AU668615B2 - Oral pharmaceutical administration device - Google Patents

Description

0 *0 0 668615

AUSTRALIA

Patents Act 1990 COMPLETE SPECIFICATION FOR A STANDARD PATENT

ORIGINAL

Applicant(s): BIOGLAN LABORATORIES LIMITED Actual Inventor(s): William H Lee Address for Service: PATENT ATTORNEY SERVICES 26 Ellingworth Parade Box Hill Victoria 3128 Australia Title: ORAL PHARMACEUTICAL ADMINISTRATION DEVICE Associated Provisional Applications: No(s).: The following statement is a full description of this invention, including the best method of performing it known to me/us:-

II

6, la a device for retaining a sustained release or 15 buccal tablet in place in a patient's mouth.

It has been recognised, for more than 10 years, that patients in intensive care units, particularly those who require artifical ventilation, are extremely 20 susceptible to bacterial infection. In many cases, despite good nursing care, patients die from bacterial infection rather than from an original traumatic injury. Gram-negative bacteria are responsible for most of these potentially pathogenic infections. Once -2a patient has been admitted to hospital, his endogenous aerobic flora are replaced by nosocomial (hospital originating) gram-negative bacteria, such as Pseudomonas, Aclnetobacter and, Klebsiella, which may rapidly colonise the oropharynx, stomach and intenstines. Once the digestive tract has been so colonised, subsequent colonisation and infection of major organ systems mzay occur.

10 More than 80% of critically ill patients are colonised 99* 'by nosocomial gram-negative bacteria within 10 days of *.9 9 9 admission to hospital (Northey et al. (1974), Surgery, Gynaecology, and Obstetrics 139 321-5; Sheild, Hammill and Neale (1979), Intensive Care Medicine 5 15 171-81 and; Thorpe, Richards and Telfer (1979) Anaesthesia 34, 643-50) and these organisms are responsible for the majority of late infections (Rose Babcok (1975) American Journal of Epidemiology 10 495-501 and; Weinstein and Kabina (1981) American 999o ;20 Journal of Medicine 70 449-54). Considerable success has been achieved in reducing the incidence of such infection by the prophylactic administration of non-absorbable antibiotics to selectively decontaminate the digestive tract. The antibiotics are selected to -3eliminate the potentially pathogenic aerobic gramnegative micro-organisms from the digestive tract, leaving the mainly endogenous anaerobic flora substantially unaffected. This work was carried out by C. P. Stoutenbeek and H. K. F. Van Saene and co-workers since 1982 and has been reported in:- Journal of Antimicrobial Chemotherapy (1984) 14 supplement B, 203-211; Journal of Antimicrobial Chemotherapy (1987) 19 513-520 and; Intensive Care Medicine 10 (1986) 12 419-423. The non-absorbable antibiotics were administered through a nasogastric tube, in the form of an extemporaneously prepared suspension of Polymyxin E Tobramycin and, amphotericin and applied to the buccal mucosa in the form of 15 a commercially available paste (ORABASE Registered Trade Mark, available from Squibb) containing 2% polymyxin E, 2% tobramycin and 2% amphotericin B. Both preparations were administered to patients every four hours, with gastric suction being applied for the first 20 hour after administration. To prevent infections of the respiratory tract, systemic antibiotic prophylaxis may also be given to multiple trauma patients.

4- Although prophylactic and selective decontamination of the digestive tract has proven to be very successful, i4 is difficult and tim consuming in application.

These difficulties have prevented the method from becoming more widely used.

According to Patent specification No. 63,452/90 there is provided a pharmaceutical tablet or lozenge, comprising a non-absorbable pharmaceutically active agent in combination with a tablet matrix arranged for providing controlled and sustained release of said 0~**agent Into the mouth and ga stro -intestinal tract, from a buccal or sub-ling-ual location. The term non-absorbable, when used herein to describe a pharmaceutically active agent, def ines such an agent that Is not absorbed into the blood, or bodily fluids in any substantial quantity from a normal and untraumatised human digestive tract.

Preferably, the tablet matrix is formulated so as to be erodible on exposure to the fluid present within the mouth.

