EP1979244A2

EP1979244A2 - Metallized packaging blister container

Info

Publication number: EP1979244A2
Application number: EP06848703A
Authority: EP
Inventors: Praful Ramchandra Naik; Ajit Sashidharan Nair; Mohan Harakchand Bhandari; Rahul Bharadia; Ammanabrolu Balgangadhar Tilak; Sachin Chandrashekhar Itkar
Original assignee: Individual
Current assignee: Individual
Priority date: 2005-12-23
Filing date: 2006-12-22
Publication date: 2008-10-15
Also published as: BRPI0621087A2; WO2007072494A1; WO2007072505A3; EP1979244A4; MX2008006380A; WO2007072505A2; TW200733950A; AR058743A1

Abstract

A multi-layer formed, opaque to semitransparent pharmaceutical and food packaging blister container comprising a substrate of 100 to 1000 microns thickness of food grade polyvinyl chloride [PVC], and a metallized layer of thickness 0.005 to 2 microns provided at least on one side of the said substrate and optionally one food and pharmaceutical grade organic layer provided at least on one side of the substrate, having opacity in the range of between 100 to 10 % with improved moisture barrier and resistance to photo degradation properties as compared to a non metallized container, leading to the allowing of a better visual inspection abilities in comparison to a completely opaque formed container system with improved characteristics.

Description

METALLIZED PACKAGING BLISTER CONTAINER

FIELD OF INVENTION

The present invention relates to containers.

In particular, this invention relates to pharmaceutical containers.

INTRODUCTION

The expression pharmaceutical or pharmaceutical product used in this specification is deemed to include any form of tablet, capsule, ampoule, granule, liquid dosage form, pellet, slab, block, ball, condom , whether or not the product has pharmacological activity.

Products, for retail sale are frequently packaged in "blister pack" packaging. A blister pack consists of a flat backing sheet called as "lid", generally of cardboard, plastic or metal foil; and a base having a formed plastic "bubble" or "blister" , generally of transparent plastic, the backing sheet and blister being joined to form a sealed cavity in which the product rests.

There are in general two kinds of blister packs.

Push-through packs:

The lid is made of aluminium foil or an aluminium foil laminate. Aluminium foil is a material of choice for the lids on blister packs, as the thickness of the material used requires relatively little force for it to break. Consequently, the energy for rupture is low as aluminium is non-elastic. As a rule the base of the blister pack is made of polymeric material such as polyvinyl chloride (PVC), polyamides, polyoleiϊn, polyesters and laminates or multi-layered materials containing at least one of these materials and, if desired, aluminium foil.

Peel-off packs:

Other blister packs feature a base, which is covered by a lid foil. The lid foil may cover the whole of the base area and is usefully provided with a line of weakness in the region of each recess, or each recess may be covered with an individual lid segment. Within the line of weakness or on each lid segment may be a tab for gripping which enables the individual FIELD OF INVENTION

The present invention relates to containers.

In particular, this invention relates to pharmaceutical containers.

INTRODUCTION

There are in general two kinds of blister packs.

Push-through packs:

The lid is made of aluminium foil or an aluminium foil laminate. Aluminium foil is a material of choice for the lids on blister packs, as the thickness of the material used requires relatively little force for it to break. Consequently, the energy for rupture is low as aluminium is non-elastic. As a rule the base of the blister pack is made of polymeric material such as polyvinyl chloride (PVC), polyamides, polyolefin, polyesters and laminates or multi-layered materials containing at least one of these materials and, if desired, aluminium foil.

Peel-off packs:

Other blister packs feature a base, which is covered by a lid foil. The lid foil may cover the whole of the base area and is usefully provided with a line of weakness in the region of each recess, or each recess may be covered with an individual lid segment. Within the line of weakness or on each lid segment may be a tab for gripping which enables the individual

1 recess to be exposed by peeling back the lid segment. As a rule, the base and the lid are of the above-mentioned materials, whereby plastic laminates may also be employed for the lid materials.

Blister packaging is formed in one of three ways.

hi a first method, the blister package comprises a single moulded plastics sheet adapted to be folded along a central region. In one or each side of the folded region a blister (or recess or protrusion) is formed. Where such a blister is formed in each side, it is preferred that after folding of the plastics sheet the two blisters are aligned to form a single storage region. The plastics sheet is otherwise generally planar. The product to be sold is for convenience usually located within the blister prior to folding of the plastics sheet.

A second method, commonly known as captive blister packaging, comprises a planar sheet of plastics material into which a blister (or recess or protrusion) is formed, and held between a front and a back sheet of cardboard, the front sheet being provided with an opening through which the blister (but not the surrounding planar region of the plastics sheet) extends.

In a third method, the blister pack comprises a planar sheet of plastic material into which a blister is formed by hot stamping, air force, cold forming or vacuum suction method. The product to be packed is inserted in the blister and the base having blister is then sealed by a lid of plastics, laminates or aluminium foil.

Pharmaceutical blisters as packaging for pharmaceutical formulations serve to package tablets, capsules or other forms of pharmaceuticals; safely and protect them from external environmental influences which might in certain circumstances affect the pharmaceutical quality of the formulations. In this context, water or water vapour should be mentioned in particular. If water penetrates into the interior of a blister it may cause lasting changes to the pharmaceutical quality of the drug stored therein. There is also the danger that volatile substances will diffuse out of the material contained in the blister during storage and thereby alter the pharmaceutical formulation. In addition, the blisters must be so designed that the atmospheric conditions inside them remain constant, e.g., in respect of inhalable preparations, so as not to alter their particle size distribution. The blister portion of the packaging may be formed by thermoforming or cold forming a region of a planar plastic material to a desired shape, e.g., by placing the plastic material between a pair of male and female dies that are temperature controlled at a temperature sufficient to soften the plastic and pressing the male and female dies together to form an indentation or "blister" in the plastic.

In a typical thermoforming process, a rolled polymeric web supplies the blister material. As the sheet is pulled by an Idler unwinding unit that is fed to a heating station via deviating rollers the film is plasticized by contact heaters. The contact heaters can be adjusted for precise plasticization of the film by controlling the temperature, contact pressure, and heating time. By directly monitoring energy consumption, only the film is heated and not the surrounding machine or environment. Once the critical plasticization temperature is reached, the film web is fed along the conveyor rollers into the forming station.

The web is then thermoformed in a pressurized diaphragm station where the edges of the web are gripped and pulled taunt. Compressed air is then injected at critical points along the web, which correspond to the respective cavity placement sites. The cavities are formed as the PVC web sheet is drawn into the cavity moulds of the thermoforming chambers by means of the compressed air. Precisely engineered moulds create blister cavities that are uniform in size and thickness.

The multi-blistered web is then transferred to the filling station where the product to be packaged can either be manually deposited within each cavity or as is more often the case, automatically placed therein using automated feeder tubes. The filled yet open blister packs continue onward to a foil sealing station wherein the lidding foil is fed into the machine and sealed onto the thermoformed web. A sealing roller with bores corresponding to the cavities of the web, indexes and transports the PVC blister web through the sealing station at which point the heating roller fuses the lidding foil to the web thereby sealing the cavities closed.

The filled and sealed web is embossed, perforated and then cut to the appropriate sized package so that unit doses can be removed from the main package without having to remove the tablet from the package until it is ready to be taken. Pressure is exerted against the blister cavity and the product is pushed through the foil cover.

The movement of the web through the cavity forming, heating and sealing stations is intermittent. Movement of the web through the filling station however, is continuous and therefore there is a chance that the products can either be improperly disposed within the cavity or more than one may be placed therein. Such aberrations are unacceptable in large- scale commercial operations and there is therefore a need to detect when improperly filled packages occur.

Another method of forming blisters is the cold forming process. The cold-forming process is an intermittent process, and does not use heat for forming the cavities. The foil is shaped and moulded around a plug assist to form a cavity, using air pressure, typically of 7 bars, in the first stages of its operation, which is followed by product filling & sealing of Aluminium lid foil at temperatures of 180 to 200 deg. C, in the subsequent stages of its operation.

The typical machine speed in (cycles per minute) of the m/c ranges from 20 to 25 cycles per minute. As such, it is a marginally more expensive process than thermoforming, and its tooling is a bit more expensive than that of thermo formers.

The Cold Forming material structure does not form easily, so blister cavity designs cannot be too sharp, because the foil would then break. The Cold forming process ensures that the material is stretched uniformly and does not have localized stretching built into the design of the cavity.)

