WO2018104814A1

WO2018104814A1 - Kit for the controlled combination of active ingredients

Info

Publication number: WO2018104814A1
Application number: PCT/IB2017/057071
Authority: WO
Inventors: Salvatore CRUGLIANO; Carlo FRONTINI; Vincenzo FRASCINO; Francesco DARDANO; Gianfranco SANSEVERINO
Original assignee: Crugliano Salvatore; Frontini Carlo; Frascino Vincenzo; Dardano Francesco; Sanseverino Gianfranco
Priority date: 2016-12-07
Filing date: 2017-11-13
Publication date: 2018-06-14
Also published as: IT201600124234A1

Abstract

Kit (1) for controlled combination of active substances/ingredients, said kit (1) comprising: at least two active substances/ingredients, at least one container (2), at least one removable component (3), at least one gripper (4), and at least one plurality of membranes (5) represented by paraffin wax circular sheets, said container (2) comprising a bottle (6) and a cap (7), said kit (1) being characterised in that on the inner surface (6') of the bottom of said bottle (6) there can be provided a circular tray-like housing (8) suitable to stably and reversibly receive said removable component (3), said housing (8) being dimensionally complementary to the lower portion of said removable component (3), the latter comprising a cylindrical and internally hollow rod (3') from which there opens at least one bubble-like compartment (3") suitable to receive a given active ingredient/substance.

Description

"Kit for the controlled combination of active ingredients"

Description Field of the invention

The present invention relates to the field of containers for scientific use. More in detail, the present invention relates to the field of containers to be used in general in scientific laboratories, such as chemical and/or biological laboratories, and in particular in the medical field. Even more in detail, the present description relates to a peculiar type of containers adapted to accommodate substances, for use in the field of ophthalmology, which must be put into contact with each other only in the process of their administration.

Background art

It is known that for many applications in the scientific field, procedures such as, by way of non-limiting example, the solubilization of a substance in a given solvent or the mixing of two or more substances, should be carried out with predetermined steps or timing, or their use for certain applications would be ineffective. In the chemical field, in fact, there are many synthesis procedures that require that the addition of a certain component to a mixture or a solution should take place after the latter have been preheated or have been left at rest for a time interval required to reacting further components (e.g. previously added to a given solvent) before carrying out the addition of the further given component.

It is also to be considered that sometimes, operations such as the introduction of a substance, such as at the solid state, in a solution or the combination of two different solutions, also require to take place under particular conditions, for example under vacuum or in the presence of an inert atmosphere of nitrogen or argon (for example to avoid oxidizing action by air), therefore requiring the use of sophisticated techniques of manipulation and as many sophisticated instruments, such as those that characterize the known Schlenk techniques and lines. In the medical field, and in particular in the field of ophthalmology, it is known and common to use single-dose vials for the instillation of eye drops of various nature. Based on the therapeutic objective, these eye drops may require that two or more active ingredients are comprised, assuming that the latter can remain in aqueous solution/suspension, without the occurrence of precipitation phenomena and preventing the same ingredients from becoming chemically inactive and therefore ineffective for the specific application thereof. This phenomenon of deactivation occurs for example when putting fluorescein sodium and oxybuprocaine hydrochloride in solution at the same time. However, the simultaneous use of the two active ingredients in a single eye drop, typically single-dose, would represent a viable and desirable solution for diagnostic purposes in ophthalmology. A solution for obtaining an eye drop comprising the two active ingredients so that they are administered in their active form could be provided by resorting to the use of known containers provided with diaphragm cap and a waterproof membrane placed below the diaphragm cap so that the latter, suitably moved, can pierce said membrane and put in contact the two substances present in the compartments that said membrane defines inside the container prior to the breaking thereof. Typically, oxybuprocaine hydrochloride has to be placed in aqueous solution in the lower portion of the bottle, i.e. in the volume of the space below said membrane, while fluorescein can be adsorbed or resting on the upper surface of said membrane, the breaking thereof will cause the passage of fluorescein too in solution. Alternative solutions may be obtained by resorting to similar bottles in which there are, variously configured, two compartments separated by a membrane which, when suitably broken, allows the contact of the contents of the compartments defined thereby. All with the result of obtaining a solution, a suspension, a mixture, an emulsion or other formulations, comprising the two active ingredients, effectively ready for the administration thereof.

