Patent Application
20140231300
The present invention refers to a material impermeable to humidity and oxygen for packaging dietary products, cosmetics and medicinal specialities. In particular, the present invention refers to primary packaging in the form of blister packs or sachets, which comes into direct contact with the formulations of dietary products, cosmetics and medicinal specialities, such as, for example, tablets, pills, pessaries, powders, granules, suppositories, rigid capsules and soft capsules (also known as soft gel capsules).
In the pharmaceutical, cosmetic and dietary supplements sectors, the importance of the primary packaging to ensure a suitable shelf life is known, useful for the purpose of the sale of finished products, such as, for example, dietary products, cosmetics and medicinal specialities.
Primary packaging means the material, for example blister packs and sachets, that comes into direct contact with the formulations of the medicinal specialities or dietary products.
The commonly used material for blister packs and sachets may consist of paper, and various types of plastic material often combined with each other and, sometimes, coupled to a sheet or layer of aluminium.
The most commonly used types include the so-called polyethylene/aluminium/polyethylene terephthalate—PE/AL/PET, which constitutes a multilayer packaging material with three layers.
In the event of formulations containing pharmacological active ingredients and/or components with unstable biological activity and/or easily degradable, especially if they come into contact with the external environment (humidity, water vapour, light and oxygen), the aforementioned materials are not suitable to guarantee sufficient stability with the consequent degradation of the active ingredient contained therein.
The most commonly used forms of administration in the packaging of dietary products, cosmetics and medicinal specialities include tablets, pills, pessaries, powders, granules, suppositories, rigid capsules and soft capsules (also known as soft gel capsules). Said forms are commonly packaged in the primary packaging types mentioned above.
Agents that come from the external environment (humidity, water vapour, light and oxygen) can modify some chemical/physical parameters of the formulations causing instability and loss of efficacy of the active components contained. Said agents have shown to be particularly decisive in accelerating the kinetics of oxidation, hydrolytic, photochemical and putrefaction reactions. In the event that the active ingredients consist of or comprise microorganisms, said external agents (humidity, water vapour, light and oxygen) can notably influence the microbial metabolism with the formation of toxic catabolites which lead to cell death. In the probiotics sector, microorganisms that can bring beneficial effects to the health of consumers if consumed in suitable quantities and times, the efficacy over the shelf life is compromised if the microbial metabolism is not sufficiently slowed down or reduced. A sufficiently slowed down or reduced microbial metabolism is obtained not only by guaranteeing at the time of manufacturing the probiotic product an extremely reduced degree of humidity and free water, but by preventing, over the shelf life of the product, an increase in humidity and oxygen. Therefore, during the shelf life, the entry of environmental humidity and/or oxygen from outside towards the inside of said product must be prevented.
There are products based on probiotic microorganisms in which the latter are mixed or supported by a lipophilic matrix, for example vegetable oil, or by a fat matrix, for example glycerine, which as well as suffering from the above-described problem must also be compared with some oxidation phenomena which take place in the matrix itself and that are accelerated by the entry of oxygen and/or the presence of metals and other oxidising substances. In lipophilic matrices oxidation leads to the formation of substances such as aldehydes, ketones, oxidised fatty acids (conjugated trienes C18:3, conjugate acids 9,11-10,12 c,t-t,c C18:2, conjugate acids 9,11-10,12 t,t-t,t C18:2) volatile organic compounds (such as C6:0 hexanal, C9:0 nonanal) which are highly toxic for the microorganisms suspended therein (intrinsic toxicity).
Therefore, in this type of products based on probiotic microorganisms, a technologist skilled in the art must check for the absence of humidity and intrinsic toxicity to the lipophilic matrix. Furthermore, increases in humidity and/or the formation of toxic compounds must be prevented, during the shelf life of the finished products, due to the oxidation phenomena that take place because of the entry of air/oxygen into the lipophilic matrix.
Therefore, to guarantee the efficacy of products based on probiotic microorganisms until the end of their shelf life, the need emerges, not only to verify the total biocompatibility of the various substances that compose the formulation (absence of toxic substances such as polyphenols, tocopherols, free phenolic acids, aromatic polycyclic hydrocarbons etc. contained in the lipophilic matrix and/or in the other substances contained in the composition), but also to use a material to make the primary packaging having a real barrier effect against humidity and oxygen.