Vacuum thermoforming forming on the other hand is a Continuous process that involves forming thermoplastic sheets into three-dimensional shapes through the application of heat and pressure. Basically during vacuum thermoforming forming processes, plastic material is heated until it becomes pliable, and then it is placed over a mould and drawn in by a vacuum until it takes on the desired shape.

In vacuum thermoforming process, a sheet of heated plastic material is placed over a male or female mould. The typical forming temperatures range from 140 to 160 deg C. Next, the application of a vacuum draws out the air between the mould and the sheet so that the plastic conforms to the mould exactly. This is accomplished through venting holes in the mould that are joined to vacuum lines. The mould also has a water cooling system integrated into it that brings the temperature of the plastic to the set temperature needed. When the curing temperature is reached and the piece is formed, air blows back into the mould and separates the new part from the mould. This is further followed by product filling and sealing in temperature ranges of 165 to 200 deg. C.

The machine speeds ( in cycle/min.) is around 4 to 5 meters per minute, which translates to 80-100 blisters /min. High speed m/c's can deliver upto 700-800 blisters/min. depending on the blister sizes & no. of ups .

Vacuum forming involves fewer parts and tooling than injection moulding, there is great design flexibility available, from a variety of prototypes to custom made designs that can be used to cover almost any product.

United States Patent No. 4,039,080 is directed towards a tray having individual compartments for holding pills, capsules, or similar solid medication, each compartment being rectangular in plane view and arranged in a rectangular format or seven columns and a plurality of rows. The tray may be loaded with a week's medication for an individual patient with indicia adjacent each column indicating the day of the week, and indicia adjacent the rows indicating the time of day that the medication in each compartment is to be taken. A lid or cover cooperates with the wall means defining the individual compartments to mutually isolate the compartments when in the closed position. The inner surfaces of the compartments are preferably rounded in at least one plane of ease of withdrawing medication therefrom. This packaging system only gives a convenient way to pack but does not provide good moisture and gas barrier.

Preferred blisters consist of transparent or at least translucent plastics or a base foil of transparent plastics and a cover foil of aluminium. Both foils may be laminates, i.e., they may consist of a number of foils of different materials. The blisters known from the prior art do not necessarily adequately protect a formulation embedded therein from the penetration of substances from outside such as, for example, gases or vapours, particularly oxygen, carbon dioxide, water vapour and solvents, even when they are mechanically intact. Theoretically, these substances may permeate or diffuse through the topside of the blister (cover foil), the underside (base foil) or through the seam between the cover foil and base foil.

United States Patent Application No. 20050061705 relates to a new pharmaceutical blister with reduced permeability to water vapour and gas. This application teaches the coating of conventional blisters with a silicon oxide-containing functional layer to protect against gases, water vapour and organic molecules. This process is expensive and time consuming.

The use of electronic sensors as a means of detecting errors or problems in large-scale conveyor belt production has been used with limited success. United States Patent No. 4,593,515 discloses the use of an electronic sensor, which is positioned under the conveyor belt of a wrapping machine. Articles dropped from the conveyor path fall upon the sensor, which not only catches the articles but also generates a stop signal, which stops the conveyor belt so the article may be retrieved and placed back on the belt.

United States Patent No. 5,040,353 to Evans et. al. also discloses a blister packing process whereby a sensor apparatus includes a plurality of air valves for removing empty blister cavities prior to sealing. The cavities pass through a detection station, which sends a signal to the pneumatic air valves upon sensing an empty blister packet. This ignites a high- pressure airflow, which selectively separates the unfilled, empty blister cavities from the filled packs, which are ready for sealing.

United States Patent No. 4,472,922 to Romagnoli teaches a system for monitoring a blister packaging machine comprising a photosensitive detector device, which scans the blister pack carrier strip, and upon sensing an empty blister cavity activates a perforator that punches a hole into the cover strip comprising the empty blisters. An error pulse simultaneously loaded into a shift register actuates, after a suitable delay, a sorter downstream of the cutting station that eliminates the defective blister package from the regular machine output.

United States Patent No. 6,757,420 is concerned' with the problem of providing an automatic inspection device, with which it is possible to determine, with little effort and without contact, whether packages, particularly sealed blister packages consisting of a blister container and a cover film, are free of defects. This problem is solved by the use of at least two light sources, which are arranged at a certain distance from one another and each emit a light bundle at a predetermined wavelength range, whereby the emission maxima of the two light sources are offset in relation to one another. The light sources are arranged such that the packages are vertically illuminated. A CCD camera records the light reflected by the packages and the digital images are stored in a computer, so that they are available in a computer-supported image-processing and documentation system.

United States Patent No. 5,555,707 discloses a blister pack scanning device for detection and removal of overfilled or defective pharmaceutical blister packs is comprised of a photoelectric LED transmitter and sensor with a scanning beam channel bar disposed there between. The blister pack web is passed below the bar through a space precisely equivalent to the thickness of a properly filled blister. Overfilled or improperly moulded blisters will contact a bevelled edge of the bar as the web passes thereunder and the lateral movement forces the bar and its two end plates which are in juxtaposition to the transmitter and receiver respectively, to move upward, thereby interfering with the beams transmission. The interference created thereby shuts off the blister production machine and sounds an alarm for removal of the defective package.

BACKGROUND OF THE INVENTION

Polyvinyl chloride (PVC) is a relatively inexpensive packaging material but has little use in the blister packaging of sensitive drugs because of its poor moisture barrier properties. Plain PVC in flat film form in the thickness range of 100 to 400 microns has an MVTR [moisture vapour transmission rate] of 3-4 g/m²/24 hr. However when thermo or cold formed this typically increases to between 15 to 20 g/m²/24 hr. Moreover the packing created by using normal PVC film can be copied easily by any manufacturer, as it is cheaply available and therefore can be counterfeited.

Again; manufacture of PVC film in the prior art involves the use of various additives such as mordents and accelerators and non-food grade plasticizers, which renders the PVC unsuitable for the pharmaceutical applications. For pharmaceutical use only food/pharmaceutical grade can be used. Also these prior art films cannot be thermoformed easily and hence cannot be applicable for blister packaging applications.

Plasticizers are substances added to plastic compounds to improve their flexibility, extensibility and process ability. It is characteristic of plasticizer substances that they lower the melting temperature, elastic modulus and second order transaction temperature of polymers but do not alter the chemical nature of the micro molecules. By varying the concentration of plasticizers one can vary the desirable application properties of polymers. Plasticizers can be classified as re primary plasticizers and secondary plasticizers. Primary plasticizers are required to gel a polymer rapidly in the normal processing temperature range. Example: Monomeric Di and Tri esters, Di octyl Phthalate etc. Secondary plasticizers have lower gelatin capacity and limited compatibility with the polymers. Example: Petroleum derivatives consist of aliphatic, Aromatic or chlorinated Hydrocarbon.

Many polymers require high processing temperature and they may decompose at this temperature but on addition of certain stabilizers have very good heat resistance to prevent discoloration or decomposition of the polymeric material. Plasticizers also increases the flexibility of polymeric films material and impart good low temperature performance considerably, give good weathering resistance and improved chemical resistances thereby increasing the life of the PVC end products. However, there is possibility of leaching out i.e. Migration, which is a non-compliance with food content regulations, and Evaporation of plasticizers during processing. This obviated from the use of plasticizer containing PVC in the pharmaceutical and food industry.

Additives on the other hand are widely used in thermoplastic and thermosetting polymers to adjust the handling, processing the properties.

These materials are added to polymeric material to enhance or obtain specific desire properties and also some time to reduce the cost without compromising on properties.

Additives improve or modify the mechanical properties, increase the resistance to degradation during processing or application, improve the appearance of the product and improve the process ability and productivity. Examples include: Mineral particles, Fibres, Pigments, 1,4 Benzenedicarboxylic acid, Calcium carbonate, Aluminium silicate, Fatty acids, Carbon black, Ethylene methyl acrylate co polymer, Adipate, Antimony Oxide, 4,4-Isopropylidenediphenol alkyli, Methylitin 2-mercaptoethyloleate sulfide, Phosphorus acid and Pentaerythritol and the like. Use of additives and plasticizers result in polymeric film having certain heavy metals like lead, cadmium, and mercury and hexavalent chromium being present. The level of Heavy metal in polymeric material is determined by means of Atomic Absorption Spectrophotometer. The level of the heavy metal in polymeric film should not be exceeding 100 ppm by weight. It is known that within the plastic layer particles tends to migrate. The migration of particles in plastic material, which contain additives or other processing aids, which can contaminate the ingredient and even harm the consumer of the product. Universally certain migration limits (10 mg/dm²or 60 ppm.) have been specified for the usage of plastic material for food & drug packaging. Regular PVC also contains some traces Vinyl Chloride Monomer (VCM), which is not polymerized and cannot be separated after the polymerization. For food/pharmaceutical grade PVC the VCM content level in the material should be below the 1 ppm. The level of VCM content in material is determined by means of Gas Chromatography using the headspace method.

