JP2008506439A - Pharmaceutical packaging container to maintain low moisture and low oxygen levels simultaneously - Google Patents

Abstract

  The present invention relates to a device for reducing the oxygen content of air surrounding a pharmaceutical dosage form contained in an oxygen permeable bottle, and also maintains a relatively low moisture level in the air during the shelf life of the product. To do. Accordingly, the pharmaceutical packaging container contains the desiccant in the first sub-container and the self-activated oxygen absorber in the second sub-container.

Description

The present invention relates to an apparatus for reducing the oxygen content of air surrounding a pharmaceutical dosage form contained within an oxygen permeable bottle, and at the same time a relatively low moisture level in the air during the product's shelf life. It is related with the said apparatus which maintains.

BACKGROUND OF THE INVENTION Oxygen-induced drug degradation is a factor that can limit the shelf life of a drug product, usually indicated by an expiration date. In the case of drugs that are very oxygen sensitive, such degradation may make the drugs unmarketable or exclude candidate compounds from development.

  In some cases, oxygen sensitivity occurs only in the presence of certain excipients. Oxidation is not frequently accelerated by increased temperature studies based on standard Arrhenius (known in the art as “accelerated life test”), so the drug's oxygen sensitivity until drug development progresses to later stages of development. May not be allowed. At later stages of such development, re-formulation and the addition of standard antioxidants can require a significant amount of time and expense. In addition, more clinical data with new formulations may be needed. That is, a need exists in the art to reduce or eliminate oxygen-based drug instabilities that do not require formulation changes.

  In drug development, often reduce or prevent oxygen-induced drug candidate compound degradation, or provide sufficient stability for early studies without investing a lot before demonstrating the idea A need may arise. If candidate compounds are selected for further development, oxygen sensitivity can then be handled by more conventional strategies.

  In addition to the oxygen sensitivity of the pharmaceutically active ingredient in the dosage form, the dosage form itself can be sensitive to moisture. This susceptibility can be a direct reaction (eg, hydrolysis), or a physical effect such as plasticization of drugs or excipients that anchor the dosage forms to each other (“twinning”), or deliquescence (in the atmosphere For these reasons, many pharmaceutical dosage forms are packaged with an added desiccant.The most common pharmaceutically acceptable desiccant has a relative humidity (RH) of 20 It is a silica adjusted to not more than%.

  The use of metal-based oxygen absorbers in the food industry for food preservation is well known. In such a system, the metal in the reduced oxidation state reacts with oxygen in the presence of water to form a metal oxide. For example, Mitsubishi Gas Corporation introduced an iron plus carbonate sachet under the trade name Ageless ™ used to stabilize packaged foods by preventing oxidation. Other iron and metal based absorbents bind to various salts, and other additional improvements are usually metals in powder form or other subdivided forms, and oxygen permeability Immediately matched all the components of the absorbent contained in the sachet. In metal oxidation reactions, water provides the activation mechanism used in most such oxygen scavenging applications. Sachets that absorb oxygen are typically stored in a dry state that can be processed without consuming oxygen.

  Recently, food industry companies have introduced self-activating oxygen absorbers to absorb oxygen in dry food products. These relate to the combination of an adduct that retains moisture in a sachet with a metal (usually iron) (see, for example, JP 56-50618 and 57-31449; and US Pat. 725,795). European Patent Applications Nos. 864630A1 and 964046A1 describe using iron iodide and iron bromide to enable oxygen absorption in a low humidity environment without the need to bring it into water; Commercial application of this technology has not been realized.

  In the pharmaceutical industry, there are several limited reports of using oxygen absorbers to stabilize drugs. For example, in 1984, anti-inflammatory tablets were stabilized with an oxygen-absorbing sachet in a large glass (ie, oxygen-impermeable) jar at 50 ° C. for 6 months (Japanese Patent Application No. 59). -176247). The source of oxygen removed was not primarily from the permeation of oxygen through the inlet, i.e. the wall of the jar, but mainly from the upper space. Similarly, Japanese Patent Application No. 8-253638 describes a cooled pharmaceutical tablet stabilized in an impermeable bottle, either by removing nitrogen in the bottle or with an oxygen absorber. In a 1990 publication, L-cysteine in ophthalmic ointments was stored with an oxygen absorber. (That is, see Kyushu Yakugakukai Kaiho, “L-Cysteine Ophthalmic Solution Stabilized with Oxgen Absorber”, 44, 37-41 (1990)). It was stabilized by using a bottle cap having an absorbent (Japanese Patent Application No. 6-17056). U.S. Pat. No. 5,839,593 describes the incorporation of an oxygen absorber into a bottle cap backing. More recently, U.S. Patent Nos. 6,093,572; 6,007,529; and 5,881,534; and PCT Publication WO9737628 uses oxygen absorbers with parenterals and sterilization. List their specific benefits for. Installation of an oxygen absorbing sachet between an intravenous (IV) bag or a blood bag and its outer packaging is commonly used for commercial applications. Also known are syringes pre-filled with absorbent between the syringe and the outer package. EP0837069A1 discloses the use of oxygen absorbers to stabilize acarbose in gas impermeable bottles.

  U.S. Patent Nos. 6,688,468B2 and EP12343524A2 disclose the use of oxygen absorbers with pharmaceutical dosage forms in permeable packaging containers. The oxygen absorbers used in these patent applications are mostly based on iron with extra moisture adjusted by the salt slurry. These systems perform well for many pharmaceutical applications, but cause the humidity in the bottle environment to be 55-75% relative humidity, which is due to the oxygen consumption reaction reducing humidity for operation. It is necessary. Although it is possible to dry the bottle environment somewhat with a desiccant, oxygen absorbers are also typically dried by the desiccant and are almost effective at removing oxygen that permeates through the bottle wall. There will be no. As a result, the oxygen level in the bottle will not remain low enough to provide beneficial stability of the pharmaceutically active ingredient over the entire shelf life.

