PHARMACEUTICAL CONTAINER TO MAINTAIN SIMULTANEOUSLY LOW LEVELS OF MOISTURE AND OXYGENFIELD OF THE INVENTIONThe present invention relates to a device for reducing the oxygen content of air in the environment of pharmaceutical forms contained within an oxygen permeable container, while also maintaining a relatively low level of humidity in said air during the storage period of the patient. product.
BACKGROUND OF THE INVENTIONThe degradation of drugs induced by oxygen is a factor that can limit the period of storage, as is normally indicated by the expiration date, of a pharmaceutical product. In the case of drugs that are very sensitive to oxygen, such degradation can lead to non-marketable drugs or cause a candidate to be excluded from development. In some cases, sensitivity to oxygen occurs only in the presence of certain excipients. Since oxidation is often not accelerated by standard Arrhenius-based temperature rise studies (known in the art as "accelerated aging studies"), examples can be given where the oxygen sensitivity of the drug is not recognizes until the development of the drug has progressed to the advanced stages of development. In such advanced stages of development, the reformulation and addition of standard antioxidants may require considerably more time and money. In addition, more clinical data may be necey with a new formulation. Thus, there is a need in the art to reduce or eliminate oxygen-based drug instability, without requiring a formulation change. Frequently, in the development of drugs, there may be a need to reduce or avoid the oxygen-induced degradation of a drug candidate or to provide sufficient stability for the initial studies without investing many resources before verifying the concept. Once a candidate has been selected for further development, sensitivity to oxygen can be addressed through more traditional strategies. In addition to the oxygen sensitivity of a pharmaceutically active ingredient in a pharmaceutical form, the pharmaceutical form itself can be sensitive to moisture. This sensitivity may be due to direct reaction (for example hydrolysis), or to physical effects such as plasticization of the excipients of the drug, sticking to the dosage forms ("intimate pairing"), or deliquescence (absorption of atmospheric moisture). For these reasons, many pharmaceutical forms are packaged with added desiccants. The most common pharmaceutically acceptable desiccant is silica, which controls relative humidity (RH) below 20%. The use of metal-based oxygen absorbers for food preservation is well known in the food industry. In such systems, a metal in a low oxidation state reacts with oxygen in the presence of water to form a metal oxide. For example, the Mitsubishi Gas Corporation introduced iron sachets plus carbonate salts under the trade name Ageless® for use in the stabilization of packaged foods, preventing oxidation. Other oxygen absorbers based on iron and metal combined with various salts and other improvements in gradual increments were rapidly imitated, usually with the metal in the form of a powder or in another subdivided form, and with all the components of the absorbent contained in a permeable bag. to oxygen. In a metal oxidation reaction, water provides the activation mechanism used in most such oxygen uptake applications. Oxygen-absorbent sachets are usually stored dry so they can be handled without consuming oxygen. In the presence of moist food, the oxygen absorber is activated and begins to remove oxygen. Recently, companies in the food industry have introduced self-activated oxygen absorbers to provide oxygen absorption in dry food products. This has involved combining additives that maintain moisture with metals (usually iron) in sachets (see, for example, the Japanese publications SH056-50618 and SH057-31449).; and U.S. Pat. No. 5,725,795). European Patent Applications Nos. 864630A1 and 964046A1 describe the use of iodide and iron bromide to allow the absorption of oxygen in an environment with low humidity without the need for water intervention; however, the commercial application of this technology has not been made. In the pharmaceutical industry there have been some limited reports of the use of oxygen absorbers to stabilize drugs. For example, in 1984, tablets of an anti-inflammatory drug were stabilized in large glass jars (ie, oxygen-impermeable) with oxygen-absorbing sachets for six months at 50 ° C (Japanese Patent No. SH059-176247). The source of the oxygen that was eliminated was first of all the air chamber and not the access, that is, due to the permeation through the walls of the bottle. Similarly, Japanese Patent No. SH096-253638 discloses anti-catarrhal medicaments stabilized in waterproof containers by purging with nitrogen or by oxygen absorbers in the container. In a 1990 publication, L-cysteine was stored in an ophthalmic ointment with an oxygen absorber. (That is, see Kyushu Yakugakkai Kaiho, "L-Cysteine Ophthalmic Solution Stabilized with Oxygen Absorber," 44, 37-41 (1990).) In 1995, tonic vitamin C solutions were stabilized using a container lid that had an absorbent of oxygen covered with a polyolefin (Japanese Patent No. SHO94-17056). U.S. Pat. No. 5,839,593 describes the incorporation of an oxygen absorbent in the liner of a container lid. More recently, US patents US 6,093,572; 6,007,529; and 5,881, 534; and PCT publication WO 9737628 describe the use of oxygen absorbers with parenteral products and their special benefit for sterilization. The placement of oxygen-absorbing sachets between a bag of an intravenous substance (IV) or a blood bag and its outer packaging is commonly used in commercial applications. Prefilled syringes with absorbers are also known between the syringes and their outer packaging. EP 0 837 069 A1 describes the use of oxygen absorbers to stabilize acarbose in gas-tight containers. U.S. Patent 6,688,468 (32 and EP 1 243 524 A2 describe the use of oxygen absorbers with pharmaceutical dosage forms in permeable packages.) The oxygen absorbers used in these patent applications are based largely on iron with added moisture controlled by thickened salt suspensions Although these systems work well for many pharmaceutical applications, they cause humidity in the environment of the container to be 55 to 75% relative humidity, since the reaction of oxygen consumption requires moisture To function, although it is possible to dry the container environment somewhat using a desiccant, generally the oxygen absorber will also be dried by the desiccant and will be less effective in removing the oxygen that permeates through the walls of the container. oxygen level in the container will not remain low enough to provide beneficial stabilization of the pharmaceutically active ingredient during its entire shelf life. In all of the above documents, there is no description or guidance relating to the subject of how to use a self-activated oxygen absorber to absorb oxygen in an oxygen-permeable pharmaceutical container while simultaneously keeping the humidity of the medium in the container low, for example , by using a desiccant. Doing this would require the combination of a self-activated oxygen absorber, which requires water to function, with a desiccant that absorbs water. Non-iron-based oxygen absorbers that do not increase relative humidity near the absorbent unit have been marketed for use with pharmaceutical substances under the trademark PharmaKeep® of Mitsubishi Gas Corporation and Süd-Chemie Corporation. These absorbers, however, they provide only a limited absorption capacity (generally less than about 40 cc of oxygen), which is not sufficient to provide protection of the pharmaceutical substances in permeable containers during a typical storage period of at least two years. Although it is possible, in theory, to use several such units to provide sufficient oxygen uptake on a continuous basis, for common container sizes of 30-250 cc, the total number needed to maintain a low oxygen level during the period of Storage of the pharmaceutical substance would generally exclude filling with pharmaceutical forms.