Processes for improving the barrier against unwanted diffusion of substances which are known from other fields of the art, e.g., the chemical modification of plastic surfaces of petrol tanks by sulphonation or fluorination, have not acquired any significance in the packaging of pharmaceutical compositions as extensive toxicity and stability tests are required. The prior art also discloses laminate films coated with SiO_x but because of the rigid layer of SiO_x these foils are unable to deform, which means that it is impossible to form wells in order to produce a blister.

In order to achieve a broad barrier effect against gases, water vapour and organic solvents in the case of rigid plastics containers, it is known to provide the plastics container with a coating of special organic and inorganic materials. In this context reference is made to the article "Multilayer Barrier Coating System Produced by Plasma-impulse Chemical Vapour Deposition (PICVD)," M. Walther, M. Heming, M. Spallek, Surface and Coatings Technology 80 (1996), pp. 200-202, which discloses rigid plasties! containers having a layer of SiO_xC_yH₂ or TiO_xC₅H₂ as barrier layer. The coating is done by the PICVD process (plasma impulse chemical vapour deposition) which is known for example from DE 40 08 405 Cl and U.S. Pat. No. 5,154,943.

OBJECT OF THE INVENTION

The object of the invention is to provide a metallized container system. The container system which includes a blister formation which can contain a pharmaceutical product under controlled conditions of opacity and moisture.

Yet another object of the invention is to provide a metallized PVC blister pack system for pharmaceutical and healthcare products which gives better control for transmission of water vapour and light.

Yet another object of the invention is to provide a metallized plastic container system for pharmaceutical and healthcare products, which has means to facilitate visual inspection of the packed product within and at the same time moisture egress and ingress into the container and its opacity can be controlled.

In accordance with a preferred embodiment of this invention there is provided a container for pharmaceutical packaging, which has inherent properties for the protection of pharmaceutical products selectively from light, including ultra violet light and moisture.

Another object of this invention is to provide a metallized blister-packaging container with semitransparent to opaque appearance, through which a packed product may be visible.

Another object is to provide a metallized container so that an online NFD (non filled detection) system can be used on the complete packed system also.

Yet another object of this invention is to provide a container, which provides an anti- counterfeit solution since the metallizing cannot easily imitated by counterfeiters.

Yet another object of this invention is to provide a container having better aesthetics and metallic lustre and therefore creates a brand identity.

10 Still another object of this invention is to provide a container, which can be formed on both rotary, vacuum forming and flat, pressure forming thermoforming and cold forming machines with high productivity.

Yet another object of this invention is to provide a metallized container that is formed by thermoforming or cold forming process.

SUMMARY OF THE INVENTION

According to this invention, therefore there is provided a container for packaging pharmaceutical products, said container consisting of a lid element and a base element, sealingly securable to each other, the base comprising a composite multilayer film having a substrate of thickness 100 to 1000 microns of pharmaceutical grade polyvinyl chloride, at least one metallized layer of effective thickness of 0.005 to 2 microns provided at least on one side of the said substrate and optionally at least one 0.001 to 250 microns thick pharmaceutical grade predominantly organic layer provided at least on one side of the substrate to form a composite multi layer film having an opacity ranging from 90% to 100%, said base having at least one formation for holding a pharmaceutical product, said formation having a controllable opacity of 99.9% to 10% and a controllable MVTR between 0.01 to 15 g/m²/day .

Typically, the metallized layer is formed on the substrate or is applied on the substrate.

Typically, the metallized layer is formed on the substrate by at least one of the processes of metallization consisting of vacuum deposition, indirect metallization, electro less plating, electrolytic plating and lacquer painting.

Typically, the metallized layer consists of at least one metal selected from a group of metals consisting of Aluminium, Copper, Silver, Gold, Brass and Bronze.

Typically, the additional organic layer is provided on the polyvinyl chloride substrate on the non metallized side.

11 Typically, the additional organic layer is provided on the polyvinyl chloride substrate metallized side.

Typically, the organic layer is provided both on the metallized as well as the non metallized side of the polyvinyl chloride substrate.

Typically, the organic layer consists of at least one substances selected from a group of substances consisting of polyvinylidine chloride, LDPE, HDPE, cyclic-olefin copolymer, collared or colourless lacquer and silicone.

Typically, the at least one organic layer provided is laminated over the metallized layer using a tie layer, typically of polyvinylidine chloride.

Preferably, the at least one organic layer is a cast metallized polyvinyl chloride.

Typically, the at least one formation in the base is formed by thermoforming.

Alternatively, the at least one formation in the base is formed by cold forming.

Typically, the lid element is a base element, with the formations in the lid and the base element being aligned with each other.

Alternatively, typically, the lid element is a base element, with the formations in the lid and the base element are not aligned with each other.

Typically, the at least one additional organic layer is a silicone layer.

Typically, the said additional organic layer is a collared or colourless lacquer layer.

In accordance with one embodiment of the invention the opacity of the container can be controlled selectively for light of different wave lengths, particularly, UV light. In another embodiment the opacity of the container can be controlled selectively for light of a particular wavelength.

12 Particularly, the said additional organic layer is a collared lacquer permitting light of only a predetermined wavelength to pass through the layer.

Again, the metallized layer may be so provided as to permit only light of predetermined wavelengths to be transmitted thereto.

Thus invention provides a formed container having a polymer/metallic combination, its position in the multi layered structure & the individual layer thickness that provide synergy to achieve optimum & coherent functional qualities in the final composite container & metallizing effect on the substrate film by deposition of the metal layer on the base or by lamination of commonly available metallized thin films or regular 0.25 to 16 microns PVC films & various shades of metallized film by applying coloured lacquer on the top of the metallized film. Each polymeric substance is known for its diverse physical characteristic properties & hence while forming a multi-layered structure, synergy of these properties is very important to impart cohesiveness to the final film. The properties like thermal stability, elongation characteristics, flexibility, yield; seal ability, tensile strength, impact resistance, gloss, transparency & the barrier properties are characteristics of individual polymer films. This property, in turn, influences the functional qualities packaging aesthetics, cost, protection level, sealing integrity etc.

Hence selection of the composite layer position, its thickness all is very important to get functional properties for the composite film.

This invention teaches the usage of a metallized pharmacy grade PVC blister container having moisture and light control features for pharmaceutical packaging.

Particularly, this invention envisages a container structure having high to medium barrier multi layer base wall being a viable alternative for high cost polymeric / aluminium structures.

The base element of the container developed comprises a multi layered structure having an inner layer (Layer coming in contact with the range substance which is packed) made up of Poly vinyl chloride (PVC) having a thickness range between 100 to 1000 microns. This PVC film is coated with a fine metallic deposition, typically of Aluminium in the range of

13 0.005 to 2 microns. The metal deposition in such thin layers results in a metallized film with enhanced moisture barrier properties with a loss of transparency of the film resulting in a metallized semitransparent to opaque film. Alternatively, a thin polymeric film having a fine metallic deposition is applied on the inner layer.

The container envisaged in accordance with this invention has a base element having thickness above 100 micron and thin metallized films of PVC, CPP, PET or BOPP are laminated onto the PVC film of higher thickness. The metallized layer may have thickness varying from 0.005 to 2 microns.

Other layers on the film, typically one of them being a tie layer could be one or combination of Polyvinylidine chloride (PVdC) (from 0.01 micron to 100 microns); Olefins (LDPE, HDPE) (0.5 micron to 50 microns); Cyclic olefin copolymer (COC) (0.01 to 250 microns).

The packaging film for the base element of the container is formed in two ways. In one method the substrate PVC surface is in contact with the packed material & also will be in contact with the enclosing (lidding film/foil) with metallized film secured to subsequent polymeric layers by either lamination, coating or co-extrusion process preferably by using an adhesive tie layer of PVdC having thickness range between 0.01 micron to 100 micron. In the second type the metallized surface is exposed to the atmosphere with subsequent polymer coating done on the non-metallized side, which comes in contact with the material and the lidding foil for blister packing application.