  In all of the documents mentioned above, self-activated oxygen absorption to absorb oxygen in oxygen permeable pharmaceutical containers while simultaneously maintaining the environment in the container in a low moisture state, for example through the use of a desiccant. There is no disclosure or guidance on articles on how to use the agent. Doing so requires a combination of self-activating oxygen absorbers that require water to function with a desiccant that absorbs the water.

  Iron-based oxygen absorbers that do not increase relative humidity close to the absorption unit are commercially available for use with pharmaceuticals by the trademarked PharmaKeep® by Mitsubishi Gas Corporation and Sud-Chemie Corporation . However, these absorbents provide only limited absorption capacity (typically less than about 40 cc oxygen), but in permeable packaging containers for a typical shelf life of at least 2 years. It is not enough to give medicinal protection. Although it is theoretically possible to use many such units to provide continuous sufficient oxygen absorption for a typical bottle size of 30-250 cc, it is hypoxic during the shelf life of pharmaceuticals. It will generally not be possible to fill the dosage form with the much needed to maintain the level.

  For all the reasons indicated above, it is possible to provide enough oxygen absorption capacity in a convenient and cost-effective manner to allow the use of oxygen permeable pharmaceutical packaging containers for a shelf life of at least 2 years, There remains a need for oxygen absorbers that can maintain the relative humidity inside the packaging container at 50% or less, preferably 40% or less, more preferably 30% or less.

SUMMARY OF THE INVENTION The present invention provides a pharmaceutical packaging container comprising an oxygen permeable bottle containing at least one sub-container containing a self-activating oxygen absorber and at least one sub-container containing a desiccant. The sub-container is a separate unit or unit, that is, a self-activated oxygen absorber in one compartment and a desiccant in another compartment, referred to herein as a “cartridge”. It may be produced as a compartment which is separated from each other in a single unit. The present invention has a problem: the interior of the bottle is maintained at a low oxygen level to protect oxygen sensitive pharmaceuticals, and at the same time a low moisture level to protect water sensitive pharmaceuticals and / or dosage forms. To solve that. This double protection occurs even if the self-activating oxygen absorber requires moisture to function and the subcontainer or compartment in which it resides is exposed to the interior of the bottle.

In one aspect, the present invention provides a method of maintaining the oxygen content in the air inside a pharmaceutical bottle at a reduced level compared to the oxygen content in the air outside the bottle, the bottle comprising at least partly Made of a pharmaceutically acceptable oxygen permeable material and at the same time maintaining the internal air at a relative humidity of less than 50%, the following steps:
Installing first and second sub-containers in the bottle;
Applying the first sub-container containing the desiccant to expose the desiccant inside the bottle;
The second sub-container contains a self-activating metal-based oxygen absorber;
The adsorbent has the ability to reduce oxygen sufficient to reduce and maintain the oxygen content of the internal air at a level that is less than the oxygen level in the ambient (ie outside the bottle) air;
The second sub-container has an opening for exposing the adsorbent to the inside of the bottle, and the opening can capture oxygen by the absorbent in the bottle, and at the same time, the inside of the bottle is 50% or less. And having an area that limits the diffusion rate of water from the second sub-container such that it is maintained at RH, preferably 40% or less, more preferably 30% or less.

In a second aspect, the present invention provides a pharmaceutical packaging container comprising a bottle that maintains the oxygen content of air within the internal volume at a reduced level relative to the oxygen content of ambient air, which is described below:
A) said bottle made at least partially of an oxygen permeable material;
B) A desiccant disposed in a first sub-container disposed within the bottle,
The first sub-container is adapted to expose the desiccant to the interior of the bottle;
C) an oxygen absorbent based on a self-activating metal disposed in a second sub-container disposed inside the bottle;
The oxygen absorbent has the ability to capture enough oxygen to reduce and maintain the interior of the bottle at an oxygen level less than the oxygen level of the ambient air;
The second sub-container has an opening through which the absorbent is exposed to the inside of the bottle, and the opening has an inside of the bottle of 50% or less, preferably 40% or less, more preferably 30%. And having an area that can capture oxygen while limiting the rate of water dispersion from the second sub-vessel to be maintained at RH below.

In the best mode, the bottle is sealed and can be practiced in the absence of a seal, but is preferably sealed.
The term “bottle” is general and is intended to include any type or shape of a pharmaceutical container that is at least partially fabricated from an oxygen permeable material. A “pharmaceutical bottle” is one in which the oxygen permeable material produced is pharmaceutically acceptable. That is, a “bottle” includes a traditional square or spherical plastic bottle, jar, bag, pouch, or other pharmaceutically acceptable container.

“Relative humidity” is sometimes abbreviated herein as “RH” and has its usual meaning, ie, the ratio of actual humidity to humidity saturated at the same temperature.
“Packaging container” disclosed herein means a combination of pharmaceutical bottles, having a self-activated oxygen absorber and a desiccant disposed therein, each contained in each sub-container, The bottle is intended to be filled with many (usually predetermined) solid pharmaceutical dosage forms, typically tablets or capsules. The “inside” or “inside” of the bottle once filled with the first and second sub-containers described in (B) and (C) above, or additional sub-containers or cartridges described below and When contained, it means an empty volume, ie, an unoccupied volume. An empty volume is also meant in the art as the “head space” of such a filled bottle and is generally between 10 and 100 cc. The amount of headspace is not critical as more than one oxygen absorbing sub-container can be added to the bottle. In general, given the typical size of a pharmaceutical bottle and the rate at which oxygen permeates the known oxygen permeable plastics used to make the pharmaceutical bottle, the oxygen absorbing sub-container is 100- It is implemented to have holes (not covered) that are 700 microns, preferably 200-600 microns. This hole is generally round because it can be performed with a drill, but the shape is not critical and other shapes with equal range can also be used. In an alternative embodiment, the large holes are 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. Can be done. Suitable membranes are widely commercially available from, for example, General Electric Osmonics (GE Water Technologies, Trevose, PA) and Millipore Corporation (Billerica, Mass.). The total amount of pore area is defined as porosity x area and should be equal to the area of the hole having the area described above.

