(12) Patent Application Publication (10) Pub. No.: US 2011/0201685 A1 Campbell (43) Pub

Home , Amylmetacresol

US 2011 O2O1685A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2011/0201685 A1 Campbell (43) Pub. Date: Aug. 18, 2011

(54) COMPOSITIONS Publication Classification (75) Inventor: AlistairO O Campbell, Hull (GB) (51) A63L/92Int. Cl. (2006.01) (73) Assignee: Reckitt Benckiser Healthcare A6IPI/00 (2006.01) (E.UK) Limited,Imited, Slough,Slougn, BerkshiBerkSnure A6IPB65D 29/0085/00 (2006.01) (GB) (52) U.S. Cl...... 514/570; 206/530 (21) Appl. No.: 13/059,260 (57) ABSTRACT (22) PCT Filed: Aug. 18, 2009 An ingestible particulate composition comprises: a) at least e LV9 one compound selected from the group consisting of 2,4- (86). PCT No.: PCT/GBO9/O2O14 dichlorobenzyl alcohol, amylmetacresol, cetylpyridinium chloride, hexitidine, hexylresorcinol, flurbiprofen, lidocaine, S371 (c)(1), benzocaine, ibuprofen, paracetamol, pectin, menthol, and (2), (4) Date: Mar. 25, 2011 benzydamine; and b) one or more bioadhesive materials. Resulting particulate compositions have excellent flow char (30) Foreign Application Priority Data acteristics, dust Suppression, organoleptic properties and sta bility. They are highly suitable for administration direction Aug. 22, 2008 (GB) ...... O8154056 into a patient's mouth, and ingested to alleviate the symptoms Jan. 9, 2009 (GB) ...... O900288.2 of a sore throat.

Flurbiprofen Xylitol CM170 Mannitol 100SD Carbopol 974P SOdium bicarbonate, Medium Granule.

Sieve 1000m Sieve Screen

Blend Granulate with Purified Water Tumble Blend for 30minutes High Shear for 3minutes

Fluid Bed Dry 500m/h Airflow at 55°C for 15minutes

Mill 2000um Serrated

COO Mix for Mint FlavOur Screen at 500rpm Peppermint Flavour Aspartame Citric Acid Anhydrous Silicon Dioxide

Sieve 1000um Sieve Screen

Pack Blend

Aluminium Foil Stick Ribbon blend PaCKS for 20minutes Patent Application Publication Aug. 18, 2011 Sheet 1 of 6 US 2011/0201685 A1

Flurbiprofen Xylitol CM170 Mannitol 100SD Carbopol 974P SOdium bicarbonate, Medium Granule.

Sieve 1000um Sieve Screen

Blend Granulate With Purified Water Tumble Blend for 30minutes High Shear for 3minutes

Fluid Bed Dry 500m/h Airflow at 55°C for 15minutes

Mill 2000pum Serrated

COO Mix for Mint Flavour Screen at 500rpm Peppermint Flavour ASpartame Citric Acid Anhydrous SilicOn Dioxide

Sieve 1000pum Sieve SCreen

Pack Blend Aluminium Foil Stick Ribbon blend Packs for 20minutes

FIG. 1 Patent Application Publication Aug. 18, 2011 Sheet 2 of 6 US 2011/02O1685 A1

Eluate COllection Water Jacket Circulation in (Optional)

FIG. 2 Patent Application Publication Aug. 18, 2011 Sheet 3 of 6 US 2011/0201685 A1

Flurbiprofen Release Profiles

- Granular Formulation Without Carbopol -- Granular Formulation Containing Carbopol -- LOZenge '83-2 is E 36 - 7.1 664 / 56II 26t 36

0 10 20 30 40 50 60 Time (mins) FIG. 3 Patent Application Publication Aug. 18, 2011 Sheet 4 of 6 US 2011/02O1685 A1

FIG. 4 Patent Application Publication Aug. 18, 2011 Sheet 5 of 6 US 2011/02O1685 A1