An advantage of a pharmaceutical tablet or lozenge in Specification No. 63,452/90 is that when placed in a buccal Or sub-lingual location in a patient 's mouth, the tablet provides a controlled and sustained dose of the pharmaceutically active agent to the entire digestive tract.. from the mouth to the large intestine. Since the pharmaceutically active agent is non-absorbable, any systemic side effects that the agent may have are avoided and the likelihood too:t 10 of creating resistance to the agent is reduced. when the tablet matrix is chosen to be erodible, no residue or empty shell remains in a patient's mouth after the :active agent has been discharged.

V. 15 Buccal tablets, sub-lingual lozenges and conventional pharmaceutical tablets are all formulated to include pharmaceutically active components. The distinction 0: between a buccal 'tablet and a conventional pharmaceutical tablet arises from the mani~er in which a 20 buccal tablet Is used. In use, a buccal tablet is placed between the lip and the gum and allowed to dissolve, or otherwise release its pharmaceutically active component. With all hitherto known buccal tablets, this active component is then absorbed through -6 the buccal tissues of the mouth. A sub-lingual lozenge is similar, however it is designed to be placed under the tongue to dissolve, or otherwise release its pharmaceutically active component, which, conventionally, is absorbed through the sub-lingual area of the mouth.

Erodible pharmaceutical tablets formulated to provide a sustained and controlled release of a medicament from 10 within the stomach are known and, for example, may be S.

Q

formed by compressing a hydroxypropylmethyl cellulose (available from the Dow Chemical Corporation under the Trade Mark Methocel) in admixture with a pharmaceutically active ingredient and other 15 pharmaceutical excipients. See "Formulating Sustained Released Pharmaceutical Products with Methocel" The Dow Chemical Co., 1982. However, in these tablets the active Ingredient is of a type uhich acts systemically by oral administration Into the gastro-intenstinal 20 tract, followed by subsequent absorption into the blood.

Controlled release buccal tablets and sub-lingual lozenges may also be formed from hydroxypropylmethyl cellulose and a suitable medicament. However as -7suggested above, such tablets and lozenges, conventionally, contain medicaments which are absorbed through the buccal or sub-lingual tissues of the mouth.

Compositions for sustained and controlled release tablets, including buccal tablets and sub-lingual lonzenges, are described in 2ritish Patent No. 1583801 and Published British Patent Application Nos. 2061950; 10 2111386 and 2117239 and European Patent Application No.

S. S• 0157695, all in the name of Forest Laboratories Incorporated of 150 East 58th Street, New York, N.Y.

."-United States of America.

15 In a preferred embodiment in 63,452/90, the tablet matrix includes a water soluble cellulose derivative, which may be a hydroxypropylmethyl cellulose or a mixture of hydroxypropylmethyl celluloses. In a preferred 20 embodiment, the tablet matrix includes an ethyl cellulose and a salt of carboxymethyl cellulose, preferably the sodium salt.

Hydroxypropylmethyl celluloses are commercially available in several different grades. These include METHOCEL E,F,J, and K manufactured by the Dow Chemical Co in the United States, HPM, manufactured by British Celanese, Limited and )METALOSE SH manufactured by Shin-Etsu KK in Japan. The various grades available under each of the aforementioned Trade Marks represent differences in methoxy and hydroxypropyl content as well as molecular weight. The designations of the 10 various hydroxypropylmethyl celluloses are based on the 'o* viscosities of 1% aqueous solutions at 200C. The viscosities range form 15 cps to 30,000 cps.

The rate at which an active ingredient is released from 15 a tablet in accordance with 63,452/90 held S. in a buccal, or sub-lingual location and the total period over which such a tablet remains active may be determined by altering the total and relative amounts of different grades of hydroxypropylmethyl cellulose in 4e4 20 the tablet matrix. Thus, for exampl a tablet may be formulated to release its entire d,;se in a matter of minutes, or to release its dose at an even rate over a period of several hours. Up to eight hours being possible.