  Oxygen permeable bottles are made of materials that, when sealed or sealed, will allow sufficient oxygen to cause oxidative degradation of the active pharmaceutical ingredient contained over a reasonable shelf life The “reasonable quality retention period” is usually between 6 months and 3 years, typically 2 years. Such materials include any pharmaceutically acceptable and available plastics commonly used in the industry and further discussed and identified above. As noted above, the bottle is sealed and preferably sealed as part of the manufacturing operation when filled with the pharmaceutical dosage form and the at least two sub-containers (B) and (C) above. is there. Any oxygen permeable bottle that allows more than 0.2% oxidative degradation of the active pharmaceutical ingredient or compound contained during a reasonable shelf life can benefit from the present invention. The shape of the bottle is not important.

  The term “self-activating oxygen absorber” refers to a metal-based substance that removes oxygen by reacting with oxygen to chemically bond with oxygen, generally by forming a metal oxide. means. The term “activation” means that a metal-based material requires the presence of water (ie, as a reactant) that promotes the metal oxide formation reaction. Oxygen absorbers useful in the present invention are “self-activated”, meaning that they are sold as units containing the water needed to allow oxide formation, In the form of humidity controlling substances, typically present in an aqueous slurry of salt or sugar, such compositions are designed to maintain a specific humidity in an enclosed environment. A preferred metal is elemental iron that has been powdered to increase surface area. Other metals that are useful include nickel, tin, copper and zinc, although less preferred.

  When the bottle is sealed or sealed, the oxygen absorbent is the air in the bottle to a level that is less than or equal to the ambient air outside the bottle, such as the ambient air level in a warehouse or hold, or other storage environment or transport. To reduce the oxygen content. Thereafter, the absorbent is preferably 10.0% or less (ie, a volume ratio based on the volume of the upper space), preferably 3.0% or less, more preferably 1.0% or less, and most preferably 0.5%. Maintain oxygen in the air in the headspace at the following levels:

  Sub-containers (B) and (C) can be implemented as physically separate containers and are added to the bottles separately during the manufacturing process. In a preferred embodiment, and as disclosed further below, the sub-containers (B) and (C) are a unit of physically separated compartments (referred to herein as “cartridges”) ( A plurality). When considering such a cartridge, the compartments therein are denoted as (B), (C), etc., and have meanings corresponding to the letter symbols given above for sub-containers (B), (C), etc. . The cartridge can be conveniently fabricated from plastics (including the oxygen permeable plastics disclosed herein) by a suitable molding operation.

  Further preferred embodiments are described below and are adapted to contain in the bottle a separate amount of an oxygen absorbent based on a self-activating metal from that in a sub-container or canister compartment (C). The third sub-container or cartridge is enclosed. This third sub-container or compartment is designed to rapidly reduce or remove oxygen initially contained in the bottle headspace when the bottle is sealed or sealed for storage, transport, and / or sale. To work. Preferably, (D) is designed as a third compartment in a cartridge that also contains (B) and (C) as individual compartments therein. This third sub-container or compartment is designed to remove the oxygen initially present in the upper space, so that when the bottle is sealed or sealed, it is approximately the stoichiometric amount of oxygen initially present in the upper space. It is preferable to contain only enough metal and water to react theoretically. To facilitate oxygen removal from the headspace, the third sub-container or compartment is preferably compared to the opening provided in the sub-container or compartment (C) containing a self-activated oxygen absorber. A form of porous membrane that is permeable to allow the inflow of oxygen to capture less than 3% (v / v) in less than 3 days, preferably to less than 2% in 3 days, preferably less than 2% in 3 days And has an opening. Providing a very large porous area in the sub-container or compartment (D) results in a rapid oxygen removal and therefore, when the bottle is sealed or sealed, performs a relatively oxygen-free environment rapidly. can do. The sub-container or compartment (C) then maintains oxygen at a relatively low level.

  Hereinafter, the present invention will be described by reference to the cartridges and compartments therein, which is for convenience and ease of description, and the cartridges and compartments described below are also as separate subcontainers. It will be understood that it can be implemented equally.

The inlet opening to the compartment (B) containing the desiccant is also relatively much larger than the entrance to the bottle interior provided by the opening of the compartment (C) and is therefore open to the interior of the bottle. ing. The opening that exposes the desiccant in the compartment (B) to the upper space is preferably in the form of a membrane having a large pore area to avoid outflow of the desiccant from the compartment (B). Instead, a large number of small openings, such as drill holes, can be implemented separately instead of the membrane. By creating the entire opening surface area of the compartment (B) which is relatively much larger than the opening of the canister compartment (C), the interior of the bottle remains relatively dry (contains water) More dry than inside the compartment (C) that absorbs oxygen. However, this region may be limited to provide relative humidity in bottle A at a somewhat higher value than is typically maintained with a desiccant. This helps to minimize water loss from the compartment (C). The total area of the opening area of the sub-container (B) is typically at least 0.3 cm ² , preferably 0.3 cm ^{2 to} 0, regardless of whether the area is in the form of a hole or a porous membrane. Between ⁴ cm ² .