These composite films may typically be given a silicone coating for enhancing the barrier property.

The thickness of the organic layer also significantly determines the barrier properties. Mildly barrier to very barrier films are produced by coating 0 microns to 100 microns respectively. The flexibility and drawability of the film is improved by lamination of the film with LDPE. The basic strength of the film is, improved by using higher thickness PVC film for metallization. The opacity and barrier property of the film to moisture and light are improved by increasing the thickness of the metallic layer.

14 DETAILED DESCRIPTION OF THE INVENTION

For pharmaceutical , it is well recognized that the most common cause for a packaged product failing to meet its specification is its instability.

This problem is all the more prevalent in the case of moisture sensitive drugs and other additives and excipients.

"Moisture uptake" by pharmaceutical products as a result of exposure to high relative humidity (RH) affects the chemical or physical stability of moisture-sensitive products.

Provided herein below are a few examples of widely used drugs which are moisture sensitive:

Alendronate : Stable for 3 months at 40 degrees C and 75% Relative Humidity

Alfacalcidol : Moisture sensitive, can become sticky out of original Packaging

Amlodipine : Disintegrates in the presence of small amounts of water

Ciprofloxacin : May absorb a small amount of water over time.

Loperamide : Moisture sensitive and can change colour

Moisture ingress into the well-sealed primary packages occurs primarily via permeation and diffusion through the container wall.

Pharmaceuticals are typically packaged in plastic bottles, thermoformed plastic blisters, or cold-formed aluminium blisters.

MVTR which stands for "Moisture Vapor Transmission Rate", a measure of the passage of water vapour through a substance/polymer film.

15 MVTR is also a measure of breathability and is also known as WVTR "Water Vapour Transmission Rate.

Packaging material with an optimum MVTR is critical in achieving the desired quality, safety, efficacy and shelf-life for the products.

It is also well known that all substances, organic or inorganic degrade to a greater or lesser degree in the presence of light. Pharmaceutical substances are no exception.

Since Pasteur's discovery in 1846, scientists have been aware that many drugs are photo reactive, but until recently, research in this area had been somewhat limited.

It is also known that light is not only a form of packets of energy [photons] but also a form of electromagnetic radiation and different components of light have different wave lengths. For instance, visible light which occupies only a very small portion of the electromagnetic spectrum is radiation in the range of 410 to 680 nanometers. Ultra violet light which is known to be more degrading is light with wavelengths shorter than 400 nanometers. In fact ultra violet light covers a span of 380 to 100 nanometers. Of this, UV light in the range of 100 to 280 nanometers, peaking at 265 nanometers has strong degrading activity.

The photo degradation of drugs refers to complex photoreactions in the pharmaceutical product.

In drug formulations, the presence of excipients adds further complications because the excipients may increase, have no effect on, or decrease the inherent stabilities of the drug. Toxicity is a common result of the interaction of sunlight with pharmaceutical agents transported in the blood system or applied topically. The probability that the pharmaceutical product will undergo a photosensitization reaction is directly proportional to its lifetime.

Normally the photo degradation of drugs is more rapid in UV than in visible due to the former's higher energy.

Furthermore, depending on the composition of the formulation light spectrum responsible for photo degradation varies from drug to drug.

16 For example , Nifedipine and molsidomine tablets are extremely photolabile drug preparations, even at cool room light.

The light spectrum responsible for photo degradation moves towards the long- wavelength range corresponding to the bathochromic shift of light absorption in the solid state.

Aman W. and Thoma K have studied the photodegradation of photolabile substances in Pharmazie. 2003 Sep;58(9):645-50.

In the case of nifedipine tablets, incident light up to 500 nm, especially in the range between 400-420 nm, is degrading. Therefore light in this range must be blocked, typically violet to blue light. Molsidomine tablets, on the other hand, are affected only by ultraviolet light, but not by visible light. In both cases light penetrates less than 1 mm into the tablets. For nifedipine tablets the exact penetration depth can be determined due to the discolouration of the drug substance upon irradiation and Particular features of photolabile substances in tablets.

In this case of ciprofloxacin the results are more dramatic. Solutions of ciprofloxacin were irradiated with different wavebands of ultraviolet and visible radiation and the antibiotic activity of the drug was determined against Escherichia coli. A wavelength dependent loss of antibiotic activity was found with maximal effect around 320 nm; no effect occurred with visible irradiation. The degree of the decrease in activity with longer wavelength ultraviolet (UVA) radiation indicated that human exposure to sunlight through window glass (>320 nm) or UVA from tanning sunbeds may result in a significant reduction in both cutaneous and circulating levels of ciprofloxacin. G. Phillips", B. E. Johnson⁶ and J. Ferguson Department of Medical Microbiology, Ninewells Hospital and Medical School Dundee DDl 9SY, UK ^bPhotobiology Unit, University of Dundee, Ninewells Hospital and Medical School Dundee DDl 9SY, UK

This invention teaches that by providing at least one metallized layer in the base element of the container either alone or in combination with at least one suitable organic layer with or without a pigment, the opacity of the base element can be finely controlled to selectively reflect a portion of the light incident on the container and at the same time, filter degrading incident radiation. Concomitantly, by providing the mechanism of the metallized layer either alone or in combination with an organic layer and by varying the thickness of the base PVC substrate, means for controlling the MVTR of the container are

17 created, thereby giving the container the versatility of being used for pharmaceutical products affected by moisture to a greater or lesser degree.

Metallization on thin films are generally done by vaporizing Aluminium in a vacuum chamber under very high vacuum. The Aluminium vapour will be then condensed on to the film surface, which forms a thin Aluminium layer. A single monoatomic layer on the surface is oxidised to aluminum oxide and protects and stabilizes the aluminum layer.

Metallization imparts additional water vapour, gas and UV barrier properties to the film. The metallization not only protects the pharmaceutical product but also the substrate from UV degradation. The aluminium particles in the metallized layer help to reflect UV light in the band of 200 to 380 nanometers. Applying an organic layer over the metallized layer further protects not only the metallized layer but also the PVC substrate.

The invention provides a container having a base element of polymer/metallic combination, its position in the multi layered structure & the individual layer thickness that provide synergy to achieve optimum & coherent functional qualities in the multi layered base element & Metallizing effect on the thicker film by lamination of commonly available metallized thin films on regular 100-1000 micron PVC films & various shades of metallized film by applying coloured lacquer on the top of the metallized film. The unique combination of a metallized layer and a coloured lacquer/organic layer not only provides semi transparency to the formation in the final container, but allows for fine control of the light being transmitted through the film to prevent photo degradation of the product. At the same time the MVTR of the film at the site of the formations is also controlled depending upon the inherent characteristic of the product required to be packed in the container. Incident light is typically controlled in two ways: the metallized layer reflects a portion of the incident light even in the deformed configuration. At the same time by selectively providing one or more pigments in the organic layer, either by itself or in combination with the metallized layer, light of predetermined wavelengths is filtered out.

Each polymeric substance is known for its diverse physical characteristic properties & hence while forming a multi-layered structure, synergy of these properties is very important to impart cohesiveness to the final film. The properties like thermal stability, elongation characteristics, flexibility, yield, seal ability, tensile, strength, impact

18 resistance, gloss, transparency & the barrier properties are characteristics of individual polymer films. This property, in turn, influences the functional qualities packaging aesthetics, cost, protection level, sealing integrity and the like. Hence selection of the composite layer position, its thickness all is very important to get functional properties for the composite film.

The packaging container can be thermoformed or cold formed. Typically, the substrate PVC surface is in contact with the packed material & also will be in contact with the enclosing (lidding film/foil) with metallized film secured to subsequent polymeric layers by either lamination, coating or co-extrusion process preferably by using an adhesive tie layer of PVdC having thickness range between 0.01 micron to 100 micron. Alternatively, the metallized surface is exposed to the atmosphere with subsequent polymer coating done on the non-metallized side, which comes in contact with the material and the lidding foil for blister packing application.

The composite films may typically be given a silicone coating for enhancing the barrier property.

The metallization of the PVC film is done by vacuum deposition or sputtering process or electrolysis process. Thickness of metallization deposition can be determined as a function of electrical resistivity (ohms) of the metallized surface or in certain cases its optical density. Additional layers of polymeric material such as olefins are applied by lamination process. An organic layer such as a PVdC layer is formed by dispersion coating method on the metallized PVC film. Lamination and coating could be done in either on the metallized side or the non-metallized side of PVC.

