Uses of polymer packaging and pharmaceutical compositions for preservation

Abstract

The present invention relates to a package for storing a sterile pharmaceutical composition, comprising at least an inner layer of polypropylene having a thickness of 200 to 800 μm and an outer layer made of polyethylene, the outer layer being in contact with the environment and having a thickness of 300 to 1000 μm. The present invention also relates to a method for the sterile storage of a pharmaceutical composition using such a package.

Description

[Technical Field]

[0001] Object of the invention This invention relates to the field of polymers, specifically to polymer packaging such as vials that can be used to store sterile pharmaceutical compositions. [Background technology]

[0002] Sterilization is a crucial, even essential, operation in the manufacturing process of pharmaceutical compositions. In fact, most pharmaceutical compositions must be manufactured and stored under sterile conditions before administration to patients in order to prevent the introduction of pathogens and maintain optimal chemical and physical stability. In methods for the sterile storage of pharmaceutical compositions, the sterilization step may be performed either on the packaging / pharmaceutical composition assembly or on each of them (they are all obtained separately in a sterile environment, and then the pharmaceutical composition is filled into the packaging).

[0003] The European Medicines Agency (EMA) recently published new guidelines (EMA / CHMP / CVMP / QWP / 850374 / 2015) on the conditions that must be met for the sterilization of medical and veterinary products, including pharmaceutical compositions (active substances and excipients) and the packaging containing such pharmaceutical compositions. Wherever possible, these guidelines recommend that the final sterilization step of the pharmaceutical composition (if any) be performed in its final packaging.

[0004] There are various types of methods commonly used to sterilize empty packaging (i.e., packaging without pharmaceutical compositions inside) or packaging containing pharmaceutical compositions. Examples include wet or dry heating sterilization, irradiation, and gas sterilization, which should be performed last if heat or irradiation is unsuitable. Guidelines recommend wet heating sterilization in cycles of several minutes at a temperature of 110–121°C. For dry heating sterilization, a period of at least two hours at a minimum temperature of 160°C is recommended. Regarding irradiation sterilization, the reference irradiation dose is at least 25 kGy.

[0005] Therefore, these various sterilization methods require specific conditions to obtain an optimal sterile pharmaceutical composition, and the packaging containing the pharmaceutical composition must withstand those conditions without issue. More specifically, the packaging must exhibit properties such as resistance, stability, mechanical resistance, or robustness, transparency, and impermeability to environmental factors (light, oxygen, temperature) during and after the sterilization process, in particular, so that the sterile pharmaceutical composition can be stored for as long as possible. Similarly, the acceptable pharmaceutical packaging itself must not alter the quality of the pharmaceutical composition it contains. Conversely, the pharmaceutical composition must not alter the quality of the packaging.

[0006] Therefore, there is now a need to develop and provide new packaging that is resistant to increasingly severe or demanding sterilization conditions, such as those recommended by the new EMA guidelines, and that enables the continuous storage of stable and sterile pharmaceutical compositions. [Overview of the project]

[0007] Faced with this challenge, the inventors propose a novel resistant packaging for the storage or preservation of sterile pharmaceutical compositions. The packaging includes a specific polymer outer layer that, in particular, enables the packaging to withstand the sterilization conditions recommended by EMA guidelines while maintaining its robustness. More specifically, the inventors have shown that, surprisingly, packaging comprising at least one polyethylene polymer outer layer with a thickness of 300 to 1000 μm retains its overall resistance when subjected to high dose irradiation (approximately 40 kGy), thus enabling the sustained storage of sterile pharmaceutical compositions.

[0008] Accordingly, the present invention relates to packaging, particularly packaging for storing sterile pharmaceutical compositions, comprising at least one inner layer of polypropylene having a thickness of 200 to 800 μm, and an outer layer made of polyethylene, the outer layer being in contact with the environment and having a thickness of 300 to 1000 μm.

[0009] According to a particular embodiment, the polypropylene inner layer has a thickness of 300-700 μm, 350-650 μm, 400-600 μm, preferably 450-550 μm, and more preferably about 500 μm. According to another particular embodiment, the polyethylene outer layer has a thickness of 400-800 μm, 450-750 μm, 500-700 μm, preferably 550-650 μm, and more preferably about 600 μm. According to a preferred embodiment, the polyethylene outer layer further comprises at least one anti-UV colorant.

