(12) INTERNATIONALAPPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT) (19) World Intellectual Property Organization International Bureau (10) International Publication Number (43) International Publication Date 19 August 2010 (19.08.2010) WO 2010/092468 Al

(51) International Patent Classification: DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, GT, A61K 31/015 (2006.01) A61P 1/04 (2006.01) HN, HR, HU, ID, IL, IN, IS, JP, KE, KG, KM, KN, KP, A61K 47/36 (2006.01) KR, KZ, LA, LC, LK, LR, LS, LT, LU, LY, MA, MD, ME, MG, MK, MN, MW, MX, MY, MZ, NA, NG, NI, (21) International Application Number: NO, NZ, OM, PE, PG, PH, PL, PT, RO, RS, RU, SC, SD, PCT/IB20 10/000275 SE, SG, SK, SL, SM, ST, SV, SY, TH, TJ, TM, TN, TR, (22) International Filing Date: TT, TZ, UA, UG, US, UZ, VC, VN, ZA, ZM, ZW. 12 February 2010 (12.02.2010) (84) Designated States (unless otherwise indicated, for every (25) Filing Language: English kind of regional protection available): ARIPO (BW, GH, GM, KE, LS, MW, MZ, NA, SD, SL, SZ, TZ, UG, ZM, (26) Publication Language: English ZW), Eurasian (AM, AZ, BY, KG, KZ, MD, RU, TJ, (30) Priority Data: TM), European (AT, BE, BG, CH, CY, CZ, DE, DK, EE, PCT/IB2009/000254 ES, FI, FR, GB, GR, HR, HU, IE, IS, IT, LT, LU, LV, 13 February 2009 (13.02.2009) IB MC, MK, MT, NL, NO, PL, PT, RO, SE, SI, SK, SM, TR), OAPI (BF, BJ, CF, CG, CI, CM, GA, GN, GQ, GW, (72) Inventor; and ML, MR, NE, SN, TD, TG). (71) Applicant : GHISALBERTI, Carlo [BR/BR]; Rua Luis Dias 85/61, ITAIM - BIBI, BR-04542-080 Sao Paulo - Published: SP (BR). — with international search report (Art. 21(3)) (81) Designated States (unless otherwise indicated, for every — before the expiration of the time limit for amending the kind of national protection available): AE, AG, AL, AM, claims and to be republished in the event of receipt of AO, AT, AU, AZ, BA, BB, BG, BH, BR, BW, BY, BZ, amendments (Rule 48.2(h)) CA, CH, CL, CN, CO, CR, CU, CZ, DE, DK, DM, DO,

(54) Title: COMPOSITION COMPRISING ALGINATES AND D-LIMONENE TO TREAT GERD AND DYSPEPSIA (57) Abstract: The invention refers to nutritional and pharmaceutical compositions for the use in the treatment and relief of GERD and dyspepsia in mammals, including humans The compositions comprise a combination of alginates of low and high molecular weight and d-limonene in microdispersed form. This combination can be further improved with an antacid or an essen tial oil with high cholinesterase inhibitory activity. COMPOSITION COMPRISING ALGINATES AND D-LIMONENE T O TREAT GERD AND DYSPEPSIA

FELD OF THE INVENTION The invention relates to a composition comprising alginates and d-limonene in micrαdispersed form to treat gastroesophageal reflux disease (GERD) add dyspepsia. Preferably the composition also comprises an antacid to improve heartburn symptoms, or the d-limonene is further admixed with an essential oil to enhance the. cholincsterase inhibitory action.

