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1. (WO1997017037) INTRAORAL ADMINISTRATION DEVICE AND SYSTEM
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Intraoral administration device and system

The object of the present invention is an intraoral administration device comprising an elongated, substantial-ly plate-like curved oral screen designed to conform to the teeth and intended to be positioned in the space between the teeth and the lips. The object of the present invention is also an administration system, which comprises the administration device according to the inventi-on in combination with an active agent.

By means of the administration system according to the invention it is possible to provide a sustained local therapeutic effect in the region of the mouth and throat which is adapted to take into account the eruption order of the teeth and the location of the salivary glands, while simultaneously satisfying the physiological sucking need and craving for sweetness of small children, using small dosage levels tolerated by children and without causing malocclusions, especially when the sucking need of the child continues too long from the orthodontic point of view.

Various dispensing pacifiers are known (for example US-patent 4,078,566, GB-patent application 2 181 957A; EP patent 0 494 904, Fl-patent application FI-A 921411, US patent 5,395,392; and the commercially available CANNON babysafe Minifeeder) . Suhonen (1992) has presented the theoretical background for the use of a pacifier like administration device which slowly releases fluorides, xylitol, monoclonal caries antibodies or lactoperoxidase enzyme components into the mouth, in a prophylactic method for the prevention of dental caries. The operability of a dispensing pacifier for releasing sodium fluo-ride, xylitol and sorbitol from a tablet has been established in vitro , and the administration from a pacifier of passive vaccines against microbes causing oral di- seases has been suggested (Suhonen et al, 1994) . A pacifier prototype for dispensing sodium fluoride, xylitol and sorbitol has in our field trial with children of the age of 16 months proved to be a functioning means with potential for development for the treatment of diseases of the mouth and throat of children in the sucking-age. In our follow-up study it also became evident that in the group of children that had accepted the test pacifier, there appeared significantly less often infection of the middle ear (otitis media, 48 % versus 70%) than in the comparison group. Recently it has been shown that xylitol also inhibits the growth of Streptococcus pneumoniae (pneumococcus) (Kontiokari et al 1995) . According to one report (October 1996) the use of a xylitol bubble gum several times a day has reduced infection in the middle ear in kindergarten children in Oulu. The mouth cavity can thus be an area of primary defense in the battle against bacteria aiming for the middle ear.

In the continuous follow-up of our study cohort, it has been established that malocclusions in children using a pacifier become significantly more common when the use of the pacifier continues beyond the age of two. For this reason, taking into account the individual dentoalveolar jaw development, the pacifier should be given up at the stage of eruption of the deciduous molars which, on an average, coincides with that age, at which stage the sucking-need of a child optimally should already have changed into a chewing-need (Laitinen 1995) . To prevent malocclusions Varrela and Alanen (1995) have presented an extensive pacifier study with an aim at finding a pacifier model which broadens the dental arch of the upper jaw. Prolonged pacifier sucking has also been alleged to cause middle ear infection (Niemela 1984) . On the other hand, if the pacifier is taken away from a child too early, he easily becomes a thumb-sucker which, from the point of view of bite development, is an even worse habit than sucking a pacifier. Also deciduous dentition destroyed by early caries attack cause displacements and maloc-clusion of the permanent teeth.

According to the invention, an administration device of the oral screen type has now been developed, by means of which an active agent can be slowly released into the mouth of a child, especially after the pacifier stage, in a manner preventing deformation of occlusion.

The invention is based on a so-called oral screen, that is an elongated, substantially plate-like device with an arcuate longitudinal cross-section, to be inserted in the space between the lips and the teeth. The administration device is characterized in that the oral screen comprises containers for an intraorally administrable agent which containers are provided with means, such as holes or apertures, allowing the free entrance of saliva into the containers and its exit therefrom.

