Ocular treatment device

The present invention relates to a device for ocular treatment and, in particular, to that type of device which is used in the administration of fluids for ocular treatment in the form of jet and / or small droplets.

Fluids for ophthalmic treatment are usually administered in the form of eye drops or aliphs. The use of drops has many disadvantages, but, first of all, it is noticeable the difficulty with which the drops are accepted by the patient.

The drops are relatively large, and the instinctive blinking, caused by the impact of the drop with the eye, limits the amount and proportion of the fluid that contacts the surface of the eye to be taken care of.

Usually less than 10% of the 50 µl drop can be effective, the rest being lost through drainage, both externally and through nasolacrimal drainage, so the use of expensive treatment fluids is a waste, leading to loss of treatment effectiveness. Usually, the same observations can be claimed when using the aliphs, but the levels of waste can be reduced by carefully managing them. The higher viscosity of the aliphys reduces the tendency to drain or wash them.

It is known (PCT / GB 95/01482) various devices for various techniques for administering eye treatment fluids. These devices generally consist of techniques whereby the treatment fluid is dripped from a reservoir and discharged in a controlled manner. , in the eyes. While these techniques are used, many disadvantages arise especially from the repeated use of multidose orifices, namely the difficulty of maintaining the sterility of the liquid for treatment, in a system in which the doses are dropped from a tank and passed through a reusable orifice without the use of preservatives. The use of different types of preservatives is discussed by some concerns and can be analyzed and studied, also in pp. 8-11 of the Ophthalmic Drug Delivery Systems (Drugs in the Pharmaceutical Sciences, Volume 58), published in 1993 by Marcel Dekker.

There are also known inventions [US 3934585] which describe a variety of mechanisms for administering unit doses of fluid for treatment in the human eye. These doses are kept in the administration tubes and fit, only when necessary, in the mechanisms where the treatment is required. The mechanisms are operative only when applying compressed air to one end of the tube, resulting in the release of the treatment fluid at the other end.

The technical problem, which the present invention seeks to solve, is to minimize or eliminate the need to use preservatives in ophthalmic treatment fluids, without the risk of contamination.

The device according to the invention solves the proposed problem by having a unit container for the treatment fluid, containing a watertight enclosure, at which the portion of a wall has at least one opening, the enclosure being pressurized so as to discharge the contents by at least said opening. The opening has a diameter so chosen that it is capable of generating a jet and / or small discrete drops of the treatment fluid released through it.

The portion of the container wall, formed by openings or openings, is characterized by a flat portion of the enclosure wall, and the enclosure is usually in the form of an inflated package, with the portion of the base wall flat. A number of advantages have been observed, which arise in particular from the adoption of the unplanned portion of the wall in which the opening or openings are formed. In particular, it was observed that the adoption of the form

RO 117294 The dome block, in the respective wall portion, may result in better performances of the containers in use and will certainly facilitate other advantageous developments of the containers.

In a preferred embodiment of the invention, the unit container for the treatment liqueur 50 contains an enclosure in which a portion of the wall is dome-shaped and is formed with at least one opening in the top region of the dome-shape, the enclosure being adopted to give a sealed volume to the liquid for the treatment, and pressurized to release the contents of the sealed volume, at least through said opening. One or more portions of the wall may also be defined as having a dome shape, 55 complementary to the opening, and are capable of releasing the contents of the container.

The enclosure of the unit container, according to the invention, can be pressurized by applying an external force on a part of the enclosure as opposed to the portion of the wall formed by openings or openings. However, where the respective portion of the wall is flat, this way of pressurizing the contents of the enclosure can create high pressures in the portions of the wall, especially around the opening or openings. In certain situations, this may result in a drop in the wall portion around the opening or openings that may result in the contents of the enclosure being unloaded. By locating the opening at the top of the dome shape, these pressures are reduced.

single opening or a network of openings may be practiced in the wall portion 65 of the container. Certain networks are possible, given the choice will be influenced, in particular, by a large number of factors. A large number of openings will disperse the liquid for treatment over a large area of ​​the targeted area. Smaller openings produce narrower jets and / or smaller drops that will have a greater deceleration in their passage to the target area. However, this can allow the use of 70 higher pressure. A single opening can direct a jet or beam directly to the target area, but will reduce the time required to administer the treatment fluid, upon contact with the blink area. Preferably, the minimum opening diameter should be at least 10 pm, in order to avoid spraying small drops when they have to perform their task. The use of a single opening, with a diameter of 75 100pm, is generally preferred. The intention of creating the opening refers to the creation of the possibility of making small drops, but not less than 20 pm, in order to avoid the creation of a spray liquid that could be inhaled.