MembraCe

DOnOr Phase > Clamp

Sample Port Aperture

ReCeiver Phase

Magnetic Flea

FIG. 5 Patent Application Publication Aug. 18, 2011 Sheet 6 of 6 US 2011/0201685 A1

-- Tingle n=6 50 —s- Granules Without Carbopol n=6 45 40 35 30 25 E-1 -1 / 20 -1 : 1 -H1 11 - 0 10 20 30 40 50 60 70 Time (min) FIG. 6 US 2011/020 1685 A1 Aug. 18, 2011

COMPOSITIONS pain relief and reduce inflammation in the throat. Although, Some granular compositions are known these do not include a bioadhesive and are rapidly washed away from the throat. 0001. The present invention relates to pharmaceutical 0008. In accordance with a first aspect of the present compositions, and in particular to pharmaceutical composi invention there is provided an ingestible particulate compo tions for the treatment of sore throats. sition comprising: 0002 Sore throats are often treated by sucking a sugar 0009 a) at least one compound selected from the group based lozenge. The lozenge contains at least one compound consisting of 2,4-dichlorobenzyl alcohol, amylmeta which is active against Sore throats. In addition, the Sucking cresol, cetylpyridinium chloride, hexitidine, hexylresor action results in the production of saliva which lubricates the cinol, flurbiprofen, lidocaine, benzocaine, ibuprofen, throat and reduces the pain and discomfort experienced by an paracetamol, pectin, menthol, and benzydamine; and individual. 0.010 b) one or more bioadhesive materials. 0003) A boiled sugar lozenge is a glass or supercooled 0011 Preferably the composition is a flowable particulate, liquid, and at extremely high viscosity has an amorphous by which we mean that it may be poured from a container, e.g. non-crystalline State. In this state, other constituents can be a Sachet, in the manner of Sugar or salt. dissolved or Suspended (colours, flavours, pharmacological 0012 Preferred one or more compounds include but are actives etc). The moisture content of Such a lozenge is low (c. not limited to 2,4-dichlorobenzyl alcohol, amylmetacresol, 2%). Some of this moisture is in a free state, but much of the hexylresorcinol, and flurbiprofen and combinations thereof. moisture is not. This gives a stable chemical and physical In a preferred embodiment the at least one pharmaceutically environment. active compound is selected from flurbiprofen. 0004. However, small increases in the moisture content of 0013 The compositions of the present invention can also such lozenges have the following detrimental effects. The comprise a bicarbonate and/or an organic acid. The compo Viscosity of the glass is reduced, which leads to a gradual sition of the present invention may effervesce in the mouth of cold flow of the lozenge. The presence of free water pro the patient; the bicarbonate, and the organic acid, preferably vides a reaction medium in which accelerated degradation of forming an effervescent couple. added components can occur. Water causes the lozenge to becomesticky and both unattractive and difficult to handle by 0014 Examples of bicarbonates are alkali metal bicarbon packing equipment or by the user. Water is involved in ates Such as Sodium and potassium bicarbonate and alkaline hydrolysis of the disaccharide bond in Sugar, catalysed under earth metal bicarbonates. One or more different bicarbonates acid conditions provided by the typical inclusion of flavour may be used. enhancing organic acids. Cleavage of the disaccharide bond 0015 The bicarbonate when present is suitably present in forms glucose and fructose, which are both more hygroscopic the compositions of the present invention in an amount up to than Sugar (sucrose) and tend to accelerate the absorption of 15%, preferably 5 to 10 wt %; this being the cumulative further water from the surrounding environment. The reduc amount when there is more than one bicarbonate present. tion in the Sugar content compromises the physical hardness 0016 Preferably the organic acid is a carboxylic acid. of the lozenge. In some cases complete liquefaction of the Most preferably it is a polycarboxylic acid. Preferably it has lozenge can occur. As the absorption of water is an accelera 2-5 carboxylic acid groups, more preferably 3-4 carboxylic tive process, low initial water content and the exclusion of acid groups, especially 3. Examples of preferred organic even Small quantities of water from the lozenge environment acids include citric acid, tartaric acid, malic acid, Succinic are important to maximise shelflife. For a medicated lozenge acid, ascorbic acid, adipic acid and fumaric acid. containing pharmaceutical ingredients, the issue of Stability 0017. The molar ratio of organic acid(s): bicarbonate is particularly significant as compared to confectionery loZ (combined weight when more than one is present) can be: enges. For example, a much longer shelf life required of (0.018 3 (acid): 1 (bicarbonate); medicinal products, the health risks associated with chemical (0.019 2 (acid): 1 (bicarbonate); change mediated by increased water content, and the higher 0020 1 (acid): 1 (bicarbonate); value of the goods spoiled. 