DETAILED DESCRIPTION FIG. 1 illustrates a preferred embodiment of the present invention designed to provide oxygen absorption with low moisture for an extended period of packaged product. In FIG. 1, “A” generally represents a pharmaceutical bottle made entirely or partially of oxygen permeable plastic. Bottle A is preferably sealed and most preferably sealed using a heat induction seal (HIS) 1 made from a metal wheel and an adhesive that produces a bond between the bottle and the wheel. The pharmaceutical dosage form 3, preferably tablets, capsules, etc. are placed in the pharmaceutical bottle A. A cartridge, generally designed as 5, is also located in the pharmaceutical bottle A and is composed of three separate compartments B, C and D for illustration purposes only, separated from each other by separating agents 7 and 9 A wall, preferably made of the same material as the rest of the canister 5, for example manufactured integrally therewith as part of the molding process. Compartment B contains a desiccant such as silica gel (not shown) and is exposed to the interior of the bottle by means of porous membrane 11 so that the relative space between compartment (B) and the headspace of the bottle Can be freely exchanged, and moist air enters bottle A and dry air remains in the compartment. The second compartment D contains a self-activated oxygen absorber present in an amount sufficient to remove oxygen in the initial upper space of bottle A. The compartment D allows relatively free access by the compartment D to the oxygen-containing air in the upper space of the bottle A that causes the capture of oxygen. The third compartment C contains sufficient self-activated iron absorbent (ie, metal and moisture) to capture oxygen that permeates through the bottle wall during the shelf life of the product. The compartment C contains an opening 15 that can be implemented in the form of a hole, tube or microporous filter. The cross-sectional area of the opening is such as to give bottle A a sufficient oxygen scavenging rate to match the oxygen transfer rate, however, this area is the total quality retention period of the pharmaceutically active ingredient, The openings are such that the rate of moisture loss from compartment C is limited so that there is adequate moisture in the compartment (ie, to allow metal oxide formation). Some moisture escapes from the compartment (C), but the rate is small compared to the moisture absorption capacity of the desiccant of subunit “D”. This is an important feature of the present invention, i.e., the cross-sectional area of the opening (s) of the compartment (C). This area, on the other hand, is large enough to efficiently capture oxygen from the inside of the bottle during product retention, thereby eliminating or reducing oxidative degradation of the pharmaceutical product. On the other hand, this region is small enough to limit the amount of moisture that escapes from the compartment (C) below what can be removed by the desiccant of the quality maintenance engine.

As described above, the opening, when implemented as a circular hole, has a diameter of 100-700 microns and corresponds to a cross-sectional area of about 0.8 × 10 ^{−4 to} 38 × 10 ⁻⁴ cm ² . The shape of the opening is not critical and other shapes with equal cross-sectional areas can be implemented equally effectively.

  FIG. 2 shows the rate of moisture trapped by desiccant silica gel as a function of opening diameter (eg, compartment (C)) through a barrier having a single tube of varying diameter (determined experimentally). Demonstrate deformation. 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 rate of moisture transfer out of a cartridge having a high humidity compartment (C) can be controlled in a predictable manner by selecting a suitable size of the opening.

  FIG. 3 shows the rate of oxygen capture by iron as a function of the cross-sectional area of the opening (ie, the tube) through a barrier having a single tube implemented therein. The data show that the oxygen capture rate, ie the compartment (C), can be controlled in a predictable manner depending on the size of the opening.

In FIG. 1, a pharmaceutical container A is a bottle or other container for dispensing pharmaceutical dosage forms. The bottle is designed to protect the dosage form from mechanical harm and to limit exposure of the dosage form contained therein to light and contamination in the environment. Glass bottles in some cases work effectively due to the low (essentially absent) permeability of glass to oxygen and moisture and are within the scope of the present invention. However, due to the risk of glass breakage and the additional cost of work, the bottles are preferably made entirely of plastic, usually entirely, and essentially all of such plastics are oxygen permeable to varying degrees. It is. Plastics suitable for use in making pharmaceutical bottles generally include plastics such as low density polyethylene (LDPE), high density polyethylene (HDPE), polypropylene (PP), polystyrene (PS) and polycarbonate (PC). . Oxygen permeability of these materials is in the range of from 3500cc mil / (m ² day atm) for PS 9500Cc up mil / (m ² day atm) for LDPE. Other suitable packaging container materials are polyester (PET, PEN), nylon, polyvinyl chloride (PVX), poly (vinylidene chloride) (PVDC), poly (tetrafluoroethylene), etc., and one or more It includes a laminate containing a layer of such material. The present invention provides, in a preferred embodiment, a cartridge that can be added to a pharmaceutical bottle and provides a significant decrease in oxygen and moisture levels, including such a decrease in permeation rate as disclosed above.

An oxygen permeable bottle is filled with a predetermined amount of oxygen sensitive drug and a cartridge according to the invention and then sealed, for example by capping or capping or sealing with a lid that is twisted closed. . When the bottle is sealed, the preferred seal is a heat induction seal (HIS). Other useful seals include adhesives such as pressure sensitive adhesives, thermal adhesives, photocured adhesives, and two-component mixture adhesives (eg, epoxy resins). Adhesion can also be performed by techniques such as ultrasonic welding that do not require an adhesive. In order to prevent any damage to the contents such as chipping or cracking of the unit dosage form, a packing material (eg cotton) may optionally be added to the bottle before sealing. HIS is commonly used in the pharmaceutical industry to seal the mouths of plastic bottles as a means to protect the dosage form from the environment and to prevent (and clarify) any contamination. The induction seal and the bottle are preferably adapted to achieve an acceptable seal. Guided seal procedures are well known to those skilled in the art. For a detailed description, see “Inductin Sealing Guidelines”, R.A. M.M. Cain (Kerr Group, Inc.), 1995; F. Zito “Unraveling the Myths and Mysteries of Induction Sealing”, J. Am . Packing Tech. , 1990.

