US20060186005A1

US20060186005A1 - Terminally sterilizing pharmaceutical package

Info

Publication number: US20060186005A1
Application number: US11/358,188
Authority: US
Inventors: Sina Ebnesajjad; Ann Hriciga; Paul Brothers
Original assignee: Individual
Current assignee: EIDP Inc
Priority date: 2005-02-24
Filing date: 2006-02-21
Publication date: 2006-08-24

Abstract

The present invention relates to a terminally sterilized package containing a liquid pharmaceutical, and comprising a receptacle having an opening therein for receiving the pharmaceutical and a closure adhered to the opening, wherein at least the interior surface of the receptacle is made of perfluoropolymer.

Description

BACKGROUND OF THE INVENTION

1. Field of the Invention
This invention relates to pharmaceutical packaging, and more particularly to such packaging that is sterilized while containing the pharmaceutical in liquid form
2. Description of Related Art
WO 01/02885 A1 discloses a single-dose package for a liquid pharmaceutical that can be terminally sterilized, i.e. the sterilization takes place with the pharmaceutical residing in the sealed package in accordance with the European Pharmacopeia, 3^rded., p. 283 (1997) and EU Regulation (Committee of Proprietary Medicinal Products, Section 5, Manufacturing Process, Note for Guidance. Sterilization is carried out by autoclaving the package, i.e. contacting it with steam at a temperature of 121° C. (250° F.) for 20 min. Terminal sterilization, as compared to separate sterilizations of the pharmaceutical and the package, is disclosed to give the highest level of sterility assurance. The package in this publication is disclosed to be polypropylene; this package is described in terms of being dimensionally stable during the sterilization.
Typically, small amounts of pharmaceutical are present in a package such as described in '2885. For example, U.S. Pat. No. 6,468,548 B1 discloses an ophthalmic pharmaceutical composition in which the active ingredient, dexamethasone or ketotifin salt, is present in a concentration preferably of 0.001 to 0.1 wt %, along with excipients and additives, such as carrier, solubilizer, tonicity agent, preservative, buffer, and water. To the extent that a package absorbs the liquid pharmaceutical during terminal sterilization, the absorbed pharmaceutical is not available to provide therapeutic effect when the contents of the package are delivered to the person, such as to the eye of a person. Only a small amount of absorption can substantially reduce the amount of pharmaceutical available for medicinal effect.
C. C. C. S Karlgard et al. “In vitro uptake and release studies of ocular pharmaceutical agents by silicon-containing and p-HEMA hydrogel contact lens materials”, International Journal of Pharmaceutics, 257 (2003) pp. 141-151, discloses uptake and release of several ophthalmic liquid pharmaceuticals by soft contact lens for the purpose of delivery of the pharmaceutical to the eye of a person.
WO 2004/060099 discloses the terminal sterilization of soft contact lens in a package, but no pharmaceutical is present, i.e. no medicine is present for the purpose of providing therapeutic benefit to the wearer of the lens. In this patent publication, an additive is added to the package material of construction to prevent the contact lens from sticking, adhering, or adhesion (anti-stick additive) to the package during the hydration of the lens. This publication discloses suitable materials of construction for the package as being polypropylene, polyethylene, nylon, olefin-copolymers, acrylics, rubbers, urethanes, polycarbonates or fluorocarbons, all used in combination with an additive to prevent the aforesaid sticking (adhesion). The preferred materials of construction of the package are disclosed to be polymers and co-polymers made of polypropylene, polyethylene. The package also contains a liquid medium, preferring an aqueous solution such as saline solution, containing physiological buffer for the purpose of protecting the lens. U.S. Pat. No. 4,691,820 discloses the preference for polypropylene over polyethylene for heat sterilizability.
If a pharmaceutical were added to the polypropylene package of '60099 along with the soft contact lens and subjected to terminal sterilization as proposed in '2885, undesirable absorption could result. The absorption of the pharmaceutical by the polypropylene packaging arises from conditions created by the sterilization process. The effect of heating to at least 121° C. to provide the sterilization effect causes the polymer to expand, opening up the molecular structure of the polymer. It is this expansion that creates vacancies (micropores) in the polymer molecular structure that leads to the absorption of the liquid pharmaceutical. In addition, since the package is sealed during sterilization, the increase in internal pressure within the package caused by the heating tends to drive the liquid pharmaceutical into the surface of the polymer forming the package.
Title 21—Foods and Drugs, of the U.S. Code, and in particular 21 CFR 211.94(a) states the following: “Drug product containers and closures shall not be reactive, additive, or absorptive [emphasis supplied] so as to alter the safety, identity, strength, quality, or purity of the drug beyond the official or established requirements.” Strict observance of this Section requires the packaging to be non-absorbent.
Secundum Artem, Packaging, Storage and Distribution of Compounded Pharmaceuticals, published on the website www.paddocklabs.com in May, 1999, discloses the problem of the loss of a drug (pharmaceutical) by sorbing onto and into the plastic packaging material, and discloses the solution to this problem by pre-adding a substance such as serum albumin to the package, followed by addition of the drug. The disadvantage of this solution is the potential undesirability of having the pre-added substance present with the drug, e.g. toxicity or other harmful effect, and the tendency of this absorption blocking effect being nullified in the sterilization process.
There remains a need for terminally sterilized packaging for a pharmaceutical that does not absorb the pharmaceutical.