[0010] According to another aspect of the present invention, the packaging further comprises a central layer of a gas barrier agent located between an inner layer of polypropylene and an outer layer of polyethylene, having a thickness of 10-250 μm, 10-200 μm, 20-80 μm, preferably 20-50 μm, and more preferably about 30 or 50 μm. The central layer of the gas barrier agent preferably contains ethylene-vinyl alcohol.

[0011] The specific packaging of the present invention also, - A polypropylene inner layer with a thickness of approximately 500 μm, - A central layer containing ethylene-vinyl alcohol and having a thickness of approximately 30 or 50 μm, and -Includes at least one of the following: a polyethylene outer layer having a thickness of approximately 600 μm.

[0012] The packaging preferably includes two adhesive separator layers, each having a thickness of 5 to 50 μm, preferably about 10 μm, the two adhesive separator layers being located between the inner layer of polypropylene and the central layer of the gas barrier agent, and between the outer layer of polyethylene and the central layer of the gas barrier agent, respectively.

[0013] According to a preferred embodiment of the present invention, the polyethylene is low-density polyethylene.

[0014] The present invention also relates to packaging described in this application, further comprising a sterile pharmaceutical composition. The sterile pharmaceutical composition is preferably an aqueous or non-aqueous composition. According to a preferred embodiment, the non-aqueous composition is an oily composition. In particular, the sterile pharmaceutical composition comprises an active ingredient selected from amoxicillin, buserelin, toltrazuril, diclazuril, or cephalexin.

[0015] According to a preferred embodiment of the present invention, the packaging is a bottle or a vial.

[0016] The present invention also relates to the use of the packaging described in this application for storing sterile pharmaceutical compositions.

[0017] The present invention also relates to a method for sterile preservation of pharmaceutical compositions, a) A step of adding a pharmaceutical composition to the packaging described in this application, The present invention relates to a method comprising the step of sterilizing a package containing a pharmaceutical composition. According to a preferred embodiment, the package containing the pharmaceutical composition in step b) is sterilized by gamma irradiation, preferably at a dose of 15 to 40 kGy. [Modes for carrying out the invention]

[0018] The present invention provides a packaging that enables long-term storage of a sterile pharmaceutical composition. More specifically, the packaging is resistant to sterilization conditions, particularly high-dose gamma-ray irradiation, and stable under these conditions, can be impermeable to oxygen and water, and has the advantage of maintaining its transparency.

[0019] As used in this application, the term "about" is understood by those skilled in the art and can vary to a certain degree depending on the context in which it is used. If some uses of this term are not clear to those skilled in the art, depending on the context, "about" means plus / minus 20% of the stated value, preferably plus / minus 10%.

[0020] Packaging The present invention relates to a packaging, particularly a packaging for storing a sterile pharmaceutical composition, comprising at least one inner layer of polypropylene having a thickness of 200 to 800 μm and an outer layer made of polyethylene, the outer layer being in contact with the environment and having a thickness of 300 to 1000 μm.

[0021] According to the present invention, the packaging comprises at least one inner layer of polypropylene.

[0022] "Inner layer" means the layer located inside the packaging. Thus, the inner layer corresponds to the layer that is in contact with the pharmaceutical composition when it is present in the packaging.

[0023] The polypropylene (or polypropene) polymer, also referred to in this application by the initials "PP", has the chemical formula -(CH2-CH(CH3)) n -. Polypropylene results from the coordination polymerization of propylene monomers (CH2=CH-CH3) in the presence of a catalyst such as those used in the Ziegler-Natta process. Polypropylene has a density of about 0.9 g / cm 3 , more precisely 0.895 to 0.920 g / cm 3It has a density and a Young's modulus (also referred to as elastic modulus or tensile force) of 1.1 to 1.6 GPa (gigapascals). There are three different types of polypropylene. The first type contains only propylene monomers in a solid semi-crystalline form and is called "homopolymer of polypropylene". The second type corresponds to a random propylene / ethylene copolymer. This contains, in addition to propylene monomers, 1 to 8% molar amount of ethylene monomers. Finally, the third type corresponds to a homopolymer of polypropylene that further contains a phase of a random propylene / ethylene copolymer having 45 to 65% molar amount of ethylene monomers. This is called a polypropylene impact copolymer. Commercially available polypropylene is, for example, polypropylene Aceso® PPM R021 by Total and polypropylene BORMED SB815MO by Borealis. According to a preferred embodiment of the present invention, the polypropylene forming the inner layer of the packaging is a random propylene / ethylene copolymer containing 3% molar amount of ethylene monomers.