BACKGROUND GERD and dyspepsia are common ailments in the upper gastro-intesltinal (Gl) tract. Stress directly affect the digestive tract and aggravate bad digestion and GERD, with more than 25% of the population in Western Countries experiencing heartburn once or more times per month, while just 11% in Eastern Asia have at least a monthly heartburn episode. The symptoms include difficulty swallowing, regurgitation of stomach acid and/or food, hoarseness, coughing and irritation of larynx, throat and/or esophagus, whilst the untreated disorders may seriously aggravate, e.g. leading to gastroesophageal cancer. Current therapies in GERD and dyspepsia aim at suppress gastric acid secretion or enhance the gastro-intestinal motility to limit the exposure of the esophagus to acidic gastric contents. Common drugs thus include proton pump inhibitors* histamine H2- blockers, prostaglandin analogues, sulphated polysaccharides, and antacids. A non-prescription approach is provided in U.S. Pat. No. 6,420,435 which discloses a method of treating GERD and related conditions with limonene, presently marketed as EsophaGuard™ by WRC Laboratories, Inc, (Galvesto π, TX, USA). U.S. Pat. No. 2008248136 aims to improve limonene by the combination with antacids, while U.S. Pat. No. 2008292693 combines limonene with Aloe v, hydrocollois. Hydrocolioids are used to reduce the symptoms of heartburn and GERD, as disclosed by G B 2349570; WO 01/661 19; and EP 1859786. Among hydrocolloids, alginates are well-known for their efficacy in GERD therapy. The performance of alginates in GERD was first claimed by Reclcitt Colmann Prod. Inc., presently Reckitt Benckiser Healthcare (UK) in US 4,140,760 an in several other patent applications. The combinations of alginates and antacids such as Gaviscon™, Algicon™, Rennie™, Topaal™ provide an efficient symptomatic relief of OERD (World J Gastroenterol. 2006; 12(5):747-54). Actually, a meta-analysis ranked the alginate formulations as the mosij efficient among the non-prescription treatments of GERD (Tran, Lowry, El-Serag; Alilment Pharmacol Ther, 2007, 25(2): 143-53). Although alginate-based raft products are often categorized among antacids, they are indeed different. Unlike traditional antacids which chemically neutralize gastric acid, or histamine H2-receptor antagonists which pharmacologically reduce acid secretion, alginate rafting products appear to act primarily by a physical, rather than a chemical or pharmacological means. This action provides the rapid onset of action of conventional antacids and a longer effective duration. Although some alginate formulations provide significant neutralization capacity, there does not appear to be a stringent requirement to neutralize bulk gastric contents to achieve efficacy. However, the formulations comprising alginates have a limitation in term of the time needed for the gastric emptying after meal. In fact, the average residence time for Gaviscon at fast is around 3 hours (Beckloff et al. J Clin Pharmacol. 1972; 12:1 1-21). Therefore, there is still a request to ameliorate the therapeutic approach by improving the gastric coating effect while fastening meal transit, so to alleviate the discomfort associated with GERD 1, dyspepsia (indigestion), heartburn and similar QJI disorders.

SUMMARY The invention provides an efficient composition for treating GERD and dyspepsia comprising alginate in combination with microdispersed d-lϊmonenet to improve the coating effect onto the internal/distal mucosa while adding a proki etic action, i.e. fasten the gastric emptying. The invention also provides a comprising a mixture of high and low molecular weight alginates in combination with microdispersed d-limonene. The invention also provides a composition as described above to treat GERD and dyspepsia further comprising an antacid. The invention further provides a composition as described above to treat GERD and dyspepsia, wherein d-limonene is blended with an essential ail having high cholinesterase inhibitory activity. The invention furthermore provides a method for the treatment of GERD and dyspepsia in a subject in need thereof by administering a compositions comprising a mixture of high and low molecular weight alginate and microdispersed d-limoneπe, which may be further improved with the addition of an antacid and/υr an essential oil with high cholinesterase inhibitory activity.