As a result of exposure to oxygen, any pharmaceutical dosage form 3 containing an oxygen sensitive pharmaceutical compound that is susceptible to degradation can be placed in a pharmaceutical bottle. Examples of oxygen sensitive materials that are subject to decomposition upon exposure to oxygen include materials such as amines (as salts or free bases), sulfides, allyl alcohols, phenols, alcohols, aldehydes, etc. included. In addition, some basic pharmaceutically active materials or compounds, especially amines with pKa values in the range of about 1 to about 10, more specifically in the range of about 5 to about 9, often undergo oxygen degradation. And thus can benefit from the present invention, and some pharmaceutically active materials or compounds are less than or equal to about 1300 mV relative to Ag / Ag ⁺ , more preferably Ag / Ag ⁺ Having a redox potential less than or equal to about 1000 mV. Suitable pharmaceutically active compounds are atorvastatin (especially when used in amorphous form), pseudoephedrine, tiagabin, acitretin, acinretin, lescinamine, lovastatin, tretinoin, isotretinoin, simvastatin, ivermectin, verapamil Oxybutynin, hydroxyurea, selegiline, esterified estrogens, tranylcypromine, carbamazepine, ticlopidine, methyldopahydro, chlorothiazide, methyldopa, naproxen, acetominophen, erythromycin, bupropion, rifapentine, penicillamine, mexiletine, verapamil , Diltiazem, ibuprofen, cyclosporine, saquinavir, morphine, celto Including [[2-methoxy-5- (1-methyl) phenyl] methyl] -2-(diphenylmethyl) -1-azabicyclo [2.2.2] octan-3-amine - phosphorus, cetirizine, N. The present invention is particularly suitable for stabilizing high energy dosage forms against oxidation. Examples of high energy dosage forms include amorphous forms and small particle size dosage forms. A preferred example of a high energy form of the drug is by spray drying the drug as a dispersant in combination with the enteric polymers described in EP1027886A2 and EP901786A2, each incorporated herein by reference. Can be prepared. Suitable enteric polymers include those described in patent applications WO0147495A1, EP1027886A2, EP1027885A2, and US application 2002 / 0009494A1, which are incorporated herein by reference.

  The present invention can additionally stabilize the excipients in the dosage form against oxidative degradation. For example, discoloration, detrimental reactivity with the active ingredient of the drug, or degradation leading to changes in dosage form performance such as dissolution rate or degradation rate. Non-exclusive examples of excipients commonly used in pharmaceutical formulations and that can be stabilized by application of the present invention are poly (ethylene oxides), poly (ethylene glycols), and poly (oxyethylene) alkyl ethers. including.

  The present invention provides a reduction in the degree of oxidative degradation or decolorization, but such degradation or decolorization can be measured by light absorption analysis or reflectance spectroscopy and / or chromatographic analysis, in particular HPLC analysis. The present invention does not need to eliminate such degradation entirely; however, the practice of the present invention is compared to samples stored in the absence of the cartridge / oxygen absorber disclosed herein. In some cases, degradation of at least about 20%, more preferably about 50%, and most preferably about 75% is preferably reduced.

  The shape of the cartridge is not critical, but the cartridges described herein can be in a generally tubular form to facilitate high speed bottle insertion. The cartridge can be a canister, ie a tubular container having the desired number of compartments and having either or both of the end compartments that can be opened to facilitate filling. The end of the tube can be flat or circular, convex or concave as desired. Cartridges can be made as known in the art using a suitable mold and molding process, typically by injection molding using a temperature-forming polymer.

The desiccant (subcontainer or compartment B) provides a low relative humidity for the pharmaceutical packaging container. The desiccant for use in the practice of the present invention can be any available desiccant. Preferred desiccants include those commonly used in the pharmaceutical industry that have sufficient capacity to manipulate the combination of moisture transfer into the bottle and the moisture emitted by the self-activated oxygen absorber. Suitable desiccants are described in L. Dobson, J.M. Packing Technology. 1, 127-131 (1987). A preferred desiccant is silica gel. The desiccant can be supplied in the form of a sachet, cartridge, or canister.

  It is desirable to maintain the relative humidity in bottle A at a level that minimizes water loss from compartment C while still providing dosage form protection from the negative effects of humidity. For this effect, the barrier 11 can be made to limit the moisture transfer rate. This rate limitation can be achieved using a somewhat limited moisture permeable membrane (depending on material or thickness) or by a suitable selection of materials with appropriate permeability. The choice of material and surface area can be made based on experimentation and depends on the specific moisture sensitivity of the dosage form used. In general, the permeability of the barrier 11 to moisture is such that the relative strength in the bottle A is 40% or less RH, more preferably 30% or less (for reference, 30 ° C. and 75% RH). Those that are maintained (under storage conditions) are desired.

The amount of desiccant used is preferably sufficient to manipulate the transfer of moisture through the walls of the pharmaceutical bottle during storage, depending on the humidity of the external environment. For the conditions of 30 ° C. and 60% RH, the permeation rate of water through a 60 cc HDPE bottle with internal humidity kept at RH of 40% or less is estimated to be about 0.25 mg / day (91 mg / year) Is done. In addition, it is preferred that there be enough desiccant to handle water loss from the oxygen absorber (estimated to be about 146 mg / year as discussed below). Silica gel has the appropriate ability to maintain a relative humidity of less than 40% at about 0.5 mg H ₂ O / mg silica. That is, the amount of silica gel installed in the sub-container or compartment B is between 475 and 1100 mg, and the moisture and absorbent compartment (C from the external permeation during a reasonable quality retention period based on the size of the compartment opening. ) Is the amount that will absorb both the moisture that escapes internally. One skilled in the art will recognize that similar calculations can be made for different bottle materials with different water permeability, headspace volume, and different conditions of temperature and relative humidity. The cartridge compartment is constructed such that it physically separates the desiccant from direct contact of the pharmaceutical ingredients, but traps moisture from within the pharmaceutical packaging container.