BRIEF SUMMARY OF THE INVENTION

The present invention satisfies this need by providing packaging that is non-absorptive with respect to the liquid pharmaceutical during terminal sterilization. In one embodiment, the present invention can be defined as a terminally sterilized package defining a container for liquid pharmaceutical and containing said pharmaceutical, the container comprising a receptacle having an opening for receiving the pharmaceutical and a closure for the opening, at least the interior surface of the receptacle being made essentially of perfluoropolymer. Because the surface area of the interior surface of the receptacle is much greater than the interior surface of the closure, rendering the interior surface of the receptacle non-absorbent, provides most of the benefit of the present invention. In the preferred embodiment, the interior surface of the closure is also essentially of perfluoropolymer. Thus, in this embodiment, the interior surface of the container is essentially of perfluoropolymer.
The use of essentially perfluoropolymer to contain liquid pharmaceutical during sterilization is a new application for essentially perfluoropolymer. Just as polypropylene expands to become absorbent for the liquid pharmaceutical during sterilization, essentially perfluoropolymer also expands when subjected to heating, but surprisingly does not absorb the liquid pharmaceutical. One aspect of this surprise is the fact that essentially perfluoropolymer expands at least as much and even more than polypropylene. The linear thermal expansion of polypropylene, whether homopolymer or copolymer, is 10×10⁻⁵mm/mm/° C. (C. Maier and Teresa Calafut, Polypropylene, The Definitive User's Guide and Databook published by Plastics Design Library 1998, p. 121), as compared to at least 17×10⁻⁵mm/mm/° C. for the most common melt-fabricable perfluoropolymers (DuPont product handbooks—Teflon® FEP fluoropolymer resin, publication number 220338D January 1998, and Teflon® PFA Fluorocarbon Resins, publication 234398C, June, 1995).
Another aspect of the present invention is the process for terminally sterilizing a liquid pharmaceutical while minimizing therapeutic loss thereof, comprising providing a container for said liquid pharmaceutical, said container comprising a receptacle having an opening for receiving said liquid pharmaceutical and a closure for said opening, adding said liquid pharmaceutical to said receptacle, applying said closure to said opening thereby forming said package, and sterilizing said package and thereby said liquid pharmaceutical within said package, at least the interior surface of said receptacle being made essentially of perfluoropolymer, whereby said liquid pharmaceutical is not absorbed by receptacle during said sterilization.