Therefore, the need remains to be able to provide a material that can ensure a shelf life of at least 24 months for dietary products, cosmetics and medicinal specialities, in particular for products containing probiotic microorganisms that are in contact with a lipophilic matrix. Furthermore, the need remains to be able to provide a material for making primary packaging for bottles, vials, blister packs and sachets that is impermeable to water vapour and oxygen but, at the same time, has breakage characteristics such as to allow breaking with simple finger pressure on the cavity of the blister pack and cutting characteristics such as to allow the sachet to be opened with the fingers. Even more particularly, the need remains to be able to provide a blister pack that enables the packaging of soft capsules (soft gel capsules) containing a lipophilic matrix and microorganisms.
The Applicant has given a suitable response to the above-mentioned need by creating a new material for packaging medicinal specialities, dietary products and cosmetics comprising at least two layers of aluminium coupled to each other, said material having a final thickness such as to maintain the breakage and cutting characteristics necessary to enable practical and easy use.
In a preferred embodiment, the material of the present invention can be schematically illustrated as polyamide/multilayer material of aluminium/polyethylene [PA/(AL)n/PE] or polyamide/multilayer material of aluminium/polyvinyl chloride [PA/(AL)n/PE], where n is comprised from 2 to 10, preferably from 2 to 5, even more preferably from 3 to 4.
Advantageously, the material of the present invention having at least two layers of aluminium (double layer) it guarantees a much lower permeability with respect to a same material having a single layer of aluminium (single layer), of the same final thickness as the double layer, especially with reference to water vapour and oxygen. The material with two layers of aluminium of the present invention has numerous advantages with respect to the same material with a single layer of aluminium, with the same final thickness.
The present invention refers to a material, a blister pack and a sachet which have the characteristics as shown in the appended claims.
Other preferred embodiments of the present invention are described in the following detailed description and such embodiments will be claimed in the appended dependent claims.
A blister pack is a term used for different types of pre-established plastic packages used as containers, for example, single-dose containers, for medicinal specialities, cosmetics and dietary products. The two main parts of the blister pack are the cavity obtained thanks to a sufficiently deformable material by temperature increase and a breakable aluminium cover. The cavity usually contains the medicinal speciality or the dietary or cosmetic product, whereas the cover can display the information on the contents or the manufacturer.
The permeability of polymeric materials is known for many materials. Table 1 shows, for some materials, the oxygen transmission rate OTR (cm3m−2d−1atm-1 at 23° C., 50% RH) and the water vapour transmission rate WVTR (gm−2d−1 at 23° C., 75% RH) of composite films containing 12 μm of PET.
A single sheet of laminated aluminium has a water vapour permeability value of 0.1 g/m2/day and an oxygen permeability value of 0.1 g/m2/day.
Despite the permeability data of single layer aluminium against water vapour and oxygen being very low, the Applicant has experimentally verified that, due to the handling which the material undergoes during the whole production chain leading to the manufacturing of the primary packaging, in actual fact said material, due to the deformations suffered during the various operations, is absolutely inadequate for guaranteeing an effective barrier against external agents, water vapour and oxygen.
The Applicant has conducted an experiment in which blister packs formed by a cavity made with a multilayer material PVC/PP/EVOH/PP/PVC and a cover made with single-layer sheet of laminated aluminium (blister 1) were placed on stability. It should be noted that the multilayer material PVC/PP/EVOH/PP/PVC has a central element consisting of PP/EVOH/PP to which a layer of PVC is coupled, on both the external layers, in order to improve the use practicality and enable the coupling with the aluminium.
In detail, the materials used in blister pack 1 are:
A): Multilayer material PVC/PP/EVOH/PP/PVC to produce the cavity of blister pack 1, and
B): Single-layer sheet laminated in aluminium (AL) to produce the cover of blister pack 1.
Said materials as per points A) and B) have the following characteristics (the numbers identify the thickness in μm).
Table A shows the composition of the material as per point A).
Table A1 shows the barrier characteristics of the material as per point A).
Table B shows the composition of the material as per point B).
Table B1 shows the barrier characteristics of the material as per point B).
Within the cavity of blister pack 1 soft gel capsules were packaged in gelatine containing an oily suspension of soy oil (77% w/w) and the probiotic microorganism B. breve BR03 DSM 16604 in microencapsulated form in a lipidic matrix (23% w/w and having a load of 100 billion CFU/g).
In a preferred embodiment of the invention, the probiotic microorganism is coated with at least a coating of vegetable origin.
In a preferred embodiment, the fats of vegetable nature are selected from the group comprising the saturated vegetable fats having a melting point comprised from 35° C. to 75° C., preferably comprised from 45 to 65° C. Advantageously from 50 to 60° C.