Another advantage, by adopting the dome shape and containing the opening (s), results in easier downloading of the entire contents of the enclosure. 80 If the device used for pressurizing the enclosure is of the type of a piston or hammer, the operative end may be of a form complementary to that of the cupola, so it is inverted with that of the dome shape of the portion of the wall, so as to allow the entire discharge of the the whole enclosure.

portion of the enclosure wall of the container may be endowed with a cover 85 removable over the opening or openings, which cover is removable only before the contents of the enclosure are unloaded. In this way, the content is protected from contact with the environment, until use.

In another arrangement, each opening in the portion of the enclosure wall may be closed by a membrane adapted to the rupture above the pressurized enclosure. These means demonstrate that the treatment fluids can be held sterile in the containers described according to the invention. Consequently, the need to use preservatives in fluid content is minimal or can be eliminated.

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The use of a portion of the dome-shaped wall, in the preferred containers, according to the present invention, facilitates the creation of a sealed volume, separately inside the enclosure. In these circumstances, the removable lid, placed over openings or openings, no longer becomes necessary, or at least the requirements for sealing the contents can be reduced. According to this aspect of the invention, which can also be applied to a container without having the portion of the dome-shaped wall with openings or openings, a partition wall may be included in the enclosure, this partition wall separating the wall portion with the opening or openings, by the region through which the enclosure defines a watertight volume. The partition wall is adapted, prior to the break, to the unloading of the contents from the enclosure. Accordingly, the partition wall may be adapted to rupture above the pressurized enclosure, as part of the action of unloading the contents of the sealed volume, through openings or openings, in the portion of the wall. However, the partition wall can be adapted to rupture due to external forces, before pressurizing the enclosure. If the container is suitable, as an individual unit or as part of a tape, to the dispensing device, a mechanism may be included to apply the tensile force over the container, to breaking the partition wall even before the enclosure is pressurized.

According to the invention, when a container defines a watertight volume with a partition wall, it is understood that this watertight volume can be formed as an individual component of the previous container, by attaching it to the portion of the wall formed by openings or openings. This feature also offers a large number of benefits, first of all in the manufacture of packages containing a lot of complete containers. The manufacture of these individual components allows them to be checked separately, to detect defects prior to incorporation into the package. It also facilitates the possibility of creating packages with different dose contents; fluids for different treatments or different quantities of the same fluid, as well as the possibility that a plurality of individual components are arranged in a common dome shape of the wall portion, whereby fluids for different treatment can be kept in isolation, but mixed prior to discharge, through openings or openings. The containers, according to the invention, are intended to provide simultaneous or successive distributions, in the form of jet or small drops, or sometimes in the form of streams or spray drops, which may be diffuse or collinear.

□ A characteristic range for the size of the opening or openings in the portion of the enclosure wall is made up to 1OOO pm or, preferably, from 20 to 200 pm. The range of preferred sizes is especially between 100 and 150 pm. 0 single opening or a network of openings which can be properly used by: drilling, drilling, electroforming or laser drilling in the plastic film or in the film that defines the portion of the wall. □ Nickel foil is usually preferred for electroforming.

The distribution form that is suitable for the specific ophthalmic treatment, in other words a single opening or multiple openings and their arrangement, will be dictated by the need to achieve a sufficient weight at the impact with the response of the eyelid, with the minimal adverse reaction or with an unpleasant sensation. eye. Thus, if a large amount of fluid needs to be provided, capable of ensuring distribution prior to the patient's blinking and at a tolerable impact rate, multiple openings will be used instead of a single opening to achieve a sufficient fluid release rate.

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The unit containers, according to the invention, may be loaded so that each enclosure contains a prescribed unit dose, usually not less than 10 pm. However, larger volumes, such as 20, 50 or 100 pm, may be required, for example, for irrigation of the eye surface. A lot of containers can be delivered in the form of an appropriate package, on a common substrate, and preferably in the form of a tape with containers arranged sequentially along it.

Unloading the contents of the enclosures into containers, according to the present invention, can be simply accomplished, by causing the enclosure wall to break in front of the portion having the opening or openings, preferably through a mechanical system. The wall may include a reinforced portion to guide the rupture.

For example, the enclosure may be crushed on the opposite side of the wall portion by a piston, hammer or console mechanism, an action that will allow moisture to control the speed of the mechanism, with sufficient impact when unloading and designing the content at a minimum, predetermined distance. In another embodiment, the enclosure may be formed as a cylindrical chamber, with a portion of the wall in opposition, formed as a piston moving against the portion of the wall, forcing the contents of the enclosure to exit through openings or openings.