However, most of these bottles, which undoubtedly represent notoriously valid solutions for obtaining the above formulations, show as a main limitation the one related to the impossibility to prepare the formulation of interest extemporaneously, as in the case where it is required to use specific amounts of active ingredient that may be different from those present in precursors of pre-packaged formulations. In addition, the majority of the known bottles do not allow, if not resorting to sophisticated manufacturing embodiments, comprising a plurality of active ingredients, each in its own compartment In fact, the majority of said known bottles comprise at most two compartments. Examples of containers for the storage of drugs placed in different compartments within the same container are described in the following documents:

Document JP2009062094 describes a type of flexible, sterile containers for the storage of drugs and for the delivery of mixtures thereof. Such containers comprise seals, separating the various components of the container, which are broken by suitably manipulating the container, thereby allowing the components to be mixed.

Document WO2015030249 describes a container for liquids, typically for eye drops, which can be discharged from said container even without directing the discharge of the liquid downwards.

Document JP2004016318 instead describes a multi-compartment container for containing drugs comprising a desiccant and deoxidizing agent.

Document JP2009160266 instead describes a multi-compartment container which prevents the mixing of two types of drugs included in respective compartments divided by a partition. The object of the present patent application for industrial invention is to propose a special container, for use in the scientific field, and specifically ophthalmological, which allows the introduction, both at industrial level and in extemporaneous mode, of precursors of formulations of active ingredients such as to be brought into contact with each other in a selective manner and, if required, only in the process of their administration.

Description of the invention

The present description relates to a novel and innovative type of containers to be used in the scientific field, for example in chemical or biological laboratories and in the medical field. More specifically, the present description relates to a kit of components comprising at least one container and a set of additional components adapted to the implementation of a container for the containment of several substances, typically active ingredients, in a separate configuration, so that each component is in a special compartment irrespective of the peculiar formulation taken by the active substance/ingredient Even more in detail, the present description relates to a special kit that allows the extemporaneous preparation of formulations comprising one or more active ingredients that can be mixed or in general be put into contact only when required, thus avoiding, for example, that a prior mixing of the components, or active ingredients, may result in the deactivation of the same principles which may take place, for example, as a result of their relatively long stay within a given solvent. In more detail, the following description will make particular reference to a kit comprising components for the implementation of a container for eye drops based on fluorescein sodium and oxybuprocaine hydrochloride as the use of two active ingredients in one eye drops would be useful for diagnosis in ophthalmology. It should therefore be noted that in the present description, it is assumed that the use of the subject kit is extended to the preparation of formulations comprising many other active substances or ingredients of interest in the scientific field and not limited to the medical diagnostic field. In general, said kit is in fact suitable for preparing various formulations in the chemical field.