0021 1 (acid):greater than 1 (bicarbonate); 0005. It would, therefore, be desirable to develop an alter 0022. 1 (acid):at least 1.5 (bicarbonate); native product for treating sore throats which avoids the use of a Sugar-based lozenge. 0023. 1 (acid):at least 2 (bicarbonate); and 0006. In the present invention it is an important object of 0024. 1 (acid):3 (bicarbonate). preferred embodiments to achieve a flowable particulate 0025. A preferred effervescent couple is sodium bicarbon composition which can be administered directly into the ate and citric acid. mouth. The issues Surrounding the oral administration of 0026. Preferably the particulate composition contains at lozenges are quite different to the issues Surrounding the oral least 0.3 wt % organic acid, more preferably at least 1 wt %, administration of particulate compositions, for example loZ more preferably at least 2 wt %, and most preferably 2.5 wt %. enges may simply be Swallowed or more preferably may be These values denote the cumulative amount when there is Sucked. Sucking stimulates the release of saliva, which can more than one organic acid present; and are based on total lubricate the throat reducing the pain and discomfort, or the weight of the composition. perception thereof. When a particulate composition is admin 0027 Suitably the one or more bioadhesive materials is a istered it potentially has a rapid drying effect in the mouth, polymeric or oligomeric compound; preferably a polymeric and there is no Sucking to mitigate that effect. or oligomeric compound having a high molecular weight up 0007. The development objective of this formulation was to several million Daltons. to produce a granule format as a delivery method for Suitable 0028 Preferred one or more bioadhesive materials are pharmaceutically active compounds in order to give localised selected from the group comprising carbomers, such as Car US 2011/020 1685 A1 Aug. 18, 2011 bopol 974P and Carbopol 941 P, xanthan gums, locust bean 0041 Most preferably the single-pack dosage form is gum, alginate, carageenan, or cellulose. Other Suitable car adapted to dispense its contents to a point or Small area within bomers can be used. the mouth, preferably on the tongue, rather than to a wide 0029 Preferred compositions of the invention do not con area. Thus it is preferably a pack which may also be termed a tain a polyvinyl pyrrolidone, or acacia. targeted outlet pack. It may, for example, be a tubular 0030 The one or more bioadhesive materials is preferably ampoule, but is preferably a stick-form sachet. Stick-form present in an amount up to 10 wt %, preferably up to 5 wt %, Sachets are available for food products e.g. sauces and soluble most preferably up to 3 wt %. In each case these definitions coffee granules. A Stick-form Sachet comprises, essentially, a denote the cumulative amount when there is more than one slim envelope or tube, preferably formed of flexible material, bioadhesive material present; and are based on the total and sealed at its ends. One end is removed (e.g. torn off) by the amount of the components. user, who can then dispense its contents through the open end 0031. The compositions of the present invention may also e.g. using a pouring action. Preferably a suitable stick-pack comprise further optional components. Sachet has an aspect ratio of at least 2, more preferably at least 0032. The compositions of the present invention may also 3, and most preferably at least 5 (whereas a conventional comprise one or more diluents, one or more colourings, Sachet may have an aspect ratio of typically, 1.3). Aspect ratio Sweetenings, flavourings, pH adjusting ingredients, fillers, is defined for the purpose of this specification as the ratio of flow aids, preservatives, antioxidants, moisture Scavengers, the length of the sachet to the maximum width in its central colourants and processing aids. Other suitable excipients can region (away from the sealed ends) measured when the Stick also be included. When the compositions of the present inven pack Sachet is loaded with its intended single dose of com tion are intended for use as Sustained releasing compositions position of the invention (i.e. the diameter, when the stick they will also comprise at least one active ingredient Suitable pack Sachet is in a cylindrical form). for specific