THIRUVUUTTUUNTURUS009913869B2 (12 ) United States Patent ( 10 ) Patent No. : US 9 , 913 ,869 B2 Cifter et al. (45 ) Date of Patent: Mar. 13 , 2018 (54 ) FORMULATIONS COMPRISING ( 56 ) References Cited EXTRACTS U . S . PATENT DOCUMENTS @(71 ) Applicant: MONTERO GIDA SANAYI VE 5 ,904 ,924 A 5 /1999 Gaynor et al. TICARET A . S ., Istanbul ( TR ) 2004 /0126441 A1 7 / 2004 Pushpangadan et al . 2007/ 0014877 Al * 1/ 2007 Chatterjee et al...... 424 / 725 2012 /0309837 A1 * 12 /2012 Banerjee ...... A61K 9 /0078 @( 72 ) Inventors : Ümit Cifter , Istanbul ( TR ) ; Nazife 514 /630 Arabacioglu , Istanbul (TR ) ; Özlem 2015 / 0273003 Al 10 / 2015 Cifter et al . Toker , Istanbul ( TR ) 2015 / 0273009 Al 10 /2015 Cifter et al . 2015 /0290253 A1 10 / 2015 Cifter et al . @(73 ) Assignee : MONTERO GIDA SANAYI VE TICARET A . S ., Istanbul ( TR ) FOREIGN PATENT DOCUMENTS CH 676931 A5 3 / 1991 @( * ) Notice : Subject to any disclaimer, the term of this CN 1876167 A * 12 / 2006 CN 101204386 A * 6 / 2008 patent is extended or adjusted under 35 CN 101637347 A 2 / 2010 U . S .C . 154 (b ) by 84 days. CN 101695563 A 4 / 2010 CN 102 100900 A 6 /2011 ( 21) Appl. No .: CN 102343077 A 2 /2012 14 /436 ,346 CN 102641367 A * 8 / 2012 CN 102698233 A 10 / 2012 ( 22 ) PCT Filed : Oct. 17, 2013 DE 421745 A1 * 10 / 1993 DE 4211745 Al 10 / 1993 EP 1520584 AL 4 / 2005 ( 86 ) PCT No. : PCT/ EP2013 / 071750 EP 1829548 AL 9 / 2007 wo WO - 2009 /011498 A 1 / 2009 § 371 (c )( 1) , WO WO - 2012 /084075 A 6 / 2012 (2 ) Date : Apr. 16 , 2015 wo WO - 2014 / 060525 AL 4 / 2014 WO WO - 2014 /060533 A1 4 / 2014 (87 ) PCT Pub . No. : W02014 /060529 WO WO - 2014 /060539 A1 4 /2014 PCT Pub . Date : Apr. 24 , 2014 OTHER PUBLICATIONS (65 ) Prior Publication Data Fazio , Tolerance , Safety and efficacy of Hedera helix extract in inflammatory bronchial diseases under clinicalpractice conditions: US 2015 /0290268 A1 Oct . 15 , 2015 A prospective, open , multicentre postmarketing study in 9657 patients. Phytomedicine, ( Jan . 2009 ) vol. 16 , No. 1 , pp . 17 - 24 . * Foreign Application Priority Data Percival , Use of echinacea in medicine . Biochemical pharmacology , ( 30 ) ( Jul. 15 , 2000 ) vol. 60 , No . 2 , pp . 155 - 158 .* Aimbire et al. , “ Effect of hydroalcoholic extract of Zingiber Oct. 18 , 2012 ( TR ) ...... a 2012 12023 officinalis rhizomes on LPS - induced rat airway hyperreactivity and Oct. 18 , 2012 ( TR ) ...... a 2012 12042 lung inflammation ,” Prostaglandins Leukot Essent Fatty Acids. 77 (3 -4 ): 129 -38 (2007 ) . (51 ) Int. Ci. Cohen et al. , “ Effectiveness of an herbal preparation containing A6IK 36 /28 ( 2006 . 01 ) echinacea , propolis , and vitamin C in preventing respiratory tract A61K 47 / 10 ( 2017 .01 ) infections in children : a randomized , double -blind , placebo - con trolled , multicenter study, ” Arch Pediatr Adolesc Med . 158 ( 3 ) :217 A61K 9 /00 ( 2006 .01 ) 21 ( 2004 ) . A61K 47 / 26 ( 2006 .01 ) Fazio et al. , “ Tolerance, safety and efficacy of Hedera helix extract A61K 36 / 185 ( 2006 .01 ) in inflammatory bronchial diseases under clinical practice condi A6IK 36 / 25 ( 2006 .01 ) tions : a prospective , open , multicentre postmarketing study in 9657 A61K 36 / 9068 ( 2006 .01 ) patients ,” Phytomedicine. 16 ( 1 ) :17 -24 (2009 ) . A61K 35 /644 ( 2015 . 01 ) (Continued ) A61K 36 / 258 (2006 . 01) A61K 36 / 484 ( 2006 . 01 ) Primary Examiner — Qiuwen Mi A61K 36 /61 ( 2006 .01 ) (74 ) Attorney , Agent, or Firm — Clark & Elbing LLP ; (52 ) U . S . CI. Susan M . Michaud CPC ...... A61K 36 /28 (2013 . 01 ); A61K 9 /0053 (2013 .01 ) ; A61K 9 / 0095 ( 2013 .01 ) ; A61K (57 ) ABSTRACT 35 /644 ( 2013 .01 ) ; A61K 36 / 185 (2013 .01 ) ; The present invention relates to a formulation comprising A61K 36 / 25 ( 2013 . 01 ) ; A61K 36 /258 extracts of Hedera helix , Pelargonium sidoides and Echi ( 2013 .01 ) ; A61K 36 / 484 ( 2013 .01 ) ; A61K nacea purpurea for use in the treatment, prevention of, or 36 / 9068 (2013 .01 ) ; A61K 47/ 10 (2013 .01 ) ; the alleviation and / or elimination of the symptoms of vari A61K 47/ 26 (2013 .01 ) ; A61K 36 /61 ( 2013 .01 ) ous respiratory tract diseases , as well as to a method for (58 ) Field of Classification Search preparing this formulation . CPC ...... A61K 36 / 00 See application file for complete search history. 33 Claims, No Drawings US 9, 913 , 869 B2 Page 2

( 56 ) References Cited International Search Report and Written Opinion for PCT Applica tion No. PCT /EP2013 /071766 , dated Jan . 23 , 2014 ( 10 pages ) . Kemmerich et al . , “ Efficacy and tolerability of a fluid extract OTHER PUBLICATIONS combination of herb and ivy leaves and matched placebo in Hofmann et al. , “ Efficacy of dry extract of ivy leaves in children adults suffering from acute bronchitis with productive cough . A with bronchial asthma a review of randomized controlled trials ," prospective, double -blind , placebo -controlled clinical trial, " Phytomedicine. 10 ( 2 -3 ): 213 -20 ( 2003 ). International Preliminary Report on Patentability for PCT Applica Arzneimittel Forschung . /Drug Research . 56 ( 9 ) :652 -60 ( 2006 ) . tion No . PCT/ EP2013/ 071741 , dated Apr. 21 , 2015 ( 6 pages ) . Matthys et al. , " Efficacy and safety of an extract of Pelargonium International Preliminary Report on Patentability for PCT Applica sidoides (EPs 7630 ) in adults with acute bronchitis . A randomised , tion No. PCT/ EP2013 / 071750 , dated Apr. 21 , 2015 ( 7 pages ). double -blind , placebo -controlled trial, ” Phytomedicine. 10 (Suppl International Preliminary Report on Patentability for PCT Applica 4 ) : 7 - 17 ( 2003 ) . tion No . PCT/ EP2013 /071758 , dated Apr. 21, 2015 (6 pages ) . Matthys et al ., “ Pelargonium sidoides preparation ( EPs 7630 ) in the International Preliminary Report on Patentability for PCT Applica treatment of acute bronchitis in adults and children , " tion No . PCT/ EP2013 /071766 , dated Apr. 21, 2015 ( 6 pages ) . Phytomedicine. 14 ( Suppl 6 ): 69 - 73 (2007 ). International Search Report and Written Opinion for PCT Applica Search Report and Written Opinion for Turkish Application No. tion No . PCT/ EP2013 /071741 , dated Jan . 23 , 2014 ( 9 pages ) . TR201212043 , dated Jul . 18 , 2013 ( 18 pages ) . International Search Report and Written Opinion for PCT Applica Search Report and Written Opinion for Turkish Application No. tion No . PCT/ EP2013/ 071750 , dated Jan . 23 , 2014 ( 11 pages ). TR201212044 , dated May 14 , 2013 ( 9 pages ) . International Search Report and Written Opinion for PCT Applica tion No . PCT/ EP2013 /071758 , dated Jan . 23 , 2014 ( 9 pages ). * cited by examiner US 9 , 913 , 869 B2 FORMULATIONS COMPRISING HERBAL the " nervus vagus” in the stomach , causing a cough EXTRACTS response . A study by S . Fazio et al . published in the January 2009 issue of “ Phytomedicine ” tested a dried leaf extract on FIELD OF INVENTION 9657 patients with acute and chronic bronchitis , including 5 children . Accordingly , it was observed that following one The present invention relates to a novel formulation , week , cough and chest pain disappeared or improved in 95 % comprising Hedera helix extract , Pelargonium sidoides of patients . extract , and extract. Pelargonium sidoides (African Geranium , Umckaloabo ) The present invention further relates to a method used for is a species widely used in the treatment and preven preparing a formulation comprising extracts of Hedera 10 tion of, or in the alleviation and /or elimination of the helix , Pelargonium sidoides , and Echinacea purpurea , as symptoms of cold and respiratory tract disease (pharyngitis , well as to the use of this formulation in the treatment and sinusitis , acute bronchitis , tonsillitis ). It was determined to prevention of various respiratory tract diseases, or in the be effective in increasing the generation of natural killer alleviation and /or elimination of the symptoms thereof in cells and tumor necrosis factor alpha , and to enhance the mammalians, particularly in humans . release of interferon beta . Pelargonium sidoides has antiviral properties strengthening the immune system . It further has BACKGROUND OF INVENTION both antibacterial effects and antioxidative properties against some bacteria . Apart from that, it was also reported In recent years , the use of various herbs and / or herbal to boost the immune system of the respective organism and medical products for the prevention of diseases, alleviating 20 to have expectorant action by increasing the ciliary beat the effects thereof, or for treating diseases have been gradu frequency of respiratory epithelial cells . In a multicenter ally increasing in all societies . Throughout the human his study conducted by the Pneumology Department of a Ger tory, there have been and still are attempts for treating many man University Hospital (2000 ) on acute bronchitis patients , diseases (diabetes , jaundice , dyspnea , etc . ) by using some including adults , children , and infants , it was determined herbs. According to the records of the World Heath Orga - 25 that an extract of the roots of Pelargonium sidoides reduced nization (WHO ) , a large proportion of the world ' s popula - the severity of the symptoms after 7 days treatment from 6 . 