DETAILED DESCRIPTION OF THE INVENTION

The perfluoropolymers used to define the container of the liquid pharmaceutical in the package of the present invention are modified polytetrafluoroethylene (PTFE) and the melt-fabricable perfluoropolymers. As indicated by the prefix “per”, the monovalent atoms bonded to the carbon atoms making up the polymer chain are all fluorine atoms. Other atoms may be present in the polymer end groups, i.e. the groups that terminate the polymer chain.
“Essentially of perfluoropolymer” and “essentially perfluoropolymer” means that the perfluoropolymer can contain up to about 1 wt % hydrogen. This hydrogen, if present, is substituted directly or indirectly on the carbon atoms making up the polymer chain. The hydrogen substituent, if present, will typically be present as the repeat unit —CH₂— or —CH₂—CH₂— in the polymer chain or as the substituent —CH₃on a chain carbon atom. If hydrogen is present in the perfluoropolymer, preferably its amount present is no greater than about 0.5 wt % based on the weight of the essentially perfluoropolymer (perfluoropolymer plus hydrogen contained therein). The presence of a small amount of hydrogen in the perfluoropolymer does not detract from its non-absorbency with respect to the pharmaceutical enclosed within the receptacle of the essentially perfluoropolymer. For simplicity, the expressions “essentially of perfluoropolymer” and “essentially perfluoropolymer” and the like as used herein refers both to the perfluoropolymer, i.e. not containing any hydrogen, and to the perfluoropolymer that does contain the small amount of hydrogen.
Melt-fabricable means that the polymer is sufficiently flowable in the molten state that they can be fabricated by melt processing such as extrusion or injection molding to produce products having sufficient strength so as to be useful. The essentially perfluoropolymer does not contain any anti-stick additive, i.e. the perfluoropolymer is free of any additive that increases the anti-stick attribute of the perfluoropolymer itself.
With respect to modified PTFE, this will be described by first referring to the unmodified PTFE, namely polytetrafluoroethylene (PTFE) homopolymer. PTFE homopolymer is not flowable in the molten state, so that it cannot be melt-fabricated. It typically has a melt viscosity of greater than 10⁹Pa·s at 380° C. (melt creep as described in U.S. Pat. No. 3,819,594). Instead, articles molded from the homopolymer are solidified by sintering at a temperature above the melting point. While the sintered article has integrity, it is difficult to carry out the sintering process so that the molded article is free of micropores. Thus, the container of PTFE homopolymer would tend to be absorptive of liquid pharmaceutical. Modified PTFE, however, can be used to make the container of the package of the present invention and provide a non-absorptive surface facing the liquid pharmaceutical in the container. Modified PTFE is a copolymer of tetrafluoroethylene with a small amount, e.g. less than 0.5 mol % of modifying perfluoro-comonomer, which while improving the flowability of the polymer particles in the sintering process such that they can sinter to a pore free-article, nevertheless has such a high melt viscosity, like that of the homopolymer (melt creep greater than 10⁹Pa·s), that the modified PTFE cannot be melt-fabricated. Examples of modified PTFE are disclosed in U.S. Pat. No. 3,142,665 wherein hexafluoropropylene is disclosed as the modifying comonomer, and U.S. Pat. No. 3,819,594, wherein perfluoro(propyl vinyl ether) is disclosed as the modifying comonomer. The linear thermal expansion of modified PTFE is greater than 13.5×10⁻⁵mm/mm/° C.
With respect to the melt-fabricable perfluoropolymers, which may or may not include a small amount of hydrogen, the melt flow rate (MFR) of these perfluoropolymers is preferably at least about 1 g/10 min, more preferably at least about 10 g/10 min, even more preferably at least about 20 g/10 min, and most preferably, at least 26 g/10 min, as measured according to ASTM D-1238 at the temperature which is standard for the resin (see for example ASTM D 2116-91a and ASTM D 3307-93). These MFRs correspond to a melt viscosity of about 10³to 10⁴Pa·S. Examples of perfluoropolymers that can be used in the composition of the present invention include the copolymers of tetrafluoroethylene (TFE) with one or more perfluorinated polymerizable comonomers, such as perfluoroolefin having 3 to 8 carbon atoms, such as hexafluoropropylene (HFP), and/or perfluoro(alkyl vinyl ether) (PAVE) in which the linear or branched alkyl group contains 1 to 5 carbon atoms. Preferred PAVE monomers are those in which the alkyl group contains 1, 2, 3 or 4 carbon atoms, respectively known as perfluoro(methyl vinyl ether) (PMVE), perfluoro(ethyl vinyl ether) (PEVE), perfluoro(propyl vinyl ether) (PPVE), and perfluoro(butyl vinyl ether) (PBVE). The copolymer can be made using several PAVE monomers, such as the TFE/perfluoro(methyl vinyl ether)/perfluoro(propyl vinyl ether) copolymer, sometimes called MFA by the manufacturer. The preferred perfluoropolymers are TFE/HFP copolymer in which the HFP content is about 9-17 wt %, more preferably TFE/HFP/PAVE such as PEVE or PPVE, wherein the HFP content is about 9-17 wt % and the PAVE content, preferably PEVE, is about 0.2 to 3 wt %, to total 100 wt % for the copolymer. These polymers are commonly known as FEP. Other preferred polymers are TFE/PAVE copolymers, generally known as PFA, having at least about 1 wt % PAVE, including when the PAVE is PPVE or PEVE, and typically containing about 1-15 wt % PAVE. When PAVE includes PMVE, the composition is about 0.5-13 wt % perfluoro(methyl vinyl ether) and about 0.5 to 3 wt % PPVE, the remainder to total 100 wt % being TFE, and as stated above, may be referred to as MFA.
