methods.

In a preferred embodiment of the invention, the coating is a metal or metal compound, more preferably a metal coating.

The coated container of the present invention is an ampoule having a coating of metal or metal compound. The ampoules may be single or one of ampoule strips. In use these coatings have been found to have the effect of sealing the contents of the ampoule, reducing the loss of the ampoule contents to the outside, and reducing the contamination of the contents from the outside.

Ampoules are generally made of plastic materials, in particular low or high density polypropylene or polyethylene, or other polymers used in the production of ampoules or in the beverage industry, for example polyethylene terephthalate. Ampoules will also generally contain a medicament, such as an inhalation drug or an injectable drug, in combination with a pharmaceutically acceptable carrier.

The seal does not need to be perfect, but after testing for the required period, it is necessary to meet the regulatory authority's requirement that the contents be adequately protected so that no further steps are imposed, e.g. in the case of ampoules, the provision of external envelopes by pouches. It is desirable to be enough to satisfy. Thus, the coating may cover at least 50% of the outer surface area of the ampoule, or at least 70%, 80%, 90% or 95% of the outer surface area of the ampoule. Very preferably substantially all of the ampoule outer surface is coated.

If the ampoule strip is coated and one ampoule is separated from the strip, as a result there will be a side end or side of the ampoules of the remaining end which is not coated and thus exposed, but this will reduce the overall sealing effect of the coating even if degraded. Only slightly degraded-the exposed part occurs at the junction with the adjacent ampoule, which is small relative to the total surface area and which is generally the largest in thickness of the plastic. As such, the present invention is useful for coating an ampoule made of a single container or ampoule and strip and designed to be separated one by one.

The coating material can be selected from a variety of metals and metal compounds that can be coated, for example, on ampoules. The coatings are aluminum, copper, carbon, chromium, silver, zirconium, tantalum, tungsten, titanium, cobalt, gold, palladium, platinum, and their alloys, including steel, and compounds of metals and gases, such as carbon nitride, These compounds include tin oxide, indium oxide, silicon dioxide. Some of these coating materials are more expensive than others, and in the case of containers such as ampoules that are made in large quantities and are used essentially for single use, the coating preferably comprises aluminum, titanium, chromium, silver, copper, or mixtures or alloys thereof. Particularly preferred coatings comprise or consist of aluminum, titanium, chromium or tetrahedral amorphous carbon.

In order to apply the coating, a number of different techniques can be employed. Suitable coating methods include, for example, physical vapor deposition and arc deposition by sputtering. Sputter coatings also optionally have UV lacquers to protect the coating and improve adhesion.

As an example of physical vapor deposition, sputtering deposition is performed in a vacuum chamber where atoms, typically argon atoms, are ionized and accelerated to collide with the target material, namely aluminum. The coating material is vaporized through a physical process rather than by a chemical or thermal process. Argon atoms release aluminum atoms when they collide with the target, and these released aluminum atoms then collide with the container being coated, so this process applies a concentrated coating. Argon (Ar) ions can then be generated in an ion gun that transfers kinetic energy and directs the ions to the target being sputtered, or in a plasma containing Ar ⁺ and electrons.

Chemical vapor deposition, or CVD, is a generic name for a group of processes involving the deposition of solid materials from the gas phase, and in some respects is similar to physical vapor deposition (PVD). PVD differs in that the precursor is a solid, and the material to be deposited is evaporated from the target of the solid and deposited on the substrate. Although CVD is suitable for the present invention in some cases, the high temperatures generally required define the materials that can be coated. CVD can also be very expensive for large scale manufacturing of disposable products such as ampoules.