The invention also relates to devices for discharging the fluid for treatment, from watertight enclosures of containers of the type described above. Such devices contain a package of containers; a mechanism for feeding the containers successively, at the dosing station, and means for activating, on the premises, the containers, at the dosing station that downloads the contents of the enclosure. The invention may also refer to a manual feed device, wherein the feed is made for individual containers or packages so that they are manually fed to the required dosing station. When the portion of the container wall of the container has a lid, the device may include means for removing it, prior to downloading the contents of the enclosures. These means can be synchronized with the feeding mechanisms.

Unloading the contents of the enclosure at the metering station to the above device is preferable to be pressurized so that the liquid is forced through openings or openings in the respective portion of the enclosure wall. However, in another embodiment, an electrostatic technique may be used, which is described in detail in the specification of the European patent EP 0224352. For this alternative, the invention uses a modified unit container, in which the enclosure is not pressurized, but has a wall which includes a slim portion for connection to an electrical potential source, and which, by applying it to such potential, generates a charge. electric in the contents of the containers and their discharge through at least one opening.

In the unloading devices according to the invention, in which the unloading of the contents of the containers is achieved by pressurizing the enclosures, the preferred means are of the type of a physical mechanism, such as a crushing unit which can activate directly on the outside of the enclosure, on the opposite side of the portion. wall formed by the opening or openings. This may be in the form of a piston-cylinder mechanism, a mechanism which can also be used to move an opposite portion of the wall into the cylindrical enclosure, as described above.

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Another technique, which can be used for pressurizing the enclosure in containers according to the invention, uses piezoelectric elements. Such elements allow the degree of pressurization achieved to be carefully controlled and can be arranged, for example, in front of the enclosure face opposite the wall portion, or in the form of a ring around the enclosure body. In another arrangement, such an element may be operated selectively or repeatedly, at the discrete discharge of small drops or at a discharge with a rapid sequence. The element may be in the form of an ultrasonic transducer, one that is usually suitable for generating a spray through the network of openings in the wall portion of the enclosure.

Other features of the devices described, according to the invention, relate to increasing the success of providing the liquid for treatment, to the desired target. To keep the eye open, a light, usually white, can be used. Alternatively with the given light, a colored system can be used, system in which different colors indicate the stage of treatment. For example, the device may give a red eye color, which will change to green only after the predetermined dose has been shipped.

Various devices, according to the invention, can also include a certain number of features that are already established in the dosage devices of different kinds. The number of containers in the device will of course be finished, and a dose recorder may be included to provide indications of the number of remaining doses to be delivered. A delay mechanism may also be included to prevent inadequate delivery of multiple doses. In combination with the characteristics of the dose delivery signal, referred to above, this may have a significant benefit.

The devices according to the invention may be personal, used manually, or may be used on a more ordered basis in institutions. For any use, means may be provided to provide a suitable space between the device and the eye to be treated, space that can be adjusted, especially to devices adapted for use in institutions. In connection with the above, it can be observed that the mechanisms described in the present invention may be capable of delivering a jet and / or small drops effectively horizontally or vertically upwards, over the minimum distance, and for this purpose it is not required that a the device should be arranged to operate only above the eye.

In addition to the containers and devices set forth above, the present invention also relates to means for generating jet and / or small drops for treatment, using such containers and devices. The treatment methods used in all situations require precision when generating the jet and / or small drops at the respective treatment position.

The device according to the invention has the following advantages:

- increased accuracy in jet targeting;

- increased possibilities of adaptability to the patient.

The following is an example of embodiment of the invention, in connection with FIG.

1 ... 19, which represents:

FIG. 1, perspective view of the device in which the enclosure of a unit is crushed when releasing its contents;

FIG. 2 is a detailed view of the crushing unit of the device of FIG. 1;

FIG. 3 is a perspective view of the device in which a piston mechanism is used to release the contents of the enclosures;

FIG. 4, a detailed view of the piston unit of FIG. 3;

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FIG. 5, a perspective view of the device in which a piezoelectric unit is used to release the contents of the enclosures:

FIG. 6, a detailed view of the piezoelectric unit of FIG. 5;

FIG. 7 is a perspective view of a device similar to FIG. 5 and 6, intended to use individual containers;

8 is a detailed view showing a container which has been used at the piezoelectric unit;

- Fig. 9, perspective view of a device, which uses an electrostatic charging system when releasing the contents of the enclosures;

FIG. 10 is a detailed view of a unit dosing station in FIG. 9;

FIG. 11, a cross-section through a preferred container according to the invention;

FIG. 12a, 12b and 12c, cross-sections for different stages of manufacture of containers, according to the invention;

FIG. 13, a cross section through another type of container according to the invention;

FIG. 14 is a plan view of the length of the band or of the crossbody formed with the bag-shaped unit containers according to the invention;

FIG. 15, schematic presentation of a simple compression device for releasing the contents of the bags of the type illustrated in fig. 14;

FIG. 16 is a view of the device of FIG. 15, activated to release the contents of the bags;

FIG. 17, cross section through another type of dose unit container, according to the invention.