-9- In a preferred embodiment, the non-absorbable pharmaceutically active agent is a non-absorbable antibiotic agent, or a mixture of such agents, Preferably, said antibiotic agent or agents is or are selected to have a narrow spectrum of activity and to be active only against selected potentially pathogenic organisms. A tablet or lozenge in accordance with these preferred embodiments may be administered to a patient, in a buccal or sub-lingual location, in order to 10 provide the patient with a sustained prophylactic dose Sof antibiotics and to selectively decontaminate the patient's digestive tract. Thus the complexities of the previously practiced method of prophylactic and selective decontamination of the digestive tract, 15 including the use of a nasogastric tube extemporaneously prepared antibiotic mixtures and gastric suction, may be replaced by the simple and regular administration of a tablet to the buccal or sub-lingual area 20 of the patient's mouth.

In a further embodiment in 63,452/90, the non-absorbable antibiotic agent is a non-absorbable aminoglycoside, a non-absorbable polymyxin, a non- 10 absorbable polyene, a non-absorbable substituted imidazole derivative, or a mixture of such agents.

Preferably, a tablet includes at least two and preferably three suc antibiotic agents. More preferably the antibiotic agents belong to different ones -of the above classes.

The non-absorbable aminoglycosAide may be a non-absc -bable form of tobramycin, frarncyetin, neomycin, netilmicin, gentamicin, or streptomycin.

The non- absorbable polymyxin may be colistin sulphate, sulphur methylated colistin. The antifungal polyene may be nystatin or axphotericin B. The non-absorbable substituted imidazole derivative may be *000 15 non-absorbable forms of ketoconazole, miconazole or, clotrimazole.

In a furth~er embodiment, the tablet matrix comlyrises a salivation promotion agent,. an inert tablet filier and an inert tablet lubricant. Varying the amount and nature of the f illers and lubrica, in a tablet or lozenge, provides a further method of adjusting the rate of release of an active Ingredient -and the period over which the ingredient is released.

11 In an alternative embodiment, the non-absorbable agent is selected for treating the digestive tract of immuno compromised patients, such as those with leukaemia or HIV infection or others who have undexgone transplant surgery. In a further alternative embodiment the non-absorbable agent is benzylmetronidazole.

Two buccally administered pharmaceutical preparations are currently available in the United Kingdom. The 10 first is sold under the Trade Mark SUSCARD BUCCAL by.

Pharmax Ltd. of Bourne Road, Bexley, Kent. and includes lactose in its formulation, together with

S.

glyceryl trinitrate as the active ingredient. The second preparation is sold under the Trade Mark 15 BUCCASTEM by Reckett and Colman Ltd. of Dansom Lane, to Hull, North Humberside. and contains sucrose in its fornTulatton, together with prochloroperazlne maleate as the active Ingredient.

20 Since both lactose and sucrose are carigenic it is most likely, in view of their site of administration, that repeated use of buccal tablets or sub-lingual lozenges containing these sugars will cause dental caries. The risk of causing dental caries would be 12 particularly acute with sustained and controlled release buccal tablets or sub-lingual lozenges including sucrose or lactose, because these must reside in a patient's mouth for long periods of time.

According to 63,452/90 there is provided a pharmaceutical tablet or lozenge for administration in a buccal or sub-lingual location, comprising a pharmaceutically active agent in combination with a non-carigenic sugar. Preferred non-carigenic sugars include sorbitol, mannitol and, xylitol. Advantageously, prolonged use of a tablet will not promote the formation of dental caries in a patient's teeth.

4 Surprisingly, the administration of buccal or sub-lingual tablets that include non-carigenic sugars does not cause the gastro-intestinal disturbances, that normally are associated with the use of such sugars.

20 This is believed to be because such disturbances result from an immediate administration of the sugar in gram quantities; whereas a typical buccal tablet includes about 100 mg of sugar and the sugar from the tablet is released more slowly than with a conventional tablet.

13 In a preferred embodiment in 63,,452/90, a buccal tablet or sub-lingual lozenge comprises less than 200 mg of non-carigenic sugar and preferably less than 100 mg of non-catigenic sugar.

In a further preferred embodiment in 63,452/90 a buccal tablet or sub-lingual lozenge 10 includes a water soluble cellulose derivative, which may be a hydroxypropylmethyl cellulose or a mixture of 9 Shydroxypropylmethyl celluloses. In a preferred embodiment, the tablet includes an ethyl cellulose and a salt of carboxymethyl cellulose, preferably the 15 sodium salt.