DETAILED DESCRIPTION In accordance with the present application, the efficacy of alginates ahd d-limonene in the treatment of GERD and dyspepsia can be enhanced by their combined used in a single nutritional/ pharmaceutical composition. In a preferred embodiment, the invention provides a composition to treat GERD and dyspepsia comprising alginates and microdispersed d-limonene. d-Limonene is the major component of citrus rind oil thereto obtained by a press out process, optionally refined by a steam extraction. The collected oil is separated, distilled to recover certain flavor and fragrances, and the collected to recover a food-grade 95% d-limonene. A further distillation affords a high-grade d-limonene, since the material to be used i the invention preferably has purity greater then 95%, more preferably greater than 98%. The high purity d-limonene is required to limit the presence of residual (fragrance) aldehydes and acids of which may impart a strong flavour to the composition and/or deteriorate by oxidation. Such d-limonene is supplied, e.g., by Florida Chemical Comp. Co (Winter Haven, FL, USA) as high purity, food-grade d-limonene (98+%). The microdispersed d-limonene is capable to afford the gastric coating on the internal and distal stomach mucosae while it help in fastening the meal transit, therefore with an improve of the discomfort associated with dyspepsia. Differently from simethicone which were added to several alginate formulations (e.g. Sedomag™), d-Iimonene has limited defoaming properties, so that the formation of the alginate raft is preserved. The expression "microdispersed" herein is equivalent to "microemulsionated" or "microencapsulated" or "microabsorbed" or any lingual variation thereof refers herein to a solid or liquid droplet or granule of any shape with a size below 1 mm, preferably below 100 µm which is capable of holding therein a substantial amount of d-limonene. Microemulsionated d-Iimonene can be obtained by emulsification of d-limonene in water or in a hydroalcoholic solution (e.g. ethanol-water) in the presence of food-grade surfactants including nonionic such as ethoxylated sorbitan esters, polyglycerol esters, sugar ester; and/or anionic such as K or Na oleate, bis(2-ethylhexyl) sodium sulfosuccinate, and phosphatidylcholine; as well as co-emulsifiers such as polyols (e.g. propylene glycol and glycerol), moπoglycerides; and mixture thereof. Microincapsulated d-limonene can be obtained by coacervation, e.g. as in WO 051 05290, to afford gelatine microcapsules with 30% to 65% of d-iimo ene content. Microabsorbed d-limonene can be obtained by physical absorption onto a colloidal granulated (porous) silica, e.g. VP Aereoperl™ 300 Pharma or Sipernat™ 2200 from Degussa (Germany) to afford adsorbed microparticules with 20% to 50% d-Hmonene. In a preferred embodiment of the invention, the composition of the invention includes from 50 to 800 mg, preferably from 100 to 500 mg, more preferably from 200 to 300 mg of d-limonene per unit dose, i.e. d-limoneπe from 0.5% to 8%, preferably from 1% to 5%, more preferably from 2% to 3% w/v of a 10 ml-single dose, liquid formulation. The present invention is characterized by the novel use of the efficacious combination of microdispersed d-lirnonene with alginates. Alginates are mixed polyuronic acids variably composed of residues of D-mannuronic and L-guluronic acids obtained from brown algae belonging to the order Phaeophycae, commonly from Laminaria spp, e.g. L. hyperborean. The term "alginates" as used herein includes alginic acids and salts thereof such as sodium, potassium or ammonium salt, or bivalent calcium or magnesium salt and mixture thereof of the alginic acid ("alginate salts'"). The composition according the invention may comprise a mixture f low and high molecular weight alginates, hereinafter "LMW alginates" and "MMW alginates", respectively. HMW alginates suitable for our purposes are supplied., a.g., by Cargill (Wayzata, MN.. USA) as Satialgine™, Algogel™, Cecalgum™ types; or by ISP (Columbia, Maryland, USA) as Manucol™ and Manugel™, or by FMC Biopolymcr AS Philadelphia, PA, USA) as Protanal™ and Protacid™ series. Suitable LMW alginates are supplied by FMC Biopolyrner as Protacid™ F 120 NM and Protana LFR 5/60. In a preferred embodiment, the composition of the invention includes: i) from 100 to 700 mg, preferably from 250 to 500 mg, more preferably from 300 to 400 mg in total of two or more alginates for unit dose; and ii) from 100 to 500 mg, m or preferably from 200 to 300 mg of microdispersed d-limonene per unit dose. In an embodiment, the composition of the invention includes: at least one HMW alginate and a LMW alginate, i.e. i) from 1% to 10%, preferably 2.0% to 8%, more preferably 2.5% to 7%, especially 4% to 6% in total of two or more alginates, of which from 0 to 90% comprises a LMW alginates, and from 100% to 10% comprises a HMW alginate; and ii) microdispersed d-limonene. The precise dose of the alginates and d-ltmonene combination that a e applied in the unit dosage form may be ascertained by conventional methods. The specific dosage level required for a particular subject will depend on a number of føctors, including severity of GERD and/or dyspepsia and the administration of other medicaments, such as antacids, proton pumps inhibitors, histamine H2-receptor antagonists, and NSAIDs. It is recommended that the unit dosage form is administered as soon as symptoms occur, preferably after a 30 minutes after meal if episodes are associated with dyspepsia. The solid unit dosage form is preferably administered together with an amount of liquid that can be water, juice or any other beverage usually in the range from 100 lo 500 ml. Depending on the dosage for, 1 to 4 tablets 4 times a day after meals and at bedtime or as needed are required, followed by half a glass of water or other liquid. The liquid dosage form do generally not require the intake of an additional liquid. The actual dose an individual needs could be readjusted in response to the amount of food or the individual's sensitivity to particular foods, beverages or spices. In an embodiment, the composition of the invention also comprises an antacid. The term "antacid(s)" as used herein refers to any compound which neutralize hydrochloric acid. Antacids are already used to address the acute symptoms of several digestion-related disorders such as duodenal and gastric ulcers, stress gastritis, GERD, pancreatic insufficiency, biliary reflux, and constipation. In the frame of the present invention an antacid may be usefully added to exert a fast action on gastric secretion.