[0024] According to the present invention, the inner layer of the packaging made of polypropylene has a thickness of 200 to 800 μm. More specifically, the inner layer of polypropylene has a thickness of 300 to 700 μm, 350 to 650 μm, 400 to 600 μm, 420 to 580 μm, 430 to 570 μm, 440 to 560 μm, 450 to 550 μm, 460 to 540 μm, 470 to 530 μm, 480 to 520 μm, 490 to 510 μm, preferably about 500 μm.

[0025] According to the present invention, the packaging includes at least one outer layer of polyethylene.

[0026] "Outer layer" means the layer located on the outer periphery of the packaging. Therefore, it corresponds to the layer in contact with the environment.

[0027] Polyethylene, also referred to by the initials "PE" in this application, has the chemical formula -(CH2-CH2) n-It is produced from the radical polymerization of ethylene monomer (CH2=CH2) at a temperature of approximately 200°C under very high pressure (1800-3000 bar). Various types of polyethylene exist, including low-density polyethylene ("LDPE"), linear low-density polyethylene ("LLDPE"), medium-density polyethylene ("MDPE"), and high-density polyethylene ("HDPE").

[0028] As the name suggests, LDPE stands for Medium-Density Polyethylene (MDPE) (0.926~0.940 g / cm³). 3 ) and high-density polyethylene (HDPE) (0.941~0.965 g / cm³) 3 ) is lower than the density of 0.92 g / cm³. 3 Approximately, or more precisely, 0.895-0.925 g / cm³ 3 LDPE has a density of 0.5 to 1.2 Gpa, which is explained by its branching rate, which is higher than that of MDPE and HDPE. LDPE has a Young's modulus of 0.1 to 0.3 Gpa. LDPE can be of petroleum or fossil origin, or plant origin. Examples of fossil-derived LDPE include Bormed® LE6607-PH, sold by Borealis, and Purell PE 3020 D, sold by LyondellBasell. MDPE has a Young's modulus of 172 to 379 MPa. Examples of commercially available MDPE include the Lumicene® series of MDPE sold by Total. HDPE has a Young's modulus of 0.5 to 1.2 Gpa. HDPE can be of petroleum or plant origin. Plant-derived, or "biogenized," HDPE, like all bio-sourced materials, has the effect of reducing the ecological or environmental footprint. Fossil-derived HDPE is, for example, HDPE BM6246LS sold by Sabic. Plant-derived, or bio-sourced, HDPE is, for example, LDPE "SGF 4950" sold by Braskem.

[0029] According to a preferred embodiment of the present invention, the polyethylene is low-density polyethylene.

[0030] According to certain embodiments of the present invention, the low-density polyethylene is of plant origin. LDPE is preferably produced from plants such as sugarcane. The use of this type of “biogenized” LDPE in the outer layer of packaging has the effect of reducing the ecological or environmental footprint of the packaging compared to the use of fossil-derived LDPE. A specific “biogenized” or plant-derived LDPE is, for example, LDPE “STN7006” sold by Braskem.

[0031] According to the present invention, the outer layer of the packaging made of PE has a thickness of 400 to 800 μm. More specifically, the outer layer of PE has a thickness of 450 to 750 μm, 500 to 700 μm, 550 to 650 μm, 560 to 640 μm, 570 to 630 μm, 580 to 620 μm, 590 to 610 μm, preferably about 600 μm.

[0032] A preferred packaging of the present invention for storing sterile pharmaceutical compositions comprises at least one inner layer of polypropylene having a thickness of about 500 μm, and an outer layer made of polyethylene, preferably low-density polyethylene, the outer layer being in contact with the environment and having a thickness of about 600 μm.