9 9 9 Further embodiments in 63,452/90 Invention include hydroxypropyl cellulose, tablet lubricants, such as magnesium stearate, stearic acid, sodium fumarate and colloidial silicon dioxide plus other components, such as flavourings and artifical sweetners, such as aspartame.

14 The pharmaceutically active Ingredient In the composition in 63,452/90 may t be selected f rom a vide range of possibilites. It may be systemically absorbable through the buccal muCosa or sub-lingual tissues of the mouth,? or be non-absorbable for administration to the entire digestive trc. Examipl es of activ ingredients suitable for use In compositions in accordance with the second aspect of this invention include antacids,, *eo* 10 anti-inflaiatory substances, coronary vasodilators, .*cerebral vasodilators, peripheral vasodilators., anti-infectives, psychoteoptics, anti-manics, *stimulants, anti-histamines,. laxatives, decongestants, vitamins, gastro-intestinal sedatives., anti-diarrheal preparations, anti-anginal drugs, axtiaxrythmics, anti-hypertensive drugs, *vasconstrictors, anti-coagulants, anti-thrombotics, analgesics,. anti-pyretics,, hypnotics, sedatives,.

anti-emetics, anti-nau siants, anti-convul sants, neuromuscular agents, hyper- and hypoglycaemic agents, thyroid preparations, diuretics, anti-spasmodics, mineral and nutritional additives, anti-obessity drugs, anabolic agents, anti-asmatics, expectorants, cough sixrpressants, antibiotics and 15 other anti-microblal agents, topical analgesics and local anaesthetics and, polypeptides.

In a preferred embodiment of the invention, in 63,452/90, the tablet matrix Includes a non-carigenic sugar, such as sorbltol, mannitol or, xylitol.

Advantageously, the prolonged use of a tablet in 10 accordance with this preferred embodiment in 63,452/90 will not promote the So.

formation of dental caries in a patient's teeth.

Furthermore, as set out above, administration of buccal or sub-lingual tablets that include non-carigenic 15 sugars does not cause the gastro-intestinal disturbances, normally associated with the use of such sugars. This is believed to be because such disturbances result from an immediate administration of the sugar in gram quantities; whereas a typical buccal tablet includes less than 100 milligrams of sugar and the sugar from the tablet is released slowly over a significant period of time.

16 A difficulty, which has been encountered during the past and in connection with buccal tablets, is that such a tablet may become dislodged from between a patient's lip and gum, before all of its active ingredient has been released. The risk of this eventuality is more acute with patients in intensive care units, who are often partially or totally unconscious, Accordingly the present invention provides a tablet retaining device comprising means engageable to a patient and means for 0* accommodating and retaining a pharmaceutical tablet or lozenge, wherein the device is arranged to hold a tablet or lozenge in a location with a patient's mouth, 0 from which an active ingredient, from the tablet or 0. lozenge, is releasable by the action of the patient's i saliva or other fluid within the mouth.

.Advantageously, a device in accordance with the present invention can be used to accommodate and retain a pharmaceutical tablet, comprising a pharmaceutically active agent in combination with a tablet matrix arranged to provide controlled and sustained release of said agent, on 17 exposure to a fluid in a patient's mouth. The pharmaceutically active agent can be non-absorbable and the device, therefore, used in a method of treating a patient'a mouth and gastro-intestinal tract with such a non-absorbable agent. Preferably, the device is used to hold a tablet or lozenge in accordance with the 63,452/90 for use in any of the treatments in which tablets or lozenges in accordance with 63,452/90 may 10 be used. The most preferred of these treatments is S" that of providing a patient with a sustained prophylactic dose of antibiotics, to selectively decontaminate the patient's digestive tract.

In a preferred embodiment, a device according to the Sthird aspect of the invention is arranged to hold a tablet in a buccal location between a patient's gum and lip. This preferred embodiment can be used in conjunction with a conventional buccal tablet, or in conjS'ction with a buccal tablet in accordance with No. 63,452/90 18 An advantage of devices in accordance with the present invention is that, when one is used to hold a tablet in the mouth of a partially or totally unconscious patient, there is no risk of that patient inadvertantly swallowing or choking upon the tablet.

In a most preferred embodiment, the means engagable to a patient are arranged to be engaged upon one, or a 10 plurality of teeth. Also, the device may be configured to hold a plurality of appropriately located tablets.