Antacids useful herein include aluminium carbonate (A12(CO3)3), aluminium hydroxide (A1(OH)3), aluminium hydroxy-carbonate (AICO 3OH), dihydioxy aluminium sodium carbonate (NaAlCO^OHh), calcium carbonate (CaCOs), calcium bicarbonate (Ca(HCO3)2), calcium phosphate (Ca3(PO4,)2), magnesium aluminate (Mg(AlO )S), magnesium alumino silicates (MgAlSiO*), magnesium carbonate (MgCOs), magnesium bicarbonate (Mg(HCOj) ) magnesium glycinate (MG(GIy)^), magnesium hydroxide

(Mg(OH)2), magnesium oxide (MgO), magnesium trisilicate (Mg2S Os) sodium bicarbonate (N-1HCO3), sodium carbonate (NaaCOs), potassium bicarbonate (KI-ICO3), potassium carbonate (K2CO3), and hydrated form thereof, and mixtures thereof. Preferred antacids in the present invention are alkali metal carbonates or bicarbonates. Other preferred antacids are magnesium or aluminium hydroxides. In an embodiment, the composition of the invention includes antacids from 100 to 2500 mg, preferably 150 to 1500 mg, most preferably 250 to 1000 mg per unit dose. In another embodiment, in the composition of the invention the d-lirnonene is blended with an essential oil (EO) having a significant acetylcholine esterase AChE) and/or butyrrylcholine esterase (BChE) inhibitory activity. The EO useful as active carrier include those obtained from the following plants: Anethum graveoJens, Foeniculum vulgare, Melissa officinalis, Lavandula officinalis, Ocimum bctsilicutn, Origanum onites, Origanum vulgare, Origanum munitiflorum, Origanum majorana, Salvia solarea, Salvia officinalis, Satureja cnneifotia, Salvia lavandulaefolia. Preferred EO herein are preferably those from Origanum .ψp., alvia spp, or Eucalyptus spp,