3 tion (70 - 80 % ) makes use of herbs for therapeutic or pro - to 0 . 9 according to the average bronchitis severity score . A phylactic purposes. Additionally , around 25 % of study published in “ Acta Paediatrica” in April 2010 , showed prescription drugs in developed countries are composed of that preparations extracted from herbal roots were much plant based active agents ( vinblastine , reserpine , quinine , 30 more effective in the treatment of acute bronchitis as com aspirin , etc . ) ( Farnsworth et al . , 1985 ) . pared to placebo . A study group of children aged 6 to 18 Particularly following the end of the 1990s , the discovery years , taking the herbal extracts experienced less coughing , of new areas of use for medical and aromatic herbs and the sputum , and bed rest times versus placebo . By assessing the increasing demand for natural products have increased the results of four placebo - controlled clinic trials , the research use potential thereof day by day . 35 ers at the Medical Center , the University of Pittsburgh , Herbal medical products have long been in use for the concluded that a standardized extract of Pelargonium treatment or prophylaxis of respiratory diseases . In the sidoides showed a much better performance in alleviating treatment or prophylaxis of these diseases which are typi- the bronchitis symptoms versus placebo in a 7 -day treatment cally caused by viruses, bacteria , and/ or fungi, it is quite period . significant both to eradicate these harmful organisms and to 40 Echinacea purpurea , the purple coneflower , is a plant boost the immune system of the affected individual. This is species widely used in the prophylaxis and /or treatment of because the immune system is comprised of processes infection , cold , cough , bronchitis , flu , in the treatment of providing protection against diseases , as well as recognizing infection of the urinary system , in the treatment of the sore and eliminating the pathogenic and tumor cells in a living throat and toothache , in boosting the immune system , and being . The system scans the organism against any kind of 45 externally , in the treatment of snakebite , eczema , psoriazis , foreign substances , entering or contacting the former, from acne , wounds and burns . Echinacea purpurea is known to viruses to parasitic worms of a wide variety , and distin - have immunostimulant, anti - inflammatory , antibacterial, guishes them from the organism ' s own healthy cells and antiviral , antifungal, anticancer, cicatrizant activities . The tissues . The immune system can even distinguish substances compounds accounting for these activities are thought to be with very similar features from each other to such an extent 50 polysaccharides , glycoproteins , alkylamides , and caffeic that even proteins having a different amino acid can be acid derivatives ( cichoric acid , echinacoside ) . Echinacea distinguished from the equivalents thereof . The function of purpurea supports the production of interferon , thereby the immune system is primarily to prevent harmful foreign strengthening the defense system of the respective organism . substances from entering the respective organism , or upon Interferon activates the natural killer cells and induces these entry , to retain the substances at the place of entry , or to 55 cells to bind to and destroy infected cells or tumor bearing prevent or delay their spreading therein . cells . Interferon is effective in releasing the enzymes Hedera helix (English Ivy ) is one of the plant species used destroying the genetic structure of viruses and inhibiting in the production of herbal products for the treatment and their reproductive and spreading capabilities . prevention of diseases , and /or for the alleviation and /or In prior art, there are many formulations , which comprises elimination of the symptoms thereof. Hedera helix , com - 60 herbal agents or combinations of herbal agents , are dis prising saponins, phenol, and alkaloids, is known to be used closed . For example, WO2009 /011498 A1 discloses a com for the treatment of cough , parasites, skin diseases , bron - position for the treatment of infection in the form of a syrup chitis , and chronic respiratory tract diseases . Various studies comprising Pelargonium sidoides ; EP1829548 A1 discloses have been performed to demonstrate the effect of Hedera a composition comprising an extract of Pelargonium helix on said diseases . For instance , Erik van Wyk and 65 sidoides; KEMMERICH BERND at al .: “ Efficiency and Michael Wink stated in “ Medicinal of the World ” that tolerability of a fluid extract combination of thyme herb and the expectorant action of Hedera Helix works by stimulating ivy leaves and matched placebo in adults suffering from US 9 ,913 ,869 B2 acute bronchitis with productive cough . A prospective , physical properties of this formulation should be made ideal double -blind , placebo -controlled clinical trials ” to provide high patient compliance . ( ARZNEIMITTEL FORSCHUNG . DRUG RESEARCH . Having said that, it is quite difficult to ensure the require ments mentioned above in the formulations comprising Acv EDITO CANTOR VERLAG , AULENDORF , DEe use , vol of. 5 herbal agents . Due to some characteristic chemical , biologi 56 , no . 9 , 1 Jan . 2006 , pages 652 -660 ) discloses the use of 5 cal, and physical properties of herbal agents incorporated in the combination of extracts of thyme herb and ivy leaves for a formulation , some difficulties are experienced in obtaining the treatment of acute bronchitis ; FAZIO S et al. : " Toler a formulation comprising such substances, and having both ance , safety and efficacy of Hedera helix extract in inflam good physical stability and ideal features in terms of patient matory bronchial diseases under clinical practice conditions : compliance . A prospective , open , multicenter postmarketing study in The physical properties and the physical stability of a 9657 patients” , (PHYTOMEDICINE , GUSTAV FISCHER formulation are influenced directly from the characteristic VERLAG , STUTTGART, DE , vol. 16 , no . 1 , 2009 , pages properties of herbal agents contained therein . Some aspects 17 - 24 ) discloses a composition in the form of a syrup of herbal agents contained in a formulation , such as having a bad taste , a bad scent, a bad color and similar physical comprising dried Hedera helix extract ; HOFFMANN D et 15 properties , becoming easily oxidized , and providing a suit al. : “ Efficacy of dry extract of ivy leaves in children with able medium for the reproduction of microorganisms nega bronchial asthma — a review of randomized controlled tri tively influence the physical properties and physical stability als” , ( PHYTOMEDICINE , GUSTAV FISCHER VERLAG , of that formulation . Additionally , in case a formulation STUTTGART , DE , vol. 10 , no . 