The oral screen (OS) is a device known in orthodontology which is kept in the space (vestibulum oris, VO) between the teeth (T) and the lips (L) to push backward front teeth protruding in an open bite caused by a pacifier, lip-sucking or visceral act of swallowing (Fig. 1) . In addition to oral screens individually manufactured in a dental laboratory, serially produced screens of different size are available, which are provided with a ring and are elastic or made from a harder plastics material (the first ones were made in 1956, the material being polyamide, Dr. E. Schδnherr, Radebeul. DDR; presently known manufacturers: Dentaurum, Germany; Dentamar, Holland, My-ofunctional Research Co., Australia), which are sold and used for the main indication of strengthening poorly de-veloped lip muscles and for breaking detrimental habits. It is known to provide the screen with additional means for guiding the position of the tongue or prominences for guiding the bite, such as a cap for the lower front teeth to bite into (Prof. R. Hinz, Heme, West-Germany, material "Duralan", year 1974; DE 3 840 178 Al) . In a distal occlusion, the cap facilitates in keeping the device in place and accommodates the masticatory muscles so that growth is possible in the condyle area, which in favourable instances, in addition under the control of the inclined plane of the cap, moves the lower jaw permanently forward in an orthognathicly more correct position with respect to the skull base. Also a combination of an oral screen and a sucking piece of a pacifier is known (CH-pa-tent 662 271 A5) . There is need for orthodontic
prophylaxis (Laitinen 1995, Varrela and Alanen 1990) . There is, however, one problem with respect to taking an oral screen into use, namely pacifier users under the age of 3 and thumbsuckers under the age of 4 do not want to keep it in the mouth. When training the use of an oral screen, it can in a transitional period, in order to facilitate the adaptation process, initially be provided with a pacifier-like sucking piece which is acceptable to the child. One should, however, relatively soon get rid of the model provided with a sucking piece.

According to our invention, an oral screen of the known type has been provided with containers for the agent to be released into the mouth. One idea according to our invention is that when a good tasting substance, for example non-cariogenic xylitol (X) is placed in the dispensing containers in the cheek flanges of the oral screen (OS) , and the xylitol slowly dissolved primarily under the effect of saliva secreted from the glandula parotidea (parotid saliva, PS) gives the children a pleasant taste sensation (Fig. 2) , such a device can be used to wean already a 2-year old child from teeth-dama-ging sucking habits, such as a sweet bottle, pacifier and perhaps also thumbsucking. As it, in addition, prevents mouth breething (Darby 1890) , the nose cavities are en- larged and remain open more easily, reducing simultaneously the risk for middle ear infection. Xylitol as such prevents middle ear infection (Uhari et al 1996) . In mouth breathers, when the mouth is open, the stretched strong cheek muscles compress and flatten the upper jaw bone, whereby crossbites are easily developed on the sides. The oral screen removes the pressure of the muscles on the upper dental arch, allowing the arch to broaden freely, for example pushed by the pressure exerted by the tongue when swallowing. The taste buds in the tongue tip are sensitive to sweet. When the substance containers according to the invention are placed in the back and to the sides near the parotid gland duct (Fig. 2) , the sweetener dissolved by the saliva (Xd) makes the child ins-tinctively move the tip of the tongue. The pressure of the tongue resulting therefrom should reduce the risk for crossbites at the canine tooth area.

A suitable sweetening agent for use in the said applica-tion would be, for example, xylitol, which per se has several beneficial effects on the teeth (Arends et al . 1984, Muhlemann et al . 1970, Mέikinen 1978, Makinen and Isokangas 1988, MSkinen and Scheinin 1982, Scheinin and Makinen 1975, Sδderling and Pihlanto-Leppala 1989, Sδder-ling and Scheinin 1991, Touster 1960) . Further possible non-cariogenic sweetening agents for the said use are i.a. saccharin, acesulfam-K, cyclamate, aspartame, alita-me, thaumatins, rebaudocides, glycyrrhizin, sucralose and neohesperidin dihydrocalcone, although some of these are restricted in use and for others the safety testing and practical experience are still insufficient (Grenby
1991) .

Xylitol is not able to cause bacterial acid production wherefore it is a cariostatic agent (Miihlemann et al .

1970, Scheinin and Makinen 1975). In addition to the said cariostatic effect xylitol possesses apparent bacterial adhesion and accumulation inhibiting properties, and consequently it can reduce caries and middle ear infection in long term and frequent administration (Makinen 1978, Isokangas 1994, Kontiokari et al 1995, Uhari et al .
1996) . Contrary to, for example sorbitol, xylitol causes in bacteria a so called "futile xylitol cycle" which uses much energy (Sδderling and Pihlantoo-Leppέila 1989) . Many so called xylitol products contain more than 30 % sorbitol. Such products should not be used in our administra-tion system, unless they are used together with further effective caries inhibitors, such as sodium fluoride. The Xylitol-Fludent fluoride tablet which is in general use in Finland, contains sorbitol 50 %. Due to its sweet taste, children usually take it eagerly, and due to its so-dium fluoride content it is suitable for use in the administration device according to the invention. By applying the oral screen strategy, it is possible to create for hours an oral fluid environment around the erupting teeth, which according to our studies have appa-rent caries preventing properties. Care has to be taken that the sweetening or other agents used are not ca-riogenic, i.e. do not cause caries. Preparations, wherein the proportion of xylitol as a sweetening agent is over 70%, can usually be held as cariostatic and safe for the teeth. A disadvantage of xylitol and other polyols is, however, their slow absorption from the intestine, especially in small children, whereby large doses can lead to osmotic diarrhea.