Polytetrafluoroethylene micropowder is a low molecular weight PTFE, which because of its low molecular weight, is melt-flowable. While PTFE micropowder is melt-flowable, it is not melt-fabricable, because the article produced by melt flow and solidification (cooling) lacks strength, i.e. an extruded strand of PTFE micropowder is so brittle that it is difficult to handle without fracturing the strand. It has no practical strength. In contrast, the melt-fabricable perfluoropolymers used to make the container of the packaging of the present invention are extrudable or injection moldable or melt-fabricated by other technique to form tough, flexible strands, and with respect to article of the present invention, containers of sufficient strength to withstand normal handling.
The essentially perfluoropolymers and other polymers used in the present invention can be fabricated into the container of the package of the present invention by conventional techniques, depending on the configuration of the container and the choice of perfluoropolymer being used. The present invention is not limited to any particular configuration or design for the container. Suitable configurations are such as those depicted in U.S. Pat. Nos. 4,691,829 and 5,467,868 and in WO 01/28885 A1. Such configurations and additional configurations include bottles, jars, trays, bowls, cans, cups and bags, all with closures appropriate for the particular configuration. Examples of fabrication processes are extrusion, injection molding, and blow molding for the melt-fabricable essentially perfluoropolymers and compression molding for the modified PTFE. Either essentially perfluoropolymer or perfluoropolymer can be thermoformed from a film form into the desired shape for the container.
The container of the package of the present invention comprises a receptacle for the liquid pharmaceutical, i.e. the container has an opening through which the pharmaceutical can be added to the receptacle. The container also comprises a closure for the opening in the receptacle, such that when the liquid pharmaceutical is loaded into the receptacle and the closure is applied, the interior or inner surface of the resultant container and its contents form a closed system, which when sterilized, isolate the interior of the container from the outside environment, thereby retaining the sterilized condition. Either the entire closure or a portion thereof is removable from the opening in the receptacle to provide access to the contents of the receptacle. Alternatively, the closure may remain in place, sealing the receptacle, and the pharmaceutical contents can be removed by piercing the closure with a withdrawal mechanism, such as a hypodermic needle, after appropriate sterilization or disinfection of the closure being pierced. The package may also have additional structure beside the container such as a handle portion extending from the receptacle, which can be made of the same or different material of construction as the receptacle.
The essentially perfluoropolymer forming the receptacle can be present in laminates or non-laminates, i.e. single layer thickness or unsupported film. In the case of laminates, the essentially perfluoropolymer forms the interior surface of the receptacle, and the exterior surface comprises lamina or layer of a material designed to impart desired properties to the container. Examples of such material are non-perfluorinated polymer, such as polypropylene, polyamide, or polyester to strengthen the receptacle, in case a thin layer of essentially perfluoropolymer is desired for the interior surface. These lamina can be adhered together using an adhesive, such as polyurethanes and epoxy resins, as disclosed in Petrie, E. M. Chapter 10, Plastics and Elastomers as Adhesives, Handbook of Plastics and Elastomers, C. A. Harper, ed, McGraw-Hill, NY (1975). Additional adhesives are disclosed in A. H. Landrock, Adhesives Technology Handbook, Noyes Publications (1985), such as nitrile phenolics (p. 163), hotsetting phenolics (p. 165), polybenzimidazole (p. 166), polyimide (p. 168), and polysulfone (p. 170) Surface treatments of the essentially perfluoropolymer to enhance adhesion are well-known in the art, as disclosed in Petrie and Landrock; see for example pp. 87 and 88 of Landrock. Preferably the receptacle is made of a single layer of directly molded essentially perfluoropolymer, which has an advantage over a two-step thermoforming process and over a multilayer structure by avoiding possible adverse affects to the bond between lamina structure caused by sterilizing. The thickness of the receptacle, whether a single layer thickness or a laminate will generally be in the range of 0.1 mm to 5 mm, typically 0.25 mm to 2.5 mm, and more typically within the range of 0.5 mm to 1.5 mm, depending on the size of the receptacle and its intended use. Preferably the receptacle is transparent enough that the contents of the package can be seen through the thickness of the receptacle, so that any visual defect in the contents of the package can be observed before the package is provided to customers.