The thickness of the organic layer, typically of PVdC in combination with the metallized layer determines the moisture barrier properties. Mildly barrier to very moisture barring films can be selectively produced. The flexibility and drawability of the film is improved by lamination of the film with other materials such as LDPE. The basic strength of the film is, improved by using higher thickness PVC film for metallization. The opacity and barrier property of the film is improved by increasing the thickness of the metallic layer and by adding pigments in the organic layer, typically lacquers. Thus for instance if violet light is required to be blocked then typically a lacquer with a sunset yellow pigment can

19 be used. If blue light needs to be blocked then a red pigment may be used. If indigo light needs to be blocked then an orange pigment needs to be used and vice versa.

EXAMPLES

Examples of typical blister pack in accordance with this invention are provided in following accompanying examples.

Moisture vapour transmission rate is the measure of the permeability of water vapour through the film/package under specified conditions of temperature & humidity and is denoted in gm/(m². 24 hr.) at 38⁰C & 90% RH. Moisture barrier property and pack integrity of packaging was determined with accurate MVTR measurement. Optimum packaging selection, protection level of composite designs, package configuration, closure efficiency of seal/cap design & shelf life prediction of the packed product at various , climatic conditions all can be accurately carried out with precise measurement of MVTR. In the below given examples the testing was done using MOCON Permetan MVTR measuring instrument. The moisture that permeates through the film is carried by the carrier gas and analysed by the IR modulated detector giving accurate and fast results of MVTR.

Opacity of the container was checked using a Spectrophotometer [make X rite] which indicates relative opacity of plastic film, with a single pass of the light source through the material, the system measures relative light transmission on a scale of 0 to 100 Opacity Units, representing perfectly transparent to purely opaque materials, respectively using a visible light source and a photoelectric detector. This instrument was also used to determine the colour variation by measuring I₅ a, b values which denotes the lighter and darker shades, bluer and yellower shades, and greener and reder shades.

For measuring the Opacity, the flat film sample was first kept in a black ground and the light reflected from the sample was determined. Further the sample was kept on a white back ground and the reflected light was determined . Further reading were taken on the reflection from the white back ground without the sample. Opacity of the film was then calculated based on the analysis of these readings.

The same set of readings and analysis was performed on the formed portion [blisters] on the film. The figures in the examples represent an average of the readings taken at about 8

20 different areas on the sample. The instrument was also used to measure L, a and b values and therefore calculations were obtained for the transmitted blocked and reflected wave lengths of light from the sample.

All samples were tested for UV transmission before and after deformation and no UV rays were detected to be transmitted by any of the metallized film samples either before or after deformation. It can therefore be concluded that the base element constructed in accordance with this invention will block all UV radiation incident thereon from the pharmaceutical product packed therein.

EXAMPLE 1

A 250 micron PVC film was Aluminium metallized by vacuum deposition method with thickness of 0.05 micron. A 10 micron PVDC layer was applied on the PVC film by dispersion method on non metallized side.

Opacity of the film was 97.04 % measured before blister formation.

MVTR of the film was 0.53 g/m /day measured before blister formation.

The said film was deformed on a blister packing machine, wherein metallized side was facing outside the pack and not touching the packed product.

Opacity of the film was 33.78 % measured after blister formation.

MVTR of the film was 3.11 g/m²/day measured after blister formation.

An analgesic formulation of Paracetamol in tablet dosage form was packed in each blister with 25 micron VMCH coated Aluminium as the lidding foil.

Each blister pack was scanned by visual inspection and by automated laser scanner for empty blisters and broken tablet in blisters. An accuracy of 100 % was achieved over a quantity of about 5000 blister packs, by both methods of inspection, which clearly indicated suitability of metallized PVC for blister pack.

EXAMPLE 2

A 200 micron PVC film was Aluminium metallized by vacuum deposition method with thickness of 0.04 micron. A 20 micron PVDC layer was applied on the PVC film by dispersion method on non metallized side.

Opacity of the film was 96.14 % measured before blister formation.

MVTR of the film was 0.47 % measured before blister formation.

The said film was deformed on a tablet blister packing machine, wherein metallized side was facing outside the pack and not touching the packed product.

21 Opacity of the film was 25.91% measured after blister formation.

MVTR of the film was 2.46 g/m²/day measured after blister formation.

EXAMPLE 3

A 250 micron PVC film was Aluminium metallized by vacuum deposition method with thickness of 0.04 micron. A 35 micron PVDC layer was applied on the PVC film by dispersion method on non metallized side and metallized side.

Opacity of the film was 96.14 % measured before blister formation.

MVTR of the film was 0.34 g/m²/day measured before blister formation.

Opacity of the film was 25.9 % measured after blister formation.

MVTR of the film was 1.64 g/m²/day measured after blister formation.

EXAMPLE 4

A 200 micron PVC film was Aluminium metallized by vacuum deposition method with thickness of 0.04 micron. A lO micron PVDC layer was applied on the PVC film by dispersion method on non metallized side. A 2 micron colourless lacquer was applied on

PVC film on metallized side.

Opacity of the film was 96.14 % measured before blister formation.

MVTR of the film was 0.62 g/m²/day measured before blister formation.

22 The said film was deformed on a tablet blister packing machine, wherein metallized side was facing outside the pack and not touching the packed product.

Opacity of the film was 25.9 % measured after blister formation.

MVTR of the film was 3.54 g/m²/day measured after blister formation.

One set of medium sensitive antibiotic formulation in capsule form was packed in each blister with 25 micron VMCH coated Aluminium as the lidding foil.

Each blister pack was scanned by visual inspection and by automated laser scanner for empty blisters and broken capsule in blisters. An accuracy of 100 % was achieved over a quantity of about 5000 blister packs, by both methods of inspection, which clearly indicated suitability of metallized PVC for blister pack.

EXAMPLE 5

A 300 micron PVC film was Aluminium metallized by vacuum deposition method with thickness of 0.04 micron. A 23 micron PVDC layer was applied on the PVC film by dispersion method on non metallized side. A 3 micron red coloured lacquer was applied on PVC film on metallized side.

Opacity of the film was 96.29% measured before blister formation.

MVTR of the film was 0.42 g/m /day measured before blister formation.

Opacity of the film was 26.95 % measured after blister formation.

MVTR of the film was 2.09 g/m²/day measured after blister formation.

The film effectively blocked the transmission of light having wave lengths for violet, indigo and blue light.

23 EXAMPLE 6

A 250 micron PVC film was Aluminium metallized by vacuum deposition method with thickness of 0.05 micron. A 10 micron LDPE layer was applied on the PVC film by lamination method on non metallized side.

Opacity of the film was 97.09 % measured before blister formation.

MVTR of the film was 0.71 g/m²/day measured before blister formation.

Opacity of the film was 34.4 % measured after blister formation.

MVTR of the film was 4.97 g/m²/day measured after blister formation.

A set of Ethambutol hydrochloride formulation in tablet form was packed in each blister with 25 micron VMCH coated Aluminium as the lidding foil.

EXAMPLE 7

A 350 micron PVC film was Aluminium metallized by vacuum deposition method with thickness of 0.08 micron. 55 microns PVdC layer is applied by reverse gravure technique and 30 micron LDPE layer was applied on the PVC film by lamination method on non metallized side.

Opacity of the film was 99.89 % measured before blister formation.

MVTR of the film was 0.20 g/m²/day measured before blister formation.

Opacity of the film was 69.40 % measured after blister formation.

MVTR of the film was 1.0 g/m²/day measured after blister formation.

One set of lozenges tablets dosage form was packed in each blister with 25 micron VMCH coated Aluminium as the lidding foil.

24 EXAMPLE 8

A 150 micron PVC film was Aluminium metallized by vacuum deposition method with thickness of 0.03 micron. A 15 micron LDPE layer was applied on the PVC film by lamination method on non metallized side and metallized side.

Opacity of the film was 95.31% measured before blister formation.

MVTR of the film was 1.16 g/m²/day measured before blister formation.

Opacity of the film was 21.34 % measured after blister formation.

MVTR of the film was 7.95 g/m²/day measured after blister formation.

EXAMPLE 9

A 400 micron PVC film was Aluminium metallized by vacuum deposition method with thickness of 0.08 micron. A 25 micron LDPE layer was applied on the PVC film by lamination method on non metallized side^". A 23 -micron PVdC is coated on PVC film on metallized side.