delivery to the stomach, such as a drug. Preferred 0042. Alternatively the composition could be provided in diluents are Xylitol, and/or mannitol, and/or isomalt, and/or a bulk pack containing a composition of the invention sucrose. Preferred sweeteners include aspartame. Preferred together with dosage metering information or means (for flavours include peppermint and coolmix for mint powder. A example a scoop or dosing cup). preferred excipient is a salt Such as sodium chloride, potas 0043. In accordance with a further aspect of the present sium chloride. invention there is provided a targeted outlet pack which nec 0033 Preferably the compositions of the invention do not essarily deposits the composition onto a small area within the contain chloestyramine. mouth, and containing a single dose of an ingestible particu 0034 Preferably, of course, all components of the inven late composition as defined in the first aspect. tion are ingestible, and deemed acceptable by regulation 0044) The targeted outlet pack may be further defined in authorities. accordance with the preceding paragraphs, and is preferably 0035. Preferably the compositions do not contain magne a stick-pack Sachet. sium Stearate. More preferably they do not contain any Stear 0045. In accordance with a further aspect of the present ates or hydrogenated fats. Preferably they do not contain any invention there is provided a composition of the invention as press aids, or mould release agents. Preferably they do not defined herein for use in a method of treatment of the human contain any tabletting aids. Preferably they do not contain or animal body by therapy. apatite, including carbonated apatite. 0046. A composition of the present invention may thus be 0036 Preferred compositions of the present invention used in a method of treatment of the human or animal body by remain in a flowable form, permitting them to be dispensed therapy, especially in the treatment of Sore throats. straight into the mouth e.g. by spoon or by pouring. Prefer 0047. The composition of the present invention may be ably they are in a powder and/or granule form. Preferably they used in the manufacture of a medicament for the treatment of may be regarded as a mixture of powder and granules. Even if Sore throats or for use as a Sustained releasing or targeted they comprise powder they preferably substantially do not delivery composition. release dust into the air. Thus they are preferably without 0048. The composition of the present invention may be propensity to cause coughing or choking due to inhalation. used in a method of treating Sore throats or for Sustained 0037 Preferably the mean particle size of the composition releasing or targeting a delivery composition, which com as determined using sieve methods is not greater than 1.0 mm, prises orally administering to a Subject in need thereof or and is preferably not greater than 0.5 mm. Preferably it is at liable to need an effective amount of the composition. least 0.1 mm. Preferably the particulate composition used in 0049. The composition is generally administered in an the present invention has substantially no particles which amount of from 1 to 100, preferably 5 to 50 mg, more pref would not pass through a 1 mm standard sieve. erably 5-15 mg of pharmaceutical active, per dose. 0038 Preferably the composition is provided with a flow 0050. The composition of the present invention is prefer aid. Typically the flow aid is silicon dioxide. ably flowable, Substantially without clumping, and Substan 0039. In a further aspect of the present invention there is tially without releasing powdery or dusty materials which provided a single-pack dosage form (which may otherwise be might induce coughing. Any tendency to become overly called a unit dosage pack) containing a single dose of a sticky in the mouth appears to be reduced by the fact that it is composition in accordance with the first or second aspect of not powdery, and by the fact that the acid and/or the efferves the present invention. A single pack dosage form could be an cence it causes stimulates the release of saliva, and aids dis ampoule or may be provided by a well of a blister pack, but is persion by agitation, preventing clumping. In addition, it is preferably a sachet. believed that the production of effervescence assists in the 0040 Preferably a single-pack dosage form for use in the formulation Sticking/adhering to a user's throat. In the present invention contains from 0.5 to 2 grams of composi embodiment of the invention which employs a stick-pack tion, more preferably from 0.75 to 1 grams. article, or another means for directing the particulate compo US 2011/020 1685 A1 Aug. 18, 2011