[0033] According to a particular embodiment, the outer layer of the packaging, preferably low-density polyethylene, further comprises at least one additive. The additive is, for example, an antioxidant, a plasticizer, a stabilizer, a lubricant, a colorant (or "pigment"), or a mechanical strengthening agent. The outer layer of the packaging preferably further comprises at least a colorant, preferably a colorant having anti-UV properties. According to a more preferred embodiment, the outer layer of the packaging polyethylene comprises a colorant having anti-UV properties. The packaging comprising an outer layer further comprising at least one anti-UV colorant is particularly suitable for the storage of sterile pharmaceutical compositions that are sensitive to ultraviolet light. According to a particular embodiment, the anti-UV colorant is present in an amount of 5% or less of the total weight of the outer layer, particularly in proportions of 5%, 4%, 3%, 2%, and 1%, preferably in proportions of 3% by weight of the total weight of the outer layer. The colorants include, for example, the Colorant Cleartint® series of products sold by Milliken, the Mevopur® series of products sold by Clariant, and products sold by the Gabriel-Chemie Group, such as reference HP 79860 UV.

[0034] According to certain embodiments of the present invention, the package further comprises a central layer of a gas barrier agent. The package comprising the central layer of the gas barrier agent is particularly suitable for the preservation of a sterile pharmaceutical composition that is sensitive to gases, particularly oxygen. The "central layer of the gas barrier agent" means a central layer of the gas barrier agent located between an inner layer of polypropylene and an outer layer of low density polyethylene. Due to its position, the central layer is thus not in contact with the environment when it is present in the package and is also not in contact with the sterile pharmaceutical composition. The central layer of the gas barrier agent preferably has a thickness of 10 to 250 μm, 10 to 200 μm, 20 to 80 μm, 30 to 70 μm, preferably 20 to 50 μm, and even more preferably about 30 or 50 μm. According to even more particular embodiments of the present invention, the package further comprises a central layer of a gas barrier agent located between an inner layer of polypropylene and an outer layer of polyethylene and having a thickness of 10 to 250 μm, 10 to 200 μm, 20 to 80 μm, preferably 20 to 50 μm, and even more preferably about 30 or 50 μm.

[0035] The central layer of the gas barrier agent preferably comprises ethylene-vinyl alcohol or polyglycolic acid, preferably ethylene-vinyl alcohol.

[0036] Ethylene-vinyl alcohol, also referred to herein by the initials "EVOH", is a copolymer having the chemical formula -(CH2-CHOH) x -(CH2-CH2) y It results from the polymerization of ethylene monomer and vinyl acetate monomer followed by hydrolysis. The copolymer EVOH is defined by the molar amount (%) of ethylene. The lower the percentage of ethylene in moles, the better the gas barrier agent properties. According to preferred embodiments, EVOH comprises 20 to 60%, 27 to 47%, and even more preferably about 32% moles of ethylene. Examples of EVOH include the products EVAL F101 and SOARNOL sold by KURARAY and GOSHEI.

[0037] Polyglycolic acid, also referred to in this application by the acronym "PGA," is a biodegradable and thermoplastic polymer of plant origin. PGA exhibits improved properties, particularly with respect to gas barrier effect, heat resistance, moldability, transparency, and durability. An example of a commercially available PGA is KUREDUX, a product of KUREHA.

[0038] Another preferred packaging of the present invention for the storage of sterile pharmaceutical compositions is at least, - An inner layer of polypropylene having a thickness of approximately 500 μm, - Containing ethylene-vinyl alcohol, a central layer having a thickness of approximately 30 or 50 μm, -Includes a polyethylene outer layer having a thickness of approximately 600 μm.

[0039] The packaging may optionally include one or more adhesive separator layers that may be located between the inner layer of PP and the outer layer of PE, or between the inner layer of PP and the central layer of the gas barrier agent, and between the outer layer of PE and the central layer of the gas barrier agent.

[0040] The adhesive separator layer is formed from polymers such as polyethylene, polypropylene, EVOH, polyamide, polycarbonate, polystyrene, and polyterephthalate, and contains an adhesive modified with functional groups suitable for the supporting polymer. This includes, for example, commercially available products of the trademark ADMER® by Mitsui Chemical, corresponding to polypropylene or polyethylene modified with maleic anhydride. An example of polyethylene modified with maleic anhydride is product ADMER® NF408E.

[0041] In particular, the adhesive separator layer has a thickness of 5 to 50 μm. More specifically, the adhesive separator layer has a thickness of 5 to 40 μm, 5 to 30 μm, 5 to 20 μm, 5 to 15 μm, preferably about 10 μm.

