| Package and device for simultaneously maintaining low moisture and low oxygen levels -> Monitor Keywords |
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Package and device for simultaneously maintaining low moisture and low oxygen levelsRelated Patent Categories: Special Receptacle Or Package, For Ampule, Capsule, Pellet, Or GranulePackage and device for simultaneously maintaining low moisture and low oxygen levels description/claimsThe Patent Description & Claims data below is from USPTO Patent Application 20070163917, Package and device for simultaneously maintaining low moisture and low oxygen levels. Brief Patent Description - Full Patent Description - Patent Application Claims
FIELD OF THE INVENTION [0001] The present invention relates to a device for reducing the oxygen content of the air surrounding pharmaceutical dosage forms contained within an oxygen-permeable bottle, while also maintaining a relatively low moisture level in said air during the shelf-life of the product. BACKGROUND OF THE INVENTION [0002] Oxygen induced drug degradation is a factor that can limit the shelf life, usually as indicated by the expiration date, of a drug product. In the case of drugs that are highly oxygen-sensitive, such degradation may render a drug unmarketable or cause a candidate to be excluded from development. [0003] In some cases, oxygen sensitivity occurs only in the presence of certain excipients. Since oxidation is often not accelerated by standard Arrhenius-based increased temperature studies (known in the art as "accelerated aging studies"), instances can occur in which the oxygen sensitivity of the drug is not recognized until drug development has progressed into late stages of development. At such later stages of development, reformulation and addition of standard antioxidants can require considerably more time and money. In addition, more clinical data may be necessary with a new formulation. Thus, a need for reducing or eliminating oxygen-based drug instability, without requiring a formulation change, has existed in the art. [0004] Often in drug development, a need may arise to reduce or prevent oxygen-induced degradation of a drug candidate or to provide adequate stability for initial studies without investing a lot of resources prior to proof of concept. Once a candidate has been selected for further development, oxygen-sensitivity can then be addressed by more traditional strategies. [0005] In addition to oxygen sensitivity of a pharmaceutically active ingredient in a dosage form, the dosage form itself can be sensitive to moisture. This sensitivity can be due to direct reaction (e.g., hydrolysis), or to physical effects such as plasticization of drug or excipients, sticking of dosage forms together ("twinning"), or to deliquescence (absorption of atmospheric moisture). For these reasons, many pharmaceutical dosage forms are packaged with added desiccants. The most common pharmaceutically acceptable desiccant is silica, which controls the relative humidity (RH) to below 20%. [0006] The use of metal-based oxygen absorbers in the food industry for preservation of foods is well known. In such systems a metal in a reduced oxidation state reacts with oxygen in the presence of water to form a metal oxide. For example, Mitsubishi Gas Corporation introduced iron-plus-carbonate salt sachets under the trade name Ageless.TM. for use in stabilizing packaged foods by preventing oxidation. Other iron and metal-based oxygen absorbers combined with various salts and other incremental improvements quickly followed suit, usually with the metal in the form of a powder or other subdivided form, and with all components of the absorber being contained within an oxygen permeable sachet. In a metal oxidation reaction, water provides the activation mechanism used in most such oxygen-scavenging applications. Oxygen-absorbing sachets are generally stored dry where they can be handled without consuming oxygen. In the presence of moist foods, the oxygen-absorber is activated and begins removing oxygen. [0007] Recently, companies in the food industry have introduced self-activated oxygen absorbers to provide oxygen absorption with dry food products. These have involved combining moisture-holding additives with the metals (usually iron) in sachets (See, e.g., Japanese Publications SHO56-50618 and SHO57-31449; and U.S. Pat. No. 5,725,795). European Patent Application Nos. 864630A1 and 964046A1 describe the use of iron iodide and bromide to allow oxygen absorption in a low humidity environment without the need to bring in water; however, commercial application of this technology has not been realized. [0008] In the pharmaceutical industry, there have been some limited reports of using oxygen absorbers to stabilize drugs. For example, in 1984, tablets of an anti-inflammatory drug were stabilized in large glass (i.e., oxygen-impermeable) jars with oxygen absorbing sachets for six months at 50.degree. C. (Japanese Patent No. SHO59-176247). The source of the oxygen being removed was primarily from the headspace and not from ingress, i.e., due to permeation of oxygen through the walls of the jar. Similarly, Japanese Patent No. SHO96-253638 describes cold remedy powders stabilized in impermeable bottles by either nitrogen purging or with oxygen absorbers in the bottle. In a 1990 publication, L-cysteine in an ophthalmic ointment was stored with an oxygen absorber. (See, i.e., Kyushu Yakugakkai Kaiho, "L-Cysteine Ophthalmic Solution Stabilized with Oxygen Absorber," 44, 37-41 (1990).) In 1995, tonic solutions of vitamin C were stabilized using a bottle cap having an oxygen absorber covered with a polyolefin (Japanese Patent No. SHO94-17056). U.S. Pat. No. 5,839,593 describes the incorporation of an oxygen-absorber into the liner of a bottle cap. More recently, U.S. Pat. Nos. 6,093,572; 6,007,529; and 5,881,534; and