For all the reasons indicated above, there remains a need for an oxygen absorber that is capable of providing, conveniently and at an efficient cost, sufficient oxygen absorption capacity to be usable with oxygen-permeable pharmaceutical containers for at least two years of storage period, but also allowing the relative humidity within the container to remain below 50%, preferably less than 40%, more preferably less than 30%.
BRIEF DESCRIPTION OF THE INVENTIONThe present invention provides a pharmaceutical package comprising an oxygen permeable container containing therein at least one sub-container containing a self-activated oxygen absorber and at least one sub-container containing a desiccant. The subcontainers may be separate or unitary units, that is, manufactured together as separate compartments within a single unit, referred to herein as a "cartridge", containing the self-activated oxygen absorber in a compartment and the desiccant in a separate compartment. . The invention solves a problem, namely that the interior of the container is maintained at a low oxygen level to protect the oxygen sensitive pharmaceutical substances and also at a low humidity level to protect the pharmaceutical substances and / or pharmaceutical forms sensitive to oxygen. humidity. This double protection occurs even when the self-activated oxygen absorber requires moisture to operate and the sub-container or compartment in which it resides is exposed to the interior of the container. In one aspect the invention provides a method for maintaining the oxygen content of the air within a pharmaceutical container at a reduced level relative to the oxygen content of the air outside the container, said container being made at least in part from a permeable material to pharmaceutically acceptable oxygen, while simultaneously maintaining said indoor air with a relative humidity less than 50%, comprising the steps of: disposing, within said container, a first and second subcontainers, said first sub-container contains a desiccant and is adapted to expose said desiccant to said container interior, said second subcontainer contains a self-activated oxygen absorber based on metal, said absorber having sufficient oxygen reducing capacity to reduce and maintain the oxygen content of said indoor air at a level that is lower that the oxygen level of the ambient air (is deci r, outside the container), said second subcontainer has a hole that exposes said absorber to the interior of said container, said orifice has dimensions that allow said absorbent from inside said container to capture oxygen while simultaneously limiting the diffusion rate of said container. water from said second subcontainer such that the interior of said container is maintained below 50% RH, preferably below 40% RH, more preferably below 30% RH. In a second aspect the invention provides a pharmaceutical container comprising a container that maintains the oxygen content of the air within its interior volume at a reduced level relative to the oxygen content of the ambient air, comprising: A) said container , which is manufactured at least in part with an oxygen-permeable material, B) a desiccant disposed within a first sub-container disposed within said container, said first sub-container is adapted to expose said desiccant to said container, C) an absorbent of metal-based self-activated oxygen disposed within a second subcontainer disposed within said container, said absorber has sufficient oxygen scavenging capacity to reduce and maintain the interior of said container with an oxygen level less than the oxygen level of the ambientsaid second subcontainer has a hole that exposes said absorbent to the interior of said container, said orifice has dimensions that allow for the uptake of oxygen while limiting the rate of diffusion of water from said second sub-container such that the interior of said container is maintained by below 50% RH, preferably below 40% RH, more preferably below 30% RH. In most embodiments the container is closed, and preferably sealed, although it is possible to carry out the invention in the absence of a seal. The term "container" is intended to be general, and to include any type or form of pharmaceutical container that is manufactured at least in part from an oxygen permeable material. A "pharmaceutical container" is one in which the oxygen permeable material with which it is manufactured is pharmaceutically acceptable. In this way "container" includes traditional square or round plastic containers, bottles, bags, cases or other pharmaceutically acceptable containers. "Relative humidity", sometimes abbreviated as "HR" in the present specification, has its usual meaning, that is, the ratio of the real humidity to the saturation humidity at the same temperature. The "package" described herein refers to the combination of a pharmaceutical container having disposed therein a self-activated oxygen absorber and a desiccant, each contained in its own subcontainer, the container is intended to be filled with a number of solid dosage forms (usually predetermined), as a rule tablets or capsules. "Inside" or "inside" of the container refers to the free volume, ie, unoccupied of the container once filled and containing the first and second subcontainers described in sections (B) and (C) above, or subcontainers or additional cartridges, as described below. Free volume, also referred to in the "air chamber" technique, of such filled containers is generally between 10 and 100 ce. The amount of air chamber is not critical since more than one oxygen absorbing sub-container can be added to the container. In general, given the typical size of a pharmaceutical container and the rate at which oxygen is permeated through the known oxygen-permeable plastics used to make pharmaceutical containers, the oxygen-absorbing sub-container is made to have a hole (uncovered). ) which is 100-700 microns in diameter, preferably 200-600 microns. The hole will be generally round because it can be made with a drill, although the shape is not critical and other shapes that have an equivalent area can also be used. In an alternate embodiment, a larger hole can be made and can be covered with a microporous material having a porosity generally between 0.05 and 0.2, and a thickness between 0.5 and 2.5 mm. Suitable membranes are widely available commercially, for example from General Electric Osmonics (a division of GE Water Technologies, Trevose, PA) and from Millipore Corporation, (Billerica, MA). The total amount of pore area, defined as the times of porosity of the area, should be equivalent to the area of a hole having dimensions as described above.