[0042] According to a preferred embodiment of the present invention, the packaging comprises two adhesive separator layers, each having a thickness of 5 to 50 μm, preferably about 10 μm, the two adhesive separator layers being located between the inner layer of polypropylene and the central layer of the gas barrier agent, and between the outer layer of polyethylene and the central layer of the gas barrier agent, respectively.

[0043] In the context of this application, the adhesive layer is also represented by the symbol " / ". Thus, packaging according to the present invention, comprising at least one adhesive layer, can be represented as follows, depending on whether or not a central layer of a gas barrier agent comprising ethylene-vinyl alcohol is present: PP / PE, and PP / EVOH / PE.

[0044] Another preferred packaging of the present invention for the storage of sterile pharmaceutical compositions is at least, - An inner layer of polypropylene having a thickness of approximately 500 μm, -An adhesive separator layer having a thickness of approximately 10 μm, -Includes a polyethylene outer layer having a thickness of approximately 600 μm.

[0045] Another preferred packaging of the present invention for the storage of sterile pharmaceutical compositions is at least, - An inner layer of polypropylene having a thickness of approximately 500 μm, -An adhesive separator layer having a thickness of approximately 10 μm, -Containing ethylene-vinyl alcohol, a central layer having a thickness of approximately 30 μm, -An adhesive separator layer having a thickness of approximately 10 μm, -Includes an outer layer of low-density polyethylene having a thickness of approximately 600 μm.

[0046] The preferred packaging is represented as follows: "PP (500 μm) / EVOH (30 μm) / LDPE (600 μm)" in the following examples.

[0047] Another preferred packaging of the present invention for the storage of sterile pharmaceutical compositions is at least, - An inner layer of polypropylene having a thickness of approximately 500 μm, -An adhesive separator layer having a thickness of approximately 10 μm, -Containing ethylene-vinyl alcohol, a central layer having a thickness of approximately 50 μm, -An adhesive separator layer having a thickness of approximately 10 μm, -Includes an outer layer of low-density polyethylene having a thickness of approximately 600 μm.

[0048] The preferred packaging is represented as follows: "PP (500pm) / EVOH (50pm) / LDPE (600pm)".

[0049] composition Another aspect of the present invention relates to the packaging described in this application, further comprising a sterile pharmaceutical composition.

[0050] "Pharmaceutical composition" means any pharmaceutical composition containing an active ingredient. A pharmaceutical composition also includes a veterinary composition. According to a preferred embodiment of the present invention, the pharmaceutical composition is a veterinary composition.

[0051] The active ingredients generally include therapeutic and pharmaceutical products, prophylactic agents, diagnostic agents, and any other agents that can prevent and / or treat or diagnose pathological conditions, infections, or diseases in humans or animals. More specifically, the active ingredients include antibiotics, in particular beta-lactams, e.g., amoxicillin; cephalosporins, e.g., cephalexin; and tetracyclines, e.g., oxytetracycline; anti-infective agents, anticoccidial agents, e.g., diclazuril and toltrazuril; vaccines, e.g., vaccines containing antibodies, antibody fragments, peptides, proteins, interferons, interleukins, cytokines, and vitamins; nonsteroidal anti-inflammatory agents, e.g., meloxicam and indomethacin; anthelmintic and antiparasitic agents, e.g., praziquantel, pyrantel, ivermectin, permethrin, fipronil, and dinotefuran; insect growth regulators; antiviral agents; cardiac stimulants, e.g., digoxin; antihypertensive agents; diuretics; therapeutic agents for the treatment of heart failure, e.g., spironolactone; and angiotensin-converting enzyme inhibitors, e.g., benazepril; and estrus and ovulation inducers and synchronizers, e.g., buserelin. The active ingredients also include diagnostic agents, which may be polypeptides, nucleic acids, polysaccharides, lipids, glycoproteins, glycolipids, carbohydrates, and drugs that enable the labeling of specific tissues, such as drugs containing radioisotopes, magnetic markers, fluorescent markers, chemiluminescent markers, and enzyme markers.

[0052] The sterile pharmaceutical composition preferably contains an active ingredient selected from amoxicillin, buserelin, toltrazuril, diclazuril, or cephalexin.