Preferred non-limiting formulations for buccal tablets us with the table retaining device of the present invention are detailed in 63,452/90.

According to one embodiment of the present invention there is provided a tablet retaining device comprising a clip for engaging a tooth or teeth for accommodating and retaining a pharmaceutical tablet or lozenge. The device is arranged for holding a tablet or lozenge in a location within a patient's mouth from which an active ingredient, from the tablet or lozenge, is releasable by the action of the patient's saliva, or other fluid within the mouth, and the clip comprises a pair of resiliently partable jaw members arranged to resiliently grip the tooth or teeth.

In a preferred embodiment, the device is arranged to hold a tablet or lozenge in a buccal location, between a patient's gum and lip.

In another preferred embodiment the means for accommodating the tablet or lozenge comprises a second clip for resiliently gripping the tablet or lozenge. Each of the first and go.

second clips may comprise a pair of resiliently partable jaw plates. A leg member may extend between the clips and provide one jaw plate for each clip. At least one of the jaw plates of the second clip may be perforated. The second clip may be dimensioned to hold a plurality of tablets.

o In another preferred embodinment, the device is moulded from a sesilient plastics resin 4* material.

In yet another preferred embodiment, the device comprises a pharmaceutical tablet or lozenge. The tablet or lozenge may be a buccal tablet or a sustained release tablet.

.19 A tablet retaining device, in accordance, with this Invention will now be described, by way of example only, with reference to the following drawings: :Figure 1 is a f ront view of a f irst such device; Figure 2 is a rear view of the device shown in Figure 1; *o Figure 3 is a section A-Alin Figure 1; 15 Figure 4 is a front view of a second device in accordance with the present Invention; Figure 5 shows a patient's mouth with a device, as shown in Figure 1, engaged therein; and Figure 6 Is a view of the same patient's mouth as shown in Figure but with the top lip raised so that the.

tablet retaining device is fully visible.

20. The tablet retaining device illustrated in Figures 1 to 3 is formed from a resilient plastics resin material, such as polystyrene, polycarbonate, or an acrylic plastic resin such as polymethylmthacrylate. The tablet retaining device is integrally formed, preferably by moulding, and includes an elongate leg member 1 which forms a part of and links first and second channel section clip portions 2 and 3.

The elongate leg member 1 has a rectangular cross .section, is of substantially uniform thickness along :its length and, defines first and second parallel outwardly facing surfaces 5 and 6. A first end portion 7 of the elongate leg member 1, has a greater width 15 than the remainder thereof. The first end portion 7 of ~.:the elongate member 1 provides a first rectangular jaw plate 4 for the first clip portion 2. The first clip portion 2 further comprises a second rectangular jaw .**plate 8, spaced apart from the first jaw plate 4 and parallel thereto. A bridging portion 9, extending fromu a first margin 10 of the second rectangular jaw plate 8 to meet the first surface 5 of the elongate leg member 1, where the first end portion 7 broadens out fromi the remainder thereof, completes the first clip portion 2.

Both the jaw plates 4 and 8 are substantially square in outline, with facing surfaces of substantially the same area.

The second clip portion 3 comprises a first jaw plate 11, defined by a second end portion 21 of elongate leg member 1, a second rectangular jaw plate 12, spaced apart from the first jaw plate 11 and substantially parallel thereto, and a bridging portion 13. The 0 bridging portion 13 is in the form of an extension to Sthe elongate leg member 1, which curves through approximately 180, to extend into the second rectangular jaw plate 12 of the second clip portion 3.

The second jaw plate 12 of the second clip portion 3 S"faces the second surface 6 of the elongate leg member 1; whereas the second jaw plate 8 of the first clip portion 12 faces the first surface 5 of the elongate leg member 1.

The second jaw plate 12 of the second clip portion 3 is of a greater width than the first jaw plate 11 of the second clip portion 3, the remainder of the elongate 22 leg member I and the jaw plates 4 and 8 of the first clip member 2.

The f Irst. and second jaw plates 4 and 8 of the first clip member both define an array of ciruclar crosssection holes 14. The holes 14 defined by the first jaw plate 4 are In register with corresponding holes 14 defined by the second Jaw plate 8.