Opacity of the film was 99.86 % measured before blister formation.

MVTR of the film was 10.29 g/m²/day measured before blister formation.

Opacity of the film was 65.2 % measured after blister formation.

MVTR of the film was 1.62 g/m²/day measured after blister formation.

25 EXAMPLE 10

A 200 micron PVC film was Aluminium metallized by vacuum deposition method with thickness of 0.08 micron. A 10 micron LDPE layer was applied on the PVC film by lamination method on non metallized side. A 2 micron green collared lacquer was applied on PVC film on metallized side.

Opacity of the film was 99.89 % measured before blister formation.

MVTR of the film was 0.49 g/m²/day measured before blister formation.

Opacity of the film was 69.5 % measured after blister formation.

MVTR of the film was 3.98 g/m /day measured after blister formation.

EXAMPLE I l

A 250 micron PVC film was Aluminium metallized by vacuum deposition method with thickness of 0.05 micron. A 10 micron HDPE layer was applied on the PVC film by lamination method on non metallized side.

Opacity of the film was 97.24 % measured before blister formation.

MVTR of the film was 0.70 g/m /day measured before blister formation.

Opacity of the film was 36.23 % measured after blister formation.

MVTR of the film was 4.90 g/m /day measured after blister formation.

26 EXAMPLE 12

A 300 micron PVC film was Aluminium metallized by vacuum deposition method with thickness of 0.04 micron. A 20 micron HDPE layer was applied on the PVC film by lamination method on non metallized side.

Opacity of the film was 96.54 % measured before blister formation.

MVTR of the film was 0.78 g/m²/day measured before blister formation.

Opacity of the film was 28.90 % measured after blister formation.

MVTR of the film was 4.85 g/m²/day measured after blister formation.

EXAMPLE 13

A 150 micron PVC film was Aluminium metallized by vacuum deposition method with thickness of 0.06 micron. A 15 micron HDPE layer was applied on the PVC film by lamination method on non metallized side and metallized side.

Opacity of the film was 98.24 % measured before blister formation.

MVTR of the film was 0.65 g/m²/day measured before blister formation.

Opacity of the film was 56.82 % measured after blister formation.

MVTR of the film was 5.11 g/m²/day measured after blister formation.

A set of Ethambutol hydrochloride formulation in tablet dosage form was packed in each blister with 25 micron VMCH coated Aluminium as the lidding foil.

27 EXAMPLE 14

A 200 micron PVC film was Aluminium metallized by vacuum deposition method with thickness of 0.06 micron. A 10 micron HDPE layer was applied on the PVC film by lamination method on non metallized side. A 2 micron colourless lacquer was applied on

PVC film on metallized side.

Opacity of the film was 98.14 % measured before blister formation.

MVTR of the film was 0.63 g/m²/day measured before blister formation.

Opacity of the film was 53.76 % measured after blister formation.

MVTR of the film was 4.78 g/m²/day measured after blister formation.

EXAMPLE 15

A 200 micron PVC film was Aluminium metallized by vacuum deposition method with thickness of 0.06 micron. A 10 micron HDPE layer was applied on the PVC film by lamination method on non metallized side. A 5 micron violet coloured lacquer was applied on PVC film on metallized side.

Opacity of the film was 98.39 % measured before blister formation.

MVTR of the film was 0.63 g/m²/day measured before blister formation.

The said film was deformed on a flat bed blister packing machine, wherein metallized side was facing outside the pack and not touching the packed product.

Opacity of the film was 62.1% measured after blister formation.

MVTR of the film was 4.78 g/m²/day measured after blister formation.

Each blister pack was scanned by visual inspection and by automated laser scanner for empty blisters and broken capsule in blisters. An accuracy of 100 % was achieved over a

28 quantity of about 5000 blister packs, by both methods of inspection, which clearly indicated suitability of metallized PVC for blister pack.

The base effectively blocked the transmission of red light through it.

EXAMPLE 16

A 250 micron PVC film was Aluminium metallized by vacuum deposition method with thickness of 0.06 micron. A 100 micron cyclic-olefm copolymer layer was applied on the

PVC film by lamination method on non metallized side.

Opacity of the film was 97.94 % measured before blister formation.

MVTR of the film was 0.35 g/m²/day measured before blister formation.

Opacity of the film was 48.54% measured after blister formation.

MVTR of the film was 1.68 g/m²/day measured after blister formation.

EXAMPLE 17

A 150 micron PVC film was Aluminium metallized by vacuum deposition method with thickness of 0.06 micron. A 20 micron cyclic-olefm copolymer layer was applied on the

PVC film by extrusion coating on non metallized side.

Opacity of the film was 97.94 % measured before blister formation.

MVTR of the film was 0.57 g/m²/day measured before blister formation.

Opacity of the film was 48.54 % measured after blister formation.

MVTR of the film was 3.85 g/m²/day measured after blister formation.

29 Each blister pack was scanned by visual inspection and by automated laser scanner for empty blisters and broken tablet in blisters. An accuracy of 100 % was achieved over a quantity of about 5000 blister packs, by both methods of inspection, which clearly indicated suitability of metallized PVC for blister pack.

EXAMPLE 18

A 150 micron PVC film was Aluminium metallized by vacuum deposition method with thickness of 0.06 micron. A 20 micron cyclic-olefin copolymer layer was applied on the

PVC film by extrusion coating method on non metallized side and metallized side.

Opacity of the film was 97.94 % measured before blister formation.

MVTR of the film was 0.57 g/m²/day measured before blister formation.

Opacity of the film was 48.54 % measured after blister formation.

MVTR of the film was 3.85 g/m²/day measured after blister formation.

EXAMPLE 19

A 200 micron PVC film was Aluminium metallized by vacuum deposition method with thickness of 0.06 micron. A 190 micron cyclic-olefin copolymer layer was applied on the

PVC film by lamination method on non metallized side. A 4 micron colourless lacquer was applied on PVC film on metallized side.

Opacity of the film was 97.94 % measured before blister formation.

MVTR of the film was 0.25 g/m²/day measured before blister formation.

Opacity of the film was 48.54 % measured after blister formation.

MVTR of the film was 1.09 g/m²/day measured after blister formation.

30 A set of Ethambutol hydrochloride formulation in tablet form was packed in each blister with 25 micron VMCH coated Aluminium as the lidding foil.

EXAMPLE 20

A 200 micron PVC film was Aluminium metallized by vacuum deposition method with thickness of 0.06 micron. A lO micron cyclic-olefin copolymer layer was applied on the

PVC film by lamination method on non metallized side. A 3 micron red coloured lacquer was applied on PVC film on metallized side.

Opacity of the film was 98.09 % measured before blister formation.

MVTR of the film was 0.59 g/m²/day measured before blister formation.

Opacity of the film was 52.35 % measured after blister formation.

MVTR of the film was 4.18 g/m²/day measured after blister formation.

A set of Nifedipine formulation in tablet form was packed in each blister with 25 micron

VMCH coated Aluminium as the lidding foil.

The container effectively blocked light in the wavelength below 650 nanometre from reaching the packed products.

EXAMPLE 21

A 150 micron PVC film was Aluminium metallized by vacuum deposition method with thickness of 0.05 micron. A 35 micron PVDC layer was applied on the PVC film by dispersion method on non metallized side.

Opacity of the film was 97.04 % measured before blister formation.

MVTR of the film was 0.33 g/m²/day measured before blister formation.

31 The said film was deformed on a blister packing machine, wherein metallized side was facing outside the pack and not touching the packed product.

Opacity of the film was 33.80 % measured after blister formation.

MVTR of the film was 1.67 g/m²/day measured after blister formation.

A set of highly sensitive multi vitamin capsules form was packed in each blister with 25 micron VMCH coated Aluminium as the lidding foil.

EXAMPLE 22

A 250 micron PVC film was Aluminium metallized by vacuum deposition method with thickness of 0.08 micron. A 20 micron PVDC layer was applied on the PVC film by dispersion method on non metallized side.

Opacity of the film was 99.74% measured before blister formation.

MVTR of the film was 0.33 g/m²/day measured before blister formation.

Opacity of the film was 63.9 % measured after blister formation.

MVTR of the film was 1.94 g/m²/day measured after blister formation.

EXAMPLE 23

A 250 micron PVC film was Aluminium metallized by vacuum deposition method with thickness of 0.08 micron. A 15 micron PVDC layer was applied on the PVC film by dispersion coating method on non metallized side and metallized side.

Opacity of the film was 99.74 % measured before blister formation.