In a preferred embodiment, saturated vegetable fats can be used having a certain degree of hydrophilicity which can be selected from the group comprising mono- and di-glycerides of saturated fatty acids, the polyglycerols esterified with saturated fatty acids and the saturated fatty acids free.
The saturated fatty acids can be selected from the group comprising from 8 to 32 atoms of carbon, preferably from 12 to 28 atoms of carbon, even more preferably from 16 to 24 atoms of carbon.
Advantageously, the coating lipid is selected from the group comprising polyglyceryl-6-distearate, glyceryl dipalmitate-stearate, saturated fatty acids, hydrogenated vegetable fats of non lauric origin, hydrogenated palm fats or stearin.
In a first embodiment, the probiotic bacteria are coated with a single coating (mono-coated). In practice, single coating is created with one same lipid. Advantageously, the single coating is formed by polyglyceryl-6-distearate or by glyceryl dipalmitostearate (E471).
In a preferred embodiment, the weight ratio between the lyophilised microorganism and the lipidic coating substance coating it is 50:50 or 40:60.
In a second preferred embodiment, the probiotic bacteria are double coated. In practice, double coating is performed in succession with two lipids that are different from each other (double coating).
Advantageously, the two lipids are selected from the group comprising a hydrogenated palm fat (melting point=60° C.) and a glycerol dipalmitate-6-stearate (melting point=57-60° C.). The two lipids are sprayed onto the lyophilised bacteria in succession, that is, double coating is applied onto the lyophilised product: the first with hydrogenated palm fat and the second with glycerol dipalmitate-6-stearate in a 3:1 ratio to each other.
The soft gel capsules are made continuously by a system called a moulder in technical jargon which, starting from gelatine liquidised by melting at a suitable temperature, first forms a thin sheet by making the gelatine pass through two steel rollers; subsequently, two sheets of gelatine are moved towards each other and are sealed on the sides and on the bottom while the needle of a volumetric pump injects the oily suspension constituting the formulation into the pocket that is being formed. When the needle is retracted, the upper end is also sealed, causing the formation of the complete soft gel capsule. The soft gel capsules thus formed are dried in a hot air current and collected.
In a preferred embodiment the soft gel capsules comprise a lipophilic matrix, preferably a vegetable oil, for example corn oil, a thickener consisting of wax or fat with a melting point comprised from 50° C. to 80° C., for example bees' wax, or even more preferably glycerol monostearate.
The blister packs 1 containing the soft gel capsules are placed on stability, in parallel to reference primary packaging (reference barrier) known to the prior art for its impermeability characteristics against water vapour and oxygen in the following conditions:
The data in Tables 2 and 3 shows that the primary packaging of blister pack 1 does not represent a suitable barrier since strong mortality has been verified compared with the results of the soft gel capsules in the reference primary packaging. After 4, 5 months, there is a half-life of 339 days versus 28 days in case (i)—Table 2, and 192 days versus 17 days in case (ii)—Table 3.
In order to verify the cause of such mortality, the Applicant assessed the quantity of total water and free water present in the oily suspension, present in the soft gel capsule, containing the bacteria for the stability of 6 months compared with the initial one: no increase in either free water or total water was highlighted. This means that the mortality of the bacteria is not due to an increase in their metabolism made possible by the increase in bioavailable water but, due to another toxicity factor triggered by the entry of air and therefore of oxygen in the oily suspension. This evidence is borne out by the consideration that since it is soy oil, particularly rich in strongly unsaturated linoleic acid, it can be easily oxidised, quickly causing a radical cascade.
The Applicant then set out to find out whether the entry of oxygen had taken place through the layer of aluminium (AL) that constitutes the cover of the blister pack or through the multilayer material that constitutes the cavity of the blister pack.
Therefore, some stability tests were arranged, at the above-mentioned operating conditions, comparing the stability of the soft gel capsules packaged in sachets made with both faces in multilayer material PVC/PP/EVOH/PP/PVC like those of blister pack 1, with that of the same soft gel capsules packaged in multilayer sachets of PET/AL/PE that represent the reference barrier as per Tables 2 and 3.
The stability data obtained after 1 year shows substantial equivalence of the two types of packaging, highlighting that the layer that had enabled the passage of oxygen into blister pack 1 was the single layer of aluminium.
A possible explanation can be found considering that the sheet of aluminium has during manufacturing extremely good impermeability values against water vapour and oxygen, but that these performances could easily decline following handling and/or deformations due to the particular processing and storage conditions. It appears that the processing conditions contribute to increasing the permeability of the sheet of aluminium. Said increase in permeability is not due to cracks and/or collapses in the sheet of aluminium, but to deformations/dilations of the pores (intrinsically present) in the sheet of aluminium itself since the pores are a constructive element of the sheet of laminated aluminium.