In the arc deposition method, the ion containing plasma is generated in a vacuum between the anode and the target, generally the cathode. In a filtered cathode arc, ions from the plasma are directed towards the substrate past a filter designed to remove neutral particles such as macromolecules. Ions are deposited on the surface to form a coating. Filtered vacuum cathode arcs can be applied at lower temperatures, even lower than sputter coaters, below 70 ° C. and to room temperature, and are particularly desirable for such temperature sensitive materials as plastics. However, plastics that can withstand temperatures up to about 120 ° C. can be coated using sputtering techniques. Metal or carbon or alloy coatings can be prepared using filtration cathode discharges, and the compounds also employ the introduction of reactive gases into the coating chamber in proximity to the substrate.

These various deposition techniques are well known in the art. Detailed descriptions of thin film technologies including physical vapor deposition and vacuum arc deposition can be found in John A. Thornton and DW Hoffman, Thin. Solid Films , 171, 5 (1989); J. Vossen and W. Kern, eds., Thin Film Processes , Academic Press, NY, 1978 and Handbook of Vacuum Arc Science and Technology by: Boxman, RL; Sanders, D .; Martin, PJ © 1995 William Andrew Publishing / Noyes. Sputter devices are available from numerous commercial sources, including CPFilms Inc. of Martinsville, USA. FCVA devices are also available in Singapore's Nanofilm Technologies International Pte. Ltd is available from numerous commercial sources, including Ltd. Filtration cathode vacuum arc technology is also described in US Pat. Nos. 6,761,805, 6,736,949, 6,413,387 and 6,031,239, the contents of which are incorporated herein by reference. In the present invention, the coating is preferably applied by physical vapor deposition or arc deposition.

Prior to coating of the article, it is often desirable to perform cleaning or other preparation of the surface to remove contaminants and improve adhesion of the coating. In the container of the present invention, aqueous washing is generally sufficient. In embodiments of the present invention wherein the article to be coated is made of or includes a polymer, such article can be cleaned using known procedures, except that more careful handling may be required. In addition, during the aqueous cleaning the polymer may absorb water which must then be removed to achieve vacuum coating adhesion. The coating can be attached without any treatment in which case an aqueous wash can also be omitted.

The article will only be kept clean for a short period of time unless in special circumstances, such as in a dry nitrogen-purged container, or a UV / ozone chamber. One option is to provide a cleaning and / or surface treatment station as part or in parallel arrangement with the coating station. Another consideration is that the newly formed or shaped polymer will not require any surface treatment for the proper attachment of the coating to be obtained, as in the blow-fill-sealing process that is generally used for ampoule formation.

In the use of the present invention, ampoules can be prepared by forming ampoules and applying a coating to the ampoules. Known methods of forming ampoules are by blow-fill-sealing (BFS), and the coating step is typically immediately after the BFS step and may be conveniently added to the ampoule manufacturing line prior to the packaging and / or labeling step. Ampoules generally contain about 1 mL to about 5 mL (extractable volume) of solution.

The coating is designed to achieve sealing of the container as described above. Suitable thickness is at least 20 nm, preferably at least 50 nm, and suitably at most 50 microns, preferably at most 20 microns. In addition, the coating thickness may be at least about 100 nm and at most 10 microns.

In a particular embodiment of the invention, the ampoule is made of a plastic material and comprises an aluminum coating applied by sputter coating. More specifically, the ampoule contains a solution of inhaled pharmaceutical in a pharmaceutically acceptable carrier. Thus, in one embodiment of the invention used, the blow-fill-sealing technique is used to obtain an ampoule containing 2.5 ml of a composition containing salbutamol in saline. The ampoule is made from LDP and discharged from the charging device in 10 strips. The strip was coated with an outer coating of aluminum applied to a thickness of about 300 nm using a sputter coater to give a glossy metallic appearance. The ampoules are not overwrap but are packaged in the usual way. Patients receive ampoules in strips and remove them one at a time. The remaining ampoule remains a strip (now of reduced size) until the next ampoule is removed and used and all the ampoules are used up.