FIG. 18, schematic presentation of a device for releasing contents from containers of the type of fig. 17;

FIG. 19, graph showing the myotic response of the rabbit subjects to a treatment, using the device of fig. 18.

The device for ocular treatment according to the invention and shown in FIG. 1, contains a room 2, provided with a bonnet 4, open at one end, and with a metering station 6, of the device disposed at its base. The device for ophthalmic treatment has a hood 4, which serves to certify that the dosing station 6 is located correctly and at a suitable distance from the eyes for the treatment to be effective.

The containers for supplying the device are mounted on a strip 8, extending from a power cord 10, around the surface in front of the dosing station 6 and on the winding of a coil 12. A capstan 14 is provided to wind the strip 8 on the place of the next container, at the dosing station, to release their contents. A button 16 is provided for initiating the activation of the dosing station, when charged individually.

The enclosure of each container on the tape 8, in the form of an inflated package 18, is positioned at a continuous inlet 20, as can be seen in FIG. 2. The open face of the inflated package 18 is closed by a continuous metal sheet 22, and over each swelling the foil has ten 40µ openings, electroformed in it. The upper foil forms a lid layer 24, which is progressively removed from the foil, until the swollen package 18 reaches the dosing station 6. The cover layer 24 is removed by a spring supported on the coil winding 26 and which pulls the cover layer 24 around

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RO 117294 Bl of a guide bar 28, on top of the flow of the dosing station. □ Another similar guide bar 28 is located on the underside of the dosing station, and the strip 8 is held in position by means such as sleepers 30, also supported by the spring. The crossbars 30 are positioned between them at a distance equal to the size of the inflated package 18, positioned along the strip 8 so that they serve to position the package centered at the dosing station 6.

The dosing station, shown in fig. 2, includes a piston 32, caught in a block 34, which is mounted in a housing 36, located inside it by means of gripping means 38. To cause the release of the contents of the inflated packages 18 through the openings in the sheet 22, the button 16 is depressed, so as to release the arch, unheralded in the figure but known in itself, which charges the pinion 32 against the swollen package 18 and crushed, through the sheet 22. The cap 14, after release, is so constructed as to catch the following inflated package 18, loaded and in line with the piston 32. The cap 14, which is also coupled to the piston 32, allows it to retract to its previous starting position. , at the inflated package 18, freshly loaded and reaching the release position.

In the treatment device shown in fig. 3, some container enclosures 40 are mounted on a band 42, having an aspect like that of FIG. 1. extended from a loaded coil 44, bandwidth passing to a dosing station 46 and, on a coil winding 48, coupled to a winch 50, for winding. The seat in which the entire device 52 is located has a piston 54, but it will be observed that the orientation of the seat relative to the hood in this case is different.

At the dosing station, which is better shown in fig. 4, each container enclosure 40 is successively aligned with the piston 54, of the cylindrical mechanism 56. Each enclosure 40 is cylindrical and has at the front end a hole 58, with one or more openings. This end is closed by a sealed foil 60. The other end of the enclosure 40 is closed by a silicone plunger 62, and when the metering station is activated by the plunger 54 the plunger 62 is engaged, and thus the contents of the enclosures are compressed. This compression forces the contents through the hole 58, with one or more openings, simultaneously with the removal of the seal sheet 60, and the contents are discharged as a sprayed liquid, as shown, in a direction 64.

The device for ocular treatment, as shown in FIG. 5 and 6, in some situations, is similar to the one in fig. 1 and 2, but from the point of view of the discharge, this is done by means of a piezoelectric element. A strip 66, containing discrete containers, was twisted, via a capstan 68, inside a container next to a dose 70. The dosing station has a chamber 72, of the container, and is aligned with a piezoelectric annular transducer 74. The alignment is made while a lid layer 76 is removed in the same manner as in the device of FIG. 1. Removing the lid 76 again exposes a metal sheet 78, extending over the enclosure 72, and forms ten electroformed openings, of 40 μ.