An oxygen permeable container generally refers to one made of a material that, when closed or sealed, will admit sufficient oxygen to cause oxidative degradation of the active pharmaceutical ingredient contained during a reasonable storage period, a "reasonable storage period" which it is usually between six months and three years, as a rule two years. Such materials include any of the available pharmaceutically acceptable plastics that are commonly used in the industry and which are discussed and further identified below. As indicated above, the container is one which, as part of the manufacturing operation, is closed and preferably sealed once it has been filled with pharmaceutical dosage forms and at least the two subcontainers (B) and (C) described previously. Any oxygen permeable vessel that allows oxidative degradation of more than 0.2% of the active ingredient or pharmaceutical compound contained during its reasonable storage period may benefit from this invention. The shape of the container is not critical. The term "self-activated oxygen absorber" refers to a metal-based substance that removes oxygen by reacting with it to chemically bind to it, generally forming a metal oxide. The term "activated" means that the metal-based substance requires the presence of water (i.e., as a reagent) to conduct the metal oxide formation reaction. The useful oxygen absorbers of the present invention are "self-activated", which means that they are sold as a unit containing the water necessary to make possible the formation of the oxide, the water is normally present in the form of a substance that controls the humidity, as a rule an aqueous slurry of a salt or a sugar, such compositions are designed to maintain a specific humidity in a closed environment. The preferred metal is elemental iron, powder to increase its surface area. Other metals that are useful, although less preferred, include nickel, tin, copper and zinc. The oxygen absorber reduces the oxygen content of the air inside the container, once the container has been closed or sealed, at a level that is below the oxygen level of the air surrounding the exterior of the container, for example the ambient air in a warehouse or transport compartment, or other storage environment or means of transport. Therefore, the absorbent maintains the oxygen in the air in the air chamber at a level preferably below 10.0% (i.e., in volume, based on the volume of the air chamber), preferably below 3.0% , more preferably below 1.0%, most preferably below 0.5%. The subcontainers (B) and (C) can be created as physically separate containers that are added to the container separately in the manufacturing process. In a preferred embodiment, and as further described below, the subcontainers (B) and (C) are formed as physically separate compartments of a single unit, referred to as a "cartridge" in the present invention. When it comes to such a cartridge, the compartments inside it are called (B), (C), etc. to have a meaning corresponding to the letter designations given above for the subcontainers (B), (C), and so on. The cartridge can be advantageously manufactured from a plastic (including the oxygen permeable ones described herein) by an appropriate molding operation. A preferred additional embodiment, illustrated below, concerns the inclusion, in said container, of a third sub-container or compartment (D) of the cartridge adapted to contain a quantity of self-activated oxygen absorber based on metal separated from that of the subcontainer. or compartment (C) of the boat. This third sub-container or compartment functions to reduce or rapidly eliminate the oxygen initially contained in the container's air chamber once the container has been sealed or sealed for storage, transportation, and / or sale. Preferably, (D) is organized as a third compartment in a cartridge that also contains, as individual compartments within it, (B) and (C). Because this third sub-container or compartment is designed to remove the oxygen initially present in the air chamber, it preferably only contains enough metal and water to react approximately stoichiometrically with the oxygen initially present in the air chamber once the container has been removed. closed or sealed. To facilitate the removal of oxygen from the air chamber, the third sub-container or compartment has a hole, preferably in the form of a porous membrane having a permeability such that the oxygen flow allows the entire air chamber to be oxygen-free. below 3% (V / V) in less than 3 days, preferably below 2% in 3 days in relation to the orifice provided in the sub-container or compartment (C) containing the self-activated oxygen absorber. Providing a much larger pore area in the sub-container or compartment (D) allows for the removal of oxygen quickly and, therefore, quickly dispose of a relatively oxygen-free medium once the container has been sealed or sealed. Therefore, the sub-container or compartment (C) keeps the oxygen at a relatively low level. From now on, the invention will be described by reference to cartridges and the compartments therein, it being understood that this is for convenience and ease of description, and that the cartridges and compartments described hereinafter can also be organized equivalently as separate subcontainers. The access opening to the compartment (B) containing the desiccant is also relatively much larger, therefore more open to the interior of the container, than the access to the interior of the container provided by the orifice of the compartment (C). The opening that exposes the desiccant from the compartment (B) to the air chamber is preferably in the form of a membrane, which has a large pore area, to prevent the desiccant from being poured out of the compartment (B). Alternatively, a plurality of small holes, such as drill holes, can be separately made in place of a membrane. By making the total surface area of holes in the compartment (B) relatively much larger than the hole in the can compartment (C), the interior of the container remains relatively dry, much drier than the interior of the oxygen-absorbing compartment (which contains water) (C). This area, however, can be restricted to provide a relative humidity in the container A at a somewhat higher value than that which is generally maintained with desiccants. This serves to minimize the loss of moisture from the compartment (C). The total area of the area of the holes in the subcontainer (B), whether the area in the form of holes or a porous membrane, is as a rule at least 0.3 cm2, preferably between 0.3 cm2 and 0.4 cm2.
