us2 cu») United States cz) Patent Application Publication Mehta (54) FORMULATIONS FOR THE TREATMENT OF DISORDERS OF THE MOUTH, THROAT AND RESPIRATORY TRACT (71) Applicant: Ras Mehta, Kowloon (HK) (72) Inventor: Raman Mehta, Kowloon (LIK) Appl. Nox 18735,361 PCT Filed: Jun, 10, 2016 (85) PCTNo: — PETAB2016/000795 $371 XD. (2) Date: Dees 1, 2017 G0) Foreign Application Priority Data Jun, 10, 2018 (EP) 151713842 Publication Classification (1) Ince. AGIK 369066 (2006.01) AGIK 30185 (2006.01) 201801691751 ao) Pub, No.: US 2018/0169175 Al (43) Pub. Date: Jun, 21, 2018 AGIK 369068 (200601) 61K 9/00 (2006.01), GIP 102 (200501), A61P 11702 (2006.01), A6IP 11/04 200501), (62) USC CC a. AGIK 36/9066 (2013.01), AOTK 36/185 (2013.01), AIK 369068 (2013.01): 461K 2300700 (2013.01); ABLP 1/02 (2018.01) AIP HA? 2018.01}; ABIP THM 2018.01) “A6IK 9/0056 (201301) on A RACT The present invention relates to fommlations containing a combination of exteacts from Curewma longa, Puniow era ‘natum aod Zingiber oficinale, acting synergistically in the treatment and prevention of disorders of the mouth, throat ‘and respiratory tract; the formulation i especially active on isorders of bacterial origin, e.g. those occuring in patients affected by common cold aad fu snd thei complications. The present formulations are particularly useful in the reduction of incidence of sores throat and their infections And in the olimination of antibiotic use, especially among infants and the elderlyUS 2018/0169175 Al FORMULATIONS FOR THE TREATMENT (OF DISORDERS OF THE MOUTH, THROAT AND RESPIRATORY TRACT. STATE OF THE ART {0001} Inflammation an bacterial infection of the throat With plague formation are symptoms that aecompany’ com- ‘on influenza, cld and winter diseases. The common cold js wenerally considered the most common human disease, alleting people in all counties and social contexts. Adults may have 1Wo to five colds every year, particularly’ ia ‘rovided communities and in winter, chillrn in contact with ‘other children may have six to ten cold episodes every year, ‘with up to twelve colds'year for kindergarten of school children, (1-10) Hossever, some episodes may’ be minimally symptomatic 0002} ‘The common cold and fh are viral diseases local- ‘ved in the upper respiratory’ tract; eexponsible ofthe inlee- tion are generally for 40% rhinavirs, for 10% coronavinis ‘and ia minor proportion adenovirus, parsingloenza. vies {ollawed by bacterial infection. (1-6) Cold episodes may be associated with symptoms such as nasopharyngitis, thine ‘pharyngitis, increase in temperature, ear and throat com- plications and respiratory problems. Common symptoms ‘ay include cough (usualy few days aller the onset), sore throat, runiy nose and fever. Symptoms disappear in five t© ten days, In some cases, particularly ia older, higher-sk subjects, residual symptoms may ast upto three weeks. The frequency of common cold episodes tends to increase in ‘okler subjects and in patients at risk, mainly due to dteriration of the immne system, Influenza is particularly ‘dangerous in the elderly due to the frequent serious and Ldbilitating complications, leading at serious risk of death, 0003) In industrialized countries, panieulay in crowded ‘communities, 30% of the population may be affected every ‘winter. The costs due to lost working hours, medications, ‘complications and altered social interactions are significant, An effective vaccine is not available as many diferent Viruses (which albo change overtime) are involved. Hand cleaning and washing may reduce the exchange of viruses ‘Aspisa, supplements, particularly vitamin C and zine, my be ellectve in decreasing the rate of eas and the length of ‘each episode, (4-8) Analgesies and antipyretics may allevi- ‘ate specific symptoms. (9-16) Decongestants (ie, pseu ‘doepledrine ipratropium and other nasal spray) may reduce the symptoms of a runny nose. The symptoms associated ‘with a minny nose may be controlled by antihistamines but these products may cause significant adverse eactons such as drowsinos, impuired attention and driving performance ‘The cold disorders sometimes involve eomplications due to the onset of bacterial infections easing fever and pain, In these cases antibiotic or bacteriostatic treatment is necessary jin addition to the symptomatic treatment. Antibiotics are lowering the body's defenses giving rise to frequent relapses particularly in children. Cough and cold medications in children (<6 years) yenerally are not advised as they may ‘cause significant side eects and complications and provide "unproven benefits. About 30% of older patients may develop ‘complications (upper respiratory tract infection, bronchitis, pneumonia). In high-risk subjects (severe risk’ conditions, heavy smokers, diabetes, handicapped subjects, patonts with previous, chronic cardiovascular or pulmonary prob- Jems), complications may he severe and cause hospital ‘admission With increasing social/uman costs, Jun. 21, 2018 [0004] At the moment n0 specific treatment or prevention or colds is available, New products with good tolerability be used also in prevention ae today very requested. [00S] Various plant remedies have been proposed for ‘wcating cold-rlated diseases; these natural provers may Jhwe lesser toxicity than synthetic drugs, yet they often show a lesserless consistent activity, Plant extracts and mixtures thereof are also generally proposed: sometimes, combina- ‘ions of medicinal plants ae also “conservatively” proposed, i.e. involving the combination of a very lange number of active agents aginst 2 multitude of unrelated diseases, s0 as to provide u widest spectrum of aetvities; yet the aetivity of specific active agents present in the mixture against specific (Groups of) diseases remains unknown: for example, the patent publiation 3P2013001666 describes a mutrientcom- Position for treating a variety of conditions including ath- ferosclerosis, cancer, cell damage, diabetes, cranial never disease, cerebral infretion, dementia, parkinson’s disease, slimentary mocoss disease, lung/bronchus disorder, inflam- ‘mation, menopausal disorder, rheumatism, atopic disease, containing inter alia, curcuma longa extract (used in lower ratios than in the present invention), silylbum mariamum sood, emblica oficinals extract, wheat bran, Japanese tea leaf extract, sesame extract, pomegranate seed extract, gin- ger extroct, Soy isoflavone, Withaniaroot, becopa monnier- ileal, ete. Other publications disclose compositions for a narrower medical indication, but fil 1 individuslize the combination of agents on which the preseat invention is ‘based. For example, the utility model DE 20 2009 002 126 describes a nurtive composition useful fr treating subjects ‘under chemo-/radiotherapy: the composition contains «m= tinude of vitamins, minerals, carotenoids, omega-3 fatty acids, pomegranate extract and at least one extract chosen from broccoli, ginger and curewma: in the exemplified compositions, the active ingredients of the present invention represent a minority part of the total active ingredients present, The pateat application WO-A1-2011/068812 Geseribes compositions for treating the orl cavity eontain- ing atleast thee of Parca granatum, Moristica fragrans, Zingiber officinale and Zizyphus joazeiro, and an adaitional extract selected fom another 38 plans: there is no specific disclosure of the combination on which the present inven- tion is based. [0006] The publication Drugs of dhe Future, 2008, 33(4), pp. 329-346 describes separately the activites of Punica ‘granatum, Curcuma fonga of Zingiber officinale: the doen ihe general biochemical effects of these tive components (antionidont, st-inflam- ‘matory, antimicrobial, anticancer, antimtagenie), with no suggestion or teaching oa how to optimize their activities the document does rot suggest any specific combination of these ageals, nor it prospects a possible synergism among them, [0007] Very tite research was so far performed in iden- tifying specific combinations of more than two extracts: in particular, no guidance is given to identily specific combi- ‘ations possibly capable to offer more than just overalapping effects in the pathologies ofthe mouth, throat and respiratory SUMMARY [0008] It has now been discovered that a combination of | extracts of Curcwma longa, Punica granatum and Zingiber officinale displays a siong synergistie activity on disordersUS 2018/0169175 Al ‘of the mouth, throat and respiratory tract this activity, involving a strong antimicrobial elle, is particularly useful ‘aunt affections oecurring during common cold and fu, Objects of the invention are dhe aforesaid combination of ‘exracs, the relevant pharmaceutical compositions, methods ‘of preparation, and use thereof in the irstneal prevention of disorders of the miowth, throat and respiratory trat. In particular, the invention encompasses the aforesaid combi- nation of extaci for use in the treatment/prevention of said disorders, andthe corresponding methods of treatment DETAILED DESCRIPTION OF THE INVENTION 10009] Curcuma donga is the botanic name of turmeric. Punica granatum is the botanic name of pomegranate, Zingiber officinale is the botanic name of ginger. For each Of these plant, the botanic and common name are wed herein indifferently [0010] Throughout this description and claims, whenever ‘weight (or weight pecent) amounts of extracts are distlosed, they are ahways meant as “dry” extracts, ie. considering ‘only the weight of the aon-liguid ingredients of the extract likewise, whenever weight (or weight pereent) amounts of specie ingredients within an extract are disclosed, they are always ealeulated by reference tothe extract in “dy” form. [0011] "Nevertheless, the combinations formulations/phar- ‘aceutical eompositions/nses abjects ofthe present inven- tion are not limited to using dried extracts, but extend also to using liquid and fuid extrcts. Any types of extracts ca be used herein, indifferently from their specific method of ‘extnction and thir physical status [0012] -Curcuma fonga extracts are wally obtained from roots and rhizomes of the plant. They contain curcumino‘ds jn association with other plant components working as natural vehicles, Total alcoholic extracts are preferably sed: they can be prepared eg. according the modalities of Ayurveda system of medicine (Turmeric extract, by extrac- tion of Cureuma thyzomes with ethanol: they typically ‘contain 20-30% wt curcuminoids, preferably 25% wt, referred to the dry extact. [0013] Purica grananum extracts are typically obtained from the whole fruit They have a polyphenol content generally ranging from 60 t0 95% wt., preferably 75%: ‘llagic acid) and polymers thereof (punicalgines) are the main aetive components of the extract: they are nomally present in the extract in 2 minimum amount of 30% wt, preferably more than 40% wt, referred tothe dried extract. Ina proferred embodiment, the extract can be prepared hy cextiacting the whole f ‘acetone, concentrating the extracts to water a the aqueous solution, alter elimination of insoluble ‘through absorption of polyphenos ona polystirenic polyphenols are recovered from the resin by elution with ‘ethanol and then concentrated to dryness [0014] Zingiber oficinate exact is usually obtsined from Thizomes. It is preferably a lipophilic extract; it contains from 20 o 50% of a mixture of gingerols+shoagols, elerred to the dred extract. Ina preferred embodiment, ii obtained by extraction of the dried rhizomes with n-Hexane or with (CO, in supercritical condition at a temperature of 45°C. and a pressure of 220 bars, 10015] In one embodiment of the invention, the three aforementioned extracts are the sole active agents used (this ‘does not preclude the joint use of pon-active agents, i, Jun. 21, 2018 vehicles and formulation excipients, including those poss bly having « pharmaceutical elfec as a side activity: the Jatter may sil be used in modes/amounts conform to their rule as vebicleexcipien) [0016] Alternatively, adltional active agents may be ‘sed, but on condition thatthe combination of extracts oF the invention remains prevalent, ie 0017] said combination of Curcuma longa, Punica ‘granatum and Zingiber officiate accounts for more than $0% (or, preferably, more than 75%, 85%, 90% 95% or 99%) by weight of the total active agents present andr any possible aetive agent additional to Said Curciona longa, Punica granatum and Zingiber officinale is prevent in at amount at least 50% by ‘eight lower than the lowest among said Curewna Tonga, Punica granatum avd Zingiber officinale: ‘accordingly a combination of, for example, 60 mg ‘meric extract, 20 mg pomepranate extract and 10 mg ‘ginger extract, will allow the presence of additional ‘clive agents, each one being present in amounts of S img or lower [018]. Furher in the invention, Curcuma Longa is gen- cally present in higher concentrations compared tothe 880 other members, Le. Zingiber Offiinale and Punica grana- tum, i. the weight ratio among, these three active agents, based on their dred extracts, i: 6(22):2(21}1(20.5), where the data in parenthesis represent possible weight ratio variations for each component [0019] According to another preferred embodiment, the Tormulations cousin the thee extacts within the following ‘weight intervals, per dosage unit, refered to dried extracts Pico prone ct 40% lige a des) “10 0 me Brac iat ent ee 39 ginger 2020 oe [0020] According to. a more prefered embodiment the content per dosage unit, referred to dried extracts, i ge fat ne a 3% ine 10 ms cach of these amounts being variable within a range of 215% [0021] _ futher referred embostiment concems the slow release formulation tablet described in example 1 of this application, or the orodispersible mucoadhesive tablet ‘described in example 2 of this application, wherein the ‘weight of each of the formulation ingredients ean vary within a range of =15% 0022] Most