The dosing station, shown in fig. 6, in this use, contains a piston 80, mounted in a cylinder 82, located in a housing 84, by means of gripping means 86. Depressing a button 88 activates a spring for positioning the piston 80

RO 117294 Bl against the inflated enclosure 72, but only for positioning the piezoelectric annular transducer 74 around the body. Means itself known and not inherited in the figure activate the translator 74 in contact with the space around the swollen enclosure and thus release the contents by opening it in the metal foil. hereinafter, as shown above and with reference to FIG. 1 and 2, the band winding on the cap 68 pulls the piston 80. However, in this positioning, the capstan 68 activates a knife, for detaching the use of the inflated enclosure, from the strip 66, which is then ejected through an opening from the device housing.

in FIG. 7 and 8 a simplified version of the device of FIG. 5 and 6. In this embodiment, the containers are supplied separately and a housing 90 of the device is provided with a storage compartment 92 for the container reserve. When the device is activated, a container 94 must be removed from the storage compartment 92 and manually fitted to the ring transducer 96, fixed at the base of a bonnet 98 of the housing. □ battery 100 and an electronic part 102 are disposed in a chamber 104, located between the storage compartment 92 and the transducer 96. When using such a charging system, a lid 106 is removed from the visible face of the container 94, so that to expose the portion of a wall 108 of the enclosure and which forms a 50µ orifice. When the electronic part 102 is activated, by means of a button itself known and not inherited in the figures, the ring transducer 96 mounted around the container 94 releases the contents through the orifice.

As can be seen in FIG. 8, the enclosure of the container 94 is reinforced on an inner perimeter, through a portion 110. It directs the rupture of the enclosure, by contraction of the annular transducer, and the internal form also serves to decrease the speed of release of the fluid through the orifice. Fig. 9 and 10 illustrate another embodiment of the invention, in which the contents of the container enclosure are released through an electrostatic charging system. A cover strip 112, of the containers 114, is stored in a housing 116, with a capstan 118, for advancing the strip 112 and positioning the container 114 at a dosing station 120, described in detail in the part referring to fig. 1 and 2. In this embodiment, some enclosures 122, of the containers 114, are made of an electrically conductive material. A contact 124, located at the metering station 120, when engaging the enclosure wall, and a known and non-inherited switch itself, are activated, by means of a distributor button 126, to ensure the electrical potential from a generator 128 to the enclosure wall for charging the contents. , and forces its release through an opening 130. The power for generator 128 is provided by a battery 132, also located in the housing 116. Since the walls of the enclosure in each container are conductive, they must be insulated from each other by the strip 112, so as shown in FIG. 10, the tape has an isolated portion 134, between the containers 114.

For devices, the supply can be made, according to the invention, to the supply of different fluids, at the target site, in the composite treatment. Thus, the containers contain different fluids, which can be included in the feed of the dosing stations, and the containers that are mounted on a band or band can be predetermined for a chosen sequence. For example, an anesthetic or diagnostic aid, such as fluorescent substances, may be included in the various variants of tape-mounted containers.

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Fig. 11 and 13 illustrate containers, in a preferred embodiment, for use in the devices described above, which have a double dome shaped construction. The container shown in FIG. 11 defines an enclosure 202, in which an amount of fluid 204 is held, for treatment. The bottom of the container, as shown, is formed as a package inflated into a sheet formed of a base laminate sheet 206, which is closed with an upper sheet 208, laminate sheet, which is formed as a dome in which is defined the upper part of the enclosure 202. The base of the sheets 206, 208 is connected and, where the sheets are in contact with each other, the enclosure is isolated.

In the upper part of the upper sheet portion 208 an opening 210 is formed, which is covered with a cover sheet 212, with the outer surface of the upper sheet 208 being insulated around the opening 210. The cover sheet 212 is usually made of sheet plastic or sheet metal. In use, the container shown in FIG. 11, is suitable in the device located in the enclosure 202, by means such as the piston or a pressurized air source, for forcing the base sheet 206, where the bottom of the enclosure 202 is formed, from the opening 210, and against upper sheet 208. The cover sheet 212 is removed, and the contents pushed. Accordingly, the treatment fluid 204 in the enclosure 202 is released by opening 210 to the chosen target.