sition onto a particular region of the tongue, there is a further 0062 FIG. 2 illustrates the IVOR model used to determine benefit; administering the particulate material to large areas the improvement in bioadhesion of the present invention; of the mouth surfaces is detrimental in terms of the user's perception of the pleasantness of the experience: a large part 0063 FIG. 3 illustrates the in vitro flurbiprofen-release of the mouth may thereby become gummy. data obtained; 0051. The compositions of the present invention may be 0064 FIG. 4a illustrates the image obtained for a non prepared by mixing the ingredients. It is especially preferred Carbopol containing formulation; to mix certain components together in particulate form and 0065 FIG. 4b illustrates the image obtained for a Car then granulate them using a Suitable granulating agent Such as bopol containing formulation of the present invention; water, a C-C alcohol Such as ethanol or isopropanol, or a mixture thereof, before adding the remaining components. 0066 FIG. 5 illustrates a FRANZ cell used to determine Other granulating agents may be used, and cellulose deriva the ability of the formulation to deliver an active pharmaceu tives such as HPMC and starch paste. A preferred starch paste tical agent locally; and uses water as the granulating solvent. C-C polyols or grades 0067 FIG. 6 illustrates the results obtained using the of polyalkylene glycol may also be used as granulating FRANZ cell. agents. 0052 Components which are suitably granulated in this way are the pharmaceutically active component, the bicar EXAMPLES bonate, the one or more bioadhesive materials and the dilu 0068. The components and quantitative amounts of the entS. composition are shown in the following Tables: 0053. In a yet further aspect of the present invention there is provided the use of a bioadhesive material to retain a particulate composition which comprises a pharmaceutically Example 1 active compound in the oral cavity. 0054 The pharmaceutically active compound can be 0069 selected from the group comprising 2,4-dichlorobenzyl alco hol, amylmetacresol, cetylpyridinium chloride, hexitidine, hexylresorcinol, flurbiprofen, lidocaine, benzocaine, ibupro fen, paracetamol, pectin, menthol, and benzydamine. Particu Component Quantity (mg) Function larly preferred compounds are 2,4-dichlorobenzyl alcohol, Flurbiprofen 8.750 Active ingredient Xylitol CM170 31S.OOO Diluent amylmetacresol, hexylresorcinol and flurbiprofen. Mannitol 100SD 384.945 Diluent 0055 Preferred one or more bioadhesive materials are Carbomer 974P 25.500 Bioadhesive? selected from the group comprising carbomers, such as Car Granulation aid Sodium bicarbonate, 63.750 Effervescent bopol 974P and Carbopol 941 P, xanthan gums, locust bean medium granule gum, alginate, carageenan, or cellulose. Other Suitable car Cool Mix for Mint 506070 19.670 Flavour bomers can be used. TP0504 Peppermint 201500 TP0504 S.100 Flavour 0056. In a yet further embodiment there is provided a Aspartame 4.2SO Sweetener method of improving the local effect of a pharmaceutically Citric acid anhyrous 21.2SO Effervescent active compound by administering to an individual aparticu Silicon dioxide 1785 Flow aid late composition which comprises a pharmaceutically active compound and a bioadhesive material. Total 8SO.OO 0057 The pharmaceutically active compound can be selected from the group comprising 2,4-dichlorobenzyl alco hol, amylmetacresol, cetylpyridinium chloride, hexitidine, Example 2 hexylresorcinol, flurbiprofen, lidocaine, benzocaine, ibupro fen, paracetamol, pectin, menthol, and benzydamine. Particu 0070 larly preferred compounds are 2,4-dichlorobenzyl alcohol, amylmetacresol, hexylresorcinol and flurbiprofen. 0.058 Preferred one or more bioadhesive materials are selected from the group comprising carbomers, such as Car Component Quantity (mg) Function bopol 974P and Carbopol 941 P, xanthan gums, locust bean Flurbiprofen 8.750 Active ingredient gum, alginate, carageenan, or cellulose. Other Suitable car Xylitol CM170 31S.OOO Diluent bomers can be used. Mannitol 100SD 359.945 Diluent Carbomer 974P 25.500 Bioadhesive? 0059. In the context of the present application a bioadhe Granulation aid sive material is water-swellable, but water-insoluble, and Sodium bicarbonate, 63.750 Effervescent adheres to a surface such as a mucus membrane or skin tissue. medium granule Flavour 24.770 Flavour The water used for swelling, may be provided by the body of Aspartame 4.2SO Sweetener the treated animal. Such as by gastric fluid or by mucosal Citric acid anhyrous 21.2SO Effervescent secretions such as Saliva. Sodium Chloride 2S.OOO Excipient 0060. The present invention is further described in the Silicon dioxide 1785 Flow aid following Examples and Figure in which: Total 8SO.OO 0061 FIG. 1 illustrates a process for preparing the formu lation of the present invention; US 2011/020 1685 A1 Aug. 18, 2011