In an embodiment, the composition of the invention includes said ECj) and d-limonene at a ratio from 1:1 to 1:10, preferably from 1:2 to 1:4 w/w. The composition according to the invention may further comprise physiologically acceptable excipient(s) and carriers. As used herein, a composition or compound is "physiologically acceptable" if it is suitable for use with humans and/or other animals without undue adverse side effects such as toxicity, irritation, and allergic response. The physiologically acceptable excipie πt can be solid diluents, disintegrants. granulating agents, lubricants, thickeners, flavouring, colouring, wetting, emulsifying, and dispensing agents, preservatives, isotonic agents, fillers, sweeteners, antioxidants, coating materials, buffering agent, and so on. The composition of invention may be medicinal, i.e. pharmaceutical or nutraceutical preparation obtainable by conventional techniques. A s used herein, the term "nutritional" refers to dietetic supplements and food products, usually from natural sources, having nutritional/pharmaceutical benefits. The nutritional and pharmaceutical composition of invention may use solid, semi-solid, or liquid vehicle/carriers to facilitate the delivery of the active ingredients. Examples of suitable unit dosage forms are tablets, capsules, coated pills, powders in sachets, powder in packets, granules, wafers, as well as liquid preparations such as syrup, emulsion, milky cream and elixirs. Examples of suitable unit dosage forms are coated tablets, capsules, coated pills, powders, powder packets, granules, wafers, and the like, as well as liquid preparations. Tablets can be used either coated by sugar or compressed or film coating to speed up swallowing and dissolution in the stomach. In another embodiment, the invention encompasses the use of a nutritional/ pharmaceutical composition as described above for the preparation of a medicament for treating GERD and related disorders such as dyspepsia, non-ulcer dyspepsia (NUD), functional dyspepsia, as well as temporary acid reflux symptoms due to pregnancy. The invention is elucidated by way of the following, non-restrictive examples. EXAMPLES

Preparative Example 1—Microemulsionated d-limonene A microemulsion is prepared by blending water and glycol, then adding the surfactant system, and finally adding >98% d-limonene with tocopherol. After miixing together, a stable clear microemulsion is formed having the following composition. Ingredient Quantity (% w/v) Propylene glycol 12 Decaglycerol moπooleate 8.3 POE (20) sorbitan monostearate 6.8 POE (20) sorbitan tristearate 0.3 d-Limonene 98% 33 Tocopherol 0.01

Water q.b to lOO ~ ~ ~ "~ ~~ " " Preparative Example 2 - Emulsionated d-limonene A coarse microemulsion is prepared by blending >9&% d-limonene with BHT, then potassium oleate, After mixing, an emulsion with the following composition is formed. Ingredient Quantity (% w/v) Potassium oleate 20 POE (20) sorbitan tnonooleate 0.5 d-Limonene 9S% 20 BHT 0.01 Water q.b to 100

Preparative Example 3 - Mioroadsorbed d-limonene An adsorbed silica is prepared by blending d-limonene with 0.1% tocopherol. After dry-mixing and grinding with two part by weight of the VP Aereoperil™ 300 Pharma (Degussa, Germany), a white powder comprising 33% w/w of d-limonetje is produced. Preparative Example 4 Microencapsulated d-limonene

Microencapsulated d-limonene with diameter between 50 and 200 µni ijs obtained by coacervation following the procedure of PCT/IB09/00254, carried out at (Essepi Sotteri e Prospero SrI (Cormano, Italy) affording microcapsules with ~50% loade d-limonene.

Example 1 - Suspension with alginates and microemulsionated d-limonenø The alginates are suspended in water under stirring, then the other ingredients are added and, finally, the microemulsion with d-limonene. Ingredient Quantity (per 10 ml) LMW sodium alginate 350 mg HMW sodium alginate 150 mg Emulsion of preparative Ex, 1 (33% limonene) 0.9 ml Potassium hydrate 2 mg Parabeπs (methyl and propyl) 5 mg Sodium sorbate 35 mg Sucralose 5 mg Water q.b, to 10 ml

Example 2 - Suspension with alginates, microemulsionated d-limonene and an antacid A similar procedure of Example 1 is applied with the further addition of 200 mg of potassium bicarbonate before the microemulsionated d-limonene is added .