BRIEF DESCRIPTION OF THE DRAWINGSFigure 1 is a front view of a container having a cartridge disposed therein in a preferred embodiment according to the invention. Figure 2 is a graph illustrating the rate of water removal by the desiccant as a function of the size of the orifice of the compartment (B). Figure 3 is a graph illustrating the rate of oxygen consumption of an autoactivated iron-based oxygen absorber in the compartment (C) as a function of the size of the orifice.
DETAILED DESCRIPTION OF THE INVENTIONFigure 1 illustrates a preferred embodiment of the present invention designed to provide oxygen absorption with low humidity over a prolonged period in a packaged product. In Figure 1, "A" represents a pharmaceutical container, which is generally manufactured, in whole or in part, with an oxygen permeable plastic. The container A is preferably sealed, most preferably with a hot induction seal (HIS) 1 made with a sheet of metal and an adhesive which attains the union of the container to the sheet. Disposed within the pharmaceutical container A are the pharmaceutical forms 3, preferably tablets, capsules or the like. Also disposed within the pharmaceutical container A is a cartridge, generally designated 5 and comprised, only for the sake of explanation, of three separate compartments B, C, and D, separated from one another by the dividers 7 and 9, which are walls preferably made of the same material as the rest of the can 5 and manufactured integrally therewith, for example as part of a molding process. The compartment B contains a desiccant (not shown) such as silica gel and is exposed to the interior of the container by means of the porous membrane 11, which thus allows relatively free exchange between the compartment (B) and the air chamber of the container, whereby the moist air from inside the container A enters and the dry air leaves the compartment. A second compartment D contains a self-activated oxygen absorber present in sufficient quantity to remove the initial oxygen in the air chamber in the container A. The compartment D contains the porous membrane 13 which allows relatively free access of the compartment D to the air containing oxygen in the air chamber of container A, which thus performs the uptake of oxygen. A third compartment C contains sufficient self-activated iron absorber (i.e. metal and moisture) to capture the oxygen that permeates through the walls of the container during the storage period of the product. The compartment C contains a hole 15 that can be made in the form of a microporous hole, tube or filter. The cross-sectional area of the orifice is such that it achieves a sufficient oxygen uptake rate to equalize the oxygen access rate in container A, however the area is such that the orifice limits the rate of moisture loss from the compartment C so that there is adequate moisture in the compartment (i.e., to allow the formation of the metal oxide) throughout the storage period of the pharmaceutically active ingredient. Some moisture escapes from the compartment (C), but the rate is small in relation to the moisture absorbing capacity of the desiccant in the subunit "D". This is a critical feature of the invention, that is, the cross-sectional area of the hole (or holes) in the compartment (C). On the one hand, the area is large enough to achieve effective oxygen uptake from the interior of the container during the storage period of the product, thus eliminating or reducing the oxidative degradation of the pharmaceutical product.
On the other hand, the area is small enough to limit the amount of moisture escaping from the compartment (C) to no more than the desiccant can remove during the storage period. As previously indicated, if the hole is made as a circular hole, it should have a diameter of 100 to 700 microns, which corresponds to a cross-sectional area of approximately 0.8 x 10"4 to approximately 38 x 10" 4 cm2. The shape of the hole is not critical, and other shapes having equivalent transverse areas can be effected equally effectively. Figure 2 shows the variation (experimentally determined) in the rate of moisture uptake by the silica gel desiccant as a function of the diameter of the orifice (eg, in compartment (C)) through a barrier that has she a single tube of variable diameter. The data points in the graph were measured while maintaining the external environment at 40 ° C and 75% relative humidity (RH). The graph shows that the moisture transfer rate of a cartridge with a high humidity compartment (C) can be controlled in a predictable way by choosing a suitable size for the orifice. Figure 3 shows the rate of oxygen uptake by iron through a barrier having a single tube made therein, as a function of the cross-sectional area of the orifice (ie, the tube). The data shows that the rate of oxygen uptake, ie, by the compartment (C) can be controlled in a predictable manner depending on the size of the orifice. In Figure 1, the pharmaceutical container A is a container or other container for dispensing pharmaceutical dosage forms. The container is designed to protect a pharmaceutical form from mechanical damage and to limit the exposure of pharmaceutical forms contained therein to light and environmental contaminants. Glass containers can function effectively in some cases due to the low (basically no) permeability of the glass to oxygen and moisture, and are within the scope of the present invention. However, due to the risk of breakage and the added expense of working with glass, the containers are preferably made, usually in their entirety, of plastic, basically all of said plastics are permeable to oxygen in various degrees. Plastics suitable for use in the manufacture of pharmaceutical containers generally involve plastics such as low density polyethylene (LDPE), high density polyethylene (HDPE), polypropylene (PP), polystyrene (PS) and polycarbonate (PC). The oxygen permeability of these materials is in the range of 88.9 ce mm / (m2 day atm) (3,500 ce mil / (m2 day atm)) for the PS at 241.3 ce mm / (m2 day atm) (9.500 ce thousand / (m2 day atm)) for the LDPE. Other suitable packaging materials include polyesters (PET, PEN), nylon, polyvinyl chloride (PVC), poly (vinylidene chloride) (PVDC), poly (tetrafluoroethylene), etc., and laminates containing layers of one or more of such materials. The present invention provides, in a preferred embodiment, a cartridge that can be added to a pharmaceutical container and that provides a significant reduction in oxygen and moisture levels, including such a reduction in the permeation rates described above. Once the oxygen permeable container has been filled with a predetermined amount of pharmaceutical forms containing an oxygen sensitive drug and a cartridge according to the invention, the container is then closed, covered with a screw cap, or stopper, or seal. If the container is sealed, a preferred seal is an induction hot seal (HIS). Other useful seals include adhesives such as pressure sensitive adhesives, thermal adhesives, photocurable adhesives, and a binary mixture of adhesives such as epoxy resins. Adhesion can also be achieved by techniques such as ultrasonic welding that does not require adhesives. A packaging material (eg, cotton) can optionally be added to the container prior to sealing to avoid any damage to the contents such as chipping or cracking of the dosage forms. HIS is normally used in the pharmaceutical industry to seal the top of plastic containers, both as a means of protecting the pharmaceutical forms of the environment as a means of avoiding (and patenting) any manipulation. The induction seal and the container are preferably matched to achieve an acceptable seal. Induction sealing processes are well known to those skilled in the art. For a detailed description see "induction Sealing Guidelines", R. M. Cain (Kerr Group, Inc.), 1995 and W. F. Zito "Unraveling the Myths and Mysteries of Induction Sealing" J.
