Dispensing – Processes of dispensing
Reexamination Certificate
1999-02-18
2002-02-26
Jacyna, J. Casimer (Department: 3751)
Dispensing
Processes of dispensing
C222S152000, C206S222000, C206S365000, C141S009000, C141S100000, C141S025000
Reexamination Certificate
active
06349850
ABSTRACT:
CROSS REFERENCE TO RELATED APPLICATION
This is the 35 USC 371 national stage of international application PCT/FR97/00989 filed on Jun. 4, 1997, which designated the United States of America.
FIELD OF THE INVENTION
The present invention provides a process for preparing an injectable pharmaceutical preparation, a device for implementing said process and the product obtained by implementing the process by means of the device.
BACKGROUND OF THE INVENTION
It is known that injectable forms are immediately bioavailable and constitute a potential passive mode of administration for the patient and an ideal treatment in urgent cases.
Another important reason for the development of parenteral forms is the use of active principles (AP) which are degraded and/or not significantly absorbed by the oral route.
Of all these AP which, for various reasons, require an injectable form, many of them are unstable in aqueous media, whether in solution, suspension or dispersion.
In order to avoid hydrolysis and all the physico-chemical problems associated with a liquid presentation (precipitation, aggregation, adsorption, crystallisation), a presentation is often used in which the AP is preserved in a solid, dried or freeze-dried form.
The preparation of the liquid form required for injection then takes place extemporaneously, just prior to injection.
This preparation consists in hydrating the solid form with the liquid medium for solubilisation or suspension of the AP.
Traditionally, this operation is carried out in a sealed bottle which contains the solid form. The liquid is introduced into the bottle by a syringe, the needle of which is capable of piercing a stopper-septum.
The liquid form is then recovered in the syringe so that it can be injected.
The time required for this delicate operation and the risks of contamination it involves led experts in medical technology to devise devices for making extemporaneous preparation simpler and more reliable, and for using the fewest possible components.
Along such lines, the patents EP-A-0 664 136, DAIKYO SEIKO, EP-0 599 649 PHARMACIA, WO-95 11051 disclose a bicompartmental or “by-pass” syringe which combines in the same syringe the liquid medium and the solid form which will be directly rehydrated in the syringe before injection.
Similarly, certain producers propose devices which combine the bottle with the syringe and control the satisfactory execution of the preparation (French patents DEBIOTECH 2 705 898, 2 715 311, 2 717 086).
Certain faults in the traditional systems are not, however, solved by said new devices, which pose problems of loss of preparation in their dead volumes, which do not render rehydration automatic and static but keep it manual and dynamic, that is, the flow of liquid and the transfers after hydration displace the solid form and, in particular, the AP. The injectable form does not, therefore, necessarily have the same distribution or homogeneity as the dry form. This constitutes a problem, particularly in the case of suspensions.
The fact that preparation is dynamic and carried out manually may lead to important differences depending on the operator, the speed with which he acts, the manner in which he loads the liquid and controls the evacuation of the air. Finally, the force with which the solid AP is hydrated is likely to lead to a relatively substantial emulsion of microbubbles of air.
The time allowed for solubilisation or suspension and agitation of the liquid medium determines the homogeneity of the preparation.
In the case of suspensions, poor homogeneity or the onset of sedimentation may lead to dose and administration problems.
The object of the invention is to propose a process for overcoming these various disadvantages.
SUMMARY OF THE INVENTION
According to the invention, the process for preparing an injectable preparation is characterised in that a dry form of an active principle under vacuum and a liquid are prepared, and said liquid is introduced into the dry form by suction by virtue of the action of the vacuum in order to form the said injectable preparation.
The process of preparation and packing under vacuum according to the invention avoids the above-mentioned problems (dead volume, manual activation, injectability) and at the same time the problems of injected liquid formulation (homogeneity, degassing).
According to a characteristic of the process, the dry form under vacuum occupies the same volume as the final form obtained after automatic hydration by a corresponding, exactly pre-determined volume of liquid.
According to an embodiment of the process of the invention, a layer of excipient is added to the dry form, said layer being used subsequent to the injectable preparation as a liquid piston in order to push the other layers and to reduce the losses of active principle during injection.
According to another embodiment of the process of the invention, the dry form is packed in a syringe fixed to an automatic rehydration device; in order to prepare the dry form, a liquid containing the active principle is frozen, a specific quantity of excipient solution is added to the surface of the frozen liquid, this excipient solution is frozen, the whole unit is freeze-dried so as to obtain, between the piston of the syringe and the solid of active principle under vacuum, a volume of freeze-dried product containing only the excipient which, after automatic rehydration and movement of the piston in order to empty the syringe, occupies a dead volume at the bottom of the syringe and of the injection needle at the end of injection.
This process of preparation and packing leads to automatic rehydration: it is sufficient for the user to activate the device for the liquid to restore the solid form to the state it was in prior to drying or freeze-drying. Activation of the device consists in bringing into contact the liquid volume and the solid volume under vacuum. After activation, extemporaneous preparation is automatic, that is, the components of the device move solely under the action of the liquid which is drawn by suction by the vacuum under which the solid formulation is placed.
This property of vacuum packing is independent of the operator, and hydration leads to an immediate return to the situation of the liquid form prior to drying or freeze-drying.
The solid form and active principle remain static during this hydration, that is, they are not displaced by the liquid.
This immediate preparation is thus directly injectable without the need to agitate it, transfer it or expel the air before injection.
This process of preparation and packing may use certain devices or containers currently available, provided that they ensure that the form under vacuum is kept under vacuum until rehydration. The component(s) of the device must allow this rehydration whilst avoiding contact with the ambient air.
This feature also leads to certain specific devices or components for this process of preparation and packing. These devices and components will be described below.
The techniques for vacuum packing the solid form in the device and the packaging are derived from existing techniques (blood sampling tube, packing under a plastic film). This vacuum packing of the solid form and of the AP is, moreover, capable of replacing inert gas blanketing (nitrogen) and improving the stability of the preparation particularly at high temperatures (thermal insulation) and the compatibility with the container (contact insulation).
The above-mentioned advantages of the process and of the devices of the invention, which will be explained below, are particularly important for certain preparations:
For a solid, readily solubilised preparation, the advantage is that of obtaining immediately a degassed liquid preparation without air bubbles.
For a solid preparation which is more difficult to solubilise, either due to its viscosity or due to the time required for solution, the formulation under vacuum avoids the emulsion of air in the liquid, simplifies and accelerates solubilisation.
For a suspension and, more especially, for a sustained-release suspensi
Jacyna J. Casimer
Societe de Conseils de Recherches et D'Applications Scienti
Young & Thompson
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