PCT publication WO 9737628 describe the use of oxygen absorbers with parenterals and their particular benefit for sterilization. Placement of oxygen-absorbing sachets between an intravenous (IV) bag or blood bag and its outer packaging is commonly used in commercial applications. Pre-filled syringes with absorbers between the syringes and outer packaging are also known. EP 0 837 o69 A1 discloses the use of oxygen absorbers to stabilize acarbose in gas-impermeable bottles. [0009] U.S. Pat. No. 6,688,468B2 and EP 1 243 524 A2 disclose the use of oxygen absorbers with pharmaceutical dosage forms in permeable packaging. The oxygen absorbers used in these patent applications are largely iron based with added moisture controlled by salt slurries. Although these systems perform well for many pharmaceutical applications, they cause the humidity in the bottle environment to be at 55 to 75% relative humidity, since the oxygen consumption reaction requires humidity to operate. Although it is possible to dry the bottle environment somewhat using a desiccant, the oxygen absorber will, in general, also be dried by the desiccant and be less effective at removing the oxygen permeating through the bottle walls. The result is that the oxygen level in the bottle will not remain low enough to provide for beneficial stabilization of the pharmaceutically active ingredient over its entire shelf life. [0010] In all of the aforementioned documents, there is no disclosure or guidance relating to the issue of how to use a self-activated oxygen absorber to absorb oxygen in an oxygen-permeable pharmaceutical container while simultaneously maintaining the environment in the container low in moisture, for example through the use of a dessicant. Doing so would require the combination of a self-activated oxygen absorber, which requires water to function, with a dessicant which absorbs the water. [0011] Non-iron based oxygen absorbers that do not increase the relative humidity near the absorbing unit have been marketed for use with pharmaceuticals under the registered trademark PharmaKeep.RTM. by Mitsubishi Gas Corporation and Sud-Chemie Corporation. These absorbers, however, provide only a limited absorption capacity (typically less than about 40-cc of oxygen), which is not adequate to provide for protection of pharmaceuticals in permeable packages for a typical shelf life of at least two years. Although it is possible, in theory, to use a number of such units to provide for adequate oxygen absorption on an ongoing basis, for common bottle sizes of 30-250 cc, the sheer number needed to maintain a low oxygen level during the shelf life of the pharmaceutical would generally preclude filling with dosage forms. [0012] For all of the reasons noted above, there remains a need for an oxygen absorber that is capable of providing, in a convenient and cost effective manner, adequate oxygen absorption capacity to be usable with oxygen permeable pharmaceutical packaging for at least two years of shelf life, but which also allows the relative humidity inside the packaging to be maintained below 50%, preferably less than 40%, more preferably less than 30%. SUMMARY OF THE INVENTION [0013] The present invention provides a pharmaceutical package comprising an oxygen permeable bottle containing therein at least one sub-container containing a self-activated oxygen absorber and at least one sub-container containing a desiccant. The sub-containers can be separate units or unitary, i.e., fabricated together as separate compartments within a single unit, termed herein a "cartridge", containing the self-activated oxygen absorber in one compartment and the desiccant in a separate compartment. The invention solves a problem, namely that the interior of the bottle is maintained at a low oxygen level to protect oxygen-sensitive pharmaceuticals and also at a low moisture level to protect moisture-sensitive pharmaceuticals and/or dosage forms. This dual protection occurs even though the self-activated oxygen absorber requires moisture to function and the sub-container or compartment in which it resides is exposed to the interior of the bottle. [0014] In one aspect the invention provides a method of maintaining the oxygen content of the air inside a pharmaceutical bottle at a reduced level relative to the oxygen content of the air outside the bottle, said bottle being fabricated at least in part of a pharmaceutically acceptable oxygen-permeable material, while simultaneously maintaining said inside air at a relative humidity of less than 50%, comprising the steps of: [0015] disposing, within said bottle, a first and second sub-container, [0016] said first sub-container containing a desiccant and being adapted to expose said desiccant to the interior of said bottle, [0017] said second sub-container containing a self-activated metal-based oxygen-absorber, [0018] said absorber having sufficient oxygen-reducing capacity to reduce and to maintain the oxygen content of said inside air at a level that is less than the oxygen level of the ambient (i.e., outside the bottle) air, [0019] said second sub-container having an orifice that exposes said absorber to the interior of said bottle, said orifice having dimensions that allow oxygen scavenging by said absorber inside said bottle while simultaneously limiting the diffusion rate of water from said second sub-container such that the interior of said bottle is maintained below 50% RH, preferably below 40% RH, more preferably below 30% RH. [0020] In a second aspect the invention provides a pharmaceutical package comprising a bottle 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: [0021] A) said bottle, which is fabricated at least in part of an oxygen permeable material, [0022] B) a desiccant disposed within a first sub-container disposed inside said bottle, said first sub-container being adapted to