Fig. 12 illustrates a container in which the individual components of the container can be prepared separately, with the fluid for treatment therein, and then attached to the top of the foil that complements the respective containers. Such a component is shown in FIG. 12a, which contains a base foil 206, formed in an inflated package, containing a quantity of fluid 204. The swollen package is closed by a layer 214, which insulates around the periphery of the swollen package from the base sheet, including a weakened portion 216, which usually sits above the swollen package. However, the component is insulated, and the treatment fluid 204, in the inflated package, is well protected upon contact with the outside atmosphere, the construction also allowing autoclaving sterilization of the insulated volume.

in FIG. 12b is shown a portion of the upper sheet 208, formed with an opening 210, for disposing over the inflated package of the component shown in fig. 12a. The assembled combination of the two constructions in fig. 12a and 12b, is shown in FIG. 12c.

Each component shown in FIG. 12a is manufactured from separate elements and may be subject to quality control examination to ensure the dosage of the components of the treatment fluid, each measured separately. Upon completion of a container, from which the treatment fluid 204 can be delivered in accordance with the invention, an upper foil 208 is stretched and isolated along the dome-shaped portion, including the opening 210, disposed in the opposite side of the inflated package, wherein the fluid for treatment is kept, 204. If a container strip is formed, on a continuous length of the upper sheet 208, then a series of dome-shaped portions are formed, which can be used to simultaneously complete and interconnect a package of containers, according to the invention. Such a package is shown in FIG. 12c.

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The use of a container, of the type illustrated in part by the package in fig. 12c, is usually similar to that in FIG. 11, with two essential differences. First, a cover sheet 212 is not necessarily required, because the treatment fluid 204 is already isolated by the volume defined by the container through the layer 214. However, some forms of cover sheet 212 may still be used, although it is understood that the contact between the cover sheet 212 and the top sheet 208, around the opening 210, does not have effective enclosure isolation at the same extension, as is done at varina shown in fig. 11. Secondly, when the enclosure is pressurized and, in particular, when the volume is watertight, containing the compressed treatment fluid 204, the first effect is to break the weakened portion 216 of the layer 214, and the weakened portion 216 may be designed so that the breakage may have place along the defined axis.

In this situation, the release is similar to the one shown in FIG. 11. The weakened portion 216 absorbs some of the crushing forces during the bursting of the swollen pack, resulting in reduced pressure and reduced tendency of the swollen pack or dome, to break or tear.

If, due to the use of the system or for any other reason, it is necessary to break the weakened portion 216 prior to the actual pressurization of the enclosure, this can be achieved. The use of the discharge device can be adapted so that the base laminate and the upper sheets 206, 208 and the layer 214 are squeezed on the other side of the inflated package, and stretched over the inflated package to break the weakened portion 216 before the plunger, for example, engaging the base sheet 206 at the bump of the enclosure. The direction of such a tightening is indicated by the arrow shown adjacent to the container shown on the left side of fig. 12c.

in FIG. 13 shows the container in which two treatment fluids can be held separately in the same enclosure in which the respective watertight volumes are closed by the weakened portion of the intermediate layer 214. The manufacture, assembly and use of the container are essentially similar to those described with reference to FIG. . 12, but in FIG. 13 also shows a piston or a hammer for delivering the fluid for treatment by opening 210.

It is appreciated that the shapes of the inflated packages, in the base foil 206, and the dome, in the upper foil, may be complementary, so that, when a piston 218 is applied to the inflated package, or to the inflated packages, shown in FIG. 13, the entire portion of the film, defined by the inflated package or the inflated packages, engages the portion of the sheet defined in the form of a dome upon complete evacuation of the enclosure from the treatment fluid or the fluids provided to be contained therein. This is important in treatments where dosages must be strictly defined.

The separate manufacture of individual components, from containers, according to the invention, not only facilitates guaranteed control, but also ensures sterilization and other preparatory procedures. In the embodiments described above, the upper laminating sheet 208 can be used only with a single opening 210, which has been formed. When, in particular, there are several openings required, the preferred material for the upper sheet 208 is a metal sheet in which the openings have been made by photoresist electroforming. Contact of the metal foils directly with the laminate base foils can have a deteriorating effect of the treatment fluid, after being exposed in the swollen package. These effects are much reduced when the fluid

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RO 117294 Bl for treatment is already limited in its own watertight volume, below the intermediate layer

214, and when the upper film 208 is connected to the intermediate layer 214.

In some cases where it is desired the easy release of the treatment fluid through the openings or openings in the dome-shaped wall portion, through which the fluid is released from any of the containers described above, the openings should have thinned the release end, and The diameter of the inlet port should usually be three times larger than the outlet port. The recommended axial length of the opening or openings is 1 to 5 times the diameter of the outlet orifice and the opening may be cylindrical in the outlet.