More detail, the kit for the controlled combination of substances according to the present invention includes at least one container in the form of a common dispenser for eye drops having a cylindrical body, a bottle and a cap, which can be either a common cap adapted to close by tightening or fit-coupling said bottle or a common system for the instillation of eye drops. One of the essential features that said container should have is the material with which said bottle is made, which must be a flexible plastic material so as to be deformable only when being manually stressed and in particular when a pressure is exerted with the thumb and index finger so as to compress it. Said kit further comprises a removable component having at least one compartment, adapted to contain one or more substances, or active ingredients, adapted to be introduced into said bottle so that the substances supported thereby do not come into contact with those present in the bottle but when the user decides that the substances present in the bottle and those contained in the removable component should be combined for a specific use thereof. As in the case of the administration oxybuprocaine and fluorescein based eye drops for diagnostic purposes. As mentioned above, in order to make the administration of the two substances effective for diagnostic purpose, it is important that the two substances are put in contact only in the process of their administration as their stay within an aqueous solution for relatively long times might lead to the deactivation of the active ingredients. In order to make it possible that the contact between the substances takes place only when the user requires it, it is essential that said removable component is made of a fragile material such as, by way of non-limiting example, LDPE or polystyrene or thin glass, so that the compartments thereof, shaped like bubbles, may be selectively broken by compressing the container from the outside up to cause the rupture breaking of a given bubble with consequent release of the substance, initially contained in the bubble, into the bottle. For example, in the case of said oxybuprocaine and fluorescein-based eye drops, the latter may already be in aqueous solution inside the bottle, while fluorescein sodium may be present in the compartment as a bubble. The breaking of the compartment would therefore cause the passage in solution of the fluorescein sodium, thus making the resulting solution ready for use with both active ingredients in the active form thereof.

In order to facilitate the construction of the container, the kit further comprises a plurality of membranes made in the shape of circular sheets of waterproof material, such as a paraffin wax film, adapted to be placed on the bottom of each compartment in such a way as to avoid, in case there are multiple compartments, that the content of a compartment may fall inside the compartment below, said compartments being coaxial and communicating. The kit further includes a suitably sized gripper for gripping said membranes and facilitating the introduction thereof into the bubble-like compartments, as it will be apparent from the following description of the preferred embodiments and by observing the accompanying figures.

Said kit for the controlled combination of substances may optionally comprise a small funnel, also suitably sized, adapted to facilitate the introduction of the active ingredient substance within a specific compartment, preventing the contamination of the remaining compartments.

Has often repeated, and irrespective of the particular embodiment, said kit advantageously allows making chemical preparations by combining the components thereof only when required, thus preventing that using preparations that already include the specific combination of interest may be unstable and sometimes ineffective.

Advantageously, said kit further allows changing parameters such as volumes, amounts and concentrations of the substances of interest, allowing preparations for specific uses to be made, unlike what happens with preparations already packaged. Brief description of the drawings

The invention will be described hereinafter in preferred embodiments thereof and with reference to the accompanying figures, in which:

FIGURE 1 shows a perspective view of kit 1 for the controlled combination of active substances/ingredients according to the present invention. The figure shows kit 1 in a peculiar embodiment thereof where the aid kit 1 comprises a container 2 equipped provided with a system for the instillation of eye drops; a removable component 3 having at least one, in the case of the subject figure three, bubble-like compartments 3" for containing in separate mode different active ingredients/substances; a plurality of membranes 5 to be placed on the bottom of compartments 3" so as to prevent the contents of a compartment from falling into the one below; a gripper 4 for gripping said membranes.

FIGURE 2 shows a front view of container 2 and of the method of use thereof for obtaining an extemporaneous preparation comprising different active ingredients/substances. More in detail, figure 2(a) shows container 2 with the removable component 3 therein prior to the release of the substances contained therein inside the container. A pair of cavities 13 is also provided for each bubble-like compartment 3", adapted to facilitate the users in breaking a specific compartment. Said cavities 13, in addition to acting as a guide for the sharp-pointed projections 10 which cause the breaking of the compartment, represent portions in which the material forming said compartment is more fragile. Figure 2(b) instead shows how one of the bubble-like compartments 3" of the removable component 3 is broken by exerting a compression of bottle 6 and by the action of the pair of projections 10 on the compartment of interest.