2 - 3 , 2003 , pages 213 - 220 ) comprises a combination of herbal agents , a correct selection discloses a composition comprising dried ivy leaves for the 20 of the herbal agents bears great importance , since more than treatment of chronic airway obstruction in children suffering one herbal agent present in the same formulation are capable from bronchial asthma. Although that there are many for - to mutually affect their respective properties . mulations in the prior art comprising combinations of herbal Under the light of the foregoing, it would be desirable to agents , the effects of a formulation comprising Hedera helix provide a formulation , as well as a process for the prepara extract, Pelargonium sidoides extract, and Echinacea pur - 25 tion of this formulation , comprising combinations of herbal purea extract are not known yet. agents , being capable to retain the physical stability for a Products to be used for medical purposes have to incoror long time, and having ideal physical properties in terms of patientpo compliance . porate the elements of quality , efficiency, and reliability . A In detail , there is a need in the relevant art to a formulation product can be a " medical ” product only by having these comprising extracts of Hedera helix , Pelargonium sidoides, elements . In order for a product prepared from a herbal 30 and Echinacea purpurea , and having ideal physical proper source to be a medical product, it has to be prepared from an ties to ensure high patient compliance and good physical efficient and standardized extract, to have established phar stability , as well as to a method for preparing this formula macological, clinical outcomes and toxicological data , and a determined stability . Therefore , it bears great significance to tion , which is simple , cost - efficient and time- saving . have a good stability for a product, produced from herbal 35 OBJECT OF INVENTION sources, to be used in the treatment and prevention of diseases , or in the alleviation and / or elimination of the The main object of the present invention is to provide a symptoms thereof. novel formulation comprising extracts of Hedera helix , Physical , chemical , and microbiological factors play role Pelargonium sidoides , and Echinacea purpurea , overcom in the stability of medicaments or other products prepared 40 ing the problems referred to above , and having advantages for medical purposes. The stability issue is not dependent on over the prior art formulations. a simple cause only, but emerges as a result of many factors . According to this main object , the formulations according Factors such as the interaction of active agents contained in to the present invention are suitable for the treatment, a product, the interaction of excipients among themselves or prevention of, or the alleviation and /or elimination of the re are 45 symptoms of various respiratory tract diseases. with active agents , pH , light, humidity , and temperature are 45 symptomsAnother onobject of the present invention is to provide a among many elements which may influence the stability of formulation with an improved physical stability , comprising such products . extract of Hedera helix , extract of Pelargonium sidoides , Until recently , the researchers deemed considerable and extract of Echinacea purpurea . importance on the chemical stability of pharmaceutical A further object of the present invention is to provide a products rather than the physical stability thereof and con - 50 formulationfor with a clear and homogeneous appearance , ducted many studies accordingly . In many instances, how comprising extract of Hedera helix , extract of Pelargonium ever, they could show how important the changes in the sidoides, and extract of Echinacea purpurea . physical structures of products are for the product quality , Another object of the present invention is to provide a and for the durability of the technologic , microbiologic , and formulation comprising extract of Hedera helix , extract of biopharmaceutical properties thereof. Accordingly , it was 55 Pelargonium sidoides, and extract of Echinacea purpurea , shown that primarily the physical stability of a product has which both maintains the physical stability and has to be maintained in order to sustain its quality and other improved physical properties as a result of using suitable features thereof, and therefore ensuring the physical stability excipients . during the development of pharmaceutical products is as A further object of the present invention is to provide a important as , or sometimes more important than ensuring 60 simple , cost- efficient, and time- saving process for preparing the chemical stability thereof. a formulation comprising extract of Hedera helix , extract of Additionally , the physical properties taken into account in Pelargonium sidoides, and extract of Echinacea purpurea. the evaluation of the physical stability of a product , particu larly the taste , scent, color , clarity , uniformity , etc . of a DESCRIPTION OF INVENTION product, also considerably influence the patient compliance . 65 For this reason , when a novel formulation is developed . The maintenance of the physical stability of a pharma besides aiming a formulation of good physical stability , the ceutical product can be ensured if no change occurs in the US 9 ,913 ,869 B2 physical structure of that product. For this reason , the between 0 . 7 % and 25 % ; between 0 . 7 % and 22 % ; between change in some physical properties of the product during a 0 . 7 % and 20 % ; between 0 . 7 % and 18 % ; between 0 . 7 % and formulation development process is determined and it is 15 % ; between 0 . 7 % and 12 % ; between 0 .7 % and 10 % ; assessed whether the physical stability is maintained . Prop - between 0 .7 % and 8 % ; between 0 .7 % and 6 % ; between erties such as the color, scent, taste , pH , clarity, viscosity , 5 0 . 7 % and 4 % ; between 0 . 7 % and 3 % ; between 0 . 7 % and uniformity , density , etc . among the physical properties of a 2 % ; between 0 . 8 % and 38 % ; between 0 . 8 % and 35 % ; pharmaceutical product are the basic physical properties playing role in an evaluation of the physical stability of that between 0 .8 % and 32 % ; between 0 .8 % and 30 % ; between product . 0 . 8 % and 27 % ; between 0 . 8 % and 25 % ; between 0 . 8 % and In the physical stability studies conducted during the 10 22 % ; between 0 .8 % and 20 % ; between 0 . 8 % and 18 % ; development of a formulation comprising Hedera helix between 0 . 8 % and 15 % ; between 0 .8 % and 12 % ; between extract and Pelargonium sidoides extract for use in medi 0 . 8 % and 10 % ; between 0 . 8 % and 8 % ; between 0 . 8 % and cine, it was surprisingly found that adding extracts of 6 % ; between 0 . 8 % and 4 % ; between 0 . 8 % and 3 % ; between another herbal agent, namely Echinacea purpurea , into the 0 . 8 % and 2 % ; between 0 . 9 % and 38 % ; between 0 . 9 % and formulation , improved the physical stability of the product, 15 35 % ; between 0 . 9 % and 32 % ; between 0 . 9 % and 30 % ; and thus, the physical properties such as the color, scent , between 0 . 9 % and 27 % ; between 0 . 9 % and 25 % ; between taste , pH , clarity , viscosity , uniformity , and the density 0 . 9 % and 22 % ; between 0 . 9 % and 20 % ; between 0 . 9 % and thereof at the time the formulation was prepared were 18 % ; between 0 . 9 % and 15 % ; between 0 . 9 % and 12 % ; maintained for a longer time such that the physical stability between 0 . 9 % and 10 % ; between 0 . 9 % and 8 % ; between was maintained as well. 20 0 . 9 % and 6 % ; between 0 . 9 % and 4 % ; between 0 . 9 % and In other words, it was found that the physical properties 3 % ; between 0 .9 % and 2 % ; between 1 % and 38 % ; between such as the color, scent , taste , density , clarity , homogeneity , 1 % and 35 % ; between 1 % and 32 % ; between 1 % and 30 % ; viscosity , and the pH which are taken into account while the between 1 % and 27 % ; between 1 % and 25 % ; between 1 % physical stability of a formulation comprising extracts of and 22 % ; between 1 % and 20 % ; between 1 % and 18 % ; Hedera helix , Pelargonium sidoides, and Echinacea purpu - 25 between 1 % and 15 % ; between 1 % and 12 % ; between 1 % rea is evaluated remained unchanged for a longer time as and 10 % ; between 1 % and 8 % ; between 1 % and 6 % ; compared to a formulation comprising extracts of Hedera between 1 % and 4 % ; between 1 % and 3 % ; between 1 % and helix and Pelargonium sidoides only . 2 % . However , it was again surprisingly observed that a pre According to the present invention , the percentage cipitate formed in the formulation when the extract of 30 Echinacea purpurea was added in an amount above 80 % amount of the Echinacea purpurea extract represents a ( w / v ) based on the total volume of the formulation to a gram - based amount of the Echinacea purpurea extract per formulation comprising extracts of Hedera helix and Pelar 100 ml of formulation . gonium sidoides. This , in turn , negatively influences the When the Echinacea purpurea extract and the Pelargo appearance , homogeneity , and clarity of the formulation . On 355 nium sidoides extract were used at a specific weight ratio in the other hand , when the amount of the Echinacea purpurea the formulation according to the present invention , i . e . when extract added to a formulation according to the present the weight ratio of the Echinacea purpurea extract to the invention was below 80 % ( w / v ) based on the total volume Pelargonium sidoides extract was in the range of 1 :0 . 