BACKGROUND OF THE INVENTION
The present invention relates to a transfer or storage device particularly, but not exclusively, for delivery or storage of a medicament, drug or vaccine, such as a syringe, transfer set, injection device or vial, wherein the major component of the delivery or storage device is preferably formed of a cyclic olefin polymer.
The development of cyclic olefin polymers has suggested the use of such polymers for manufacture of medical devices because medical devices formed of such polymers are transparent, exhibit excellent chemical resistance and may be sterilized by autoclaving or the like without damage. See European patent application EP 436,732A2. However, it has been found that medical devices, such as syringes, transfer devices and vials formed of cyclic olefin polymers are subject to stress cracking, particularly during or following sterilization, limiting the use of such polymers for medical devices. Stress cracking is defined as the crazing or cracking that may occur when a plastic under tensile stress is exposed to aggressive chemicals. The potential for environmental stress cracking is of major concern when plastics are used in medical devices because stress cracking may compromise the mechanical integrity of the device and contaminate the medicament, drug or vaccine transferred through or stored within the medical device.
Another problem with the use of cyclic olefin polymers for medical devices, such as storage or delivery devices, is adhesion of many polymers to cyclic olefin polymers following sterilization at elevated temperatures, such as autoclaving. For example, a syringe assembly includes a plunger having a stopper which withdraws fluid through the barrel tip when the stopper is withdrawn and drives fluid through the barrel tip when the stopper is advanced. Syringe stoppers are conventionally formed of a resilient synthetic rubber, such as bromo-butyl rubber, having an initial diameter greater than the internal diameter of the tubular syringe body, providing a good seal. However, when the syringe assembly is heated to the sterilization temperature of the cyclic olefin polymer and the bromo-butyl rubber stopper, the stopper firmly adheres to the cyclic olefin polymer syringe barrel making it difficult, if not impossible, to telescopically move the plunger through the tubular syringe barrel.
A similar problem exists with removable syringe tip caps or tip shields which firmly adhere or fuse to the syringe tip following heating to the sterilization temperature of the assembly. The tip caps and tip shields formed of certain polymers cannot be removed from the syringe following heating. It has also been found by the assignee of this patent application that this adhesion between various polymers and cyclic olefin polymeric transfer and storage devices following heating may also promote stress cracking. Thus, the use of cyclic olefin polymers for medical transfer and storage devices has been severely limited by these problems.
The sterilizable transfer or storage device and method of this invention solves these problems by selecting a polymer for the component in contact with the cyclic olefin polymer transfer or storage device which does not interact with the cyclic olefin polymer, even at elevated temperatures, thus permitting the use of cyclic olefin polymers for medical transfer and storage devices of the type described herein.
SUMMARY OF THE INVENTION
As set forth above, the present invention relates to sterilizable medical transfer or storage devices, such as syringes, transfer sets, vials, injection devices and the like, wherein a component, generally the major component, is formed of a cyclic olefin polymer and the device includes a second component formed of a second polymer in contact with the cyclic olefin component. More specifically, the present invention relates to the selection of the polymeric material for the second component which assures that the second component does not chemically interact with, dissolve or attack the cyclic olefin polymeric component or cause stress cracking, particularly at the elevated temperatures required for sterilization.
The polymers selected for the second member or component of the sterilizable transfer or storage device and method of this invention is based upon solubility parameters and cohesion properties explained by Charles Hansen in “The Three Dimensional Solubility Parameter and Solvent Diffusion Coefficient” by Charles M. Hansen, Copenhagen Danish Technical Press (1967) and the Hansen values for polymers are reported in Chapter 14 of “The CRC Handbook and Solubility Parameters and Cohesion Parameters,” Edited by Allan F. M. Barton (1999). Each material is defined by three points in 3D space and these three points are known as the Hansen Solubility Parameters (HSP). The Hansen Solubility Parameters may be defined as follows.