Packaging Tech., 1990. Any pharmaceutical form 3 containing an oxygen sensitive pharmaceutical compound susceptible to degradation as a result of exposure to oxygen can be placed inside the pharmaceutical container A. Examples of oxygen sensitive products that are subject to degradation due to exposure to oxygen include products such as amines or as salts or as free bases, sulfides, allyl alcohols, phenols, alcohols, aldehydes and the like. In addition, some basic pharmaceutically active compounds or products, especially amines, with pKa values in the range of about 1 to about 10, more especially in the range of about 5 to about 9, are often subject to degradation by oxygen and can therefore benefit from the present invention, as well as some pharmaceutically active compounds or products having redox potentials less than or equal to about 1,300 mV against Ag / Ag +, more preferably less than or equal to about 1,000 mV against Ag / Ag +. Pharmaceutically acceptable active compounds include compounds such as atorvastatin (especially when used in an amorphous form), pseudoephedrine, tiagabine, acitretin, rescinamine, lovastatin, tretinoin, isotretinoin, simvastatin, ivermectin, verapamil, oxybutynin, hydroxyurea, selegiline, esterified estrogens, tranylcypromine , carbamazepine, ticlopidine, hydrated methyldopa, chlorothiazide, methyldopa, naproxen, acetominophen, erythromycin, bupropion, rifapentine, 2penicillamine, mexiletine, verapamil, diltiazem, ibuprofen, cyclosporine, saquinavir, morphine, sertraline, cetirizine, N - [[2-methoxy-5- (1-methyl) phenyl] methyl] -2- (diphenylmethyl) -1-azabicyclo [ 2,2,2] octane-3-amine and the like. The invention is especially suitable for stabilizing oxidation forms of drugs with high energy. Examples of high energy drug forms include amorphous forms and drug forms with small particle sizes. A preferred example of a high energy form of a drug is prepared by spray drying a drug as a dispersion together with an enteric polymer as described in EP 1027886A2 and EP 901786A2, each incorporated herein by reference. Suitable enteric polymers include those described in patent applications WO 0147495 A1, EP 1027886 A2, EP 1027885 A2, and in the US publication. No. 2002/0009494 A1, incorporated herein by reference. The present invention can additionally stabilize excipients of the pharmaceutical form of oxidative degradation. For example, the degradation leading to discoloration, noxious reactivity with the active component of the drug or changes in the performance of the pharmaceutical form, such as rates of dissolution or disintegration. Non-exclusive examples of excipients commonly used in pharmaceutical formulations that could be stabilized by the application of the present invention include poly (ethylene oxides), poly (ethylene glycols) and poly (oxyethylene) alkyl ethers.