  The compartment D of the cartridge contains a self-activated oxygen absorber that can rapidly remove oxygen from the upper space of the pharmaceutical bottle A. This absorbent is preferably an iron-based absorbent and may be the same material as the self-activated oxygen absorbent disposed in the absorbent compartment (C). A moisture source must be provided so that the metal can scavenge oxygen. In the present invention, the water source is preferably provided in the form of a salt or sugar slurry so that it is commercially available. The compartment D is designed to rapidly remove oxygen from the upper space inside the bottle A, so it only needs to function for a few days, ie only a relatively small amount of absorbent. I need. Thus, the desiccant in compartment B will compete for moisture and will quickly deplete moisture, but the absorbent in compartment (D) can be present at high relative humidity. Preferably, the humidity source in compartment B maintains a relative humidity (RH) of about 50% or higher; more preferably about 60% or higher; even more preferably 65% or higher. A preferred moisture source is a salt or salt mixture. Particularly preferred salts are sodium chloride, potassium chloride, and potassium sulfate. Compartment D is constructed such that it physically separates the self-activated oxygen absorber from direct contact with the pharmaceutical dosage form, but traps oxygen from within the pharmaceutical packaging container. A preferred compartment (D) contains a sachet, where the containment bag is made from a porous (eg woven) material. Alternatively, the cartridge compartment (D) can itself be porous, for example by having an open cross section covered with a porous fabric or membrane.

  The amount of oxygen in the upper space of bottle A can be determined by measuring the volume of the bottle, subtracting the volume of the dosage form, and dividing the remaining volume by 5 (to account for the amount of oxygen present). it can. For example, an approximately 60 cc bottle half filled with a dosage form will have a headspace volume of approximately 6 cc of oxygen. The amount of iron used to remove oxygen should be at least stoichiometrically sufficient to exclude any oxygen due to import. Since the ability to capture oxygen by iron is about 300 cc / g, the minimum amount of iron required to remove oxygen in the headspace of a 60 cc bottle is 20 mg. Therefore, the amount of iron for this subunit is preferably between 20 and 100 mg.

  Chamber C keeps the oxygen level in the pharmaceutical bottle low during the reasonable shelf life of the product by balancing the rate of oxygen transfer into the bottle with a comparable rate of capturing oxygen. It contains enough oxygen absorber so that it can. At the same time, the rate of water loss from compartment C is low enough so that the overall moisture level of bottle A remains low due to the desiccant and within the subunits for iron activation during the shelf life Sufficient water in the subunit remains to provide the required relative humidity. It has been determined that these contradictory objectives can be met using an oxygen absorber and moisture regulating element placed in a low permeability cartridge compartment in combination with a speed regulating port (15 in FIG. 1). Yes. Preferentially, the cartridge is made from plastic and metal materials that are considered safe for contact with pharmaceutical ingredients. Examples of preferred materials include plastics such as polyethylene (PE), polystyrene (PS) and polyvinyl chloride (PVC). The cartridge is made from a permeable plastic, but the actual amount of oxygen and moisture that travels through these materials (as opposed to holes or membranes) is low due to the low surface area, which reduces the oxygen and moisture levels in bottle A. Does not significantly affect. The rate control port has the property of limiting moisture transfer while allowing sufficient oxygen transfer.

  FIG. 2 shows the rate of moisture transfer from a test environment adjusted to 75% RH at 40 ° C. to a sub-container with a fixed amount of silica gel, the sub-container having one opening, In it is implemented as a tube, as the only inlet for moisture from its environment. The amount of water transferred through the tube was monitored as a function of time and tube diameter. These data provide the basis for calculating the rate of moisture transfer from the self-activated oxygen absorbent compartment (C) to the upper space of bottle A. Once this speed of movement is calculated, it can in turn be used to calculate the amount of desiccant needed for compartment (B).

As an example, in order to function effectively for pharmaceutical applications, the relative humidity of bottle A is maintained at about 50% or less RH, more preferably 30% or less, while the RH of the compartment (C) is Preferably it is 40-70%, More preferably, it is 50-60%. Thus, the moisture transfer rate from the test system (75% RH to 10% RH) gives a value of (75-15) / (60-30) = 2.
{Where,
75 is the RH (%) of the test environment,
15 is RH maintained by the desiccant,
60 is the minimum desired RH for a functioning oxygen absorber;
30 is the desired RH of the upper space}
Can be corrected to take into account the assumed relative humidity in the product (60% RH to 30% RH).

  FIG. 3 shows the rate of oxygen transfer through a similar tube to the iron oxygen absorber. In this case, oxygen depletion of a fixed oxygen volume was used for the measurement. Again, the oxygen transfer rate was monitored as a function of tube size. The desired rate of oxygen scavenging, and therefore the hole or tube diameter, allows the oxygen scavenger to manipulate oxygen permeation into the pharmaceutical packaging container and maintain a low oxygen level (eg, 1%). It is necessary to take into account the fact that it will be necessary. As the pressure differential increases from that used in the test, the tube (or other opening) must therefore have a sufficiently large hole to compete for incremental differences in oxygen diffusion rates. Since this latter rate should be proportional to the pressure difference that lasts from 0-20.8% oxygen in the test to 0-1% oxygen in the final product, the corresponding oxygen rate seen from the graph of FIG. You should multiply by 8.

A round bottom flask made of high density polyethylene (HDPE) with a nominal volume of 60 cm ³ and a wall thickness of 37 mil (0.94 mm) is typically used to determine the amount of oxygen entering the pharmaceutical packaging container. Can be used as a simple sample. If the bottle is 4 cm in diameter and 7.3 cm high (actually it will taper to give a surface area less than this approximation), the surface area will be about 100 cm ² . . Using HDPE as the bottle material and assuming the interior of the pharmaceutical packaging container to be maintained at 1% oxygen, the rate of oxygen permeation into the bottle is:
^{4000cm 3 mil / (m 2 d} atm) × (0.18-0.009) atm × 0.01m 2 / 37mil = 0.18cm of O ₂ ³ / day can be calculated as.

