Special receptacle or package – With specified material for container or content – For content inhibitor or stabilizer
Reexamination Certificate
2002-03-15
2004-02-10
Rose, Shep K. (Department: 1614)
Special receptacle or package
With specified material for container or content
For content inhibitor or stabilizer
C206S524100, C206S524500, C206S528000, C206S540000, C424S412000, C252S188280
Reexamination Certificate
active
06688468
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to the reduction or prevention of oxidative degradation of oxygen-sensitive pharmaceutically active compounds packaged in oxygen permeable containers.
BACKGROUND
The use of oxygen absorbers in the food industry for preservation of foods is well known. However, less is known with respect to stabilization against oxidation of pharmaceuticals with oxygen absorbers. For example, Mitsubishi Gas Corporation introduced into Japan iron plus carbonate salt sachets under the trade name Ageless™ 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. In a metal oxidation reaction, water must also be present. Water provides the activation mechanism used in most applications. Sachets are generally stored dry where they can be handled without consuming oxygen. In the presence of moist foods, the sachets are activated and begin removing oxygen.
More recently, several companies have introduced self-activated oxygen absorbers to provide oxygen absorption with dry food products. These have involved combining moisture-holding additives to the metals (usually iron) in the 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 currently been realized.
Plastics containing oxygen absorbers have also become increasingly prevalent in the new packaging arena. The simplest of these is the use of “stealth absorbers” which use the same principles as above, but imbed the metal in an extrudable plastic. These are activated by moisture, generally by either being in direct contact with water or having a permeable co-extruded layer adjacent to the water. Although these systems are relatively easy to make and inexpensive, they suffer from relatively low absorption capacity and high opacity. In 1998, Cryovac and Chevron introduced ultraviolet photoinitiated oxygen absorbing plastics. In these systems, light in combination with a cobalt salt produces a radical site, which has high reactivity with oxygen. Prior to photoinitiation, the system is quite stable in air and can be extruded to provide transparent, “active packaging.” The plastics are reported to be capable of absorbing 45-78 cm
3
of oxygen per gram of plastic.
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 jars with oxygen absorbing sachets for six months at 50° C. (Japanese Patent No. SHO59-176247). The source of the oxygen being removed was primarily from the headspace and not from ingress. 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.
Oxygen induced drug degradation often limits shelf life (expiration date) or may render a drug unmarketable. In fact, drug candidates that are highly oxygen sensitive are often excluded from further development. In a number of cases, oxygen sensitivity occurs only in the presence of certain excipients. Since oxidation is often not accelerated by standard Arrhenius based increased temperature studies (i.e., accelerated aging studies), there are a number of drug candidates where the oxygen sensitivity of the drug is not recognized until drug development has progressed into late stages of development at which time a significant amount of resources has been expended. At the 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. Therefore, there is a need for a means of reducing or eliminating oxygen based drug instability without requiring a formulation change.
Even in early drug development, there is a need for oxidation prevention with a new drug candidate 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, the oxygen-sensitivity can then be preferably addressed at the earlier stage of development.
In spite of the wide use of oxygen absorbers in the food industry and more limited reports in the pharmaceutical world, there is no definite information or guidance as to the appropriateness of this technology or best practice methods for use with solid dosage form pharmaceuticals. In particular, there is no information with respect to the efficacy of oxygen absorbers in pharmaceutical packaging using a drug that has a high sensitivity to oxygen. Unlike prior reports where solid dosage forms are stored in glass, there is no reported use of oxygen absorbers with highly permeable plastic packaging for pharmaceutical applications. In addition, there is no information describing relatively low moisture conditions to minimize physical problems (e.g., tablet sticking, disintegration, or dissolution) and chemical stability issues (e.g., hydrolysis).
SUMMARY
The present invention provides a pharmaceutical kit comprising a sealed oxygen permeable container (preferably sealed with a heat-induction seal (HIS)) having deposited therein an oxygen-sensitive drug in a solid unit dosage form and at least one oxygen absorber (preferably a self-activated absorber). The oxygen absorber may be provided in a sachet, cartridge, canister (preferably a cartridge) or any other means of containing the absorber such that the absorber is physically separated from the solid dosage forms deposited in the container and has sufficient oxygen permeability to remove at least a portion of the oxygen in the air within the container. The sealed oxygen permeable container may also include a desiccant.
In a preferred embodiment, the oxygen-sensitive drug is in a high-energy drug form (e.g., amorphous form and nanoparticle sized drug form). A preferred example of a high-energy drug form is a dispersion prepared by spray-drying the drug with an enteric polymer
Definitions
As used herein, the term “unit dose” or “unit dosage” refers to physically discrete units that contain a predetermined quantity of active ingredient calculated to produce a desired therapeutic effect. A “solid unit dosage form” refers to a solid form (e.g., powder, softgels, lyophiles, suppositories, capsules or tablets intended either for ingestion, or other methods of entering the body for medical purposes either directly or by constitution with other materials including liquids) containing a unit dose of the active ingredient.
The term “drug” refers to a pharmaceutically active ingredient(s) and any pharmaceutical composition containing the pharmaceutically active ingredient(s). Pharmaceutical compositions include formulations as well as dosage forms or medicament
Benson Gregg C.
O'Gorman Carmella A.
Pfizer Inc.
Richardson Peter C.
Rose Shep K.
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