1 to of the formulation , no precipitate was observed . Accordingly 1 : 35 , it was surprisingly observed that this had a synergistic and more specifically , the present invention relates to a 40 effect on the physical stability of said formulation . Thus , by formulation comprising extracts of Hedera helix , Pelargo - providing an improved physical stability ; the quality , reli nium sidoides and Echinacea purpurea , wherein the per - ability , and the shelf life of the formulation according to the centage amount of the Echinacea purpurea extract is below present invention are increased . 80 % ( w / v ) based on the total volume of the formulation . Accordingly , the ratio by weight of the Echinacea pur Under the light of the foregoing, the present invention 45 purea extract to the Pelargonium sidoides extract in said provides a formulation , which is both homogeneous and formulation is between 1 : 0 . 1 and 1 : 35 , preferably between clear, and has an improved physical stability . 1 :0 . 2 and 1 :25 , and more preferably between 1: 0 .6 and 1 : 18 . According to a preferred aspect of the present invention , In a preferred aspect of the present invention , said for the percentage amount of the Echinacea purpurea extract in mulation is administered by oral route . On the other hand , said formulation is below 60 % ( w / v ) , and more preferably 50 infants , children , elders or those individuals having difficulty between 0 . 5 % and 40 % ( w / v ) , e . g . between 0 . 5 % and 38 % ; in swallowing can not easily use solid oral dosage forms. For between 0 . 5 % and 35 % ; between 0 . 5 % and 32 % ; between this reason , as well as to ensure high patient compliance and 0 . 5 % and 30 % ; between 0 . 5 % and 27 % ; between 0 . 5 % and a successful treatment course , the formulation according to 25 % ; between 0 . 5 % and 22 % ; between 0 . 5 % and 20 % ; the present invention is preferably presented in a liquid oral between 0 . 5 % and 18 % ; between 0 .5 % and 15 % ; between 55 dosage form and particularly in the form of a syrup . 0 . 5 % and 12 % ; between 0 . 5 % and 10 % ; between 0 . 5 % and The percentage amount of the Hedera helix extract in an 8 % ; between 0 . 5 % and 6 % ; between 0 . 5 % and 4 % ; between orally - administered syrup formulation according to the pres 0 . 5 % and 3 % ; between 0 . 5 % and 2 % ; between 0 . 6 % and ent invention is between 0 .05 % and 20 % ( w / v ) , preferably 38 % ; between 0 . 6 % and 35 % ; between 0 . 6 % and 32 % ; between 0 . 1 % and 15 % ( w / v ) , and more preferably between between 0 . 6 % and 30 % ; between 0 .6 % and 27 % ; between 60 0 . 25 % and 10 % ( w / v ) based on the total volume of the 0 .6 % and 25 % ; between 0 .6 % and 22 % ; between 0 . 6 % and formulation , whereas the percentage amount of the Pelar 20 % ; between 0 . 6 % and 18 % ; between 0 . 6 % and 15 % ; gonium sidoides extract is between 0 .05 % and 30 % ( w / v ) , between 0 . 6 % and 12 % ; between 0 .6 % and 10 % ; between preferably between 0 .1 % and 20 % ( w / v ), and more prefer 0 . 6 % and 8 % ; between 0 . 6 % and 6 % ; between 0 . 6 % and ably between 0 . 2 % and 15 % ( w / v ) based on the total volume 4 % ; between 0 .6 % and 3 % ; between 0 . 6 % and 2 % ; between 65 of the formulation . Here , the percentage amount of the 0 . 7 % and 38 % ; between 0 . 7 % and 35 % ; between 0 . 7 % and Hedera helix extract is the gram -based amount of the 32 % ; between 0 . 7 % and 30 % ; between 0 . 7 % and 27 % ; Hedera helix extract per 100 mlof formulation , whereas the US 9 , 913 , 869 B2 percentage amount of the Pelargonium sidoides extract is ably between 0 .05 % and 25 % ( w / v ) and more preferably the gram -based amount of the Pelargonium sidoides extract between 0 .05 % and 10 % ( w / v ) , based on the total volume of per 100 ml of formulation the formulation . In another aspect, the ratio by weight of the Hedera helix In a further aspect of the present invention , a formulation extract to the Pelargonium sidoides extract in said formu - 5 according to the present invention further comprises extract lation is between 1: 0 .1 and 1: 45 , preferably between 1: 0 .25 of Zingiber officinale in addition to the extracts of Hedera and 1 : 25, and more preferably between 1 :0 . 5 and 1 : 15 . helix , Pelargonium sidoides, Echinacea purpurea and In a further aspect, the formulation according to the Propolis . present invention comprising Hedera helix extract , Pelar- , Zingiber officinale , is a medical herb comprising gonium sidoides extract , and Echinacea purpurea extract etherified essential oils containing Zingiberene , zingiberol, may be administered by oral, parenteral, ocular, nasal, gingerol and shogol, and has been used worldwide from very buccal, sublingual, and topical route . early times . Ginger is preventive against cancer based on In the formulations according to the present invention stopping the Epstein -barr virus activity . 6 -Gingerol and comprising the above indicated amounts and ratios of the 1 6- paradol, among the active agents of ginger , are effective in Hedera helix extract , the Pelargonium sidoides extract , and stopping promyelocytic leukemia by impairing the DNA the Echinacea purpurea extract, no changes occurred in the synthesis . It also has anti- inflammatory effect , is effective properties including the taste , scent, appearance , viscosity , against arthritis and headache , and is bacteriostatic . It is pH , and clarity thereof, for a relatively longer time period , further used against nausea , spasms, and fever in the chil as compared to those formulations comprising the Hedera 20 dren . Based on its antiseptic effect, it is also used against helix extract and the Pelargonium sidoides extract only, and gasgastroenteritis! and even against food poisoning . It prevents thus a more prolonged physical stability was provided . the coagulation of blood and has blood thinning effect. It In a further aspect of the present invention , beside the supports the cardiovascular system by rendering the platelets Hedera helix extract, the Pelargonium sidoides extract, and less adhesive , this in turn causes a decrease in the problems the Echinacea purpurea extract comprised in said formula - 25 of the circulation system . It is appetizing and is used against tion , the formulation may preferably further comprise the constipation . At the same time, it has warming and calming extracts of at least one of Propolis , Glycyrrhiza glabra , effects in cough , flu , cold , and other respiratory tract dis Zingiber officinale and root (preferably Panax eases . ginseng ) , which are known to be useful in the treatment, When a formulation according to the present invention prevention of, or in the alleviation and /or elimination of the 30 further comprised Zingiber officinale extract described symptoms of various respiratory tract diseases, as well as in above in addition to the extracts of Hedera helix , Pelargo boosting the immune system . nium sidoides, Echinacea purpurea and Propolis , it was In another aspect of the present invention , a formulation found that the Zingiber officinale extract prevented the according to the present invention further comprises extract 36 physical changes resulting from harmfulmicroorganisms in of Propolis besides the extracts of Hedera helix , Pelargo - the formulation . Based on its antiseptic effect , the Zingiber nium sidoides , and Echinacea purpurea . officinale extract prevents the reproduction and /or prolifera Propolis is one of the most important bee products . This tion of microorganisms in the formulation , so as to delay the important bee product is antibacterial, antifungal, and anti - occurrence of changes in the physical properties such as the viral, as well as shows many useful biological activities, 40 color, taste , scent, pH , etc . due to these microorganisms and such as anti- inflammatory , anti -ulcer , local anesthetic , anti - thus contributes to maintaining the physical stability of the tumor, immunostimulant activities . In chemical terms, formulation for a relatively longer time period . The percent Propolis comprises a wide variation of extremely complex age amount of the Zingiber officinale extract contained in a and potent terpenes , benzoic acids , caffeic acids , cinnamic formulation according to the present invention is between acids , and phenolic acids . It has a high flavonoid content. 