Example 3 I0082. The resulting dried granule mass is milled through a Serrated Screen to produce a uniform granule particle size. 0071 I0083. The cool mix for mint and peppermint flavours, aspartame, citric acid and silicon dioxide are sieved through a 1000 um screen and then mixed with the milled flurbiprofen Component Quantity (mg) Function granules using a ribbon blending technique. The resulting blend is stored in a polythene lined container. Flurbiprofen 8.750 Active ingredient Xylitol CM170 31S.OOO Diluent I0084. Before packing, the bulk granule blend is mixed for Mannitol 100SD 384.945 Diluent 10 minutes using a tumble blend technique to ensure that no Carbomer 974P 25.500 Bioadhesive? segregation of the product has occurred during transport from Granulation aid manufacture to packing areas. Sodium bicarbonate, 63.750 Effervescent medium granule I0085. The granules are transferred into the packing line Flavour 24.770 Flavour hopper and then 0.85 grams is filled into individually formed Aspartame 4.2SO Sweetener Stick packs. Citric acid anhyrous 21.2SO Effervescent I0086. In use the formulation is poured into the mouth and Silicon dioxide 1785 Flow aid the granules start to effervesce. It is believed that when the Total 8SO.OO granules are placed in the mouth, the effervescence (citric acid/bicarbonate reaction) provides the necessary shear force to effectively extend and fully hydrate the carbopol, provid 0072 Flurbiprofen is a potent non-steroidal anti-inflam ing an aqueous dispersion in a short time. The product is then matory drug (NSAID), which has been shown to be effica immediately Swallowed, as a semi-gelled aerated mass of cious in the treatment of sore throat in a number of phase II saliva and polymer, with the active constituent (flurbiprofen) and phase III clinical studies. in dissolution/suspension. It is believed that the carbopolgel 0073 Xylitol and mannitol are widely employed as phar will adhere to the throat surface as it is swallowed, and form maceutical diluents. They also exhibit a cooling effect on an adherent film or gel layer. In this layer the flurbiprofen dose dissolution in the mouth. will be retained and localised, rather than immediately trans 0074 Carbomer is used in pharmaceuticals as a thickening ferred to the stomach by Swallowing. This localisation per or gelling agent, and forms very high Viscosity gels at low mits a local (topical) action of flurbiprofen on the throat concentrations and has good film forming properties. How tissues. It is also believed that the gel layer reduces the irri ever, in the formulation of the present invention the primary tation in the throat, and provides a soothing sensation by role is to give a coating sensation when the product dissolves physical means in addition to the pharmacological (antiin in the mouth. The excipient is also used as a granulation aid flammatory) action of the flurbiprofen. and helps hold the ingredients together and therefore produc I0087. The bioadhesion and active delivery of the formu ing a more durable granule. The carbomer also holds the lations prepared in the Examples were tested for using an components together, preferably in a form which flows, and IVOR model and a FRANZ cell. The IVOR model, FRANZ yet which substantially does not release into the air fine par cell and results obtained therefrom are illustrated in the Fig ticulates, i.e. “dust', which could cause a patient to cough or U.S. choke. I0088. The IVOR model was designed to enable the gran 0075 Sodium bicarbonate and citric acid enable the prod ule to be added on a platform at the top of the slope to mimic uct to effervesce. the mouth/tongue. Artificial saliva applied in at intervals was 0076. In order to optimise the flow of the blend during used to wash the product and simulate natural Swallowing granule manufacture and packing, silicon dioxide, a flow aid, action. (30 slope to 15° slope). Using the in vitro oesoph was added. Silicon dioxide also acts as a moisture scavenger, ageal retention model the retention profiles for the active thereby minimising moisture up take from the productingre flurbiprofen was determined over a period of 90 minutes. dients. I0089. A comparison was made between formulae with and 0077. The granule is manufactured with a high shear without Carbopol and against a marketed lozenge product granulation technique using purified water for the process containing the same amount of flurbiprofen per sample. solvent. The wet mass is fluid bed dried to constant percent 0090 The retention profiles shows differences in surface weight by weight moisture content then milled through a adhesion between the alternative formats. Overall the profile Serrated Screen to produce a more uniform particle size. of the lozenge and the granule samples can be described as 0078. The flavours, aspartame, citric acid and silicon diox fast initial active release (75% after 5 minutes) followed slow ide are blended into the milled granules and then packed into residual active release (greater for the formulation of the aluminium foil stick packs to produce the final product. present invention than for lozenges or granules without Car 007.9 The following particulate composition was pre bopol) pared as follows: (0091. At 90 minutes approx. 100% of the flurbiprofen has 0080 Flurbiprofen, xylitol, mannitol, carbomer and been release from the surface for all samples sodium bicarbonate are sieved through a 1000 um screen and 0092. The addition of Carbopol to the formulation then pre-mixed using a tumble blend technique. The blended enhances retention on the model surface and still allows the powders are then granulated with 4.5% w/w purified water for active to be released in a timeframe suitable for the treatment three minutes using a PMA150 (GEA) granulator. of sore throats. The control formulation without Carbopol 0081. The wet granule mass is then transferred into a will not adhere to the target surface and does not slow the T/SG3 (GEA) fluid bed drier and dried for 15 minutes at a release of the active as much as the formulation of the present temperature of 55° C. with the airflow set at 500 m/h. invention. US 2011/020 1685 A1 Aug. 18, 2011