The present invention provides a reduction in the degree of oxidative degradation or discoloration wherein such degradation or decolorization can be measured by light absorption or by reflection spectroscopy and / or by chromatographic analysis, namely, HPLC analysis. The invention needs not to totally eliminate such degradation; however, the practice of the present invention preferably reduces degradation by at least about 20%, more preferably by about 50% and most preferably by about 75% when compared to samples stored in the absence of the oxygen cartridge / absorber as described In the present memory. Although the shape of the cartridge is not critical, the cartridges described herein may be generally tubular in form to facilitate high speed insertion into the container. The cartridge can have the shape of a boat, that is, a tubular container with the desired number of compartments and having one or both end compartments that can be opened to facilitate filling. The ends of the tube may be flat or circular, convex or concave, as desired. The cartridge can be manufactured, as is known in the art, using a suitable mold and molding process, as a rule injection molding with a thermoformable polymer. The desiccant (sub-container or compartment B) provides a low relative humidity in the pharmaceutical container. The desiccant for use in the practice of the invention can be any available desiccant. Preferred desiccants include those normally used in the pharmaceutical industry, which have a sufficient capacity to handle the combination of moisture access in the container and moisture released by the self-activated oxygen absorber. Suitable desiccants are discussed in R. L. Dobson, J. Packaging Technol., 1, 127-131 (1987). A preferred desiccant is silica gel. The desiccant can be supplied in the form of a pouch, cartridge or canister. It is desirable to maintain the relative humidity in the container A at a level which, while still providing protection of the dosage forms from the adverse effects of moisture, minimizes the loss of moisture from compartment C. For this purpose, the barrier 11 can be do to limit the moisture transfer rate. This limitation of the rate can be realized using a somewhat limited moisture permeation membrane (by virtue of the material or thickness) or by the appropriate choice of a material having an appropriate permeability. This selection of material and surface area can be made based on experiments and depends on the particular moisture sensitivity of the pharmaceutical form used. In general, it is desirable that the permeability of the moisture barrier 11 be such that the relative humidity in the container A is maintained at or below 40% RH, more preferably below 30% RH, under storage conditions , as a reference, 30 ° C and 75% RH. The amount of desiccant used is preferably sufficient to handle moisture access through the walls of the pharmaceutical container for the duration of storage, which depends on the humidity of the external medium. For conditions of 30 ° C and 60% RH, the water permeation rate in an HDPE container of 60 ° C with an internal humidity that remains below 40% RH can be estimated at approximately 0.25 mg / day ( 91 mg / year). In addition there is preferably sufficient desiccant to handle the moisture loss of the oxygen absorber (estimated at about 146 mg / year, as discussed below). The silica gel has an approximate ability to maintain a relative humidity below 40% of approximately 0.5 mg H20 / mg of silica. In this way, an amount of silica gel to be placed in a subcontainer or compartment B is between 475 and 1100 mg, an amount that will absorb both the moisture of the external permeation and the moisture escaping internally from the absorbent compartment (C), in based on the size of the compartment opening, during a reasonable storage period. Those skilled in the art will recognize that similar calculations can be made for different container materials that have different rates of water permeation, air chamber volumes, and for different temperature and relative humidity conditions. The cartridge compartment is constructed such that it physically separates the desiccant from direct contact with the pharmaceutical ingredients, yet allows the moisture to be collected from within the pharmaceutical container. The cartridge compartment D contains a self-activated oxygen absorber capable of rapidly removing oxygen from the air chamber in the pharmaceutical container A. This absorbent is preferably an iron-based absorbent and can be of the same material used as a self-acting oxygen absorber. placed inside the absorbent compartment (C). To allow the metal to capture oxygen, a source of moisture must be provided. In the present invention, and since it is commercially available, this source of moisture is preferably provided in the form of a slurry of a salt or sugar. Because compartment D is designed to rapidly remove oxygen from the air chamber within container A, it only needs to operate for a few days, and thus requires only a relatively small amount of absorbent. The absorbent of the compartment (D) can therefore be at a high relative humidity, although its moisture decreases rapidly according to the desiccant in compartment B competes for moisture. Preferably, the moisture source in compartment B maintains a relative humidity (RH) above about 50%; more preferably above 60%; even more preferably above 65%. Preferred sources of moisture are salts or mixtures of salts. Especially preferred salts are sodium chloride, potassium chloride and potassium sulfate. The compartment D is constructed such that it physically separates the self-activated oxygen absorber from direct contact with dosage dosage forms, however it allows oxygen to be collected from within the pharmaceutical container. Preferred compartments (D) contain pouches in which the containment bag is made of a porous material (eg, fabric). Alternatively, the compartment (D) of the cartridge can in turn be porous, since it has an open section covered with a porous fabric or membrane. The amount of oxygen in the air chamber in the container A can be determined by measuring the volume of the container, subtracting the volume of the dosage forms and dividing the remaining volume by five (to take into account the abundance of oxygen). For example, in a container of approximately 60 cc that has been filled to half with pharmaceutical forms, the volume of the air chamber will be approximately 6 cc of oxygen. The amount of iron used to remove oxygen, and excluding any oxygen due to access, should at least be stoichiometrically sufficient. Since the oxygen absorbing capacity of iron is approximately 300 cc / g, the minimum amount of iron necessary for the removal of oxygen from the air chamber of a 60-ce container is 20 mg. Therefore, the amount of iron for this subunit is preferably between 20 and 100 mg. Compartment C contains sufficient oxygen absorbent to allow the oxygen level in the pharmaceutical container to remain low during the reasonable storage period of the product by