In another embodiment of the invention, the ampoule is made of plastic material and comprises a coating of aluminum, chromium or titanium applied by sputter coating or filtration cathode arc and contains a solution of the injectable pharmaceutical in a pharmaceutically acceptable carrier. . The solution may be, for example, water for injection or saline for injection. Typical volumes are up to 30 ml, up to 25 ml, up to 20 ml, up to 15 ml or up to 10 ml. Ampoules can be made of five, ten, fifteen or more strips, and can be used off as needed, as in other embodiments.

In another embodiment of the invention, the plastic ampoule is coated with a titanium layer applied to a thickness of about 150 nm by sputter coating.

In another embodiment of the invention, the plastic ampoule is coated at about 100 nm with tetrahedral amorphous carbon.

Although embodiments of the invention have been described with reference to coatings applied to ampoules, in certain embodiments the invention relates to a container for containing a liquid, more generally made of a plastic material and comprising a coating of a metal or metal compound. Such a container may be made of a polymer comprising polyethylene or polypropylene and may have a maximum fill volume of up to 100 ml, preferably up to 50 ml, more preferably up to 20 ml. The container is useful for liquid containing volatiles that otherwise permeate the plastic container to an unacceptable extent.

A method of reducing moisture escape from a container made of a plastic material, comprising applying a coating comprising a metal or a metal compound to an outer surface of the container, and a method for Provided is a method of sealing a container made of a plastic material, comprising applying a coating comprising. Also and preferably, the coating and application thereof in these methods are as described in connection with the above embodiment of the present invention.

Another particular method of the present invention relates to a method of sealing an ampoule, wherein the ampoule is about 0.5 ml to 10 ml of an inhalation pharmaceutical or injectable pharmaceutical (eg, for injection or saline) in a pharmaceutically acceptable carrier. And applying a coating of the metal or metal compound to the ampoule over at least about 70% of the ampoule outer surface.

The coating of the invention has additional or alternative properties, ie a label can be applied over the coating. As such, another method of the present invention is a method of applying a label to an ampoule comprising applying a coating of a metal or metal compound to the ampoule and applying a label to the coating.

The label can be attached to the coated ampoule using an adhesive. The label may also be sprayed or printed onto the coated ampoule, for example ink is sprayed onto the coated ampoule.

In various embodiments the invention provides numerous advantages, some, some or all of which may be found in any given embodiment. Ampoules are sealed by the present invention; For example, it reduces water loss and reduces contamination from the outside. Because of the shape of the ampoule, the ampoule is still made of, for example, 5, 10, 30, etc. strips, but the process effectively seals each ampoule individually. This is an improvement in packaging the ampoule strips in the pouch, since the remaining ampoule is substantially sealed even when the ampoule is removed from the strip-this is when both pouches containing many ampoules are exposed to the surroundings and In contrast.

After application of the coating, it is relatively easy to apply the label to the ampoule or print with conventional ink, without limitation by the choice of ink or the presence of a previously applied solvent.

In addition, ampoules coated with a metallic coating according to the invention have a pronounced appearance. The coating is continuous, does not fall easily and is resistant to abrasion, such as friction.

In another embodiment, the applied coating comprises a polymer applied or deposited using a vapor deposition method. Methods for vapor deposition of polymer films are described, for example, in US Pat. No. 6,022,595; 4,013,532; 4,673,588; And 4,921,723, the contents of which are incorporated herein by reference. Specific methods of applying a coating of poly para xylene are described, for example, in Medical Device Technology, January / February 2006, ppl 0-11.

As such, the ampoule of an embodiment of the invention comprises a coating of a polymer deposited by vapor deposition. The coating may be or include poly para-xylene and the polymer coating of the present invention is suitably applied by chemical vapor deposition.

In this embodiment, the barrier properties of the deposited polymer film allow for improved container sealing.

Ampoules can be prepared by forming ampoules and applying a coating to the ampoules. In another embodiment of the invention, in particular the ampoule contains a solution of an inhalation pharmaceutical or injection pharmaceutical in a pharmaceutically acceptable carrier.