0093. The data from the FRANZ cell demonstrates that the 16. Use of a flowable particulate composition comprising inclusion of bioadhesive polymers retards the release and at least one pharmaceutically active compound selected from transport of flurbiprofen ensuring that the localised target the group consisting of 2,4-dichlorobenzyl alcohol, amyl (Surface adhered to) receives a continuous and long lasting metacresol, cetylpyridinium chloride, hexitidine, hexylresor dose. cinol, flurbiprofen, lidocaine, benzocaine, ibuprofen, parac 0094. A formulation without such properties will deliver etamol, pectin, menthol, and benzydamine; and one or more the active flurbiprofen immediately and as a result the major bioadhesive materials, for the treatment of a patient by admin istration of the composition into the mouth of the patient. ity of the pain relief action will be systemic rather than loca 17. Use of at least one pharmaceutically active compound lised. selected from the group consisting of 2,4-dichlorobenzyl 0095. The formulation of the present invention ensures alcohol, amylmetacresol, cetylpyridinium chloride, hexiti that bioadhesion takes place in target area throat, and that that dine, hexylresorcinol, flurbiprofen, lidocaine, benzocaine, actives retained in formulation are (1) retained as part of ibuprofen, paracetamol, pectin, menthol, and benzydamine; bioadhesive function in target area and (2) the retained actives and one or more bioadhesive materials in the manufacture of are able to dissociate from the bioadhesive into surrounding a particulate composition Suitable for pouring into the mouth Volume in a suitable timeframe. of a patient. 0096. Further modifications and developments can be 18. A targeted outlet pack containing a single dose of an made without departing from the scope of the invention ingestible flowable particulate composition, the targeted out described herein. let pack being adapted to deposit the composition onto a small 1. An ingestible particulate composition comprising: area within the mouth, the composition comprising: at least one pharmaceutically active compound selected at least one pharmaceutically active compound selected from the group consisting of 2,4-dichlorobenzyl alco from the group consisting of 2,4-dichlorobenzyl alco hol, amylmetacresol, cetylpyridinium chloride, hexiti hol, amylmetacresol, cetylpyridinium chloride, hexiti dine, hexylresorcinol, flurbiprofen, lidocaine, ben dine, hexylresorcinol, flurbiprofen, lidocaine, ben Zocaine, ibuprofen, paracetamol, pectin, menthol, and Zocaine, ibuprofen, paracetamol, pectin, menthol, and benzydamine; and benzydamine; and one or more bioadhesive materials. one or more bioadhesive materials. 