preferably, the combination of the present invention i formulated as a buecal composition, 4. for local application in the buccal cavity, capable to release the active principles during a prolonged time after application, typically formulated as an orodispersible tablet or film ively the combination is A, eg. as aerosol, spray, ce. Tn particular the inventors have nnexpectdly found that the present combination of extracts, after a suitable time of permanence inthe buccal cavity ensures nn inerease in the mount of salvar lysozyme, an enzyme involved in capt awinactivating possible eavioamental contaminsatsenter-US 2018/0169175 Al ing in the mouth such as bacteria and viruses. Even more surprisingly, the found increase wae unrelated to enhanced salivaton, ie, it consisted in an enhanced salivar concen- tration of lysozyme, thus independent from the amount of secreted saliva, The present combination is this umexpect- ‘edly effective when formulated as a buccal sustained release ‘composition, exerting a very elective preventive effect fgainst bacterial of vital infection such as eommon fi, The ays ° a {0041} On randomly selected patients, the lysozyme con- ‘centration in the saliva Was evalated bere dhe fist admin- ‘stration (controls), and after 1 week of treatment (3 tablets! “aily), The results are reported in table 2 Jun. 21, 2018 TABLE 2 ‘sep mci le pops Se nae or B 3 a 3 8 ot 1 m2 os > 2 or 24 120 rn 2 ns ® ah Be [0042] To demonstrate the synergistic effect of the com> bination versus the single ingredients a pilot clinical rial has been carried out on 5 groups of 12 patients suffering of bacterial infection ofthe oral cavity: first group was treated ‘with a combination of extracts according to the invention (Sample D),3 times a day for 3 days. The remaining groups of patients were administered, under the same administra tion protocol, either: @ placebo fomnulation (Sample E), Gurctima longa exteact alone (Sample A), Punica gramatum extract alone (Sample B), or Zingiber officinale alone (Sample C); each of he single extracts was administered in the same amount as present in Sample D. One hour before and one hour afte the last treatment the patients gargled for 30 sce with physiological solution and 0.5 ml. were plated fon agar for bacterial counting after incubation for 36 h ‘according the lab standard conditions {0043} The results are reported in the following table TABLE 3 atl ou (0) silo fre ater ‘Sle A (Circa Toga) aso ory Sipe (euce gram) 440 Ba Sipe C Ginger fica) 33 me Sipe D Contauton)| ans ra Stole (Pace) 0 a [044] It can be noted thatthe effect afer treatment with ‘Sample D according tothe invention is unexpectedly higher than each of the three Samples A, B, C taken alone. The cffot of Sample D is also higher compared to the cumulated effets obtained by Samples A4B4C REFERENCES [0045] 1. Becles R, Weber O. Common cold (Online- ‘August ed), Basel: Birkh. user: 2009. p. 197 [0046] 2. Gwaliney J MJ, Halstead S 8. Contagiousness ‘of the common cold. Jounal of the American Medical “Association 1997; 278(3), [047] 3. Cohen S, Doyle WJ, Alper CM, Junicki-Deverts D, Tumer RB. Sleep habits and suseepibilicy 10 the ‘common cold. Areh Item Med 2009 169:62-7. 048} 4. Lawrence DM. Gene studies shed light on shinovirus diversity. Lancet Infect Dis 2008; (5).US 2018/0169175 Al 10049] 5, Jefferson, Del Mar C B, Dooley L, Fertoai E, AbAnsary LA, Bawazeer G A et al Physical interven: ‘ious to interrupt or reduce the spread of respieatory viruses. CADTH Technol Overy 2012: 222302. [0050] 6. Singh M, Das R R. Zine forthe common co. Cochrane Database of Systematic Reviews 2007; 2. (Feb- siary 2011), 10051) 7. Hemil. H, Chalker B, Douglas B, Hemi. H. ‘Vitamin C for preventing aad treating the common cod Cochrane Database of Systematic Reviews 2007; 3:C 000580, 10082] 8. Simasek M, Blandino D A. Treatment of the onumon cold American Family Physician 2007, 75:515- 20. 10083} 9, Kim S ¥, Chang ¥ J, Cho HM, Hovang ¥ W, ‘Moon Y'S, Nonsteroidal antiinlamnatory dogs foe the common gold. Cochrane Database Syst Re 2009: 3 [$4] 10, Essles R. Eicacy and safety of oversho- ounce analgesics in the twatmest of common cold and fo, Journal of Chnieal Phannacy and Thorapeutis 2006; 31300419. {0088} 11, Smith $ M, Schroeder K, Fahey : Oversho- counter (GTC) medications for ace cough in. children dua aduls in ambulatory setings. Covlrane Database Syst Rev 2012; §CD001831. 10086) 12. Shetrin A E, Goldman R D. Use of overshe- counter eough and cold medications in ctildren. Can Pam Physician 2005, $5:1081-3. 