[0053] "Sterile pharmaceutical composition" means any of the above-mentioned pharmaceutical compositions used in sterilization methods aimed at destroying all microorganisms. These sterilization methods include, in particular, dry heating or wet heating (autoclave) heat treatment, chemical treatments such as treatment using ethylene oxide, and treatments using ultraviolet irradiation or ionizing radiation, such as gamma-ray irradiation or beta-ray irradiation, or exposure to accelerated electron beams.

[0054] Sterile pharmaceutical compositions can exist in any form. For example, a sterile pharmaceutical composition may be a liquid composition, particularly an aqueous or non-aqueous composition. An example of a non-aqueous composition may be an oily composition. Sterile pharmaceutical compositions may also be solid compositions such as powders, compressed tablets, capsules, granules, sugar-coated tablets, hard capsules, wafer capsules, pills, tablets, or creams. Sterile pharmaceutical compositions are preferably aqueous or non-aqueous compositions. More preferably, non-aqueous sterile pharmaceutical compositions are oily compositions.

[0055] According to the present invention, the packaging is suitable for storing sterile pharmaceutical compositions. According to a particular embodiment, the packaging has a three-dimensional structure (3D structure). This particular embodiment having a 3D structure therefore excludes packaging in the form of films, particularly single-layer and multi-layer polymer films. According to a preferred embodiment of the present invention, the packaging is a bottle or a vial. According to a more preferred embodiment of the present invention, the packaging is a vial that can contain a sterile pharmaceutical composition in a volume of 10 ml, 25 ml, 50 ml, 100 ml, 250 ml, 500 ml, 1 l, 2 l, preferably 50 ml, 100 ml, 250 ml, or 500 ml.

[0056] The present invention also relates to the use of the packaging described in this application for storing sterile pharmaceutical compositions.

[0057] "Preservation of sterile pharmaceutical compositions in packaging according to the present invention" may mean preserving the physical and chemical properties of the sterile pharmaceutical composition and the packaging over time. In fact, deterioration of packaging over time simultaneously alters the originally sterile pharmaceutical composition contained within the packaging. Therefore, packaging according to the present invention enables the continuous or long-term preservation of sterile pharmaceutical compositions. More specifically, packaging according to the present invention enables the preservation of sterile pharmaceutical compositions for at least 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 15, 18, 24 months, 3 years, 4 years, 5 years, and beyond. Preferably, packaging according to the present invention enables the preservation of sterile pharmaceutical compositions for at least 6 months, preferably at least 12 months, 24 months, or 36 months.

[0058] The physical and chemical properties of the packaging are studied over time by generally comparing it to glass packaging, which is a reference packaging routinely used by those skilled in the art. The physical and chemical parameters of the packaging studied are those derived from differential scanning calorimetry, which allows access to the thermal properties of the packaging in relation to changes in physical states (melting, crystallization, glass transition) or chemical states (crosslinking, oxidation), for example. The mechanical properties of the vial can also be studied by simple drop tests, as described in the following examples.

[0059] Regarding the physical and chemical properties of sterile pharmaceutical compositions, these can be evaluated absolutely and are controlled by regulations or pharmacopoeias that specify the physical and chemical parameters to be considered and indicate the degree to which these parameters may vary. Changes in these parameters over time allow for the evaluation of the physical and chemical stability of sterile pharmaceutical compositions, and more generally, their storage over time. Parameters can be either qualitative or quantitative. Qualitative parameters that may be considered include, in particular, the color, clarity, and odor of the composition. Quantitative parameters include, for example, the dosage or titration of the active ingredient in the composition, the relative percentage of degradation products relative to the active ingredient, pH, and viscosity. In general, in the field of pharmacy, measuring the titration of the active ingredient and the relative percentage of degradation products relative to the active ingredient is sufficient to determine the stability of a pharmaceutical composition over time. Thus, a composition is considered stable if the content of the active ingredient in the composition and the relative percentage of degradation products vary proportionally so as not to significantly alter the efficacy and safety of the composition. Measurements may be taken at various time points, e.g., 3, 6, 12, 18, and 24 months, at various temperatures, e.g., 4°C, 25°C, and 40°C, and under various humidity conditions. More specifically, a composition may be considered stable if the variation in the content of the active ingredient does not exceed 10%, preferably 5%. A composition may also be considered stable if the variation in the relative percentage of degradation products is at most 10%, preferably at most 5%. These ranges are particularly recommended by the European Pharmacopoeia or described in Guideline VICH GL3. More generally, the shelf life and stability of a pharmaceutical composition are considered to be longer the smaller the variation in the titer of the active ingredient over time, and the slower the appearance of degradation products.