A first ridge 15 is defined along the edge portion of the second jaw plate 12 of the second clip member 3, see remote from the bridging portion 13, and faces the second surface 6 of the elongate leg rry.,nber 1. A second similar ridge 16 extends across the second surface 6 of the elongate member 1, facing the first ridge The same reference numerals as used above to identify parts of the device shown in Figures I to 3,r are used to identify corresponding parts of the device shown in Figure 4. The difference between the two devices is that the jaw plates 4 and 8 of the f irst, clip portion 2, of the device shown in Figure 4, are of considerably 23 greater width than the remainder of said device and the entire device shown in Figures 1 to 3.

The jaw plates 4 and 8 of the first clip portion 2 in the device shown in Figures 1 to 3 arm dimensioned and spaced apart, so as to accommodate a tablet 20,. in the manner shown in Figures 1 to The spdc..ii between the jaw plates 4 and 8 is chosen so that the tablet is resiliently gripped therebetween. Likewise, the jaw plates 4 and 8 of the f irst clip portion 2 in the device shown in Figure 4, are dimensioned to accommnodate two tablets 20 in a Bide-by-side relationship, as shown in Figure 4.

To use the device illustrated in Figures 1 to a '.:tablet 20 is pushed between the jaw plates 4 and 8 of the first clip portion 2, until it is located as shown in Figures 1 to 3 and tightly gripped between the. jaw .:plates 4 and S. The loaded device is then inserted into a patient's mouth 23 and the second clip portion 3 is engaged on e tooth 24 (see Figures 5 and The tooth Is resiliently gripped between the first and second jaw plates 11 and 12 of the second clip portion 3, in such a way the device cannot be accidentally 24 dislodged. The device is installed in the orientation shown In Figure 6, that is with the first clip portion 2, holding the tablet 20 immediately adjacent to the buccal mucosa 25 and between the latter and the patient's top lip 26 (when the top lip is in the norml relaxed position).

Fluids such as saliva, within the mouth can gain access *to the tablet 20 both through the holes 14 and through the gap between the jaw plates 4 and 8 of the f irst clip portion 2. The holes 14, in the first jaw plate 4, allow matter disolved from the tablet to pass directly into contact with the buccal mucosa 15 The illustrated devices can be used in conjunction with any fozm of tablet which it is desired to hold in the mouth while its active ingredient Is leached therefrom.

Thus# these devices may be esployed to hold 1. go:conventional buccal tablets, which include active ingredients to be absorbed through the buccal mfucosal sustained release conventional buccal tablets, sustained release tablets containing non-absorbable active ingredients, such as those in accordance with 63,452/90 and other 25 sustained release tablets whose active Ingredients may be absorbed throughout the digestive tract. Most preferably, the device irs employed together with tablets in accordance with 63,452/90 of the present Invention, especially those formulated in accordance with the particularly described foriw ,ations and examples. In this regard, a tablet produced in accordance with one of examples 1 to 6 should be placed in a device as shown in Figures 1 to 3 and the device then should be installed in a patient's mouth as shown in Figures 5 and The device and tablet should be left in place until the tablet has completely dissolved and, if necessary, removed, reloaded with a fresh tablet and reinstalled in the patient'sa mouth. The 15 time taken for a given tablet to dissolve and release its phamaceutically active component(s) is dependent upon the type and relative quantity of the Methocel (or the like) which Is used, and can be determined by carrying out appropriate trials.

Most preferably, a device as shown in Figures 1 to 3 is loaded with a tablet made in accordance with one of examples 1. to 3 in 63,452/90. such a loaded device can then be installed in a patient'sa mouth as aforesaid, to, 26 selectively decontaminate his mouth and digestive tract.

As suggested above, the rate at which any given tablet dissolves and releases antibiotic can be determined experimentally. Tablets used for selective decontamination treatment are selected to provide the dose judged appropriate for a particualr patient, over an appropriate period. Both the daily dose and the period over which it should be provided depend upon a particualr patients dispositon. Thus, for example, a Ssuitable daily dose may be provided by a tablet which dissolves completely within one hour, or at the other extreme may be provided by three, successively administered, tablets that each take eight hours to dissolve.