The terms "dome and" double dome "were used in the above description, with reference to fig. 11 and 13, in a very broad sense. They do not intend to specifically or necessarily define a symmetrical form of the opening in containers according to the invention. Other forms can be used with equivalent effects. What is important is the arrangement of the openings or openings in the peak region of the enclosure, whereby the release of fluid is directed from openings or openings, when the enclosure is pressurized.

in the system illustrated in FIG. 14, 15, and 16, individual bags 222, for the treatment fluid, are mounted on a tape 224. Each bag 222 is pear-shaped and held behind or on a support sheet 226, for use as needed. Each sack 222 has a portion 228 of the slim wall, located adjacent to a cut in the support sheet 226.

When used, the tape 225 is mounted in a device so as to locate a bag 222, at a discharge station. At the unloading station, two opposing pistons or hammers 230 are constructed so as to act on each other. This compression of the bag 222 is shown in FIG. 16, in which the contents of the bag are forced in the desired direction. The pistons or hammers 230 are then withdrawn, release the emptied bag, which is then removed, and another full bag is positioned.

The portion of the weakened wall 228 may be very small, in order to have a more precise focus when unloading on the chosen area. In addition, it may be a line with weakened portions along the diameter or, in another embodiment, a network of weak points in a certain predetermined manner.

The container shown in FIG. 17 contains juxtaposed foils 232 and 234, for example 30 pm aluminum foil laminate and 40 pm copper foil, respectively formed and held around the continuous trajectory by a layer of molten adhesive 236 so as to form a watertight balloon in which it is limited unit dose 238 to 8 µl, from the tread fluid . Each foil 232, 234 forms half of the balloon wall and, at the top of the dome formed by the copper foil layer 234, has a single opening of 100 pm, usually made by drilling, drilling, electroforming or laser drilling. Layer 236 forms edges on the other side of the balloon, and a container strip may be made over a continuous length of layer 236.

The device shown in FIG. 18 has a dosing station 240, provided with two pairs of fastening plates 242, which define a path for the container strip as shown in FIG. 17, with continuous edges, formed from layer 236, arranged

RO 117294 Bl between the respective plate pairs. When the device is ready for operation, the plates 242 are fastened together to hold the curb and then the balloon, in the proper position in the dosing station. The respective plates can be fixed by twisting, by an element 244, or by an automatic mechanism, activated by triggering the device.

Locating the container at the metering station requires alignment with a piston 246, mounted to be able to make an axial linear movement, in a main housing 248. The piston 242 is mainly supported in a panel 250, rear, mounted in the housing 248, and which is guided at the front end by a guide screw 252, to which the piston is attached. The compression between the panel 250 and the guide screw 252 is exerted by a spring 258, and the compression is provided by a ratchet 254, which engages the front of the guide screw 252. The actuation of a trigger mechanism 254 releases the guide screw 252 and the piston 246, which then it is pushed by the spring 258 when the area near the "balloon" is engaged and forces the contents of it out of the container, through an opening of 100 pm. When reconnecting the device for later use, the piston 246 is slightly retracted against the force of the spring 258, up to the guide screw 252 and then caught behind the paw 254. The guide screw 252 is counterbalanced by a counterweight 256, at the other end of the piston 24, which will later be used in pulling the piston 246 against the force of the spring 258.

The device of FIG. 18 was used to study the ocular response of rabbits to a treatment according to the invention. The rabbits selected for the study were acclimatized 4-5 days before treatment. They were immobilized for 2 days before the study, under their conditions, and subjected to the procedures involved in dosing. A device such as that shown in FIG. 18 was used for single dose administration, in spray form with 2% isotonic pilocarpine hydrochloride solution (pilocarpine HCI) on the surface of the cornea in the left eye in every 5 rabbits, the right eye not being treated. The sets were used under the following conditions:

- 100 pm diameter of the hole

- 2,5 cm distance between the hole and the eye of the animal

- the sprays directed towards the center of the cornea of ​​the eye of the animal.

The miotic response, the reduction of pupil diameter, at various intervals, following the application of HCI polycarpine solution, was monitored under constant illumination, using video photography. The diameter of the pupil of the left eye was expressed in relation to the diameter of a fixed reference aperture, located at an equal distance from a video camera. The resulting diameter was then calculated from the known diameter, compared to the reference opening.

The table below shows the diameter of the pupil from the left eye at different intervals, in the case of using the solution in the dosage test, as shown graphically in fig. 19. The table shows the diameter of the pupil (mm) when using the 2% pilocarpine HCI solution using the laboratory model swollen device, at an average of 5 rabbits.