45 0 .05 % and 30 % ( w / v ) , preferably between 0 . 1 % and 25 % Propolis is one of the most potent antibiotics found in the ( w / v ) and more preferably between 0 . 2 % and 10 % ( w / v ) , nature . It is rich in terms of amino acids and trace elements , based on the total volume of the formulation . has a very high vitamin content, and comprises at least 38 When Zingiber officinale extract is added to said formu valuable bioflavonoids . It is an invaluable antioxidant based lation , however , the taste of the formulation deteriorates on its high bioflavonoid content . It was demonstrated to 50 notably and becomes bitter . When , on the other hand , inactivate at least 21 bacteria species , 9 fungi species, 3 Glycyrrhiza glabra extract were also added to said formu protozoa ( including giardia ), and a wide spectrum of lation in addition to the extracts of Hedera helix , Pelargo viruses . nium sidoides, Echinacea purpurea , Propolis and Zingiber When a formulation according to the present invention officinale , it was surprisingly found that the taste of the further comprised Propolis extract having the features above 55 formulation and accordingly the patient compliance were in addition to the extracts of Hedera helix , Pelargonium improved . Thus, adding the Licorice extract to said formu sidoides and Echinacea purpurea , it was observed that the lation results in an improvement in the taste of formulation Propolis extract contributed to an improvement in the physi- in a natural way so that the amounts of synthetic sweeteners cal stability of the formulation . More specifically , it was to be added to the formulation are minimized or are entirely found that the Propolis extract prevented the factors nega - 60 avoided . The percentage amount of the Glycyrrhiza glabra tively influencing the physical properties of the formulation , contained in a formulation according to the present inven such as the scent, taste , pH , clarity , homogeneity and vis - tion is between 0 .01 % and 20 % ( w / v ) , preferably between cosity , and contributed to maintaining the physical proper - 0 .05 % and 15 % (w /v ) and more preferably between 0 .1 % ties and therefore the physical stability thereof for a rela - and 10 % ( w / v ) , based on the total volume of the formulation . tively longer time period . The percentage amount of the 65 In another aspect of the present invention , a formulation Propolis extract contained in a formulation according to the according to the present invention further comprises extract present invention is between 0 .02 % and 30 % ( w / v ), prefer - of Ginseng root (preferably Panax ginseng ) in addition to US 9 ,913 ,869 B2 10 the extracts of Hedera helix , Pelargonium sidoides, Echi lactose , mannitol, starch , cellulose (preferably microcrystal nacea purpurea , Propolis, Zingiber officinale and Glycyr- line cellulose ), and the mixtures thereof ; wherein the pre rhiza glabra . ferred filler is sorbitol. Ginseng root is harvested following a 6 - year cultivation Fillers are used in oral liquid formulations as a dispersing period and this part of the plant is used for therapeutic 5 medium . Fillers may also be used for setting the concentra purposes . It comprises saponins (dammaran and oleanan tion and improving the reproducibility of a formulation . derivatives ; ginsenosides ), polyacetylene derivatives , poly These excipients are used in oral liquid formulations pref erably in solution form . saccharides . The effects of Ginseng on the body are not local Sorbitol has also some physical and chemical properties and therefore one of the benefits of Ginseng is that it 10 which make it ideal to be selected as a suitable filler for use strengthens the body and assists in balancing the entire body in the present invention . It is chemically inactive and is systems. Ginseng is an antioxidant and is an important compatible with many other excipients . In addition , it is immune system improver , increasing the number of cells of easily dissolvable in water and contributes to maintaining the immune system in the body. It is useful in the treatment the stability of a formulation by increasing the viscosity of bronchitis , asthma and circulation problems. According to 15 thereof. Beside all these features sorbitol is also used as a a study conducted by American scientists , the flu risk of sweetener in pharmaceutical formulations. those individuals receiving two 200 mg Ginseng root cap - In a formulation according to the present invention , it was sules per day reduced by 31 % . In laboratory and animal found that when sorbitol was contained in an amount experiments , it was established to be effective against the between 1 % and 60 % ( w / v ) based on the total volume of the cancers of prostate , stomach , kidney , liver , large intestine , 20 formulation , it contributed both to improving the taste of the brain and the lung . It prevented the development of cancer formulation , and to the prevention of crystallization thereof in animals with induced prostate cancer . so that the homogeneity and the clarity of the formulation When a formulation according to the present invention was maintained . The percentage amount of sorbitol con further comprised extracts of Ginseng root having the fea - tained in a formulation according to the present invention is tures above in addition to the extracts of Hedera helix , 25 preferably between 5 % and 30 % ( w /v ) and particularly Pelargonium sidoides, Echinacea purpurea , Propolis , Zin preferably between 10 % and 25 % ( w / v ) , based on the total giber officinale and Glycyrrhiza glabra , it was found that the volume of the formulation . Ginseng root extracts contributed to maintaining the physi Suitable pH regulating agents which may be contained in cal stability of the formulation for a relatively longer time a formulation according to the present invention are selected ant 30 from a group comprising, but not limited to , ascorbic acid , period . More specifically , it was found that the antioxidant 30 acetic acid , tartaric acid , citric acid , sodium citrate , potas property of the Ginseng root extract added to contribute to sium citrate , sodium phosphate , tricalcium phosphate , cal the therapeutic effect of the formulation prevented any cium carbonate , sodium bicarbonate , calcium phosphates , oxidative events to occur in the formulation and to nega carbonated calcium phosphates, magnesium hydroxide and tively influence the physical properties of the formulationOn 35 the hydrates thereof and the mixtures thereof, wherein the such as the pH , taste , scent, appearance , homogeneity , etc . preferred pH regulating agents are citric acid monohydrate and thus contributed to maintaining the physical stability of and sodium citrate dihydrate . the formulation for a relatively longer time period . The According to the present invention , it was observed that percentage amount of the Ginseng root extract contained in setting the weight ratio of sodium citrate dihydrate to citric a formulation according to the present invention is between 40 acid monohydrate contained in said formulation at 1 : 2 and 0 .05 % and 60 % ( w / v ) , preferably between 0 . 1 % and 50 % thus keeping the pH at an acidic level contributed to improv ( w / v ) and more preferably between 0 . 5 % and 40 % ( w / v ) , ing the taste of the formulation and to maintaining the based on the total volume of the formulation . physical stability of the formulation , based on a constant pH . The percentage amount of the respective ingredient The percentage amount of citric acid monohydrate in said according to the present invention is found by calculating 45 formulation is between 0 .01 % and 1 % ( w / v ) , preferably the gram -based amount of the respective ingredient per 100 between 0 .02 % and 0 . 5 % ( w / v ) , more preferably between ml of formulation . 0 .03 % to 0 . 