MVTR of the film was 0.36 g/m²/day measured before blister formation.

32 The said film was deformed on a tablet blister packing machine, wherein metallized side was facing outside the pack and not touching the packed product.

Opacity of the film was 63.9 % measured after blister formation.

MVTR of the film was 2.22 g/m²/day measured after blister formation.

A set of highly sensitive multi vitamin capsules dosage form was packed in each blister with 25 micron VMCH coated Aluminium as the lidding foil.

Each blister pack, was scanned by visual inspection and by automated laser scanner for empty blisters and broken capsule in blisters. An accuracy of 100 % was achieved over a quantity of about 5000 blister packs, by both methods of inspection, which clearly indicated suitability of metallized PVC for blister pack.

EXAMPLE 24

A 100 micron PVC film was Aluminium metallized by vacuum deposition method with thickness of 0.01 micron. A 10 micron PVDC layer was applied on the PVC film by dispersion method on non metallized side. A lO micron colourless lacquer was applied on

PVC film on metallized side.

Opacity of the film was 93.44 % measured before blister formation.

MVTR of the film was 1.20 g/m /day measured before blister formation.

Opacity of the film was 15.24 % measured after blister formation.

MVTR of the film was 5.5 g/m²/day measured after blister formation.

One set of medium sensitive of herbal formulation in capsule form was packed in each blister with 25 micron VMCH coated Aluminium as the lidding foil.

EXAMPLE 25

A 100 micron PVC film was Aluminium metallized by vacuum deposition method with thickness of 0.008 micron. A 70 micron PVDC layer was applied on the PVC film by dispersion method on non metallized side. A 4 micron blue coloured lacquer was applied on PVC film on metallized side.

33 Opacity of the film was 93.46 % measured before blister formation.

MVTR of the film was 0.26 g/m²/day measured before blister formation.

Opacity of the film was 15.29 % measured after blister formation.

MVTR of the film was 1.08 g/m²/day measured after blister formation.

EXAMPLE 26

A 150 micron PVC film was Aluminium metallized by vacuum deposition method with thickness of 0.009 micron. A 25 micron LDPE layer was applied on the PVC film by lamination method on non metallized side.

Opacity of the film was 93.48 % measured before blister formation.

MVTR of the film was 2.41 g/m²/day measured before blister formation.

Opacity of the film was 15.32 % measured after blister formation.

MVTR of the film was 11.83 g/m²/day measured after blister formation.

EXAMPLE 27

A 250 micron PVC film was Aluminium metallized by vacuum deposition method with thickness of 0.04 micron. A 20 micron LDPE layer was applied on the PVC film by lamination method on non metallized side.

34 Opacity of the film was 96.24 % measured before blister formation.

MVTR of the film was 0.83 g/m²/day measured before blister formation.

Opacity of the film was 26.59 % measured after blister formation.

MVTR of the film was 5.41 g/m²/day measured after blister formation.

EXAMPLE 28

A 250 micron PVC film was Aluminium metallized by vacuum deposition method with thickness of 0.06 micron. A 30 micron LDPE layer was applied on the PVC film by lamination method on non metallized side and metallized side.

Opacity of the film was 98.09 % measured before blister formation.

MVTR of the film was 0.60 g/m²/day measured before blister formation.

Opacity of the film was 52.35 % measured after blister formation.

MVTR of the film was 4.26 g/m²/day measured after blister formation.

EXAMPLE 29

A 100 micron PVC film was Aluminium metallized by vacuum deposition method with thickness of 0.08 micron. A 10 micron LDPE layer was applied on the PVC film by

35 lamination method on non metallized side. A 6 micron white coloured lacquer was applied on PVC film on metallized side.

Opacity of the film was 99.6 % measured before blister formation.

MVTR of the film was 0.52 g/m²/day measured before blister formation.

Opacity of the film was 72.80 % measured after blister formation.

MVTR of the film was 4.6 g/m²/day measured after blister formation.

One set of medium sensitive herbal formulation in capsule form was packed in each blister with 25 micron VMCH coated Aluminium as the lidding foil.

The blister formation had a hazy appearance and effectively attenuated the the transmission of visible light through out the visible spectrum.

EXAMPLE 30

A 100 micron PVC film was Aluminium metallized by vacuum deposition method with thickness of 0.03 micron. A 40 micron LDPE layer was applied on the PVC film by lamination method on non metallized side. An 8 micron golden coloured lacquer was applied on PVC film on metallized side.

Opacity of the film was 95.84 % measured before blister formation.

MVTR of the film was 1.17 g/m²/day measured before blister formation.

Opacity of the film was 24.04 % measured after blister formation.

MVTR of the film was 8.18 g/m²/day measured after blister formation.

36 quantity of about 5000 blister packs, by both methods of inspection, which clearly indicated suitability of metallized PVC for blister pack.

The blister formation had a golden haze and effectively attenuated visible light through out the visible light spectrum particularly blue green light wave lengths.

EXAMPLE 31

A 150 micron PVC film was Aluminium metallized by vacuum deposition method with thickness of 0.05 micron. A lO micron HDPE layer was applied on the PVC film by lamination method on non metallized side.

Opacity of the film was 97.24 % measured before blister formation.

MVTR of the film was 0.76 g/m²/day measured before blister formation.

Opacity of the film was 36.23 % measured after blister formation.

MVTR of the film was 5.89 g/m²/day measured after blister formation.

EXAMPLE 32

A 250 micron PVC film was Aluminium metallized by vacuum deposition method with thickness of 0.08 micron. 100 microns PVdC is applied by air knife coating technique on the metallized side and 20 micron HDPE layer was applied on the PVdC layer by lamination method on non metallized side.

Opacity of the film was 99.7 % measured before blister formation.

MVTR of the film was 0.14 g/m²/day measured before blister formation.

Opacity of the film was 64.90 % measured after blister formation.

MVTR of the film was 0.65 g/m²/day measured after blister formation.

37 A set of Ethambutol hydrochloride formulation in tablet form was packed in each blister with 25 micron VMCH coated Aluminium as the lidding foil.

EXAMPLE 33

A 250 micron PVC film was Aluminium metallized by vacuum deposition method with thickness of 0.08 micron. A 40 micron HDPE layer was applied on the PVC film by lamination method on non metallized side and metallized side.

Opacity of the film was 99.78 % measured before blister formation.

MVTR of the film was 0.46 g/m²/day measured before blister formation.

Opacity of the film was 72.70 % measured after blister formation.

MVTR of the film was 3.41 g/m²/day measured after blister formation.

A set of Ethambutol hydrochloride formulation in dosage form was packed in each blister with 25 micron VMCH coated Aluminium as the lidding foil.

EXAMPLE 34

A 100 micron PVC film was Aluminium metallized by vacuum deposition method with thickness of 0.08 micron. A 10 micron HDPE layer was applied on the PVC film by lamination method on non metallized side. A lO micron colourless lacquer was applied on

PVC film on metallized side.

Opacity of the film was 99.62 % measured before blister formation.

MVTR of the film was.0.52 g/m²/day measured before blister formation.

Opacity of the film was 62.0 % measured after blister formation.

38 MVTR of the film was 4.56 g/ni²/day measured after blister formation.

EXAMPLE 35

A 100 micron PVC film was Aluminium metallized by vacuum deposition method with thickness of 0.01 micron. A 30 micron HDPE layer was applied on the PVC film by lamination method on non metallized side. A 3 micron golden coloured lacquer was applied on PVC film on metallized side.

Opacity of the film was 94.19 % measured before blister formation.

MVTR of the film was 2.43 g/m²/day measured before blister formation.

The said film was formed on a blister packing machine, wherein metallized side was facing outside the pack and not touching the packed product.

Opacity of the film was 17.1 % measured after blister formation.

MVTR of the film was 12.69 g/m /day measured after blister formation.

The blister formation had a light golden haze and effectively attenuated visible light through out the visible light spectrum particularly blue green light wave lengths.

EXAMPLE 36

A 150 micron PVC film was Aluminium metallized by vacuum deposition method with thickness of 0.05 micron. A lO micron cyclic-olefm copolymer layer was applied on the

PVC film by lamination method on non metallized side.

Opacity of the film was 97.04 % measured before blister formation.

MVTR of the film was 0.71 g/m²/day measured before blister formation.

39 The said film was deformed on a blister packing machine, wherein metallized side was facing outside the pack and not touching the packed product.

Opacity of the film was 33.8 % measured after blister formation.