Using the 20.8 value and factors discussed above, the hole size meeting the oxygen requirement for a 60 cm ³ HDPE bottle (to bring oxygen up to 1%) was determined to be about 500 μm in diameter. can do.

With this diameter, the amount of water lost can be estimated as 0.87 mg / day from the graph of FIG. By correcting for the system envisaged as described above, this value is 0.43 mg / day.
That is, the use of data as illustrated in FIGS. 2 and 3 will be appreciated by those skilled in the art. 3 can be used to calculate the size of the opening in the compartment (C) that efficiently captures oxygen (oxygen absorber). FIG. 2 can be used to determine the corresponding water loss from the compartment and the amount of desiccant required.

The opening (“15” in FIG. 1) of the compartment (C) for adjusting the moving speed of moisture and oxygen can be produced by the following method:
(1) One hole can be used as an opening. The holes preferably have a diameter between 100 and 700 μm; more preferably between 200 and 600 μm. The holes can be cylindrical (circles with parallel sides), conical (circles with inclined sides), or rectangular. The holes can be made by any technique known in the art. A particularly preferred method for forming the hole is to drill a hole through the cartridge using a mechanical, ultrasonic or laser drill, or to form a compartment hole in place, for example by injection molding. Including. A very porous material or mesh can be used in conjunction with this hole to prevent the escape of powder from the canister cartridge. The mesh diameter should be smaller than the fine particles in the subunit, preferably less than about 15 μm.

(2) The tube is installed through the port area. The tube preferably has an inner diameter of between 100 and 700 μm; more preferably between 200 and 600 μm. The tube is preferably sealed to the cartridge at the port area using an adhesive or by melting adjacent walls. The length of the tube can range from 1 to 25 mm. A very porous material or mesh can be used in conjunction with this tube to prevent the escape of powder from the canister cartridge. The mesh diameter should be smaller than the fine particles in the subunits, preferably less than about 15 μm.

(3) The microporous membrane is placed in the port area. This filter limits 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. A preferred membrane diameter is between 100 and 1000 μm.

The active oxygen absorbent in the compartment (C) is preferably iron. Iron is preferably in the reduced form (ie Fe ⁰ ). Iron can be subdivided, pulverized, ground, electrolyzed, or otherwise processed 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 and shelf life of the pharmaceutical packaging container “A”. As a representative example, using the round HDPR bottle described above, the amount of oxygen required to be captured is about 66 cm ³ / year. Based on the oxygen absorption capacity for about 300 cm ³ / g of iron, the amount of iron required in compartment (C) (FIG. 1) is about 220 mg. To incorporate for loss, therefore, the subunit preferably contains between about 225-500 mg of iron.

  A moisture source must be provided so that the iron can capture oxygen. In the present invention, this water supply source is preferably provided in the form of a salt or sugar slurry. The moisture regulating material should be able to regulate the moisture content of the oxygen absorber compartment. Since the rate of water loss from the compartment (C) is proportional to the difference in relative humidity between the compartment (C) and the top space of the pharmaceutical bottle itself, provide enough moisture to allow oxygen scavenging activity It is desirable to create the lowest relative humidity of the compartment (C) as much as possible. Therefore, it is preferred to adjust the humidity of the compartment (C) to between 40 and 70% RH; more preferably between 50 and 60% RH. The salt or sugar slurry that regulates humidity can be an inorganic or organic salt or salt mixture, sugar or sugar mixture, or a mixture of salt and sugar, provided that such materials have a relative humidity to the desired range. It must be adjustable. Particularly preferred materials for adjusting the relative humidity include sodium chloride, calcium nitrate, sodium hydrogen sulfate, sodium chlorate, potassium iodide, sodium bromide, magnesium acetate, sodium nitrate, ammonium chloride, potassium nitrate, potassium bromide. And magnesium nitrate. Even though some water is removed with the use of the present invention, the amount of salt or sugar used should be sufficient to provide the desired adjustment of relative humidity.

  Sufficient water must be present to handle the expected water loss for the slurry that adjusts the relative humidity of the compartment (C) during the shelf life of the product. Based on the size of the speed adjustment port “I” (FIG. 1), this speed can be kept at about 157 mg / year. In the practice of the present invention, the amount of water in the cartridge is therefore between 150 and 400 mg; more preferably between 180 and 360 mg.

  In order to adjust the relative humidity with this much moisture, the amount of salt or sugar used must be sufficient so that at least some solids remain undissolved. For example, the amount of salt or sugar can be determined by multiplying the amount of added water by the solubility of salt or sugar water. As an example, for additional magnesium nitrate that regulates humidity, this leads to a preferred amount of this adduct between 225 and 450 mg based on a solubility of 1250 mg / mL.

  The present invention provides for removal of oxygen entering the bottle through transfer as well as from air trapped within the pharmaceutical bottle (FIG. 1). It will be appreciated that in the use of an oxygen absorbing cartridge, it is possible to produce a unit having the appropriate absorption capacity for a given bottle and the desired quality retention period. Standard oxygen absorption units can also be made, but the number of such units actually applied will depend on the bottle design and shelf life.

  The oxygen absorbent need not remove 100% oxygen from the bottle's internal air; however, the absorbent is less than or equal to about 10.0% in the oxygen permeable bottle, preferably about 3.0. % Or less, more preferably less than or equal to about 1.0%, most preferably less than or equal to about 0.5% or equal to an amount that can be maintained for about 2 years. preferable.

Example
Example 1
A 20 mm Flurotec® Teflon® stopper (West Pharmaceutical Services, Jersey Shore, Pa.) Was drilled through the center with a 1.0 mm drill bit. An HPLC tube (Upchurch Scientific, Oak Harbor, WA) was cut to a length of 2 cm and pushed through a drill hole in the stopper. The tubes used include model 1520 (inner diameter 762 μm), model 1532 (inner diameter 508 μm), model 1531B (inner diameter 254 μm), model 1535 (inner diameter 127 μm), and model 1560 (inner diameter 64 μm), all Upchurch Scientific (Sciex Inc. From Oak Harbor WA).