The present invention also provides a method of reducing moisture outflow from a container made of plastic material, comprising applying a coating comprising a polymer to the outer surface of the container by a vapor deposition method such as chemical vapor deposition.

The present invention also provides an ampoule comprising from 0.5 ml to 10 ml of inhalation or injectable pharmaceutical in a pharmaceutically acceptable carrier, wherein the ampoule uses a vapor deposition method to apply a polymer coating onto at least 70% of the outer surface of the ampoule. A method of sealing an ampoule, comprising the steps of: applying a label to the ampoule and applying a label to the ampoule using a vapor deposition method; do.

Another optional and preferred feature of the invention described in the context of metal and metal compound coatings applies to coatings comprising polymers.

With respect to aspects of the invention in which other plastic containers are coated, the process generally involves the loss or loss of gas and other volatiles such as vitamins, flavors, perfumes, or the like. It is applied to packages which may be damaged by contamination. The present invention is made of a plastic material, for example LDP, and provides a cheaper packaging than glass, trilaminates, ceramics and the like.

Hereinafter, the present invention is illustrated in the following examples with reference to the accompanying drawings:

1 shows a front view of ten ampoule strips coated with aluminum according to the invention;

2 and 3 show the strip of FIG. 1 with one ampoule separated; And

4 shows a front view of ten ampoule strips coated with titanium according to the invention.

Example  One

Strips of 10 ampoules were made from low density polyethylene using a standard blow-fill-sealing device, each ampoule containing 3 ml of salbutamol solution. The ampoule was visually inspected to verify that the contents were properly charged and to manual inspection to ensure that they were all intact. An ampoule strip was introduced into a filtration cathode arc coater equipped with an aluminum target. The coater was closed and the pump was operated to working vacuum. The coating operation started and continued until the coating thickness monitor displayed a thickness of 300 nm. The coating was finished, the vacuum was released and the chamber opened.

Coated ampoules 1 are shown in FIGS. 1-3. Ten ampoules have been completely discharged from the coating chamber (FIG. 1) and have a head 3 that is twisted in use to cut the neck 2 so that the contents are released.

The resulting coated ampoule has a glossy, metallic appearance and is completely coated with a thin layer of aluminum.

The aluminum coating is continuous throughout the surface of the ampoule, smooth and without visible defects. The coating is firmly attached to the ampoule and does not fall off and is resistant to friction.

Even if one ampoule 4 is separated from ten strips (see FIG. 2), the coating does not fall off at the junction 5 between the separated ampoule and the remaining nine strips.

The integrity of the ampoule was tested to ensure that they remained intact and contained the same volume of solution as before coating. The contents of the four ampoules were individually tested using a method based on atomic absorption to determine the presence of contamination by aluminum. In each individual test, an aluminum content of less than 1 ppm above the lower limit of the measurement method was recorded, confirming that the aluminum content of the solution inside the ampoule after coating was essentially zero. The result confirmed that the ampoule wall did not burst during the coating process.

Example  2

Strips of five ampoules were prepared from low density polyethylene using a standard blow-fill-sealing device, each ampoule containing 3 ml of saline. The ampoule was visually inspected to verify that the contents were properly charged and to manual inspection to ensure that they were all intact. Ampoule strips were introduced in a filtration cathode arc device equipped with a titanium target. The instrument was closed and the pump was run to vacuum. The coating operation started and continued until the coating thickness monitor displayed a thickness of 300 nm. The coating was finished, the vacuum was released and the chamber opened.

The resulting coated ampoule 6 was shown in FIG. 4 and was observed to have a glossy appearance, substantially completely coated with a thin layer of titanium, and the coating was slightly less shiny than the aluminum coating of Example 1.

As such, the present invention provides a coated plastic container and a method of making the same.