MVTR of the film was 5.07 g/m²/day measured after blister formation.

EXAMPLE 37

A 250 micron PVC film was Aluminium metallized by vacuum deposition method with thickness of 0.08 micron. A 20 micron cyclic-olefm copolymer layer was applied on the

PVC film by lamination method on non metallized side.

Opacity of the film was 99.74 % measured before blister formation.

MVTR of the film was 0.43 g/m /day measured before blister formation.

Opacity of the film was 63.9 % measured after blister formation.

MVTR of the film was 2.95 g/m /day measured after blister formation.

EXAMPLE 38

A 250 micron PVC film was Aluminium metallized by vacuum deposition method with thickness of 0.08 micron. A 15 micron cyclic-olefm copolymer layer was applied on the

PVC film by lamination method on non metallized side and metallized side.

Opacity of the film was 99.74 % measured before blister formation.

MVTR of the film was 0.44 g/m²/day measured before blister formation.

40 The said film was deformed on a blister packing machine, wherein metallized side was facing outside the pack and not touching the packed product.

Opacity of the film was 63.8 % measured after blister formation.

MVTR of the film was 3.13 g/m²/day measured after blister formation.

EXAMPLE 39

A 100 micron PVC film was Aluminium metallized by vacuum deposition method with thickness of 0.08 micron. A lO micron cyclic-olefin copolymer layer was applied on the

PVC film by lamination method on non metallized side. A lO micron colourless polyester based lacquer was applied on PVC film on metallized side.

Opacity of the film was 99.7 % measured before blister formation.

MVTR of the film was 0.50 g/m²/day measured before blister formation.

Opacity of the film was 60.8 % measured after blister formation.

MVTR of the film was 4.0 g/m /day measured after blister formation.

EXAMPLE 40

A 100 micron PVC film was Aluminium metallized by vacuum deposition method with thickness of 0.08 micron. A lO micron cyclic-olefin copolymer layer was applied on the PVC film by lamination method on non metallized side. A lO micron red coloured lacquer was applied on PVC film on metallized side.

41 Opacity of the film was 99.73 % measured before blister formation.

MVTR of the film was 0.50 g/m²/day measured before blister formation.

Opacity of the film was 63.20 % measured after blister formation.

MVTR of the film was 4.0 g/m²/day measured after blister formation.

The¹ blister formation transmitted red light had a red haze but completely blocked violet light.

EXAMPLE 41

A 250 micron PVC film was Aluminium metallized by vacuum deposition method with thickness of 0.005 micron.

Opacity of the film was 93.0 % measured before blister formation.

MVTR of the film was 2.53 g/m²/day measured before blister formation.

The said film was cold formed in a pressure forming flat bed blister packing machine, wherein metallized side was facing outside the pack and not touching the packed product.

Opacity of the film was 14.2 % measured after blister formation.

MVTR of the film was 10.38 g/m /day measured after blister formation.

Visible light spectrum transmission was attenuated but UV wavelength was blocked completely.

42 EXAMPLE 42

A 400 micron PVC film having 0.05 micron thick aluminium metallized layer obtained by vacuum deposition method was thermoformed into a blister container. The opacity of the original film was 97.04 and MVTR was 0.64 g/m²/day. The opacity of the container was 33.8 %. MVTR of the container was 4.04 g/m²/day.

EXAMPLE 43

A 250 micron PVC film having 0.10 micron thick aluminium metallized layer obtained by vacuum deposition method was further coated with a 35 micron thick layer of PVdC. The opacity of the film was 99.82 % and the MVTR was 0.23 g/m²/day. The film was then cold formed in a pressure forming flat bed machine into a container. The opacity of the container was 79 %. MVTR of the container was 1.34 g/m²/day.

EXAMPLE 44

A 300 micron PVC film having 0.50 micron thick aluminium metallized layer obtained by vacuum deposition method. The opacity of the film was 99.94 % and the MVTR was 0.09 g/m /day. The film was then cold formed in a pressure forming blister machine. The opacity of the container was 82 %. MVTR of the container was 0.82 g/m²/day.

EXAMPLE 45

A 500 micron PVC film having 1.0 micron thick aluminium metallized layer obtained by vacuum deposition method in multiple passes. The opacity of the film was 99.97 % and the MVTR was 0.04 g/m²/day. The film was then formed in to blister form of container using a pressure forming blister machine. The opacity of the blister thus formed was 96.4 %. MVTR of the container was 0.41 g/m²/day.

Light in the visible spectrum was almost completely blocked and a transmission of light was only marginal.

EXAMPLE 45

A 600 micron PVC film having 1.5 micron thick aluminium metallized layer obtained by vacuum deposition method in multiple passes. The opacity of the film was 100 % and the MVTR was 0.02 g/m /day. The film was then formed in to blister form of container using

43 a pressure forming blister machine. The opacity of the blister thus formed was 99.4 %. MVTR of the container was 0.28 g/m²/day.

Light in the visible spectrum was almost completely blocked and a transmission of light was only minimal.

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Claims

Claims:

1. A container for packaging pharmaceutical products, said container consisting of a lid element and a base element, sealingly securable to each other, the base comprising a composite multilayer film having a substrate of thickness 100 to 1000 microns of pharmaceutical grade polyvinyl chloride, at least one metallized layer of effective thickness of 0.005 to 2 microns provided at least on one side of the said substrate and optionally at least one 0.001 to 250 microns thick pharmaceutical grade predominantly organic layer provided at least on one side of the substrate to form a composite multi layer film having an opacity ranging from 90% to 100%, said base having at least one formation for holding a pharmaceutical product, said formation having a controllable opacity of 99.9% to 10% and a controllable MVTR between 0.01 to 15 g/m²/day .

2. A container as claimed in claim 1, in which the metallized layer is formed on the substrate.

3. A container as claimed in claim I₅ in which the metallized layer is applied on the substrate.

4. A container as claimed in claim 1, in which the metallized layer is formed on the substrate by at least one of the processes of metallization consisting of vacuum deposition, indirect metallization, electro less plating, electrolytic plating and lacquer painting.

5. A container as claimed in claim 1, in which the metallized layer consists of at least one metal selected from a group of metals consisting of Aluminium, Copper, Silver, Gold, Brass and Bronze.

6. A container as claimed in claim 1, in which the additional organic layer is provided on the polyvinyl chloride substrate on the non metallized side.

7. A as claimed in claim 1, in which the additional organic layer is provided on the polyvinyl chloride substrate metallized side.

45 I

8. A container as claimed in claim 1, in which the organic layer is provided both on the metallized as well as the non metallized side of the polyvinyl chloride substrate.

9. A container as claimed in claim 1, in which the organic layer consists of at least one substances selected from a group of substances consisting of polyvinylidine chloride, LDPE, HDPE, cyclic-olefm copolymer, collared or colourless lacquer and silicone.

10. A container as claimed in claim 1, in which the at least one organic layer provided is laminated over the metallized layer using a tie layer, typically of polyvinylidine chloride.

11. A container as claimed in claim 1 , in which the at least one organic layer is a cast metallized polyvinyl chloride.

12. A container as claimed in claim 1, in which the at least one formation in the base is formed by thermoforming;

13. A container as claimed in claim 1, in which the at least one formation in the base is formed by cold forming.

14. A container as claimed in claim 1, in which the base has a plurality of formations in the form of blisters.

15. A container as claimed in claim 1, in which the lid element is a base element, with the formations in the lid and the base element being aligned with each other.

16. A container as claimed in claim 1, in which the lid element is a base element, with the formations in the lid and the base element are not aligned with each other.

17. A container as claimed in claim 1, in which the at least one additional organic layer is a silicone layer.

18. A container as claimed in claim 1, in which the said additional organic layer is a collared or colourless lacquer layer.

46

19. A container as claimed in claim 1, in which the opacity of the container can be controlled selectively for light of different wave lengths.

20. A container as claimed in claim 1, in which the opacity of the container can be controlled selectively for UV light.

21. A container as claimed in claim 1, in which the opacity of the container can be controlled selectively for light of a particular wavelength.

22. A container as claimed in claim 1, in which the said additional organic layer is a collared lacquer permitting light of only predetermined wavelengths to pass through the layer.

23. A container as claimed in claim 1, in which the metallized layer permits only light of predetermined wavelengths to be transmitted thereto.

24. A container as claimed in claim 1, which with a combination of metallized layer and the organic layer with or without a pigment provides a unique identity to the pharmaceutical product packed therein .

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