[0060] method Another aspect of the present invention relates to a method for sterile preservation of pharmaceutical compositions. Sterile preservation of compositions can be achieved according to two specific embodiments.

[0061] In a first specific embodiment, the pharmaceutical composition is first added to the packaging described above. The packaging / pharmaceutical composition assembly is sterilized by any method known to those skilled in the art.

[0062] Therefore, the present invention relates to a method for sterile preservation of pharmaceutical compositions, a) The step of adding the pharmaceutical composition to the above packaging, b) A method comprising the step of sterilizing a package containing a pharmaceutical composition.

[0063] Therefore, the method according to the present invention enables sterilization and sterile storage of pharmaceutical compositions.

[0064] In a second specific embodiment, the pharmaceutical composition and packaging are sterilized separately. The sterile pharmaceutical composition is then introduced into the sterile packaging under sterile conditions.

[0065] Therefore, the present invention relates to a method for sterile preservation of pharmaceutical compositions, a) A step of separately sterilizing the above packaging and the pharmaceutical composition to obtain sterile packaging and sterile pharmaceutical composition separately, b) A method comprising the step of adding the sterile pharmaceutical composition to the sterile packaging.

[0066] The above method for sterile preservation of a pharmaceutical composition may further include an optional step c) of preserving a package containing the sterile pharmaceutical composition under conditions suitable for good preservation of the pharmaceutical composition. For example, step c) of preservation may be carried out under vacuum, protected from light, in a dry environment, at a temperature not exceeding 20°C, and of course, various combinations of these conditions are possible.

[0067] Step b) of the sterilization performed in the above method may be carried out by any sterilization method known to those skilled in the art. In particular, step b) of sterilization may be carried out by wet heating, dry heating, gas sterilization, and irradiation. According to a preferred embodiment, step b) is carried out by irradiation, for example by gamma-ray irradiation or beta-ray irradiation, by electron beam, preferably by gamma-ray irradiation. According to a more preferred embodiment, step b) is carried out by gamma-ray irradiation at a dose of 15 to 40 kGy, or preferably 15, 25, or 40 kGy, and even more preferably 25 or 40 kGy.

[0068] The preferred method of the present invention for sterile preservation of pharmaceutical compositions is therefore, a) The step of adding the pharmaceutical composition to the above packaging, b) The step of sterilizing the packaging containing the pharmaceutical composition by gamma irradiation, preferably at a dose of 15 to 40 kGy.

[0069] Other aspects and advantages of the present invention will become apparent from reading the following examples, which should be considered illustrative and non-limiting. [Examples]

[0070] Example 1: Drop Test protocol: Twenty 100 ml vials of sample were treated with or without gamma irradiation. The samples were then filled with water and subjected to a vertical drop test from a height of 1.4 meters, either without or after irradiation. The irradiated vials were subjected to the drop test immediately after irradiation or after several months of storage under vacuum at ambient temperature.

[0071] result: The results for various vial samples are shown in Table 1 below. [Table 1]

[0072] The results in Table 1 show that the vials of the present invention, which include a polymer outer layer of LDPE with an average thickness of 600 μm, are resistant to various irradiation doses up to 40 kGy and 12 months of storage (only one vial out of 20 was damaged under the most severe conditions).

[0073] In contrast, the majority of vials containing a thin 200 μm LDPE layer ruptured immediately after irradiation at 25 kGy (15 / 20) and 40 kGy (17 / 20). Furthermore, a significant number of vials containing a thin 250 μm LDPE layer (13 / 20) ruptured under the most severe storage conditions (40 kGy irradiation and 12 months of storage).

[0074] These results indicate that a polymer outer layer of PE with a thickness greater than 250 μm, particularly 300–1000 μm, is necessary to provide packaging that is resistant to high-dose irradiation and thus allows for the long-term storage of sterile pharmaceutical compositions (at least 12 months).

[0075] Example 2: Study of gas and water barrier effects Water permeability test protocol: A 10 g molecular sieve was placed in an irradiated or unirradiated vial according to the present invention, then sealed, weighed, and placed in an artificial climate chamber at 40°C / 75%RH for approximately 3 months.

[0076] To measure the weight increase, the packaging was weighed periodically throughout this period. This allows for an assessment of the packaging's ability to allow water vapor penetration.