It is generally believed that the fluoride ion does not under normal conditions affect the colonization of mutans streptococci (MS) (Kilian et al . 1979, van Houte et al . 1978, Zickert and Emilson 1982). According to one theory, however, the fluorides, at least at stronger concentra-tions, prevent the bacteria from adhering to the tooth surface by reducing the adhering electrostatic forces (Rδlla 1977a) . Usually the caries-preventing effect of fluorides on the teeth is associated with the capacity of the fluoride ion to harden the tooth surface and promote remineralization. In addition, the fluoride ion disturbs the carbohydrate metabolism of mutans streptococci and thus reduces the acid production in plaque (Hamilton 1977, Harper and Loesche 1986).

The adhesion of bacteria can be prevented also with substances of the lectin type, which have been found spe-cies-specifically i.a. in milk and in plant seeds (for example Neeser et al . 1988). Further optionally applicable agents are non-specifically antibacterial enzymes (Lenander-Lumikari 1992) . One additional alternative is to add protecting agents in an amount sufficient to pre-vent the accumulation (aggregation) of plaque, acid production or other virulence factors, or use remineralizing agents which inhibit the damaging symptom of caries, demineralization of the tooth, of which agents the effect of the fluorides has been known for already half a centu-ry.

Interesting from the point of view of our inventive administration device are i .a . the caries antibodies produced in egg yolk (Sun GY, Taiyo Kagaku Co., Ltd, Japan) and the monoclonal mouse anti-mutans-streptococci antibodies (Ma and Lehner 1990, Ma et al . 1990). One relatively cheap method of producing antibodies is the so-called immune milk which method has been considered safe for human use. Immune milk can be produced by vaccinating a preg-nant cow against certain pathogens, whereby the cow organism forms antibodies to these diseases, which are transferred to the colostrum. The remedying effects of immune milk are long known. Also known is a caries preventing cow immune milk product, which contains specific antibodies to killed Streptococcus mutans - cells (US-patent 4,324,782). Immune milk has also been prepared against the cariogenic MS-species S . sobrinus, and the anti-MS-affect of an immune whey product has been studied also in vitro . The efficiency of a corresponding anti-S. mutans -whey product has been shown earlier in animal and human tests in adults (Michalek et al . 1987, Filler et al . 1991).

By means of an administration device which releases effective antibodies slowly into the mouth, a relatively sustained effect on the microflora of the mouth and throat is obtained with small doses. It is thus of importance that the used antibodies do not disturb the development of the normal flora which is important for the health of the mouth. As regards ear pathogenic pneumococ-ci it is expected that an octavalent polysaccharide anti-gen vaccine conjugated to a protein carrier will to a large degree remove the problem of middle ear infection due to pneumococci (Giebink 1994) . Thus Heamophilus influenzae (non-type b) and Branhamella (Moraxella) catarrhalis remain which are more difficult to treat and against which there is no known vaccine. Of these, the former is better known to its living habits. It has been shown already a long time ago that H . influenzae lives also in the mouth region, and its uncapsuled form (non-type b) is a quite common cause for recurrent middle ear infections in under 5 year olds. An IgG-antibody dispensed by the administration device against middle ear infection causing bacteria in a prophylactic manner could be surprisingly effective, even though the mechanisms are not known in detail (Kauppi et al . 1993).

An immune whey powder obtained from immune milk containing antibodies primarily of the IgG-type against middle ear infection contains also lactose, which stabilizes proteins and facilitates compressing of the powder into tablet form. It is possible to remove the lactose and replace the same at least partly with xylitol. An addition of xylitol would be beneficial because of the ex- pected additive anti-caries and anti-otitis effect, and its protein stabilizing property.

It is in principle possible to make accurate monoclonal antibodies against any virulence factor of a microbe, after it has been identified, using known hybridoma and gene manipulation techniques. Perhaps the so far most promising anti-cariotic antibody preparation is the monoclonal IgGl-type antibody against the adhesive protein antigen SA I/II of the S. mutans cell wall (Ma et al . 1990) . By treating the teeth with this antibody it has been possible to prevent the return of MS in the tooth plaque of adult humans (Ma and Lehner 1990) .