The Hansen solubility region consists of a point in 3D space defined by a non-polar dispersion interaction (Delta-D) axis, a polar or dipole interaction (Delta-P) axis and hydrogen bonding interaction (Delta-H) axis. From the location (Delta-D, Delta-P, Delta-H), a radius is projected to form a sphere which encompasses the region where liquids having HSP parameters within the inside of this sphere are generally the “attacking” the material in question, and liquids outside of the sphere are generally not attacking the material in question (See also “Environmental Stress Cracking In Plastics,” Hansen and Just, Pharmaceutical and Medical Packaging (1999), Vol. 9, 7.1 to 7.7, ISBN 87-89753-26-7. Hansen also noted that higher stress/temperature levels will enlarge the sphere (increase the radius) as well as the size and shape of the liquid molecules. Generally, the larger the molecule, the harder it is for the molecule to attack the material in question. Thus, as discussed further below, the molecular weights of the components are also important to prevent interaction. The assignee of this application has noted material interactions under ambient conditions, but material interaction is found more frequently at elevated temperatures, such as during autoclaving and annealing. As set forth above, however, the problems associated with material interaction between cyclic olefin polymers and the polymers conventionally used for components of medical devices has severely limited the use of cyclic olefin polymers in medical transfer and storage devices.
The distance between the HSP coordinate of polymer A to HSP coordinates of another material (liquid or Polymer B) is defined as Ra. The radius of the Polymer A sphere is defined as Ro. Ra/Ro is now defined by Hansen as the Relative Energy Distance (RED). Hansen reports that if Ra/Ro is less than 1, the two materials may stress crack or dissolve each other. If Ra/Ro is greater than or equal to 1, the materials do not have an affinity to one another under standard conditions. Ro is determined through experimentation described by Hansen, and the 3D distance, Ra, is defined by the equation:
(Ra)2=4(Delta-D 1-Delta-D 2)2+(Delta-P 1−Delta−P 2)2+(Delta-H 1−Delta-H 2)2
2=liquid (2nd solid in this disclosure) and
RED=Relative Energy Distance=Ra/Ro
Ra/Ro is inside the polymer sphere if it is less than 1
Ra/Ro is on the surface of the sphere if it is 1
Ra/Ro is outside the polymer sphere if it is greater than 1.
For Ticona Topas® cyclic olefin copolymers, the Hansen Solubility Parameters have been reported by Hansen to be:
Delta-D=18.0, Delta-P=3.0 and Delta-H=2.0 and Ro=5.0
For Ticona Topas, a cyclic olefin, which has seen cracking the Hansen Solubility Parameters have been reported by Hansen to be:
Delta-D=17.3, Delta-P=3.1 and Delta-H=2.1 and Ro=6.4.
The stress cracked Ticona resin has a bigger sphere, more easily attacked than non-stress cracked Topas material.
Thus, the larger the Hansen solubility difference between two polymers, the less likely the polymers will destructively interact. Experimentation by the applicant has shown that this difference is particularly important in the use of cyclic olefin polymers in medical devices which must be sterilized before use. As stated above, Hansen has also found that an increase in temperature will enlarge the sphere of interaction. For example, it has been found by the applicant that a syringe stopper will have a lower breakout force and a lower sustaining force when the relative energy distance Ra/Ro is increased to greater than 0.75 or most preferably equal to or greater than one; which prevents adhesion of the plunger stopper to a cyclic olefin polymer barrel and reduced stress cracking of the barrel at elevated temperatures, such as the sterilization temperature. For example, it has been found by the applicant that a bromo-butyl rubber stopper in a syringe formed of a cyclic olefin polymer has a breakloose force of approximately 4.5 kg., whereas a styrene-butadiene rubber stopper has a breakout force of only approximately 1.0 kg. The applicant has determined that the relative energy distance Ra/Ro of butyl rubber relative to a conventional cyclic olefin polymer is 0.3, whereas the relative energy distance Ra/Ro of styrene-butadiene rubber compared to the cyclic olefin polymer is about 1.0. Further, it has been found that a bromo-butyl rubber stopper in a cyclic olefin polymer syringe barrel will fuse to the barrel following autoclaving, whereas a styrene-butadiene rubber stopper in a cyclic olefin polymer syringe barrel will not be adversely affected by autoclaving. Further experimentation has shown that where the relative energy distance Ra/Ro of the polymer used for the plunger relative to a syringe barrel formed of a cyclic olefin polymer is greater than about 0.75, the plunger will not adversely adhere to the barrel or cause stress cracking of the barrel.