2 % based on the total volume of the formulation , In a further aspect of the present invention , said formu - whereas the percentage amount of sodium citrate dihydrate lation further comprises at least one excipient besides the is between 0 .005 % and 0 . 5 % ( w / v ) , preferably between aforesaid herbal extracts as the active agents . Accordingly, 50 0 .01 % and 0 . 25 % , and more preferably between 0 .015 % and the formulation according to the present invention comprises 0 . 1 % on the same basis . The pH of the formulation accord at least one pharmaceutically acceptable excipient selected ing to the present invention is between 2 and 6 . 5 , preferably from a group comprising fillers , solvents , pH regulating between 3 and 6 , and more preferably between 3 . 5 and 5 . 5 . agents , sweeteners , aromatic agents and preservatives . Suitable preservatives which may be contained in a for It is probable that excipient( s ) contained in a formulation 55 mulation according to the present invention are selected interact( s ) with the herbal extracts used as active agents from a group comprising , but not limited to , methylparaben and / or among themselves, such that the properties , effi - and propylparaben and the salts thereof ( e . g . sodium , potas ciency , and/ or stability of the formulation is influenced in a sium ) , sodium benzoate, citric acid , benzoic acid , butylated positive or negative manner. For this reason , the selection of hydroxytoluene and butylated hydroxyanisole , and the mix the excipients for a formulation according to the present 60 tures thereof. invention has to be made very carefully , keeping in mind the Here , it was surprisingly found that the need to include a object of the present invention . preservative in said formulation was avoided due to the Suitable fillers which may be contained in a formulation characteristic features of these extracts , particularly the according to the present invention are selected from a group antibacterial, antiviral, and / or antioxidative features of the comprising, but not limited to , sucrose , sorbitol, Xylitol, 65 same, when the above indicated percentages of herbal dextrose , fructose , maltitol, sugar potassium , aspartame, extracts were added to a formulation according to the saccharine , saccharine sodium , spray dried or anhydrous present invention . Thus, when a formulation according to US 9 ,913 ,869 B2 12 the present invention comprises the above indicated percent According to the present invention , all herbal extracts ages of herbal extracts , the physical stability thereof can be contained in the formulation can be obtained from the shelf , maintained for a longer time without containing a preser - leaf, flower, root or from the seed thereof. vative and a more natural formulation can be obtained as All extracts according to the present invention are compared to the formulation comprising a preservative . 5 obtained by using methods of the prior art . Suitable aromatic agents which may be contained in a In another aspect, the present invention provides a for formulation according to the present invention are selected mulation used for the treatment, prevention of, and /or for the from a group comprising , but not limited to , fruit aromas like alleviation of the effects of parasitic diseases , skin diseases , of orange , cherry , strawberry , banana , sourcherry , lemon , acute and chronic respiratory tract infections , cold , pharyn etc ; aromas of , anis , mint, menthol, eucalyptus, 10 gitis , angina , sinusitis , acute bronchitis, tonsillitis , bronchial vanillin , and ethyl vanillin and themixtures thereof, wherein asthma, chronic obstructive pulmonary disease, acute and the preferred aromatic agent is eucalyptus. chronic airway inflammation , lower and upper respiratory When eucalyptus was used as an aromatic agent as said tract infections, acute and chronic inflammatory bronchial above , it was observed that eucalyptus provided a supportive diseases , infections of the ear, nose , and throat, other bac effect on the action of the formulation based on the refresh - 15 terial and viral respiratory tract diseases . Additionally , the ing and smoothening effects of eucalyptus scent, and that formulation according to the present invention can be used patients receiving this formulations experienced an instant in the alleviation and / or elimination of the symptoms result relief as well as a reduction in the symptoms, and thus it ing from said diseases , in boosting the immune system , as helped them to feel better in a relatively short time . Based well as be used as an expectorant, an anti- inflammatory on said effect of a formulation according to the present 20 agent, antibacterial agent and antiviral agent, and in allevi invention comprising eucalyptus as an aromatic agent, it was ating the symptoms like cough and the sore throat. further observed that the formulation increased patient com A formulation according to the present invention prefer pliance and that the process in which the patients using this ably in a liquid oral dosage form comprising herbal agents formulation complied with the treatment was accelerated and having an improved physical stability comprises the The percentage amount of eucalyptus used as an aromatic 25 followings: agent according to the present invention is between 0 .01 % a . 0 .05 % to 20 % by weight of Hedera helix extract , and 5 % ( w / v ) , preferably between 0 . 03 % and 3 % ( w / v ), and b . 0 .05 % to 30 % by weight of Pelargonium sidoides more preferably between 0 . 05 % and 2 % ( w / v ) , based on the extract , total volume of the formulation . c . 0 . 1 % to 80 % by weight of Echinacea purpurea extract , Suitable sweeteners which may be contained in a formu- 30 d . 1 % to 60 % by weight of propylene glycol, lation according to the present invention are selected from a e . 2 % to 90 % by weight of glycerin , group comprising, but not limited to , sucralose , ammonium f . 0 .01 % to 1 % by weight of citric acid monohydrate , glycyrrhizinate , acesulfame- K , aspartame, saccharine or g . 0 .005 % to 0 .5 % by weight of sodium citrate dihydrate , sodium and calcium salts of saccharine , sodium cyclamate , h . 1 % to 60 % by weight of sorbitol, sucrose, fructose , glucose , sorbitol and themixtures thereof. 35 i. 0 . 01 % to 2 % by weight of sucralose , The percentage amount of a sweetener contained in a j . 0 .01 % to 10 % by weight of ammonium glycyrrhizinate , formulation according to the present invention is between k . 0 . 5 % to 30 % by weight of ethanol, 0 . 005 % and 20 % ( w / v ) , preferably between 0 .005 % and 1 . 0 .01 % to 5 % by weight of eucalyptus , 15 % ( w / v ) and more preferably between 0 .005 % and 10 % m . sufficient quantity of water to give a total volume of ( w / v ) , based on the total volume of the formulation . 40 1 00 ml. Suitable solvents which may be contained in a formula In a preferred aspect of the present invention , the afore tion according to the present invention are selected from a said formulation comprises the followings : group comprising , but not limited to , propylene glycol, a . 0 . 1 % to 15 % by weight of Hedera helix extract, glycerin , water , ethanol, isopropyl alcohol and similar b . 0 . 1 % to 20 % by weight of Pelargonium sidoides water - soluble polar and water - insoluble non - polar solvents , 45 extract , or the mixture thereof. In order to prepare a formulation c . 0 . 5 % to 60 % by weight of Echinacea purpurea extract, according to the present invention in an ideal manner , at d . 5 % to 30 % by weight of propylene glycol, least 5 % and preferably at least 15 % thereof has to be e . 4 % to 60 % by weight of glycerin , comprised of a solvent. f . 0 .02 % to 0 . 5 % by weight of citric acid monohydrate , A formulation according to the present invention prefer - 50 g . 0 .01 % to 0 . 25 % by weight of sodium citrate dihydrate , ably comprises propylene glycol, glycerin , water , or ethanol, h . 5 % to 30 % by weight of sorbitol, or a mixture thereof as a solvent. When the percentage i . 0 .01 % to 2 % by weight of sucralose , amount of ethanol contained as a solvent in a formulation j. 0 .01 % to 10 % by weight of ammonium glycyrrhizinate , according to the present invention is between 0 . 5 % and 30 % k . 0 .5 % to 15 % by weight of ethanol, ( w / v ), preferably between 0 . 5 % and 15 % ( w / v ) and more 55 1. 0 . 