balancing the oxygen access rate in the container with a comparable rate of oxygen uptake. At the same time, the moisture loss rate of compartment C is sufficiently low that the total moisture level in vessel A remains low due to the desiccant and enough water remains in the subunit to provide the relative humidity needed in the subunit for the activity of iron for the duration of the storage period. It has been determined that these contradictory and opposite objectives can be achieved with an oxygen absorber and a moisture controlling element enclosed in a low permeability compartment of a cartridge together with a rate controlling port (15 in Figure 1). Preferably, the cartridge is made of a plastic or metal material considered safe for contact with pharmaceutical ingredients. Examples of preferred materials include plastics such as polyethylene (PE), polystyrene (PS) and polyvinyl chloride (PVC). Although the cartridge can be made of permeable plastics, the actual amount of oxygen and moisture that is transferred through these materials (unlike holes or membranes) is low due to the low surface area and does not significantly affect the levels of oxygen and moisture in the container A. The controller's rate port has the property of restricting moisture transfer while allowing sufficient oxygen transfer. Figure 2 shows the moisture transfer rate from a controlled test environment to be at 40 ° C and 75% RH in a sub-container that has a fixed amount of silica gel, the sub-holder has a single hole, made therein as a tube, as the only entry for moisture from the environment. The amount of water that entered through the tube was controlled as a function of the time and diameter of the tube. These data provided the basis for calculating the moisture transfer rate from the compartment (C) of the autoactivated oxygen absorber to the air chamber of container A. Once this transfer rate has been calculated, can be used in turn to calculate the amount of desiccant needed for compartment (B). As an example, to function effectively in pharmaceutical applications, the relative humidity in the container A is preferably kept below about 50% RH, more preferably below 30% RH, while the RH in the compartment (C) it is preferably 40-70%, more preferably 50-60%. Therefore, the moisture transfer rate from the test system (from 75% RH to 10% RH) can be corrected to take into account the relative humidity in the product as expected (from 60% RH to 30% RH) by dividing the value by (75 -15) / (60 - 30) = 2 where 75 is the HR (in%) of the test environment 15 is the HR maintained by the desiccant 60 is the minimum RH desired to operate the oxygen absorber 30 is the desired RH of the air chamber. Figure 3 shows the rate of oxygen transfer through similar tubes in an iron oxygen absorber. In this case, the oxygen reduction of an oxygen volume fixed for the measurement was used. Again the oxygen transfer rate was controlled as a function of the tube size. The desired rate of oxygen uptake and, therefore, the diameter of a hole or tube needs to take into account the fact that the oxygen scavenger will need to handle oxygen permeation in the pharmaceutical container and maintain a low oxygen level ( for example, 1%). The tube (or other orifice) must therefore have a sufficiently large hole to compensate for the difference in gradual increases in the rate of oxygen diffusion as the difference in pressure increases from that used in the test. Since this latter rate should be proportional to the pressure difference, going from 0 to 20.8% oxygen of the test to 0 to 1% oxygen in the final product, the corresponding oxygen rate found in the graph of the Figure 3 should be multiplied by 20.8. To determine the amount of oxygen entering the pharmaceutical container, a round container made of high density polyethylene (HDPE) with a marked capacity of 60 cm3 and a wall thickness of 0.94 mm (37 mm) can be used as a representative sample. mils). If the container is 4 cm in diameter and 7.3 cm in height (actually the container will be narrowed to give smaller surface area than this approximation), then the surface area will be approximately 100 cm2. If HDPE is used as the material of the container and it is assumed that the interior of the pharmaceutical container is maintained with 1% oxygen, then the oxygen permeation rate in the container can be calculated as follows: 101.6 cm / cm (m2 d atm ) (4,000 cm3 mil / (m2 d atm)) x (0.18-0.009) atm x 0.01 m2 / 0.94 mm (37 thousand) = 0.18 em3 of 02 / day Using this value and the factor of 20.8 discussed above, it can be determined that the size of the hole to meet the oxygen requirement for a 60 cm3 HDPE container (to bring the oxygen to 1%) is approximately 500 μm in diameter. With this diameter, the amount of water loss can be estimated from the graph of Figure 2 at 0.87 mg / day. Correcting this for the intended system as described above brings this value to 0.43 mg / day. In this way those skilled in the art will assess the use of data such as those exemplified in Figures 2 and 3. Using Figure 3, the size of the hole in the compartment (C) (oxygen absorber) can be calculated to effectively capture the Oxigen. Figure 2 can be used to determine the corresponding moisture loss from the compartment and the necessary amount of desiccant. The hole in the compartment (C) that controls the moisture and oxygen transfer rate ("15" in Figure 1) can be made in the following ways: (1) A single hole can be used as a hole. The hole preferably has a diameter between 100 and 700 μm; more preferably, between 200 and 600 μm. The hole can be cylindrical (round with parallel sides), conical (round with sloping sides) or rectangular. The hole can be made by any method known in the art. Especially preferred methods of making the hole include drilling through the wall of the cartridge using a mechanical, ultrasonic or laser drill, or forming the hole of the compartment in place, for example, by injection molding. A high porosity material or mesh can be used together with this hole to prevent dust from escaping from the canister cartridge. The diameter of a mesh should be smaller than the fine particles in the subunit, preferably less than about 15 μm. (2) A tube is placed through the port area. The tube preferably has an internal diameter between 100 and 700 μm; more preferably, between 200 and 600 μm. The tube is preferably sealed in the cartridge in the port area using an adhesive or by melting the adjacent wall. The length of the tube can be in the range of 1 to 25 mm. A high porosity material or mesh can be used together with this tube to prevent dust from escaping from the canister cartridge. The diameter of a mesh should be smaller than the fine particles in the subunit, preferably less than about 15 μm. (3) A microporous membrane is placed in the port area. This filter restricts the diffusion of moisture and oxygen. Preferably, the microporous membrane has a porosity between 0.05 and 0.20 and a thickness of 0.5 to 2.5 mm. The preferred diameter of the membrane is between 100 and 1,000 μm.