expose said dessicant to the interior of said bottle, [0023] C) a self-activated metal-based oxygen-absorber disposed within a second sub-container disposed inside said bottle, [0024] said absorber having sufficient oxygen-scavenging capacity to reduce and to maintain the interior of said bottle at an oxygen level less than the oxygen level of the ambient air, [0025] said second sub-container having an orifice that exposes said absorber to the interior of said bottle, said orifice having dimensions that allow oxygen scavenging while limiting the diffusion rate of water from said second sub-container such that the interior of said bottle is maintained below 50% RH, preferably below 40% RH, more preferably below 30% RH. [0026] In most embodiments the bottle is closed, and preferably sealed, although it is possible to implement the invention in the absence of a seal. [0027] The term "bottle" is intended to be general, and to include any type or shape of pharmaceutical container that is fabricated at least in part from an oxygen-permeable material. A "pharmaceutical bottle" is one wherein the oxygen-permeable material from which it is fabricated is pharmaceutically acceptable. Thus "bottle" includes traditional square or round plastic bottles, jars, bags, pouches, or other pharmaceutically-acceptable containers. [0028] "Relative humidity", sometimes abbreviated herein as "RH", has its usual meaning, i.e., the ratio of the actual humidity over the saturated humidity at the same temperature. [0029] The "package" disclosed herein refers to the combination of a pharmaceutical bottle having disposed therein a self-activated oxygen absorber and a desiccant, each contained in its own sub-container, the bottle being intended to be filled by a (usually pre-determined) number of solid pharmaceutical dosage forms, typically tablets or capsules. The "inside" or "interior" of the bottle refers to the free, i.e., unoccupied volume of the bottle once filled and containing the first and second sub-containers described in (B) and (C) above, or additional sub-containers or cartridges, as described below. The free volume, also referred to in the art as "headspace", of such filled bottles is generally between 10 and 100 cc. The amount of headspace is not critical since more than one oxygen-absorbing sub-container can be added to the bottle. Generally, given the typical size of a pharmaceutical bottle and the rate at which oxygen permeates known oxygen-permeable plastics used to fabricate pharmaceutical bottles, the oxygen-absorbing sub-container is implemented to have a hole (uncovered) that is 100-700 microns in diameter, preferably 200-600 microns. The hole will generally be round since it can be implemented with a drill, although shape is not critical and other shapes having an equivalent area can also be used. In an alternate embodiment a larger hole can be implemented and 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 commercially available, for example from General Electric Osmonics (a division of GE Water Technologies, Trevose, Pa.) and from Millipore Corporation, (Billerica, Mass.). The total amount of pore area, defined as the porosity times the area, should be equivalent to the area of a hole having dimensions as described above. [0030] An oxygen-permeable bottle generally refers to one made of a material that, when sealed or closed, will admit sufficient oxygen to cause oxidative degradation of the contained active pharmaceutical ingredient over a reasonable shelf life, a "reasonable shelf life" usually being between six months and three years, typically two years. Such materials include any of the pharmaceutically acceptable available plastics commonly used in the industry and further discussed and identified below. As stated above, the bottle is one that, as part of the manufacturing operation, is closed and preferably sealed once it has been filled with pharmaceutical dosage forms and the at least two sub-containers (B) and (C) described above. Any oxygen-permeable bottle that allows for oxidative degradation of more than 0.2% of the contained active pharmaceutical ingredient or compound during its reasonable shelf life can benefit from this invention. Bottle shape is not critical. [0031] The term "self-activated oxygen absorber" refers to a metal-based substance that removes oxygen by reacting with it to chemically bind it, generally by forming a metal oxide. The term "activated" means that the metal-based substance requires the presence of water (i.e., as a reactant) to drive the metallic oxide-forming reaction. The oxygen absorbers useful in the present invention are "self-activated", meaning that they are sold as a unit that contains the water needed to enable the oxide-formation, the water usually being present in the form of a humidity controlling substance, typically an aqueous slurry of a salt or a sugar, such compositions being designed to maintain a specific humidity in a closed environment. The preferred metal is elemental iron, powdered to increase its surface area. Other metals that are useful, although less preferred, include nickel, tin, copper and zinc. Continue reading about Package and device for simultaneously maintaining low moisture and low oxygen levels... Full patent description for Package and device for simultaneously maintaining low moisture and low oxygen levels Brief Patent Description - Full Patent Description - Patent Application Claims Click on the above for other options relating to this Package and device for simultaneously maintaining low moisture and low oxygen levels patent application. ###  How KEYWORD MONITOR works... a FREE service from FreshPatents1. Sign up (takes 30 seconds). 2. Fill in the keywords to be monitored. 3. Each week you receive an email with patent applications related to your keywords. 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