10087] 13. Vaslev Z P, Kabad S, Villa R. Sofety and clcaey of overhe counter cosh and cold meicines for tse in children. Expert opinion on drug safety 2010 Sr283-42. {00$8} 14. Taverne D, Latte G J. Nasal decongestants foe tne common cold. Cochrane Database Syst Rev 2007 | 10089) 15. Abulawi Z H, Odhmun S'S, Alfaleh S.Ineue ‘nasal prateopinm bromide for the common cold Cochrane Database Syst Rev 10060} 16. Prater MR. Cough and the common colt ACCP evidence-based clniealprctice guidelines. Chest 2006; 12941 Suppl) 725-45 10061) 17. Guppy MP, Mickan SM, Del Mar CB, Thoming S, Rack A. Advising pata to increase Bud intake for teting acute respiratory infections. Cochrane Database Syst Rev 2011; 2:CD004419. 10062] 18. Singh M, Singh M. Heated, hunsiitedsie for the common cold Cochrane Database of Systematic Reviews 2011 5. 10063} 19. Pao 1M, Beier J, King T'S, Clapp FR, Vala, Berin CM. Vapor rub, petlatum, and n0 tweatment for children with noetumsl cough and cold symptoms. Pediateies 2010; 12610829. 10064}. 20. AroilB, Kenealy T Antbiotes for the eom- ‘mon cold and acute panvlent rhinitis, Cochrane Database Syst Rev 2005; 3 {0965}, 21. Oxuwole O, Meremikwu MM, Oyorta A, ‘Udoh EF. Honey for gute cough in chile. Cochrane Database of Sycmatie Reviews 2010 1. upper re tony trict infections. Cochrane Database of Systematic Reviews 2010 (3) 10066} 22. Kassel C, King D, Spurting GK. Saline nasal inigation for acute {0067} 23. Komos W.On call. always catch cos during the winter snd they last more than a week. 1 heard that Jun. 21, 2018 Zine and echinacea help to shorten colds. Should 1 ry them? Hary Mens Health Watch 2012; 1722 [0068] 24. Heiner K A, Hart AM, Martin LG, Rubio- Wallace S. Examining the evidence for the use of vitamin C in the prophylaxis and treatment of the common col Journal of the American Academy of Nurse Practitioners 2008: 21:295-300, [0069] 25. AI-Nakib W, Prophylaxis and treatment of ‘rhinovirus colds with zine gluconate lozenges. 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A method of preventing and/or treating disonters of the mouth, throat and respiratory tact, comprising admin- jstering toa patient in need thereo, a combination of active fagenis consisting of extracts of Curcwma Tonga, Punica _granarum and Zingiber officinale, the extracts being present in the respective Weight ratios 6(22):2¢e1):1(205) 14, A method of preventing and/or treating disorders of the mouth, throat and respiratory tact, comprising admin- istering 1 a patient in nood thereof, a combination of active fagenis consisting of extracts of Curewma longa, Punica _granatum and Zingiber officinale, the extrcts being present inthe respective weight ratios 6(22)2¢21):1(205), ‘wherein the extracts represent overall more than 50% by ‘weight of the total administered active ageats, andlor wherein each possible active agent additional to the ‘extracts is present in an amount atleast 50% by weight lower than the lowest among the extract of Cureuma Jonga, Punica grananum and Zingiberofinale 18, The method according to claim 14, wherein the extracts of Curcuma longa, Punica granatum and Zingiber ‘ficinate represent overall more than 50% by Weight ofthe total administered active agents 16, The method according to claim 1, where the extract ‘of Carewna fonga contains eurcuminoids in an amount fro 20% to 30% by weight, the extract of Punica granatum ‘ontains polyplienols in an amount from 60% t0 95% by ‘weight, and the extract of Zingiber officinale contains a ttal of gingerls and shogaols in an amount from 20% to 50% by ‘weight. 17. The method sccording to claim 13, wherein the combination is fommated as unit dose of administration, ‘comprising 20-100 mg of Curcuma longa exact 10-50 mg ‘of Punica gramanum extract, and 2-20 mg Ginger oficinale 18, The method sccording to claim 13, wherein the combination is formulated with pharmaceutical excipients 19. The method according to claim 13, wherein the combination is in a fon suitable for buccal, ora or inha- Jatory adminisiation, 20. The method acconling to claim 13, wherein the isorder is connected with bacterial activity: 21. The method acconting to claim 13, wherein the sorder is consequential to common eold or Hh 22. The method acconling to claim 13, wherein the sore is one or more among: nasopharyngits, aynophar- ingitis, sore threat, cough, runny nose, increase in body temperature, ear and/or throat complications, respiratoryUS 2018/0169175 Al fasal obstruction, malaise, 2B, The method docording to cei 13, vberein the ‘combination is coafigured for enhancing lysis of xenobiotics via contact of the combination with the sali 24. A pharmaceutical composition comprising the com- bination of extraets according to claim 13 Jun. 21, 2018