03 % to 3 % by weight of eucalyptus, preferably between 1 % and 10 % ( w / v ) , it was found to have m . sufficient quantity of water to give a total volume of an increasing effect on the solubility of the Echinacea 100 ml. purpurea extract , and thus played a preventive role against In another preferred aspect of the present invention , the precipitate formation . The formulation further comprises aforesaid formulation comprises the followings: water , propylene glycol, and glycerin as a solvent, in addi- 60 a . 0 . 25 % to 10 % by weight of Hedera helix extract , tion to ethanol. The ratio by weight of propylene glycol to b . 0 . 2 % to 15 % by weight of Pelargonium sidoides glycerin in the formulation is between 100 : 1 and 1 : 90 ; extract, preferably between 10 : 1 and 1 :20 , and more preferably c . 0 . 5 % to 40 % by weight of Echinacea purpurea extract, between 2 : 1 and 1 : 5 . d . 10 % to 30 % by weight of propylene glycol , The formulation according to the present invention can be 65 e . 10 % to 45 % by weight of glycerin , used as a pharmaceutical and/ or phytotherapeutic formula f . 0 . 03 % to 0 . 2 % by weight of citric acid monohydrate , tion , or alternatively as a food supplement. g . 0 .015 % to 0 .1 % by weight of sodium citrate dihydrate , US 9 , 913 ,869 B2 13 14 h . 10 % to 25 % by weight of sorbitol , Echinacea purpurea extract , firstly , three formulations are i . 0 .01 % to 2 % by weight of sucralose , prepared according to the present invention . These formu j. 0 .01 % to 10 % by weight of ammonium glycyrrhizinate , lations comprise : k . 1 % to 10 % by weight of ethanol, Formulation 1 : Hedera helix extract + excipients 1. 0 .05 % to 2 % by weight of eucalyptus, Formulation 2 : Hedera helix extract & Pelargonium m . sufficient quantity of water to give a total volume of sidoides extract + excipients 100 ml. Formulation 3 : Hedera helix extract & Pelargonium According to the present invention , the percentage sidoides extract & Echinacea purpurea extract + excipi amount by weight of an ingredient contained in the formu ents lation represents a gram -based amount of that ingredient per 10 . Each of the above formulations prepared for the com 100 ml of formulation . parative experimental analysis comprises same excipients in According to another object of the present invention , a the same amounts . preferred process of the present invention for preparing a Examining changes in physical properties such as pH , formulation comprises the following steps : density , viscosity, color, precipitation , taste , smell , etc of the a . adding all solvents to a production container and formulations under stress conditions is useful in evaluating stirring the resulting mixture until a homogeneous the physical stability of the formulations . Therefore , stress mixture is obtained (mixture A ) , testing is carried out on the above formulations in an b . adding inactive ingredients to the container containing drying - oven at the temperature of 50° C . as a thermal the mixture A and stirring the resulting mixture until a condition and under conditions defined in ICH Q1B Photo homogeneous mixture is obtained (mixture B ) , stability Testing of New Drug Substances and Products to c . adding the herbal extracts successively to mixture B 20 determine the physical changes of the formulations . At obtained in the preceding step and stirring the resulting specific time periods, physical analyses of the formulations mixture until a homogeneous mixture is obtained (mix ture C ) , are performed . Surprisingly , it has found that the formula d . converting the mixture C obtained into a suitable tion comprising the combination of Hedera helix extract, dosage form and filling into packages . 25 FerePelargonium sidoides extract and Echinacea purpurea Another preferred process of the present invention for extract is the most stable formulation among the formula preparing a formulation according to the present invention tions that are analysed . Comparative results obtained at the which is preferably in a liquid oral dosage form comprises end of the stress testing are given below : the following steps: Thermal Stress Testing a . adding all solvents to a production container and 30 Thermal stress testing is carried out on the above formu stirring the resulting mixture until a homogeneous - lations that are kept in a drying -oven with the temperature of mixture is obtained (mixture A ) , 50° C . throughout 10 days . During testing period , the b . adding inactive ingredients to the container containing changes in the physical properties of the formulations are the mixture A and stirring the resulting mixture until a determined , and comparative results obtained at the end of homogeneous mixture is obtained (mixture B ) , of the testing period are given below . c . adding the herbal extracts successively to mixture B 3 pH obtained in the preceding step and stirring the resulting According to the comparative results of Table 1 , the mixture until a homogeneous mixture is obtained (mix - change in pH value of the Formulation 1 and Formulation 2 ture C ) , d . subjecting the resulting mixture C to filtration and is higher than that of the Formulation 3 throughout the letting to settle , an testing period . In fact , the pH values of the Formulation 3 e . following the settling period , filling the resulting final remains almost the same throughout the testing period . It product into suitable bottles . shows that the pH value of the formulation comprising the During the production processes described above, the combination of Hedera helix , Pelargonium sioides and homogenizer and the mixer used are run at high rpm and the Echinacea purpurea is more stable that that of the other stirring process is proceeded until a homogeneous mixture 45 formulations . Surprisingly , it has also found that while the which is free of solid masses is obtained . pH value of the formulation approaches to 4 , the taste of the Experimental Studies for Evaluation of the Physical Stabil formulation becomes better, thus, the Formulation 3 has the ity best taste among the formulations . On the purpose of demonstrating stability of the formu The increase occurred in the pH values of the Formulation lation to be improved when it contains the combination of 1 and the Formulation 2 also leads to the taste of the Hedera helix extract , Pelargonium sidoides extract and formulations to be changed throughout the testing period . TABLE 1 pH values in the formulations versus time Oh 5h 21 h 29 h 44 h 54 h 5d 6 d 8d 9d 10 d For 4 . 27 4 . 35 4 . 36 4 . 38 4 . 41 4 . 39 4 ,43 4 . 45 4 .52 4 . 55 4 . 62 mula tion 1 For 4 . 16 4 . 15 4 . 17 4 . 15 4 . 12 4 . 15 4 . 15 4 . 14 4 . 16 4 . 18 4 . 25 mula tion 2 For 4 . 05 4 .04 4 . 02 4 . 04 4 . 06 4 . 03 4 .01 4 . 04 4 . 04 4 .06 4 . 04 mula tion 3 h : hour ; d : day US 9 ,913 ,869 B2 15 16 The pH values of the formulations throughout the testing (Formulation 1) , the addition of Pelargonium sidoides and / period are measured using Mettler Toledo/ Seven Multi pH or Echinacea purpurea to the formulation comprising Hed meter at room temperature ( 25º C .12° C . ) era helix prevents the precipitation and provides the For Density 5 mulation 2 and Formulation 3 to have a clear appearance and According to the comparative results of Table 2 , the to maintain this clarity throughout the testing period . increase in density of the Formulation 1 and Formulation 2 is higher than that of the Formulation 3 throughout the TABLE 4 testing period . As the same in the density of the formula tions , the increase in the viscosity of the Formulation 1 and Precipitation in the formulations versus time the Formulation 2 is higher than that of the Formulation 3 0 h 5h 21 h 29 h 44 h 54 h 5d 6 d 8 d 9 d 10 d throughout the testing period that is shown in Table 3 . For + + + + + + + + + + + TABLE 2 15 mula tion 1 Densities of the formulations versus time For - mula tion 2 Formulation 1 1 ,1289 g /mL 1 , 1604 g /mL 20 For ------Formulation 2 1 .1315 g /mL 1 ,. 1398 g /mL mula Formulation 3 1 ,1359 g /mL 1 ,1365 g /mL tion 3 d : day h : hour; 25 d : day TABLE 3 This physical analysis to determine whether the precipi Viscosities of the formulations versus time tation is occurred or not in the formulations throughout the od 10 d testing period , is performed by same analyst. Additionally , 30 Formulation 1 19 . 2 mP 22 . 