With respect to the closure for the opening in the receptacle, the closure may be mechanically engaged with the receptacle, e.g. as a screw cap, or adhered to the opening. The closure that is adhered to the opening can be an unsupported film, but typically will be a laminate (coating) of polymer facing the interior of the container and one or more additional layers imparting the desired properties to the closure, e.g. support, barrier, and or labeling layers. The polymer facing the interior of the container can be non-perfluorinated polymer, such as polypropylene, or essentially perfluoropolymer. In the case of laminated structure, the closure will typically contain a metal foil layer, such as aluminum foil. Polymer such as polypropylene is readily adherable to metal foil either through direct extrusion or through an adhesive. Essentially perfluoropolymer film can be adhered to the metal foil by surface treatment of the film, such as by exposing the film to plasma or sodium etch, and using an adhesive as described above with respect to receptacle laminates.
The thickness of the closure will depend upon its configuration. If adhered to the opening of the receptacle, the closure can have a thickness range which is the same as for the thickness of the receptacle. The closure is preferably heat sealed to the opening in the receptacle to form the closed system described above. In that case, the essentially perfluoropolymer forming the interior surface of the closure is preferably the same as the essentially perfluoropolymer forming the interior surface of the receptacle to facilitate the formation of seal between closure and receptacle that will withstand the sterilization process without loss of the seal. The heat sealing of perfluoropolymer to form a sterilization resistant seal is disclosed in U.S. Pat. No. 3,755,042. The peel away closure can be such that the entire closure peels away from the receptacle or only a portion thereof peels away, so long as the contents of the container are accessible by the user. Alternatively, the closure may include a peel strip, the pulling of which creates an opening in or removes the closure, providing access to the contents of the receptacle. The present invention also contemplates a receptacle formed by insert molding, wherein the receptacle shape is first fabricated from essentially perfluoropolymer, followed by placing this insert into an injection mold and injection molding a different polymer (non-perfluorinated polymer) such as mentioned above with respect to receptacle laminates, to form a backfilling for the essentially perfluoropolymer insert. The basic steps of insert molding are disclosed for example in U.S. Pat. No. 5,304,413. In this embodiment, the opening in the receptacle can be defined by the injection molded polymer and the same non-perfluorinated polymer can be used as the interior surface of the closure adhered to such opening. The resultant container structure comprises a receptacle of fluoropolymer, a backfill of different polymer and a closure of either fluoropolymer or the different polymer that forms the backfill. By way of example, the insert can be perfluoropolymer, the injection molded polymer can be polypropylene, and the interior surface of the closure can be polypropylene.
The volume of the container of the package of the present invention will depend on the intended purpose, including the amount of liquid pharmaceutical to be delivered upon opening of the closure. Sterility requirements would normally indicate that the entire contents be used at one time, i.e. that the container is a single dose container. Typically the volume of the container will be from 0.1 cc to 5 cc. To provide this volume, the receptacle will have a three dimensional shape to form a pocket or bowl.
With respect to the liquid pharmaceutical that is added to the receptacle prior to application of the closure to the receptacle, the pharmaceutical is that which provides a medicinal (therapeutic) effect to the user. The pharmaceutical should also be thermally stable in the sense that it should not lose efficacy during the sterilization process. The pharmaceutical is typically formulated as a composition according to the mode of administration and can be administered by any route, such as intramuscular, intraperitoneal, intradermal, and subcontaneaous injection or orally, nasally or through the eye. In cases where intramuscular injection is used, an isotonic formulation is used. In some embodiments, additives for isotonicity can include sodium chloride, dextrose, mannitol, sorbitol, and lactose. Isotonic solutions such as phosphate buffered saline may be used. Stabilizers include gelatin and albumin. The composition can include pharmaceutical acceptable carrier or diluent, depending on the mode of administration. According to the present invention, the pharmaceutical and compositional additives are present in a liquid medium, either formed from the pharmaceutical and/or added liquid. Thus, the composition can be formulated as a solution, suspension or emulsion in association with a pharmaceutically acceptable vehicle, such as water, saline, Ringer's solution, dextrose solution, and 5% human serum albumin. Liposomes and non-aqueous vehicles may be used, such as fixed oils. The vehicle may contain additives that maintain isotonicity, e.g. sodium chloride, mannitol, and chemical stability, such as buffer and preservatives. Typically, the