  For measurements for water vapor uptake, a 1 gram Sorb-It® canister (Sud-Chemie, Belen, NM) is cut open and the silica gel contents are opened in a 10 cc tubular flint type I glass vial (Wheaton Science). Products, Syracuse, NE). A stopper with a tube was crimped onto the vial and sealed, and the initial weight was recorded. The test unit was then placed in a stable chamber at 40 ° C./75% RH and weighed periodically over 2 weeks.

  For the measurement of oxygen consumption, the contents of an oxygen scavenger (Multisorb Corb., Baffalo, NY DSR # 4062B, 200 cc oxygen absorber) are cut open, the contents are injected into a vial (as above), and Within 3 minutes a stopper with a tube was crimped onto the vial and sealed. Each test unit was installed in a 250 cc HDPE bottle and then heat induction sealed under ambient air conditions. That is, each system initially contained about 21% oxygen. The bottle was stored at ambient temperature and RH (about 20 ° C. and 30% RH). At the end of 2 weeks, the oxygen level inside the HDPE bottle was measured using a Mocon PAC Check 450 (Mocon Inc., Minneapolis, Minn.) And ambient air (21% oxygen) and Mocon Inc. Of 0.5% oxygen standard.

Example 2
A cartridge can be made of cast polyethylene in two compartments having a cylindrical shape with a diameter of 0.5 inch (1.3 cm) and a wall diameter of about 1 mm. The upper compartment has one 600 μm diameter hole with a grid window (25 μm opening diameter) on the side as part of the mold. The lower compartment is 0.25 inches (0.63 cm) in height. The upper compartment is 0.5 inches (1.3 cm) high. Fill the lower compartment with 0.5 g of silica gel. A sintered polyethylene cup (porosity of 0.1) is adhered to the lower compartment for sealing with powder. Magnesium nitrate (1.0 kg) was slurried with 800 g of water to give a 44% (w: w) slurry. The upper compartment is filled with a combination of 300 mg fine iron powder (described in US Pat. No. 5,725,795) and 450 mg magnesium nitrate slurry. A cup is formed by injection-molded polyethylene in a cylinder with high porosity (0.4) walls and a top. The cup is 0.55 inches (1.4 cm) in diameter and 0.2 inches (0.5 cm) high. The cup compartment is filled with 50 mg of self-activated iron oxygen absorber (available from Multisorb Corp., Buffalo, NY) and the porous top is adhered to it. The entire cup is then adhered to the upper compartment of the cylinder. A 60 cm ³ polyethylene bottle is loaded with a pharmaceutically active tablet and one of the cartridges described above. Seal the bottle using a heat induction seal.

FIG. 1 is a front view of a bottle having a cartridge disposed therein in a preferred embodiment of the present invention. FIG. 2 is a graph illustrating the rate of water removal by the desiccant as a function of the opening size of the compartment (B). FIG. 3 is a graph illustrating the oxygen consumption rate by the self-activated oxygen absorber based on iron in the compartment (C) as a function of the opening size.

Claims (14)

A pharmaceutical packaging container comprising a bottle that maintains the oxygen content in the air in the internal volume at a reduced level compared to the oxygen content in the ambient air, comprising:
A) said bottle;
B) A desiccant disposed in a first sub-container disposed within the bottle,
Wherein the first sub-container is adapted to expose the desiccant to the interior of the bottle;
C) an oxygen absorber based on a self-activating metal disposed in a second sub-container disposed inside the bottle;
Wherein the absorbent has the ability to reduce oxygen sufficient to reduce and maintain the interior of the container at an oxygen level less than the oxygen level in the ambient air;
The second sub-container has an opening that exposes the absorbent to the interior of the bottle, the opening from the second sub-container so that the interior of the container is maintained at a relative humidity of less than 50%. The pharmaceutical packaging container comprising an area capable of capturing oxygen while limiting a diffusion rate of water.   The packaging container according to claim 1, wherein the metal used in the oxygen absorbent is selected from iron, tin, nickel, copper, and zinc. The packaging container of Claim 1 or 2 whose cross-sectional area of the said opening part is between 0.8-38 * 10 < ^-4 > cm < ² >.   The packaging container according to claim 1, wherein the opening is a hole having a diameter of 100 to 700 μM. The bottle, the oxygen permeability of the bottle is made from 3500cc mil / (m ² day atm) ~9500cc mil / polymerizable plastic with ⁽² days atm m) a is such a thickness, claim 1 5. The packaging container according to any one of 4 above.   The packaging container according to any one of claims 1 to 5, wherein the sub container is physically separated.   A packaging container according to any one of the preceding claims, wherein the sub-container is formed as a physically separated compartment (s) of an integral cartridge.   A third sub-container (D) adapted to contain a certain amount of self-activating metal-based oxygen absorbent separated from the absorbent contained in the sub-container (C) is contained in the bottle. Furthermore, the packaging container of any one of Claims 1-7 containing.   The packaging container according to claim 8, wherein the sub container (D) is physically separated from the sub containers (B) and (C).   10. Packaging container according to claim 8 or 9, wherein the sub-container (D) is designed as a compartment in a cartridge which also contains sub-containers (B) and (C) as individual compartments.   11. A packaging container according to any one of the preceding claims, wherein the bottle is made of a pharmaceutically acceptable polymer at least in part.   The packaging container according to any one of claims 1 to 11, wherein the desiccant is silica gel.   The packaging container according to any one of claims 1 to 12, wherein a metal used in the oxygen absorbent is iron.   The packaging container according to any one of claims 1 to 13, wherein the opening of the second sub-container is a hole having a diameter of 200 to 600 µM.

Images