500

505

510

515

520

525

530

535

Time measurement

<td></td><td>Dose (Omin)</td><td>+15 min</td><td>+30 min</td><td>+45 min</td><td>+1 hr</td><td>+1.5 h</td><td>+2 hr</td><td>+2.5 h</td><td>+3 h</td><td>+3.5 h</td><td>+4 h</td>

<td>Mediate</td><td> 7,8</td><td> 6,7</td><td> 6,8</td><td> 6,9</td><td> 6,8</td><td> 6,9</td><td> 7,3</td><td> 7,8</td><td> 7,9</td><td> 8,0</td><td> 7,8</td>

540

RO 117294 Bl

The devices presented in the invention can generate small droplets with a diameter of around 2DO pm, while also allowing the release of multiple small droplets, in measured doses of very small volume, 5 pl being characteristic. However, some smaller drops may be desirable in some cases, as may be larger in others. The characteristic release speed is 10 m / s, but other speeds can also be used in some particular cases. Due to the manner in which the doses are delivered, they have a much better effect than traditional treatment techniques, in which doses of 50 µl are used. Using a device like the one of the invention, in the ocular treatment a large proportion of the treatment fluid will actually have contact with the eye, leading to a lower wastage, reducing the risk of systematic absorption and less flow of the eye, eliminating the risk of causing blinking of the eye or tearing which will result in fluid wasting during treatment.

The fluids for ophthalmic treatment, which can be used with the device of the invention, can be aqueous or non-aqueous liquids, optionally containing also therapeutic or other components such as:

1. Anti-glaucoma (intraocular pressure) low components a) β-adrenoceptor antagonists, for example carteolol, cetamol, betaxolol, lelobunolol, metipranolol, timolol etc.

b) miotics, for example pilocarpine, carbacol, phisostigmime, etc.

c) sympathomimetics, for example adrenaline, dipivephrine, etc.

d) carbonic anhydrous inhibitors, for example acetazolamide, dorzolamide, etc.

e) prostaglandin, for example PGF-2 alpha

2. Antimicrobial components (including antibacterial and antifungal), for example chloramphenicol, chlortetracycline, ciprofloxacin, framicetin, fusidic acid, gentamicin, neomycin, norfloxacin, ofloxacin, polymyxin, propamidine, tertacycline, tobramycin, etc.

3. Antiviral components, for example acyclovir, cidofovir, idoxuridines, interferons, etc.

4. Aldose surplus inhibitors, for example tolestate, etc.

5. Anti-inflammatory and / or anti-allergic components, for example steroidal components such as betamethasone, clobetazone, dexamethasone, fluorometolone, hydrocorrisone, prednisolone, etc. and non-steroidal components such as antazolin, bromphenac, diclofenac, indomethacin, lodoxamide, saprophen, sodium chromoglycate, etc.

6. Artificial tear / dry eye therapies, comfortable tears, irrigation fluids, etc., such as psychological salt, water, or oils; all optionally containing polymeric components such as acetylcysteine, hydroxyethyl cellulose, hydroxymelose, hyaluronic acid, polyvinyl alcohol, polyacrylic acid derivatives, etc.

7. Diagnostics, for example fluorescent substances, pink flare etc.

8. Local anesthetics, for example ametocaine, lignocaine, oxbuprocaine, proximetacaine, etc.

9. Components that help heal corneal surface defects, for example cyclosporine, diclofenac, urogastrone and growth factors such as epidermal growth factor, etc.

10. Mydriatics and cycloplegics for example atropine, cyclopentolate, homatropin, hisocin, tropicamide, etc.

11. Components for the treatment of pterygium, such as mitomycin C, collagen inhibitors (eg batimastat).

RO 117294 Bl

590

12. Components for the treatment of macular degeneration and / or diabetic retinopathy and / or cataract prevention.

13. Components for systemic effects following blood absorption after ocular administration, for example insulin.

The above components may be in the form of acids or bases or other alternatives such as salts thereof. Combining components such as, for example, an antibacterial component with an anti-inflammatory component, may be desirable for optimizing therapy in some cases. The components may be formed as aqueous or non-aqueous solutions (for example, oily). The preparation may optionally also contain other preparation excipients, for example thickening agents such as gels, mucoadhesives and polymers, stabilizers, antioxidants, preservatives, pH tonic adjusters, etc.

It is appreciated that the devices according to the invention may contain a single unit, as well as a modular system in which the delivery mechanism and the source of the treatment liquid are assigned separately, or at least independently of one another.

Modular systems require that the treatment fluid be selected, and coupled with the desired distribution mechanism. This makes it possible for the same distribution mechanism to be used for different treatments. Such a device, according to the invention, for institutional use can make such a selection at least partly automatic.

claims