Example 3 - Suspension with alginates, microabsorbed d-limonene and antacids A similar procedure of the Example 1 is applied to a different composition comprising Ca and Mg along with microemulsionated d-limonene. Ingredient Quantity (per 10 ml) HMW sodium alginate 300 mg Calcium carbonate 1200 mg Magnesium carbonate 140 mg Powder of preparative Ex. 3 (33% Hmoneπe) 1000 mg Parabens (methyl and propyl) 20 mg Sodium saccharinate 5 mg Water q.bto 10 ml

Example 4 - Chewafyle tablets with alginates, microabsorbed d-limonenq and antacids Tablets are prepared by granulation of the previously sieved ingredients. Ingredient Quantity (per 1500 rag tablet) LMW Alginic acid 100 mg HMW Alginic acid 50 mg Calcium carbonate 680 mg Magnesium carbonate 80 mg Powder of preparative Ex, 3 (33% limonene) 950 mg Maltitol 500 mg Talc 45 mg PVP K30 15 mg Magnesium stearate 20 mg Sodium saccharinate 5 mg Water q.b, for granulation

Example 5 - Sachets with alginates, microencapsulated d-limoπene an4 antacids A powder is prepared by mixing HMW sodium alginate (300 mg), microencapsulated d-limoπene of Ex. 4 (300 mg), magnesium trisilicate (25 mg) and maltiltol (q,b. to 2 g).

In vitro Example - Cholinesterase inhibitory activity. The inhibition of acetylcholine esterase (AChE) and butyrrylcholin esterase (BChE) is assessed by the colorimetric method of Ellman et al. (Biochem Pharmacol. 1961, 7:88-95). The concentrations of test EO and pure monoterpenes, or the 50% potency

(IC5o), is monitored at increasing concentrations of the test compounds, as indicated in Table I. Test and control values assays are corrected by blanks fbr non-enzymatic hydrolysis according to Savelev S et al. (Phytother Res. 2004, 18, 315-324). TABLE I - Cholinesterase inhibition AGtE ICso oi"% inhibition (J H % Inhibition d-Limonene 13% at 70 mg/l

Salvia lavandulaefolia EO IC50 = 50 mg/1 26% at 20 mg/1

Origanum majorana EO C 0(AChEI) = 20 mg/1 10°/d at 30 mg/i

Eucalyptus globulus EO ICs0(AChEI) = 40 mg/1

Preparative Ex. 5-7 - Microemulsionated blends of d-limonene and essential oils A microemulsionated mixture of d-limonene and EO from Salvia lavandulaefolia, is prepared with the procedure of Preparative Ex. 1 using a blend of d-limonene and said EO at 3:1 w/w ratio instead of the d-limoπene alone. A microabosorbed mixture of d-limonene and distilled Eucalyptus globulus EO (97% eucalyptol) is prepared with the procedure of preparative Ex. 2 using a blend of d- limonene and 97% eucalyptol at 3:1 w/w ratio instead of the d-limone πe alone. A microencapsulated mixtures of d-limonene and EO from Origanum majorana, is prepared with the procedure of preparative Ex. 4 using a blend of d-limonene and said EO in 3:1 w/w ratio instead of the d-limonene alone. Further composition examples can be prepared using the aforesaid blends instead of pure d-limonene as in Examples 1 to 5.