The sterilizable storage device of this invention thus comprises a first member, preferably a major component, such as a syringe barrel, transfer set, vial, cartridge or the like formed from a cyclic olefin polymer and a second member or component, such as a syringe stopper, tip cap or tip shield formed of a second polymer or a composite or laminate or coating wherein the interface layer is formed of the second polymer, wherein the relative energy distance Ra/Ro of the second polymer relative to the cyclic olefin polymer is greater than 0.75 or more preferably equal to or greater than one which prevents adhesion of the second component to the first component and stress cracking. A high molecular weight/molar volume of the non-cycling olefin polymer also prevents the non-cyclic olefin polymer from attacking the cyclic olefin. In the most preferred embodiment, the cyclic olefin component has a molecular weight of at least 20,000 and the non-cyclic olefin component has a molecular weight of at least 5,000 or more preferably greater than 7,500.
A preferred embodiment of this invention is a syringe barrel formed of a cyclic olefin polymer and a plunger stopper formed of a second polymer which has the requisite relative energy distance. Another preferred embodiment is a syringe barrel formed of a cyclic olefin polymer and a tip cap or tip shield formed of a second polymer, as described. As set forth above, the syringe stopper, for example, may be formed of a styrene-butadiene or a fluorocarbon polymer. However, it is believed that other polymers, polymer/compositions would be suitable for the second polymer provided the relative energy distance Ra/Ro of the second polymer relative to the cyclic olefin polymer is greater than 0.75. In the most preferred embodiment, the relative energy distance Ra/Ro of the second polymer is equal to or greater than 0.8 or most preferably greater than 1.
Thus, the most preferred method of making a sterilized syringe assembly, for example, comprises the steps of forming a syringe body from a cyclic olefin polymer, forming a plunger stopper from a second polymer, wherein the relative energy distance Ra/Ro of said second polymer relative to said cyclic olefin polymer of the syringe body is greater than 0.75. The plunger is then telescopically received in the tubular syringe barrel with the plunger stopper in contact with the syringe barrel. Finally, the syringe barrel and plunger stopper are heated to the sterilization temperature of the syringe barrel and plunger stopper. The method of making a sterilizable syringe assembly may also include forming a tip cap or tip shield from a third polymer, which may be identical to or different from the second polymer, and wherein the relative energy distance Ra/Ro of the third polymer relative to the cyclic olefin polymer is greater than 0.75 and assembling the tip cap or tip shield on the syringe body before heating.
Thus, the sterilizable transfer or storage device and method of this invention solves the problems associated with using a cyclic olefin polymer for such medical devices and permits sterilization of the assembly without stress cracking or adhesion of the components. Other advantages and meritorious features of this invention will be more fully understood from the following description of the preferred embodiments, the appended claims and the drawings, a brief description of which follows.
As described above, this invention relates to a sterilizable medical transfer or storage device for delivery or storage of a medicament, drug or vaccine, wherein a component of the device, generally the major component, is formed of a cyclic olefin polymer. As used herein, the term “cyclic olefin polymer” is intended to broadly cover the family of cyclic olefin polymers/copolymers, including bridged cyclic olefin polymers as disclosed, for example, in the patents of Nippon Zeon Co., Ltd., including U.S. Pat. No. 5,561,208 and European patent publication EP 920 989 A2. As will be understood, however, cyclic olefin polymers are available from a variety of sources including Dow Chemical Company which makes a polycyclohexylenethylene and Ticon, a division of Celanese AG (formerly Hoechst Technical Polymers), which makes a cycloolefin copolymer under the tradename “Topas”. A suitable cyclic olefin polymer for the sterilizable transfer or storage device and method of this invention is available from Nippon Zeon Co., Ltd. under the trade name Zeonex™. As set forth above, cyclic olefin polymers have characteristics and properties which strongly recommend the use of such polymers for medical applications, including excellent transparency, chemical resistance, etc. However, such use has been inhibited by chemical interaction resulting in adhesion, dissolving or fusion with other polymers typically used for components of such medical devices and stress cracking, particularly at the elevated temperatures required for sterilization, which is generally between 120 to 125 C. for about 50 minutes.