WO2010092468A1

WO2010092468A1 - Composition comprising alginates and d-limonene to treat gerd and dyspepsia

Info

Publication number: WO2010092468A1
Application number: PCT/IB2010/000275
Authority: WO
Inventors: Carlo Ghisalberti
Original assignee: Carlo Ghisalberti
Priority date: 2009-02-13
Filing date: 2010-02-12
Publication date: 2010-08-19

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 essential oil with high cholinesterase inhibitory activity.

Description

COMPOSITION COMPRISING ALGINATES AND D-LIMONENE TO 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, (Galvestoπ, 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 GB 2349570; WO 01/66119; 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 and 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; 12:11-21).

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 GERD₁, 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 prokiπetic 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 in the invention preferably has a 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-em ulsifiers 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 05105290, to afford gelatine microcapsules with 30% to 65% of d-iimoΛene 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, more, 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 axe 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 (AICO₃OH), dihydioxy aluminium sodium carbonate (NaAlCO^OHh), calcium carbonate (CaCOs), calcium bicarbonate

(Ca(HCO3)2), calcium phosphate (Ca3(PO4,)2), magnesium aluminate (Mg(AlO₄)S), magnesium alumino silicates (MgAlSiO*), magnesium carbonate (MgCOs), magnesium bicarbonate (Mg(HCOj)₂) magnesium glycinate (MG(GIy)^), magnesium hydroxide

(Mg(OH)2), magnesium oxide (MgO), magnesium trisilicate (Mg₂SIaOs), 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., Salvia 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 excipieπt 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. As 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% loaded 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.b to 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 butyrrylcholinβ 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 U(JHb % Inhibition d-Limonene 13% at 70 mg/l

Salvia lavandulaefolia EO IC₅₀ = 50 mg/1 26% at 20 mg/1 Origanum majorana EO IC₅₀(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-limoneπe 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 of 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 officinalis, Lavandula officinalis, Ocimum basϊlicwn, Origanum onites, Origanum vulgare, Origanum munitiflorum, Origanum majorana, Salvia sclarea, Salvia officinalis, Satureja cuneifolia, Salvia lavandulaefolia, and βucalyptus -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.