[0077] Oxygen permeability test protocol: The oxygen permeability of vials according to the present invention, both irradiated and unirradiated, was measured according to standard ASTM F2622.

[0078] result: The results for various vial samples are shown in Table 2 below. [Table 2]

[0079] The results in Table 2 show that gamma irradiation does not affect the oxygen barrier properties or water vapor barrier properties of the container of the present invention.

[0080] Example 3: Study on the stability of a pharmaceutical composition protocol: Amoxicillin suspension was packed into vials (PP (500 μm) / EVOH (30 μm) / LDPE (600 μm)) according to the present invention, and then irradiated with gamma rays at four different doses (7, 15, 25, and 40 kGy). The vials were then analyzed before and after 6 months of storage at 40°C / 75% RH.

[0081] result: The results for various vial samples are shown in Table 3 below. [Table 3]

[0082] The first row of Table 3 corresponds to T0, i.e., the dose of amoxicillin and its degradation products without storage.

[0083] The results in Table 3 show that the irradiation step does not affect the stability of the amoxicillin suspension, regardless of the dose.

[0084] In fact, the concentration of the active ingredient remains within the acceptable range of + / - 5% for pharmaceutical products, and the amount of degradation products observed does not exceed acceptable levels.

[0085] The inventors have shown that the packaging according to the present invention enables the stability of pharmaceutical products stored for 6 months under accelerated conditions (40°C / 75%RH) after irradiation. These results obtained under these accelerated conditions ensure the stability of pharmaceutical products for at least 18 months at ambient temperature.

Claims

1. A package for storing a sterile pharmaceutical composition, comprising at least one inner layer of polypropylene having a thickness of 450 to 550 μm, and an outer layer made of polyethylene, wherein the outer layer is in contact with the environment and has a thickness of 500 to 700 μm.

2. The packaging according to claim 1, wherein the inner layer of the polypropylene has a thickness of 500 μm.

3. The packaging according to claim 1 or 2, wherein the polyethylene outer layer has a thickness of 550 to 650 μm.

4. The packaging according to any one of claims 1 to 3, wherein the polyethylene outer layer further comprises at least one anti-ultraviolet colorant.

5. The packaging according to any one of claims 1 to 4, wherein the packaging further comprises a central layer of a gas barrier agent having a thickness of 10 to 250 μm, located between the inner layer of polypropylene and the outer layer of polyethylene.

6. The packaging according to claim 5, wherein the central layer of the gas barrier agent contains ethylene vinyl alcohol.

7. The packaging comprises at least, The inner layer of the polypropylene having a thickness of 500 μm, A central layer containing ethylene-vinyl alcohol and having a thickness of 30 or 50 μm, The packaging according to claim 5 or 6, comprising: an outer layer of polyethylene having a thickness of 600 μm.

8. The packaging according to any one of claims 5 to 7, further comprising two adhesive separator layers, each having a thickness of 5 to 50 μm, wherein the two adhesive separator layers are located, respectively, between the inner layer of the polypropylene and the central layer of the gas barrier agent, and between the outer layer of the polyethylene and the central layer of the gas barrier agent.

9. The packaging according to any one of claims 1 to 8, wherein the polyethylene is low-density polyethylene.

10. The packaging according to any one of claims 1 to 9, further comprising a sterile pharmaceutical composition.

11. The packaging according to claim 10, wherein the sterile pharmaceutical composition is an aqueous or non-aqueous composition.

12. The packaging according to claim 11, wherein the non-aqueous composition is an oily composition.

13. The packaging according to any one of claims 1 to 12, wherein the sterile pharmaceutical composition comprises an active ingredient selected from amoxicillin, buserelin, toltrazuril, diclazuril, or cephalexin.

14. The packaging according to any one of claims 1 to 13, wherein the packaging is a bottle or a vial.

15. Use of the packaging according to any one of claims 1 to 14 for storing a sterile pharmaceutical composition.

16. A method for sterile preservation of pharmaceutical compositions, a) The step of adding a pharmaceutical composition to the packaging according to any one of claims 1 to 14, b) A method comprising the step of sterilizing the packaging containing the pharmaceutical composition.

17. The method according to claim 16, wherein the packaging containing the pharmaceutical composition in step b) is sterilized by gamma irradiation.

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