Testing Example - Performance evaluation in GERP subjects The suspension of Example 3 can be confronted with a comparative formulation such as Rennie™ suspension from Bayer Consumer Care, i.e. comprising calcium carbonate (1200 mg), magnesium carbonate (140 mg) and sodium alginate (300 mg) per 10 ml dose, The gastric emptying time can be recorded by Digitrapper E(BG of Synectics (Middlesex, UK) connected to a pc, allowing realtime visual analysis throughout the recording, with data being processed by ElectroGastroGram™ software of Gastrosofl, Inc (TX, USA). Preliminary results may indicate a 25% fastening of gastric empties for the composition of invention than to the comparative composition, with a iurther improvement up to 40% for the blend of d-limonene with Salvia EO. CLAIMS

1. The use of a combination of alginates and microdispersed d-limonene in the treatment of gastroesophageal reflux disease (GERD) and dyspepsia. 2. A nutritional/pharmaceutical composition comprising alginates and microdispersed d-limonene for the treatment of GERD, heartburn, regurgitation, non-ulcer dyspepsia gastroparesis and functional dyspepsia. 3. The composition according to claim 2 wherein said alginates is a mixture of high and low molecular weight alginates in ratio from 1:4 to 1;1 w/w. 4. The composition of claim 3 comprising: i) from 250 to 500 mg in total of high and low molecular weight alginates; and ii) from 100 to 500 mg o microdispersed d- limonene per unit dose. 5. The composition of claim 3 comprising: i) from 300 to 400 mg in total of high and low molecular weight; and ii) from 200 to 300 mg of microdispersed d-limonene per unit dose, 6. The composition of claim 2 wherein the microdispersed d-limonene is microemulasionated, microabsorbed or microencapsulated. 7. The composition of claim 2 or 3 further comprising an antacid. 8 . The composition of claim 7 wherein the antacid is a metal alkali carbonate or bicarbonate. 9. The composition of claim 7 wherein the antacid is magnesium or aluminium hydroxide. 10. The composition of claim 8 or 9 comprising from 150 to 1500 mg of antacid(s) per unit dose. 11. The composition of claim 10 comprising from 250 to 1000 mg cjf antacid(s) per unit dose. 12. The composition of claim 2 or 3 wherein the microdispersed d-limonene is blended with an essential oil having high chσliπesterase inhibitory activity. 13. The composition of claim 12 wherein the essential oil is obtained from plants selected from the group consisting of Anethum graveolens, Foeniculum vulgare, Melissa o cinalis, Lavandula officinalis, Ocimum basϊlicwn, Origanum onites, Origanum vulgare, Origanum munitiflorum, Origanum majorana, Salvia sclarea, Salvia officinalis, Satureja cuneifolia, Salvia lavandulaefolia, and ucalyptus ψp. 14. The composition of claim 13 wherein the essential oil is from Origanum spp, or Salvia spp. 15. A method for treating GERD, regurgitation, dyspepsia, sour stomaφh, and heartburn

in a subject in need thereof which comprises administering I© said subject a composition comprising alginates and microdispersed d-limonene. 16. The method according to claim 15 which comprises administering, to said subject a composition comprising alginates, microdispersed d-limonene, and an antacid. INTERNATIONAL SEARCH REPORT International application No PCT/IB 2010/000275

A. CLASSIFICATION OF SUBJECT MATTER IPC8: A61K 31/015 (2006.01 ); A61K 47/36 (2006.01 ); A61P 1/04 (2006.01 ) According to International Patent Classification (IPC) or to both national classification and IPC

B. FIELDS SEARCHED Minimum documentation searched (classification system followed by classification symbols) IPC8: A61K

Documentation searched other than minimum documentation to the extent that such documents are included in the fields searched

Electronic data base consulted during the international search (name of data base and, where practicable, search terms used) EPODOC, WPI, TXTE, TXTG, XPESP, XPRD, XPTK, EMBASE, MEDLINE, PUBCHEM

C . DOCUMENTS CONSIDERED TO BE RELEVANT

Category* Citation of document, with indication, where appropriate, of the relevant passages Relevant to claim No.