Thus, in order to administer the afore mentioned and other active agents, an administration device is used according to the invention, which at the same time functions as an orthodontic oral screen preventing the development of jaw deformities. New in the invention is the fact that the active agent in a suitable manner is combined with the oral screen, suitably in containers in the oral screen or associated therewith, in which containers the agent can be introduced in the form of a tablet, lozenge mass or a cellulose, gelatin or nonwoven fabric disc (for example Fibrella, Suominen Oy, Nakkila, Finland) "impregnated" with the agent, and from which the active agent, for example through holes, is released into the oral cavity. The characteristics of the invention are given in the appended claims.

The administration device is preferably provided with a gripping means attached to the outer surface of the oral screen, that is to the surface facing the lips or the cheeks in use, the gripping means extending outside the mouth and which can also be provided with a gripping ring.

According to one embodiment of the invention, the container is formed by a recess made in the oral screen, especially in its end regions, that is in the cheek flanges, and a lid which at least partly covers the recess. If the oral screen is made from an elastic material, the said lid can be a strip-like member forming one piece with the oral screen, which at least partly covers the recess. If the oral screen is made from a hard material, the lid can be hinged to the oral screen and provided with suitable locking means, such as a suitable locking tongue.

The container can also be a cup-like, cage- or sieve-like construction opening outward from the surface of the oral screen, especially from its outer surface, and provided with a suitable lid.

According to a further embodiment, the container can be formed from a sheath-like member made from an elastic ma-terial and slid over the end part of the oral screen in a sealing engagement with the oral screen, which advantageously is provided with a loop member to be slid and tightened over the gripping means of the oral screen.

According to another alternative embodiment, the oral screen is in two-part form and comprises a so-called casing cover, the dispensing containers being arranged in the vicinity of the end regions of the said casing cover, which, in its longitudinal direction, is provided with a sliding slot extending from the center of the cover towards its end regions, and in addition, a sliding plate slidably mounted in a groove or recess in the inner surface of the cover, allowing the containers to be opened, to which plate gripping means are attached, which are slidably mounted in the sliding slot and extending outwards therefrom through the casing cover, as well as means for locking the sliding cover and the casing plate to each other.

In the following, reference is made to the appended drawings illustrating administration devices according to our invention. The Figures show:

Fig. 1 illustrates in a schematic manner an oral screen in its place in the space between the lips and teeth. Fig. 2 illustrates the operation principle of an oral screen provided with dispensing containers in accordance with the invention.
Fig. 3 illustrates an oral screen made from an elastic material seen laterally, at an angle from above.
Fig. 4 the same in a horizontal longitudinal cross-secti-on.
Fig. 5 illustrates an oral screen provided with pill containers with hinged lids, seen from in front, at an angle from above.
Fig. 6 the same as a horizontal longitudinal cross-secti-on.
Fig. 7 illustrates the cross-section of a pill container with a hinged lid.
Fig. 8 illustrates an oral screen dispenser comprised of a sliding cover and casing plate seen from in front, at an angle from above.
Fig. 9 the same as a horizontal longitudinal cross-section, the casing plate in a position of filling with an agent, before attaching the ring, the tablet container on the right hand side being open.
Fig. 10 illustrates a hard oral screen provided with elastic sheath containers seen from in front, at an angle from above.
Fig. 11 the same as a horizontal longitudinal cross-section.
Fig. 12 illustrates a training oral screen (having a pacifier-like dispensing sucking piece) in a horizontal longitudinal cross-section.

The Figs. 3 and 4 show an embodiment of an oral screen dispenser according to the invention, which is made from an elastic material. In this case the whole device with its frame 7, ring 12 and tablet fastening means, which in this case is a strip 8 extending over the tablet container 9, is made in one part from an elastic plastic, for which purpose a stiff silicone is suitable. The strip 8 can be loosened by straightening the arched end part 16 of the cheek flange. By simultaneously pulling the strip 8 to the side, a tablet strictly matching its recess 9 can be placed underneath the strip 8. When the end part 16 is not bent any longer, it strives at regaining its original arched form, tightening the tablet in its place so that a small child cannot remove the same. The bottom of the tablet container 9 is provided with one or more holes 5. In the example, there are four holes 5 placed cylindrically on the outer periphery of the container 9, half outside the edge so that the parotid saliva flowing past the side edges of the fastening strip 8 into the container 9 can flow freely past the sides of the tablet which initially sealingly fills the bottom of the container, slowly dissolving the same, to the inner oral cavity.