The Applicant has developed a material for the production of primary packaging useful for the packaging of dietary products, cosmetics and medicinal specialities. The material of the present invention comprises at least two sheets/layers of aluminium, preferably laminated aluminium, coupled to each other through bonding with appropriate adhesive compounds that can be spread onto the external surface of the layer of aluminium and heated using the equipment and techniques known to a person skilled in the art.
In a preferred embodiment, the material of the present invention comprises or, alternatively, consists of number of sheets/layers of aluminium comprised from 2 to 10. In a preferred embodiment, the number of sheets/layers is 3 or 4 or 5. Advantageously, the number of sheets/layers is 2 or 3.
The thickness of each individual sheet/layer of aluminium is comprised from 2 to 50 μm, preferably from 5 to 40 μm. In a preferred embodiment, the thickness of each individual sheet/layer of aluminium is comprised from 7 to 30 μm, preferably from 8 to 20 μm. In another preferred embodiment, the thickness of each individual sheet/layer of aluminium is comprised from 8 to 20 μm, preferably from 10 to 15 μm. A person skilled in the art is aware that the values quoted above with reference to the thicknesses are susceptible to variations due to a tolerance which is comprised from ±2% to ±8%, usually comprised from ±4% to ±6%.
The weight the sheets/layers of aluminium used depends on the thickness of the sheet. For example, a sheet/layer of aluminium having a thickness of 20 μm has a weight comprised from 45 to 60 g/m2, preferably from 50 to 55 g/m2, for example 54 g/m2. For example, a sheet/layer of aluminium having a thickness of 9 μm has a weight comprised from 45 to 30 g/m2, preferably from 50 to 26 g/m2, for example 24.30 g/m2. A person skilled in the art is aware that the values quoted above with reference to the weights of the individual sheets/layers are susceptible to variations due to a tolerance which is comprised from ±2% to ±8%, usually comprised from ±4% to +6%.
In a preferred embodiment, the material of the present invention consists of a first and a second sheet each having a thickness comprised from 5 to 20 μm, preferably from 7 to 15 μm, for example, 10 μm. For example, two 10 μm sheets can be used. The individual sheets are coupled through equipment and techniques known to a person skilled in the art.
In another preferred embodiment, the material of the present invention consists of a first, a second and a third sheet each having a thickness comprised from 5 to 20 μm, preferably from 9 to 12 μm. For example, three 7 μm sheets or three 10 micron sheets can be used.
The individual sheets are coupled through equipment and techniques known to a person skilled in the art.
The multilayer aluminium material has the characteristics shown in Table C.
In a preferred embodiment, the material of the present invention consists of a first sheet having a thickness of 20 μm, which is coupled to a second sheet having a thickness of 9 μm. The multilayer aluminium material has the characteristics shown in Table C.
The barrier characteristics of material C are shown in Table C1.
After producing the material C) the Applicant coupled a layer of polyamide (PA) to one face of said material and a layer of polyethylene or polyvinyl chloride to the other face of said material, hence making such material a multilayer material sealable with other different materials. Such new multilayer material is called “Material D” within the scope of this patent application, identified by the acronym PA/(AL)n/PE, where n in this case equals 2.
After producing material D), the Applicant prepared a blister pack 2. The blister pack 2 consists of a cavity consisting of multilayer material PVC/PP/EVOH/PP/PVC and a cover produced with material D (PA/(AL)n/PE) whose construction and barrier characteristics have already been described above. The blister packs 2 containing the same soft gel capsules as those tested above were placed on stability.
The stability data (Tables 6 and 7) conducted up to 18 months surprisingly shows that the barrier effect of material D is such as to prevent the entry not only of water vapour, but also of oxygen hence ensuring good stability to the soft gel capsules containing the probiotic bacteria. After 18 months there is a half-life of 352 days versus 341 days—Table 6, and 156 days versus 163 days—Table 7.
Advantageously, the material of the present invention enables the production of a blister pack that is more impermeable to water vapour and oxygen with respect to the known art whilst maintaining, at the same time, the breakage characteristics that allow breaking with simple finger pressure on the blister pack cavity and the necessary cutting characteristics to allow practical and easy use.
The Applicant found that a blister pack consisting of a cavity of a multilayer material coupled to a single layer of aluminium is not able to provide an adequate barrier effect as demonstrated by the data shown in Table 1.
