Bottles and jars – Closures – Self-sealing – piercable-type closure
Reexamination Certificate
1999-01-20
2001-06-19
Pascua, Jes F. (Department: 3727)
Bottles and jars
Closures
Self-sealing, piercable-type closure
C215S261000, C215S308000, C220S371000, C220S522000
Reexamination Certificate
active
06247604
ABSTRACT:
This invention relates to containers, particularly to containers for moisture sensitive materials particularly pharmaceutical substances.
BACKGROUND OF THE INVENTION
It is frequently necessary to store moisture sensitive materials for relatively long periods in containers. In a particular example, certain pharmaceutical substances are supplied and/or stored in small vials containing one or more unit doses of the dry substance, and having a puncturable seal through which a hypodermic needle may be inserted. By means of such a needle water may be injected into the vial, the substance dissolved in situ, and the solution then withdrawn via the needle into a syringe for short-term use before hydrolysis of the moisture sensitive material. Such puncturable seals enable this operation to be sterile. During storage the presence of atmospheric moisture within the container, or the ingress of atmospheric moisture, can cause decomposition of such materials
Often moisture sensitive pharmaceutical substances are provided in containers together with an internal desiccant in the container, for example a small sachet of molecular sieve or silica gel. Clearly this is not practical when the substance has to be made up in situ within the container as described above, as contamination by desiccant on dissolution of the substance is likely.
An example of a moisture sensitive pharmaceutical substance is clavulanic acid and its salts, such as potassium clavulanate. Potassium clavulanate is both hygroscopic and readily hydrolysed by water, so for handling and long term storage of potassium clavulanate it is necessary for the immediate environment to be kept extremely dry, e.g. 30% Relative Humidity (“RH”) or less.
Potassium clavulanate is a &bgr;-lactamase inhibitor, and is often provided in a formulation in combination with a partner &bgr; lactam antibiotic. A partner which is often used in such formulations is amoxycillin. For injectable formulations, which may be dry reconstitutable powders or oily suspensions for i.m. injection amoxycillin is used in the form of sodium amoxycillin. In some forms sodium amoxycillin is a powerful desiccant, and when contained together with potassium clavulanate in a sealed vial such forms of sodium amoxycillin can exert a dehydrating effect which helps to preserve the potassium clavulanate. Other forms of sodium amoxycillin, such as the anhydrous crystalline form disclosed in EP 0131147 B are less desiccating, and although it would be desirable to use such forms in formulations together with potassium clavulanate, the problem arises that these forms can be insufficiently desicatting to protect the potassium clavulanate.
BRIEF SUMMARY OF THE INVENTION
It is an object of this invention to provide a container having an internal desiccant which inter alia is suitable for use with moisture sensitive pharmaceutical substances and allows sterile dissolution without the problem of contamination by desiccant. Other objects and advantages of the invention will be apparent from the following description.
According to this invention, a container comprises a vessel having a mouth opening and a closure capable of sealing engagement with the mouth opening. the closure comprising a closure wall having a puncturable region therein in communication with the interior of the vessel, and having on an inwardly facing region of the closure wall a desiccant material separated from the interior of the vessel by a semi-permeable membrane which permits transmission of water vapour therethrough but is substantially impermeable to liquid water.
The term “inwardly” used herein refers to directions toward the interior of the vessel unless otherwise defined.
By means of the invention, moisture-sensitive substances within the vessel may be protected by the desiccant material, and water may be introduced into the vessel by means of a hypodermic needle puncturing the puncturable region of the closure face. The substance within the vial may then be dispersed or dissolved, whilst the membrane prevents the desiccant from contacting the introduced water, so as to dissolve the substance without any contamination by the desiccant.
The vessel may suitable comprise a vial of generally conventional construction, with a neck and a mouth opening being defined by the rim of the neck of the vial. Such a vial may be made of conventional materials such as glass, rigid plastics materials etc. The vial should be made of materials which are substantially impermeable to atmospheric water vapour, or at most allow only slow ingress of water vapour in quantities which can be absorbed by the desiccant without an undesirable degree of hydrolysis of the moisture-sensitive contents. Glass is particularly suitable as a vial material.
The closure may be made of generally conventional materials, preferably pharmaceutically acceptable materials, such as plastics materials, elastomeric materials etc., or composite materials such as metal and plastics or elastomeric materials. Preferably the closure is made of plastics or elastomeric materials which are of low moisture content, of low moisture permeability and low moisture affinity. Preferably the closure is at least partly, more preferably wholly more of an elastomeric material such as a natural or synthetic rubber, thereby allowing a tight compression fit with the mouth of the vessel. The sealing engagement of the closure with the mouth opening may be by a generally conventional construction e.g. similar to a conventional stopper. For example the closure may be engaged with the rim of the neck of a vial by a screw thread, a friction/compression fitting, or a circlip-type clamp around the neck of the vial. Such constructions are known in the art. The closure may seal the mouth in a generally conventional manner, e.g. by a compression fitting of the closure wall against the rim of the mouth, or by a sealing ring compressed between the closure face and the rim of the mouth etc.
The puncturable region of the closure wall may suitably comprise a thinned region of the closure wall, and is preferably provided in a region of elastomeric material which can resiliently seal around a hypodermic needle which is inserted therethrough, so as to facilitate sterile insertion and withdrawal. The region of elastomeric material may be of integral construction with the remainder to the closure.
The desiccant may be essentially conventional, and should be a material which does not normally give off fumes or readily form fine powdery particles either inherently, or as a result of absorbing water. Conventional materials may be used, for example molecular sieves or silica gel.
To allow the puncturable region of the closure face to be in direct communication with the interior of the vessel, the distribution of the desiccant material may be such that the desiccant is located on only part of the closure wall, so that the puncturable region is situated between areas of the closure wall on which is the desiccant material, or beside of such an area. By such a construction a hypodermic needle may be inserted through the puncturable region of the closure wall without coming into contact with the desiccating material, whilst the desiccating material itself is in desiccating communication with the interior of the vessel through the membrane.
In one embodiment of the invention, the desiccating material may be distributed in the form of, or about, a ring shape on the closure wall, with the puncturable region within, e.g. near or at the centre of, the ring. Such a ring shape may for example be circular, polygonal, or oval etc., suitable conforming to the general internal section of the closure. Such a ring-shaped distribution of desiccant may be located in a corresponding ring-shaped holder or cavity in the closure wall, or alternatively a ring-shaped distribution of desiccant may be located in a holder defining a ring-shaped cavity which extends inwardly from the closure wall, the cavity opening into the interior of the container when the closure is in place on the vessel. Such a holder may suitably be in the form
Taskis Charles Bernard
Whatmore Paul John
Dinner Dara L.
Kinzig Charles M.
Pascua Jes F.
SmithKline Beecham p.l.c.
Williams Janice E.
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