The active oxygen absorbent in compartment (C) is preferably iron. The iron is preferably in its reduced form (ie, FeO). The iron can be atomized, ground, powdered, electrolyzed or otherwise treated to form a fine powder as is known in the art. The amount of iron used in the present invention can be optimized based on the permeability of the pharmaceutical container "A" and the duration of storage. Using the round HDPE container described above as a representative example, the amount of oxygen that needs to be captured is approximately 66 cm3 / year. Based on an oxygen absorption capacity for iron of approximately 300 cm3 / g, the amount of iron needed in compartment (C) (Figure 1) is approximately 220 mg. To incorporate the losses, the subunit thus preferably contains between about 225 and 500 mg of iron. To allow the iron to pick up oxygen, a source of moisture must be provided. In the present invention, this source of moisture is preferably provided in the form of a slurry of a salt or sugar. The product that controls humidity should be able to control the humidity in the oxygen absorber compartment. Since the moisture loss rate of the compartment (C) is proportional to the difference in relative humidity between that of the compartment (C) and that of the same air chamber of the pharmaceutical container, it is desirable to make the relative humidity in the compartment (C) as low as possible while still providing sufficient moisture to allow oxygen uptake activity. It is therefore preferred to control the humidity in the compartment (C) between 40 and 70% RH; more preferably, between 50 and 60% RH. The slurry of salt or sugar that controls humidity may be an inorganic or organic salt or mixture of salts, a sugar or mixture of sugars, or a mixture of salts and sugars, provided that such products can control the relative humidity in the desired interval. Especially preferred products for controlling said relative humidity include sodium chloride, calcium nitrate, sodium bisulfate, sodium chlorate, potassium iodide, sodium bromide, magnesium acetate, sodium nitrate, ammonium chloride, potassium nitrate, bromide of potassium and magnesium nitrate. It is necessary that the amount of salt or sugar used be sufficient to provide the desired control of relative humidity even when some of the water is removed in the use of the present invention. For the slurry to control the relative humidity in compartment (C) during the storage period of the product, there must be enough water to handle the anticipated loss of water. Based on the size of the controller port of the "I" rate (Figure 1), this rate can be maintained at approximately 157 mg per year. In the practice of the present invention, the amount of water in the cartridge is therefore preferably between 150 and 400 mg; more preferably, between 180 and 360 mg. To control the relative humidity with all this water, the amount of salt or sugar used must be sufficient so that at least some of the solid remains undissolved. And so, the amount of salt or sugar can be determined by multiplying the amount of water added by the solubility in water of the salt or sugar. As an example, for the moisture controlling additive magnesium nitrate, this leads to a preferred amount of this additive between 225 and 450 mg, based on a solubility of 1,250 mg / mL. The present invention facilitates the removal of oxygen not only from the entrapped air within the pharmaceutical container (Figure 1) but also from the oxygen that enters the container by access. It will be appreciated that in the use of the oxygen absorbing cartridge, a unit having the appropriate absorbent capacity for the given container and desired storage period can be organized. It is also possible to organize an oxygen-absorbing unit that is standard, but for which the number of such units applied will actually depend on the design of the vessel and the storage period. It is not necessary for the oxygen absorber to remove 100% of the oxygen in the air inside the container; however, it is preferred that the absorbent be present in an amount such that it is capable of maintaining an oxygen level of less than or equal to about 10.0%, preferably less than or equal to about 3.0%, more preferably less than or equal to about 1.0%, most preferably less than or equal to about 0.5%, for about 2 years inside the oxygen permeable container.
EXAMPLESEXAMPLE 1A Flurotec® cap of Teflon 20 mm (West Pharmaceutical)Services, Jersey Shore, PA) was drilled through the center with a 1.0 mm drill bit. A 2 cm long HPLC tube (Upchurch Scientific, Oak Harbor, WA) was cut and forced through the drilled hole in the plug. The tube used included model 1520 (762 μm internal diameter), model 1532 (508 μm internal diameter), model 1531 B (254 μm internal diameter), model 1535 (127 μm internal diameter) and the Model 1560 (64 μm internal diameter), all from Upchurch Scientific (a division of Scivex Inc., Oak Harbor, WA). To measure the absorption of water vapor, a 1 gram pot of Sorb-lt® (S? D-Chemie, Belén, NM) was opened and the silica gel content was poured into a tubular optical glass vial of Type I of 10 ce (Wheaton Science Products, Syracuse, NE). The stopper with the tube was crimped into the vial and the initial weight was recorded. The test units were then placed in a stability chamber at 40 ° C / 75% RH and weighed periodically for two weeks. For the measurement of oxygen consumption, the contents of an oxygen scavenger (DSR # 4062B, 200 cc oxygen absorber from Multisorb Corp., Buffalo, NY) were opened and the contents poured into a vial (as above) , and the stopper with the tube was crimped into the vial for 3 minutes. Each test unit was placed in a 250 cc HDPE container, which was then hot sealed by induction under ambient air conditions. In this way, each system initially contained approximately 21% oxygen. The containers were stored at room temperature and RH (approximately 20 ° C and 30% RH). After two weeks, the oxygen level inside the HDPE container was measured using a Mocon PAC Check 450 (Mocon Inc., Minneapolis, MN), which was adjusted with room air (21% oxygen) and an oxygen 0.5% of Mocon Inc.
EXAMPLE 2A cartridge was made by injection molding polyethylene into two cylindrical shaped compartments of 1.3 cm diameter (0.5 inches) and diameters of the walls of approximately 1 mm. The upper compartment had a single hole 600 μm in diameter with a lattice (diameter of the apertures of 25 μm) on the side as part of the mold. The lower compartment was 0.63 cm high (0.25 inches). The upper compartment was 1.3 cm high (0.5 inches). In the lower compartment, 0.5 g of silica gel was charged. A sintered polyethylene lid (porosity of 0.1) was adhered to the lower compartment to seal in the powder. A slurry of magnesium nitrate (1.0 kg) was made with 800 g of water to give a slurry at 44% (w / w). The upper compartment was filled with a combination of 300 mg of fine iron powder (as described in U.S. Patent No. 5,725,795) and 450 mg of the slurry of magnesium nitrate. A lid was formed by injection molding polyethylene into a cylinder with a wall and an upper part having a high porosity (0.4). The lid was 1.4 cm in diameter (0.55 inches) and 0.5 cm in height (0.2 inches). The lid compartment was filled with 50 mg of self-activated iron oxygen scavenger (available from Multisorb Corp., Buffalo, NY), then the porous top adhered thereto. All this cover was then adhered to the upper compartment of the anterior cylinder. A 60 cm3 polyethylene container was charged with pharmaceutically active tablets and one of the above cartridges. The container was sealed using a hot seal by induction.