Claims (35)

An ampoule comprising (a) a coating of a metal or metal compound deposited by vapor deposition, or (b) a polymer deposited by vapor deposition. The ampoule of claim 1 comprising a coating of a metal or metal compound. The ampoule according to claim 1 or 2, which is made of a plastic material. The ampoule of claim 1 wherein the coating covers at least 70% of the outer surface area of the ampoule. 5. 5. The ampoule according to claim 1, wherein the coating is selected from the group consisting of aluminum, titanium, chromium, silver, copper, tetrahedral amorphous carbon and mixtures and alloys thereof. 6. The ampoule of claim 1, wherein the coating is applied by physical vapor deposition or arc deposition. 7. The ampoule of claim 1, wherein the ampoule is prepared by forming an ampoule and applying a coating to the ampoule. The ampoule according to claim 1, wherein the coating is a thin film of metal. The ampoule of claim 8, wherein the coating has a thickness of at least 20 nm. The ampoule of claim 9, wherein the coating has a thickness of 20 microns or less. The ampoule of claim 1, wherein the ampoule is made from a plastics material and comprises an aluminum coating. 12. The ampoule of claim 11 containing a solution of inhalation pharmaceutical or injection pharmaceutical in a pharmaceutically acceptable carrier.  The ampoule of claim 1, wherein the ampoule is made of a plastic material and comprises a titanium coating. The ampoule of claim 13, wherein the ampoule contains a solution of an inhalational or injectable pharmaceutical in a pharmaceutically acceptable carrier. The ampoule of claim 1, wherein the ampoule is made of a plastic material and comprises a chromium coating. The ampoule of claim 15, wherein the ampoule contains a solution of an inhalational or injectable pharmaceutical in a pharmaceutically acceptable carrier. Applying a coating comprising a metal or a metal compound to an outer surface of the container. 18. The method of claim 17, comprising applying a coating over at least 50% of the outer surface of the container. 19. The method of claim 17 or 18, comprising applying the coating by physical vapor deposition or arc deposition. 20. The method of claim 17, wherein the metal is selected from the group consisting of aluminum, titanium, chromium and tetrahedral amorphous carbons. A method of sealing an ampoule, wherein the ampoule comprises 0.5 ml to 10 ml of inhalation or injection pharmaceutical in a pharmaceutically acceptable carrier, wherein the ampoule is coated with a metal or metal compound coating on at least 70% of the outer surface of the ampoule A method of sealing an ampoule comprising applying. A method of applying a label to an ampoule comprising applying a metal or metal compound coating to an ampoule and applying a label to the coating. 23. The method of claim 22, wherein the label is attached to the coated ampoule using an adhesive. The method of claim 22 wherein the label is sprayed or printed onto the coated ampoule. An ampoule made of a plastics material, the ampoule containing up to 50 ml of a solution of inhalation pharmaceutical, wherein the ampoule is coated with a metal or metal compound. An ampoule made of a plastics material, containing up to 50 ml of an injectable pharmaceutical solution, wherein the ampoule is coated with a metal or metal compound. 2. The ampoule of claim 1 comprising a polymer coating deposited by vapor deposition. The ampoule of claim 27 wherein said coating is or comprises poly para-xylene. 29. The ampoule of claim 27 or 28 wherein said coating is applied by chemical vapor deposition. 30. The ampoule of claim 27, wherein the ampoule is prepared by forming an ampoule and applying a coating to the ampoule. 31. The ampoule of any of claims 27-30, wherein the ampoule contains a solution of an inhalational or injectable pharmaceutical in a pharmaceutically acceptable carrier. Applying a coating comprising a polymer to the outer surface of the vessel using a vapor deposition method. 33. The method of claim 32, comprising applying the coating by chemical vapor deposition. A method of sealing an ampoule, wherein the ampoule comprises 0.5 ml to 10 ml of inhalation or injectable pharmaceutical in a pharmaceutically acceptable carrier, and the polymer coating is applied to the ampoule using a vapor deposition method to the outer surface of the ampoule. A method of sealing an ampoule comprising applying at least 70% above. A method of applying a label to an ampoule comprising applying a polymer coating to an ampoule using a vapor deposition method and applying a label to the coating.

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