The following examples illustrate embodiments made completely or partly from a hard plastic (for example an ABS plastic) :

Figs. 5-7 illustrate an oral screen dispenser, wherein the dispensing containers are pill casings 9 mounted in the cheek flanges of the oral screen and provided with buccally opening hinged lids 6, the hinge part 14 being placed distally. In the cross-section through the plane of the middle seam 15 (Fig. 6) , the left hand pill casing is seen with the lid 6 open. In the lid 6 and in the frame 7 in the bottom of the casing 9, there are holes 5. A locking tongue 6a functions as a locking means for the lid 6, and the lid is opened by gripping and lifting the opening rim 6b.

The Figs. 8-9 illustrate an oral screen dispenser formed by a sliding plate 7 ' and a casing cover 17. The sliding plate 7 ' is provided with a shaft 7a insertable through a mounting aperture 17a in the casing cover 17, the end part of which having recesses 7b into which a ring 12 is fastened. The sliding plate 7' is snap-shut into its groove or casing 18 in the casing cover, when the ring 12 is pulled in an outward direction. At this stage, the right hand tablet casing acting as a dispensing container 9, as seen from the direction of the child, and having a cover 6 with holes 5, is open for filling purposes. By pushing the shaft 7a of the sliding plate to the right hand edge of the sliding slot 17b in the casing cover 17, the left hand tablet casing opens for filling. In the center position of the shaft 7a, which is the normal position of the device in use, the containers 9 in a closed position, the sliding plate 71 is locked into place by means of elastic locking tongues 6a situated at the distal ends of the casing cover, a locking rim 7c in the shaft 7a preventing the sliding plate 7 ' from detaching from the groove 18 in the casing cover 17, if a pushing force were to hit the shaft 7a from the front. For cleaning purposes, the sliding plate 71 can be detached from the groove 18 in the casing cover by pushing the shaft 7a with rim 7c through the mounting aperture 17a inwards. Even in this case the parts do not detach from each other completely due to the ring 12. The ring 12 cannot be released from its recesses 7b by a child, but needs the force of a grown-up's fingers. In the sliding cover there are holes 5 at the tablet containers 9, through which the agent to be dispensed and dissolved primarily by the ef-feet of the saliva from the glandula parotidea can affect the molar teeth region.

Figs. 10 and 11 illustrate an oral screen wherein the frame 7 of the device is made from a hard plastics material and the dispensing containers with their fastening means are made from an elastic material (silicone, rub-ber) . The dispensing container unit is a flat baglike sheath structure 9 resembling the sucking piece of a pacifier, which is pulled, with the tablet 13 to be dispensed inside, over the end of the cheek flange 16 of the plate 7 and is tensioned tightly into place by stretching the loop 11 in the strap 10 of the sheath 9 facing the cheek, over the ring 12 in back of the shaft 7a. Sheaths are needed one for each cheek flange of the oral screen, the tablet recesses in the cheek flanges having in this example one smallish hole 5 made in their bottom. Saliva can freely flow through the holes 3 in the container sheath 9 and the hole 5, as well as due to the lateral clearance of the sheath, through the container 9, inside and out.

As alternative solutions, the afore described individual sheaths 9 can be combined either from their loop straps on the cheek facing side, or so, that the whole surface of the oral screen facing the teeth is covered with a fastening collar means joining the sheaths into one piece having two sheaths.

Fig. 12 illustrates a training oral screen. A child can be trained to use an oral screen while being weaned from pacifier use by providing the oral screen frame 7, on its inside, with a pacifier-like sucking piece 2, for example a dispensing sucking piece. The sucking piece 2 can suitably be made in one piece with the oral screen, for example from soft vinyl, and it can be provided with holes 3 for the active agent, its opening opening up in the oral screen 9. The opening is closed with a plug 24, the continuation part or shaft 25 of which joins two closing shafts 26 arranged substantially in a V-shaped manner with respect to each other and extending to the inside periphery 27 of the sides of the ring-shaped gripping device 12, 12a. The said construction effectively prevents the opening of the plug during use.

The pacifiers and the oral screens can be boiled. Thus the required hygienic level can be reached in domestic circumstances.

For a person skilled in the art it is evident that the invention is not restricted only to the examples shown above, but can vary within the scope of the appended patent claims.

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