liquid present will be water, within which or together with a solubilizing agent, the pharmaceutical is dissolved, i.e. the liquid pharmaceutical is an aqueous solution of the pharmaceutical. For example, a parenteral composition suitable for administration by injection is prepared by dissolving 1.0 wt % of the pharmaceutical (active ingredient) in 0.9 wt % sodium chloride aqueous solution. The pharmaceutical composition can also comprise known adjuvants, such as alum. When the pharmaceutical is received by the user through the eye, the pharmaceutical thus applied is either for the benefit of the eye (ophthalmic pharmaceutical) or is intended for transport to other parts of the body to apply therapeutic affect there. Stabilizer(s), such as EDTA, Dequest®, and Deferal® as disclosed in U.S. Pat. No. 6,468,548 can be present with the pharmaceutical to be applied to the eye to aid in the stability of the pharmaceutical. In one embodiment of the present invention, the container of the package can include the presence of a medical device in the receptacle along with the liquid pharmaceutical. The medical device is preferably a contact lens. More preferred, the contact lens is a soft lens, which means that it can absorb at least some quantity of the liquid pharmaceutical. In this embodiment, the volume of the container must accommodate the volume of the desired amount of pharmaceutical plus the volume occupied by the contact lens. When the lens is removed from the package and placed in the eye, it delivers the absorbed pharmaceutical to the eye. Delivery may be slow release, depending on the pharmaceutical and the characteristics of the soft lens. When an absorbent contact lens is in the container, other additives may also be present for the benefit of the contact lens, such as buffered saline solution.
Sterilization is carried out by heating the contents of the container to an elevated temperature, preferably at least 121° C. (250° F.), for a sufficient time to destroy all microbial life, such as by autoclaving. In the present invention, this sterilization is carried out terminally, i.e. after the pharmaceutical, and soft contact lens, if present, are placed in the receptacle and the receptacle is sealed by the closure.
The non-absorption of pharmaceutical by essentially perfluoropolymer is demonstrated by a test protocol under which pharmaceutical solution and essentially perfluoropolymer are in contact with one another during sterilizing conditions, followed by determining the amount of pharmaceutical remaining in the solution, for comparison with the starting amount. In greater detail, aqueous solutions of different dilute concentrations of pharmaceutical are prepared and subjected to ultraviolet analysis to establish the identifying UV absorbance wavelength and the correlation between peak height and concentration. The water used to dissolve the pharmaceutical is deionized so as to avoid introducing impurity into the solution. A pressure vessel is provided, made of 316 stainless steel, into which is placed a 1×22 cm sample of polymer sheet as the test specimen. This sheet is covered by 8-9 cc of the pharmaceutical solution, and the vessel is sealed with a screw cap. The vessel is then placed in an oil bath heated at 124° C. for one hour. The temperature within the vessel is measured by a thermocouple, which indicates that the temperature within the vessel reaches 124° C. in 17 min, whereby the sterilization process lasts for about 43 min. After sterilization and cooling, the vessel is opened and the solution is poured into a vial for UV analysis to determine the loss of pharmaceutical from the solution by virtue of absorption into the polymer sheet. The difference between the concentration of the pharmaceutical in the solution before and after sterilization is the amount absorbed by the polymer sheet, and thus the amount that would not be available to provide therapy when administered to a person from a container of the polymer. The UV analysis for the pharmaceutical may involve dilution of the solution before and after the sterilization, depending on the UV absorption characteristic of the pharmaceutical at the concentration involved.
When the film is polypropylene, more than 50 wt % of the pharmaceutical present in the solution is missing from the sterilized solution and thus has been absorbed into the sheet. About the same result is obtained when the polymer sheet is made separately of polychlorotrifluoroethylene, polyvinyl fluoride, ethylene/tetrafluoroethylene copolymer (50/50 mole % of each comonomer) and a mixture of polytetrafluoroethylene micropowder (25 wt %) with polypropylene. When the sheet is made of FEP, no absorption of the pharmaceutical is detectable. Results similar to the FEP sheet are obtained when the sheet is made of PFA or modified PTFE. While no absorption is detectable, the essentially perfluoropolymer can be considered non-absorptive relative to polypropylene when a small amount of absorption occurs, which is much less than for the polypropylene. Thus, the non-absorption condition can be considered to exist when the absorption is no greater than 10 wt %, preferably no greater than 5 wt % of the pharmaceutical in the polymer and therefore by the container of the package of the present invention.
The test protocol described above is repeated, except that the pressure vessel of stainless steel is replaced by a glass vial, to obtain the following results:

Wt % Pharmaceutical Absorbed

Test Polymer(sheet) diazepam cyproheptadine

FEP 3.42 0

Polypropylene 25.61 11.95

Claims

1. Terminally sterilized package defining a container for liquid pharmaceutical and containing said pharmaceutical, said container comprising a receptacle having an opening for receiving said pharmaceutical and a closure for said opening, at least the interior surface of said receptacle is essentially perfluoropolymer.

2. The terminally sterilized package of claim 1 wherein said container also contains water.

3. The terminally sterilized package of claim 1 wherein the interior surface of said closure is essentially perfluoropolymer.

4. The terminally sterilized package of claim 3 wherein said closure is peelable from said opening in said receptacle.

5. The terminally sterilized package of claim 1 wherein the amount of said pharmaceutical present in said container is a single dose.

6. The terminally sterilized package of claim 1 wherein said essentially perfluoropolymer is selected from the group consisting of non-melt-fabricable modified-polytetrafluoroethylene and melt-fabricable essentially perfluoropolymer.

7. The terminally sterilized package of claim 3 wherein said receptacle formed from a single layer thickness of said essentially perfluoropolymer.

8. The terminally sterilized package of claim 3 wherein said peelable closure is a laminate comprising a metal foil and a coating of said essentially perfluoropolymer adhered to said metal foil, said coating being heat sealed to said opening.

9. The terminally sterilized package of claim 8 wherein said coating of essentially perfluoropolymer is adhered to said metal foil through an adhesive.

10. The terminally sterilized package of claim 1 wherein the interior surface of said closure is a non-perfluorinated polymer.

11. The terminally sterilized package of claim 1 wherein said pharmaceutical is an ophthalmic pharmaceutical.

12. The terminally sterilized package of claim 1 wherein a medical device is also present in said container.

13. The terminally sterilized package of claim 12 wherein said medical device is an absorbent contact lens.

14. Process for terminally sterilizing a liquid pharmaceutical while minimizing therapeutic loss thereof, comprising providing a container for said liquid pharmaceutical, said container comprising a receptacle having an opening for receiving said liquid pharmaceutical and a closure for said opening, adding said liquid pharmaceutical to said receptacle, applying said closure to said opening thereby forming said package, and sterilizing said package and thereby said liquid pharmaceutical within said package, the interior surface of at least said receptacle being made of essentially perfluoropolymer, whereby said liquid pharmaceutical is not absorbed by said receptacle during said sterilization.

15. The process of claim 14 comprising further adding a medical device to said receptacle prior to applying said closure to said opening.

16. The process of claim 15 wherein said medical device is an absorbent contact lens.