FIGURE 3 shows container 2 of kit 1 in a peculiar embodiment thereof. More in detail, figure 3(a) shows that cap 7 of bottle 6 is a common cap adaptable to said bottle 6 by screwing or fit-coupling. Said bottle may further be provided with a tail 11 adapted to allow, by common fittings, the connection of container 2 to vacuum pumps or inert gas cylinders. The figure subject also shows the presence of a funnel 12 optionally included in kit I which can help the users in the introduction of the active ingredient substance within a specific compartment. Description of the preferred embodiments

In the preferred embodiment thereof, kit 1 for the controlled combination of substances object of the present invention comprises at least one container 2, at least one removable component 3, at least one gripper 4 and at least a plurality of membranes 5 represented by paraffin wax circular sheets. Preferably, without limitation, said kit already comprises the active ingredients/substances to be combined.

More specifically, container 2 of said kit 1 comprises: a bottle-like cylindrical body 6 and a cap 7 shaped as a common system for the instillation of eye drops. On the inner surface 6' of the bottom of bottle 6, a circular-tray housing 8 is also provided that is adapted to stably and reversibly receive said removable component 3. Said housing 8 is in fact dimensionally complementary to the lower portion of said removable component 3. More specifically, the latter comprises a cylindrical and internally hollow rod 3' from which there opens at least one bubble-like compartment 3" suitable to receive a given substance. For example, if one wants to prepare eye drops for diagnostic use, comprising an aqueous solution based on fluorescein and oxybuprocaine, said eye drops are prepared by introducing oxybuprocaine in aqueous solution into said bottle 6 and fluorescein sodium into said bubble-like compartment 3". Said fluorescein sodium may be at the solid state, or already in aqueous solution into its compartment. Only when the user decides that the two substances should be combined, he/she will manually compress bottle 6, thus causing the breaking of the bubble-like compartment 3" containing fluorescein, and the release of the latter in aqueous solution. The above while allowing the preparation of an extemporaneous formulation of active ingredients that are effectively functional for the use thereof, thus avoiding precipitation phenomena of one of the two ingredients or a complexing thereof and in general the deactivation of the specific functionality of the eye drops, which might take place if the container already included fluorescein sodium in aqueous solution of oxybuprocaine. As mentioned above, kit 1 further comprises a plurality of membranes 5 shaped as paraffin wax circular sheets adapted to be gripped by gripper 4, also included in kit 1, and be placed on the bottom of a bubble-like compartment 3" so as to prevent the content thereof from falling into the compartment below passing through said cylindrical and internally hollow rod 3'. Typically, said membranes are particularly useful when the removable component 3 has at least two of those said bubble-like compartments 3". Otherwise, if there is only one bubblelike compartment 3", said membranes 5 are still useful for covering and closing the upper end 3'" of the removable component 3 thus preventing, for example, the accidental introduction of the solution contained in bottle 6 into said removable component 3.

Preferably, but not necessarily, kit 1 is such that bottle 6 includes, on the cylindrical inner surface thereof, pairs of sharp-pointed projections 10 adapted to facilitate the user in breaking a certain bubble-like compartment 3". Typically, it is preferable that there are at least one pair, and in particular at least two sharp-pointed projections 10 at diametrically opposite points of each bubble-like compartment 3 " of the removable component 3.

In order to impart greater stability to the placement of said removable component 3, some embodiments provide for the presence of at least two, preferably four tabs 9 protruding from the inner cylindrical surface of bottle 6. Said tabs are adapted to provide a further support, along with said housing 8, to the removable component 3 inserted into bottle 6.

Further embodiments provide that cap 7 is a common cap adaptable to bottle 6 by screwing or fit-coupling. In these embodiments, but also in those where said cap (7) is represented by a common system for the instillation of eye drops, bottle 6 of kit 1 may further have a tail 11 suitable for adapting common fittings for connection to vacuum pumps or inert gas cylinders.

In all embodiments thereof, kit 1 for the controlled combination of substances may include an optional funnel 12 suitable to facilitate the user in the introduction of a given substance into a given bubble-like compartment 3", thus preventing the contamination of consecutive compartments.