2. A composition according to claim 1, wherein the com 19. Use of a bioadhesive material to retain a particulate position is a flowable particulate. composition which comprises a pharmaceutically active 3. A composition as claimed in claim 1, wherein the at least compound in the oral cavity. one pharmaceutically active compound is selected from the 20. A method of improving the local effect of a pharma group consisting of 2,4-dichlorobenzyl alcohol, amylmeta ceutically active compound by administering to an individual cresol, hexylresorcinol, and flurbiprofen. a particulate composition which comprises a pharmaceuti 4. A composition as claimed in claim3, wherein the at least cally active compound and a bioadhesive material. one pharmaceutically active compound is flurbiprofen. 21. The use as claimed in claim 19, wherein the at least one 5. A composition according to claim 1, wherein the com pharmaceutically active compound is selected from the group position further comprises a bicarbonate. consisting of 2,4-dichlorobenzyl alcohol, amylmetacresol, 6. A composition as claimed in claim 5, further comprising cetylpyridinium chloride, hexitidine, hexylresorcinol, flurbi an organic acid, wherein the bicarbonate is sodium bicarbon profen, lidocaine, benzocaine, ibuprofen, paracetamol, pec ate and the organic acid is citric acid. tin, menthol, and benzydamine. 7. A composition as claimed in claim 1, wherein the one or 22. The use as claimed in claim 19, wherein the bioadhe more bioadhesive materials is a polymeric or oligomeric sive material is selected from the group consisting of car compound. bomers, Xanthan gums, locust bean gum, alginate, carag 8. A composition as claimed in claim 1, further comprising eenan, and cellulose. a flow-aid. 23. A composition according to claim 1, wherein the com 9. A composition according to claim 1, for use in a method position further comprises an organic acid. of treatment of a human or animal body by therapy. 24. A composition as claimed in claim 7, wherein the 10. A single-pack dosage form comprising a single dose of polymeric or oligomeric compound has high a molecular a composition of claim 1, the single-pack dosage form being weight up to several million Daltons. a targeted outlet pack which necessarily deposits the compo 25. A composition according to claim 9, for use in a method sition onto a small area within the mouth. of treatment of sore throats. 11. A single-pack dosage form according to claim 10, 26. The method as claimed in claim 20, wherein the phar being a stick-form Sachet. maceutically active compound is selected from the group 12. A bulk pack comprising a bulk source of a composition consisting of 2,4-dichlorobenzyl alcohol, amylmetacresol, of claim 1, together with dosage metering means or dosage cetylpyridinium chloride, hexitidine, hexylresorcinol, flurbi information. profen, lidocaine, benzocaine, ibuprofen, paracetamol, pec 13. Use of a composition according to claim 1 in the manu tin, menthol, and benzydamine. facture of a medicament for the treatment of sore throat. 27. The method as claimed in claim 20, wherein the bio 14. Use of a composition according to claim 1 for the adhesive material is selected from the group consisting of treatment of sore throat. carbomers, Xanthan gums, locust bean gum, alginate, carag 15. A method of treating Sore throat, comprising orally eenan, and cellulose. administering to a subject an effective amount of a composi tion of claim 1.