US 2008/292693 A 1 (SONES) 27 November 2008 (27.1 1.2008) 1-14 Claims 1, 3, 12, 13

A W O 2001/035954 A 1 (WILKINS JOE S JR) 25 May 2001 1-14 (25.05.2001) Claims 1, 2

WO 2003/068246 A2 (RECKITT BENCKISER HEALTHCARE) 1-14 2 1 August 2003 (21 .08.2003) Claims 1, 3, 4, 8; Description Page 7 Lines 23-25

Further documents are listed in the continuation of Box C . See patent family annex.

* Special categories of cited documents "T" later document published after the international filing date or "A" document defining the genera) state of the art which is not considered priority date and not in conflict with the application but cited to be of particular relevance to understand the principle or theory underlying the invention "E" earlier application or patent but published on or after the international "X" document of particular relevance; the claimed invention filing date cannot be considered novel or cannot be considered to involve "L" document which may throw doubts on priority claim(s) or which is an inventive step when the document is taken alone cued to establish the publication date of another citation or other "Y" document of particular relevance; the claimed invention special reason (as specified) cannot be considered to involve an inventive step when the "O" document referring to an oral disclosure, use, exhibition or other document is combined with one or more other such means documents, such combination being obvious to a person "P" document published prior to the international filing date but later than skilled in the art the priority date claimed "&" document member of the same patent family Date of the actual completion of the international search Date of mailing of the international search report 22 June 2010 (22.06.2010) 30 June 2010 (30.06.2010)

Name and mailing address of the ISA/ A T Authorized officer Austrian Patent Office HUNGER U. Dresdner Stra βe 87, A-1200 Vienna

Facsimile No. +43 / 1 / 534 24 / 535 Telephone No. +43 / 1 / 534 24 / 363

Form PCT/ISA/2 IO (second sheet) (January 2004) INTERNATIONAL SEARCH REPORT Internationa] application No PCT/IB 2010/000275 C (Continuation). DOCUMENTS CONSIDERED TO BE RELEVANT

Category* Citation of document, with indication, where appropriate, of the relevant passages Relevant to claim No

US 6 395 307 B 1 (BANNING et al.) 28 May 2002 (28.05.2002) 1-14 Claims 1, 4

Form PCT/ISA/21 0 (continuation of second sheet (I)) (January 2004) INTERNATIONALSEARCH REPORT International application No PCT/I B 2010/000275 Continuation of first sheet

Continuation No. II: Observations where certain claims were found unsearchable (Continuation of item 2 of first sheet)

This international search report has not been established in respect of certain claims under Article 17(2)(a) for the following reasons:

Claims Nos.: 15 and 16 because they relate to parts of the international application that do not comply with the prescribed requirements to such an extent that no meaningful international search can be carried out, specifically:

Although a claim directed to a method of treatment is commonly searched on the basis of its alleged effects, the claims 15 and 16 do not contain any concrete technical features; they were therefore excluded from the search.

Form PCT'ISA/2 10 (continuation of first sheet C1)) (January 2004) INTERNATIONAL SEARCH REPORT International aoolication No. Information on patent family members PCT/IB 2010/000275

Patent document cited Publication Patent family Publication in search report date member(ε) date

us 2008292693 US A l 2008292693 2008-11-27

WO 0135954 WO A l 0135954 2001-05-25 CA A l 2388835 2001-05-25 AU A 2749001 2001-05-30 AU B2 779620B 2005-02-03 U S B l 6420435 2002-07-16

WO 03058246 MX A PA04007779 2004-10-15 U S A l 2005069583 2005-03-31 ZA A 200405848 2006-05-31 RU C2 2317087 2008-02-20 PT E 1474154E 2005-10-31 PL A l 370141 2005-05-16

US 6395307 US B l 6395307 2002-05-28 ZA A 9803707 1999-02-26 PL Bl 194696B 2007-06-29 PL B l 195410B 2007-09-28 PL A l 336724 2000-07-03 JP T 2001522368T 2001-11-13

Form PCT/ISA/210 (patent family annex) QuIy 1998; reprint January 2004)