In all embodiments thereof, kit 1 according to the present invention is such that bottle 6 of container 2 is made of flexible polymeric plastics that are flexible under the action of a manual compression, such as PE, PP, PET or EPR rubbers.

The removable component 3 is instead made of thermoplastic materials having such thickness and fragility as to allow breaking the compartment even under the action of a mild mechanical stress such as that exerted by said sharp-pointed projections 10 as a result of the action exerted by the user on the walls of container 2. Suitable material may be, by way of non-limiting example, LDPE or polystyrene. Alternatively, said removable component 3 may be made of thin glass.

Claims

Claims 1. 1. Kit (1) for controlled combination of active substances/ingredients, said kit (1) comprising: at least two active substances/ingredients, at least one container (2), at least one removable component (3), at least one gripper (4), and at least one plurality of membranes (S) represented by paraffin wax circular sheets, said container (2) comprising a bottle (6) and a cap (7), said kit (1) being characterised in that on the inner surface (6') of the bottom of said bottle (6) there can be provided a circular traylike housing (8) suitable to stably and reversibly receive said removable component (3), said housing (8) being dimensionally complementary to the lower portion of said removable component (3), the latter comprising a cylindrical and internally hollow rod (3') from which there opens at least one bubble-like compartment (3") suitable to receive a given substance, said bottle (6) being made of flexible polymeric material by manual compression, said material being PE, PP, PET or EPR, said removable component (3) being made of a fragile material, said material being polystyrene or LDPE or glass or the like, said bottle having - on the inner cylindrical surface - as many pairs of sharp-pointed projections (10) as the bubble-like compartments (3") of said removable component (3), said pairs of sharp-pointed projections (10) being suitable to facilitate the user to break a given bubble-like compartment (3"), said breaking causing the release of the active substance/s and/or active ingredient/s comprised in said bubblelike compartment/s (3") into the bottle (6), previously filled with a given active substance/ingredient

2. Kit (1) according to the preceding claim, wherein on the inner cylindrical surface of the bottle (6) of the container (2), there can be provided at least two tabs (9) projecting from said inner cylindrical surface of the bottle (6), said tabs (9) being suitable to provide - alongside the housing (8) - a further support to the removable component (3) inserted into the bottle (6), said removable component (3) having for each of the bubble-like compartments (3") thereof a pair of cavities (13) at said pair of sharp-pointed projections (10).

3. Kit (1) according to any one of the preceding claims, further comprising a funnel (12) suitable to facilitate the user in the introduction of a given substance into a give bubblelike compartment (3"), said funnel (12) preventing the contamination of consecutive compartments.

4. Kit (1) according to any one of the preceding claims, wherein the cap (7) of the bottle (6) of the container (2) is represented by a system for putting eye-drops.

5. Kit (1) according to any one of claims 1 to 3, wherein the cap (7) of the bottle (6) of the container (2) is a common cap suitable to adapt to the bottle (6) by screwing and/or fit- coupling.

6. Kit (1) according to claim 4 wherein the active substances/ingredients comprise oxybuprocaine hydrochloride and fluorescein sodium, said oxybuprocaine hydrochloride being suitable to be placed in aqueous solution in the bottle (6) of the container (2), said fluorescein sodium being suitable to be placed in at least one bubble-like compartment (3 ' ') of the removable component in solid state or already in aqueous solution (3).

7. Kit (1) according to any one of claims 1 to 5 wherein the bottle (6) comprises a tail (11) suitable for adapting common fittings for connection to vacuum pumps or inert gas cylinders.

8. Use of the kit (1) according to any one of the preceding claims, for the extemporaneous preparation of formulations of active substances/ingredients.

9. Use of the kit (1) according to claim (6) for the extemporaneous preparation of a container (2) comprising eye-drops based on oxybuprocaine hydrochloride and fluorescein sodium.

10. Kit (1) according to the preceding claim for use in a diagnostics method in the ophthalmic industry.