*0 If the patient's salivary flow is reduced, and during the routine maintenance of oral hygiene, the tablet and 20 device may be sprayed with oral cleansing fluid or an artificial salivary agent to facilitate the dissolution of the tablet.

Claims (31)

1. A tablet retaining device comprising a clip for engaging a tooth or teeth and means for accommodating and retaining a pharmaceutical tablet or lozenge, wherein the device is arranged for holding a tablet or lozenge in a location within a patient's mouth from which an active ingredient, from the tablet or lozenge, is releasable by the action of the patient's saliva, or other fluid within the mouth, and the clip comprises a *pair of resiliently partable jaw members arranged to resiliently grip said tooth or teeth. e

2. A device as claimed in claim 1, arranged to hold a tablet or lozenge in a buccal location, between a patient's gum and lip. a

3. A device as claimed in claim 1 or claim 2, wherein the means for accommodating the tablet or lozenge comprises a second clip for resiliently gripping the tablet or lozenge.

4. A device as claimed in claim 3, wherein each of the first and second clips comprises a pair of resiliently partable jaw plates. 28 A device as claimed in claim 4, wherein a leg member extends between the clips and provides one jaw plate for each clip.

6. A device as claimed in claim 4 or claim 5, wherein at least one of the jaw plates of the second clip is perforated.

7. A device as claimed in claim 6, wherein the second clip is dimensioned to hold a plurality of tablets.

8. A device as claimed in any one of claims 1 to 7, wherein said device is moulded from a resilient plastics resin material.

9. A device as claimed in any one of claims 1 to 8, further comprising a pharmaceutical tablet or lozenge. 99 9 .10. A device as claimed in claim 9, wherein the tablet or lozenge is a buccal tablet or a sustained release tablet.

11. A device as claimed in claim 9 or claim wherein the pharmaceutical tablet or lozenge comprises a pharmaceutically active agent, in combination with a tablet matrix for providing controlled and sustained release of the agent, wherein the pharmaceutically active agent is not absorbable, in a substantial 29 quantity, through a normal and untraumatised human digestive tract and the tablet or lozenge is arranged for providing controlled and sustained release of said active agent into the mouth and gastro-intestinal tract. 12 A device as claimed in claim 11, wherein the C's, ,teve L«cWc3 pharmaceutically active agent is a non-absorbableA antibiotic agent, or a mixture of such agents.

13. A method of administering a pharmaceutical composition to a patient comprising retaining a tablet 4. a S or lozenge including said composition in a device as claimed in any one of claims 1 to 9 and engaging said 4 15 device in a patient's mouth.

14. A method as claimed in claim 13, wherein said tablet or lozenge is a buccal tablet or a sustained o release tablet. A method as claimed in claim 13, wherein the pharmaceutical composition comprises a pharmaceutically active agent, in combination with a tablet matrix for providing controlled and sustained release of the agent, wherein the pharmaceutically active agent is not absorbable, in a substantial quantity, through a normal and untraumatised human digestive tract and the tablet or lozenge is arranged for providing controlled and 30 sustained release of said active agent into the mouth and gastro-intestinal tract.

16. A method as claimed in any one of claims 13-15, wherein the tablet matrix is formulated so as to be erodible on exposure to fluid present within the mouth.

17. A method as claimed in claim 16, wherein the tablet matrix includes a water soluble cellulose derivative.

18. A method as claimed in claim 17, wherein the cellulose derivative is hydroxypropylmethyl cellulose or a mixture of hydroxypropylmechyl celluloses. carboxymethyl cellulose.

20. A method as claimed in claim 19, wherein the tablet matrix includes a sodium salt of carboxymethyl cellulose.

21. A method as claimed in any one of claims 13-20, wherein the pharmaceutically active agent is a non- absorbable antibiotic agent, or a mixture of such agents. 31

22. A method as claimed in claim 21, wherein the antibiotic agent or agents is or are selected to have a narrow spectrum of activity and to be active only against selected potentially pathogenic organisms.