Even if the decay mechanism has not yet been clarified in detail, it is however certain that when the material that comprises the primary packaging does not create a sufficient barrier against the entry of water vapour and oxygen, a series of cascading events occurs, particularly in an environment with a high degree of relative humidity above 60%, which includes:
the entry of air and, hence, oxygen into the cavity, oxygen that then crosses the external wall of the soft gel capsule entering the lipophilic matrix (oil contained in the soft gel capsule as a support).
In the oil, once the substances with naturally present anti-oxidant activity have been consumed (for example, polyphenols, tocopherols, free phenolic and esterified acids) or, voluntarily added (for example vitamin E) chain oxidation reaction is triggered with the formation of many species of free radicals and super-oxidised compounds, for example, aldehydes, ketones, trienes and conjugate acids.
Both the free radicals and the super-oxidised compounds are toxic for the probiotics.
The subject matter of the present invention is a multilayer material for packaging soft gel capsules containing a lipophilic matrix and microorganisms, comprising at least two layers of aluminium coupled to each other, where each layer of aluminium has a thickness comprised from 2 to 50 μm, said material having a first face coupled to a layer of polyamide (PA) and a second face coupled to a layer of polyethylene (PE) or polyvinyl chloride (PVC) giving a multilayer material of the type PA/(AL)n/PE or PA/(AL)n/PVC, where n is comprised from 2 to 10.
In a preferred embodiment of said multilayer material, the value of n is comprised from 2 to 5, more preferably from 3 to 4.
In an embodiment of said multilayer material, a first and a second layer of aluminium each have a thickness comprised from 5 to 20 μm, preferably from 7 to 15 μm, even more preferably 10 μm.
In an embodiment of said multilayer material, a first, second and a third layer of aluminium each have a thickness comprised from 5 to 20 μm, preferably from 9 to 12 μm.
In an embodiment of said multilayer material a first layer of aluminium has a thickness of 20 μm and a second layer of aluminium has a thickness of 9 μm, wherein the material has a permeability to water vapour ≦1 g/m3/24 hours measured with method ASTM F 1249 at a temperature of 38° C. and 90% relative humidity and a permeability to oxygen ≦1 cc/m3/24 hours measured with method ASTM D 3985 at a temperature of 23° C. and 100% relative humidity.
The subject matter of the present invention comprises a cover and a cavity coupled to each other to form a housing for containing soft gel capsules containing a lipophilic matrix, preferably a vegetable oil, and microorganisms dispersed in said lipophilic matrix, said cover being produced with the material described above, in accordance with one of the above-mentioned embodiments, said cavity being produced with a multilayer material selected from the group comprising: PP/PE, PP/EVOH/PP, PVC/PP/EVOH/PP/PVC, PS/PE, PS/PE/PS, PS/EVOH/PE and PA/AL/PVC.
In one embodiment said blister pack comprises a cover and a cavity coupled to each other to form a housing to contain soft gel capsules containing a lipophilic matrix, preferably a vegetable oil, and microorganisms dispersed in said lipophilic matrix, said cover and said cavity being produced with the material described above in accordance with one of the above-mentioned embodiments.
The subject matter of the present invention is a sachet comprising a first and a second face coupled to each other to define a closed volume, in which said first and/or second face comprise the material described above in accordance with one of the above-mentioned embodiments. The coupling can be performed, for, example, through thermosealing, using the techniques and the equipment known to a person skilled in the art. The sachet may be made of two faces coupled to each other through hot thermosealing (faces hot thermosealed) where each face consists of the multilayer material described above in one of the above-mentioned embodiments. In the closed volume, there are products containing microorganisms in contact with a lipophilic matrix, for example a vegetable oil, such as soft gel capsules for example.
The subject matter of the present invention is the use of a multilayer material in accordance with one of the above-mentioned embodiments, for giving stability to products containing microorganisms.
Said multilayer material as described above can give shelf life stability to products containing microorganisms that are found in contact with a lipophilic matrix, preferably a vegetable oil, from 18 to 36 months, preferably of 24 months, at a temperature comprised from 20 to 35° C., preferably from 25 to 30° C. The shelf life stability of products containing microorganisms (for example, a soft gel capsule comprising a vegetable oil, for example a corn oil, and microorganisms) against oxygen and water vapour.
| Number | Date | Country | Kind |
|---|---|---|---|
| MI2011A001718 | Sep 2011 | IT | national |
| Filing Document | Filing Date | Country | Kind | 371c Date |
|---|---|---|---|---|
| PCT/IB2012/001848 | 9/21/2012 | WO | 00 | 3/24/2014 |