23. A method as claimed in either claim 22 or claim 23 wherein the amount of antibiotic agent, or agents, and the rate of release thereof, are selected in order to provide a patient with a sustained prophylactic dose of antibiotic agent, or agents for selectively decontaminating the patient's digestive tract. a 9. 0 *9 *i 4 9.r 0 a 0* e *409 9. 9 9 SAtz W; -32-

24. A method as claimed in any of claims 21-23, wherein the non-absorbable antibiotic agent is a non-absorbable aminoglycoside, a non-absorbable polymyxin, a non-absorbable antifungal polyene, a ion-absorbable substituted imidazole derivative, or a mixture of these agents. A method as claimed in claim 24, wherein said tablet or lozenge includes at least two antibiotic agents,

26. A method as claimed in claim 25 which includes three antibiotic agents.

27. A method as claimed in claim 25 or 26, wherein the antibiotic agents belong to different ones of the classes set out in claim 24. S 28. A method as claimed in any of claims 24-27, wherein the non-absorbable aminoglycoside is a non-absorbable form tobramycin, famcyetin, neomycin, netilmicin, gentamicin, or streptomycin; the non-absorbable polymyxin is colistin sulphate, or sulphur methylated colistin; the antifungal polyene is nystatin or amphotricin B and; the 1: non-absorbable substituted imidazole derivative is a non-absorbable form of ketoconazole, S. miconazole or coltrimazole.

29. A method as claimed in any of claims 13-28, wherein the tablet matrix comprises a salivation promotion agent, an inert tablet filler and an inert tablet lubricant. A method as claimed in claim 15, wherein the pharmaceutically active agent is selected for treating the digestive tract of ihauno compromised patients.

31. A method as claimed in claim 15, wherein the pharmaceutically active agent is benzyl-metronidazole. -33

32. A method as claimed in claim 13, wherein the tablet comprises a pharmaceutically active agent in combination with a non-carigenic sugar.

33. A method as claimed in claim 32, wherein the non-carigenic sugar is sorbitol, mannitol, xylitol, or a mixture of the foregoing.

34. A method as claimed in either one of claims 32 or 33, wherein the tablet comprises less than 200 mg of non-carigenic sugar. A method as claimed in either one of claims 32 or 33 ccmprising less than 100 mg of non-carigenic sugar,

36. A method as claimed in any one of claims 32 to 35, wherein the tablet includes a water soluble cellulose derivative. 0*

37. A method as claimed in claim 36 wherein the cellulose derivative is a hydroxypropylmethyl cellulose, a mixture of hydroxypropylmIthyl celluloses, an ethyl 9* cellulose or a salt of carboxymethyl cellulose.

38. A method as claimed in any one of claims 32 to 37, wherein the tablet fuither 9 9 comprises a tablet lubricant selected from magnesium stearate, stearic acid, sodium fumarate and colloidial silicon dioxide.

39. A method as claimed in any one of claims 32 to 38, wherein the pharmaceutically active ingredient is selected from antacids, anti-inflammatory substances, coronary vasodilators, cerebral vasodilators, peripheral vasodilators, anti-infectives, psychoteoptics, anti-manics, stimulants, anti-histamines, laxatives, decongestants, vitamins, gastro-intestinal sedatives, anti-diarrheal preparations, anti-anginal drugs, antiarrythmics, anti-hypertensive drugs, vasconstrictors, anti-coagulants, anti-thrombotics, analgesics, anti-pyretics, hypnotics, sedatives, anti-emetics, anti-nausiants, anti-convulsants, neuromuscular agents, hyper-and -34- hypoglycaemic agents, thyroid preparations, diuretics, anti-spasmodics, mineral and nutritional additives, anti-obessity drugs, anabolic agents, anti-asmatics, expectorants, cough surpressants, antibiotics and other anti-microbial agents, topical analgesics and local anaesthetics and, polypeptides. A tablet retaining device substantially as herein described with reference to any one of the accompanying drawings.

41. A method of administering a pharmaceutical composition using a table retaining device to a patient substantially as herein described. S Dated this 7th day of March 1996 PATENT ATTORNEY SERVICES Attorneys for BIOGLAN LABORATORIES LIMITED f S 1 r ABSTRACT Disclosed is a device for holding a pharmaceutical tablet or lozenge in a location within a patient's mouth, from which an active ingredient, from the tablet or lozenge, is releasable in a controlled and sustained manner by the action of the patient's saliva. A resilient clip or other engaging means holds the device in the buccal location. 0 **0 ft f o ooooo ft ft