1 mP the analysis of each formulation is performed on the same Formulation 2 21. 1 mP 21. 5 mp Formulation 3 22 . 0 mp 22 . 1 mp ground which is a white flat ground lightened with a flash light parallel to the ground . d : day The densities of the formulations throughoutbut the testingtestino 35 Color period are measured using Mettler Toledo DE40 density As shown in Table 5 , although the color change is meter at room temperature (25º C .+ 2°C .) and the viscosities observed in the formulation comprising Hedera helix alone of the formulations throughout the testing period are mea (Formulation 1) , any color change is not observed in the sured using BROOKFIELD DV - II + Pro viscosity meter at 40 formulation comprising the combination of Pelargonium room temperature ( 25º C .12° C . ) . sidoides and Hedera helix (Formulation 2 ) and in the Precipitation formulation comprising the combination of Pelargonium As shown in Table 4 , although the precipitation is sidoides, Hedera helix and Echinacea purpurea (Formula observed in the formulation comprising Hedera helix alone tion 3 ) throughout the testing period . TABLE 5 Color change in the formulations versus time 0h 5h 21 h 29 h 44 h 54 h 5d 6d 8d 9d 10 d For - light light light light light yellow yellow yellow yellow yellow yellow mula - brown brown brown brown brown tion 1 For- brown brown brown brown brown brown brown brown brown brown brown mula tion 2 For - dark dark dark dark dark dark dark dark dark dark dark mula - brown brown brown brown brown brown brown brown brown brown brown tion 3

h : hour ; d : day US 9 ,913 ,869 B2 17 18 This physical analysis to determine whether the precipi- Formulation 3 has an improved physical stability is also an tation is occurred or not in the formulations throughout the indication of having an improved chemical stability . testing period , is performed by same analyst. Additionally , The present invention shall be described further in the the analysis of each formulation is performed on the same following examples . These examples are not intended to ground which is a white flat ground lightened with a flashlash 5 limit the scope of the present invention and are to be light parallel to the ground , and the color of the formulations considered under the light of the foregoing detailed disclo is decided using a color scale . sure . Smell Example 1 It is observed that the smell of the Formulation 3 does not change whereas the smell of the other formulations change 10 Solvents are stirred in a mixer until a homogeneous throughout the testing period . This physical analysis is also mixture is obtained . Then , inactive ingredients are added performed by same analyst in the same odorless environ and are stirred until a homogeneous mixture is obtained . ment for each formulation . Finally , Hedera helix extract, Pelargonium sidoides extract , According to the thermal stress testing results , although and Echinacea purpurea extract are respectively added and the temperature at which the physical analyses are per - 15 are stirred at high speed until a homogeneous mixture is formed is high ( 50° C . ) , the Formulation 3 is less affected obtained . The resulting mixture is subjected to filtration and from the temperature in comparison with the other formu - is let to settle . Following the settling period , the resulting lations, and thus, the physical stability of the Formulation 3 final product is filled into suitable bottles. remains stable throughout the testing period . Photostability Stress Testing 20 - For determining the photostability of the formulations, the Ingredients Quantity , % photostability stress testing is carried out under conditions Pelargonium sidoides extract 0 .05 % - 30 % defined in ICH QIB Photostability Testing of New Drug Echinacea purpurea extract 0 . 1 % - 80 % Substances and Products . Two different conditions defined Hedera helix extract 0 . 05 % - 20 % Propylene glycol 10 % - 30 % in the guideline are used during the testing period : initially 25 Glycerin 10 % - 45 % formulations are kept in a photostability cabine with 200 Citric acid monohydrate 0 .01 % - 1 % Wh /m² at a constant temperature (25º C .) during 4 hours Sodium citrate dihydrate 0 .005 % - 0 . 5 % ( ICH parameter - 1 ) . After the physical analyses of the for Sorbitol 10 % - 25 % Sucralose 0 . 01 % - 2 % mulations are carried out, these formulations are kept in a Ammonium glycyrrhizinate 0 . 01 % - 10 % photostability cabine with 1 . 2 million lux hours at a constant 30 Ethanol 1 % - 10 % temperature ( 25° C .) during 10 hours ( ICH parameter - 1 ) . Eucalyptus 0 .03 % - 3 % According to the comparative results shown in Table 6 , Water q . s . the Formulation 3 is the most photostable formulation among the formulations . The Formulation 3 is less affected q . s. : Sufficient quantity ( to make up the total volume of the formulation to 100 ml). from the light stress in comparison with other formulations, 35 and thus , the change in the physical properties of the Example 2 Formulation 3 is less than that of the Formulation 1 and Formulation 2 at the end of the testing periods. Solvents are stirred in a mixer until a homogeneous mixture is obtained . Then , inactive ingredients are added TABLE 6 40 and are stirred until a homogeneous mixture is obtained . Finally , Hedera helix extract, Pelargonium sidoides extract , Photostability of the formulations and Echinacea purpurea extract are respectively added and are stirred at high speed until a homogeneous mixture is ICH parameter - 1 ICH parameter - 2 obtained . The resulting mixture is subjected to filtration and Densi- Pre Densi- Pre 45 is let to settle . Following the settling period , the resulting ty ( g cipi ty ( g / cipi final product is filled into suitable bottles . pH mL) tation Color pH mL ) tation Color For- 4 . 39 1 . 1292 4 . 51 1 . 1396 mula brown yellow Ingredients Quantity , % tion 1 50 For- 4 . 19 1 . 1316 - brown 4 .25 1. 1312 - brown Pelargonium sidoides extract 0 . 2 % - 15 % mula Echinacea purpurea extract 0 . 5 % - 40 % tion 2 Hedera helix extract 0 . 25 % - 10 % Propylene glycol 1 % - 60 % For 4 .07 1 . 1324 dark 4 .05 1 .1321 - dark Glycerin mula brown brown 2 % - 90 % tion 3 Citric acid monohydrate 0 .03 % - 0 . 2 % 55 Sodium citrate dihydrate 0 . 015 % - 0 . 1 % Sorbitol 10 % - 25 % Sucralose 0 .01 % - 2 % Consequently , these comparative results given from Table Ammonium glycyrrhizinate 0 .01 % - 10 % 1 to Table 6 demonstrate that the physical stability of the Ethanol 1 % - 10 % formulation comprising the combination of Hedera helix , Eucalyptus 0 .05 % - 2 % Pelargonium sidoides and Echinacea purpurea (Formula - 60 Water q . s . tion 3 ) is higher than that of the formulations comprising Hedera helix ( Formulation 1 ) alone or the combination of q . s. : Sufficient quantity ( to make up the total volume of the formulation to 100 ml). Hedera helix and Pelargonium sidoides ( Formulation 2 ) . In other words, the addition of Echinacea purpurea to the Example 3 formulation comprising the combination of Hedera helix 65 and Pelargonium sidoides increases substantially the physi - Solvents are stirred in a mixer until a homogeneous cal stability of the formulation . Additionally , the fact that the mixture is obtained . Then , inactive ingredients are added US 9 ,913 ,869 B2 19 20 and are stirred until a homogeneous mixture is obtained . Finally , Hedera helix extract, Pelargonium sidoides extract, Ingredients Quantity, % Echinacea purpurea extract and Glycyrrhiza glabra extract Pelargonium sidoides extract 0 .05 % - 30 % are respectively added and are stirred at high speed until a Echinacea purpurea extract 0 . 1 % - 80 % homogeneous mixture is obtained . The resulting mixture is 5 Zingiber officinale extract 0 . 05 % - 30 % subjected to filtration and is let to settle . Following the Hedera helix extract 0 .05 % - 20 % settling period , the resulting final product is filled into Propylene glycol 1 % -60 % suitable bottles. Glycerin 2 % - 90 % Citric acid monohydrate 0 . 01 % - 1 % Sodium citrate dihydrate 0 . 005 % - 0 . 5 % 10 Sorbitol 1 % -60 % Ingredients Quantity , % Sucralose 0 .01 % - 2 % Ammonium glycyrrhizinate 0 . 01 % - 10 % Pelargonium sidoides extract 0 .05 % - 30 % Ethanol 0 . 5 % - 30 % Echinacea purpurea extract 0 . 1 % - 80 % Eucalyptus 0 .01 % - 5 % Glycyrrhiza glabra extract 0 . 01 % - 20 % Water 0 .05 % - 20 % q . s . Hedera helix extract 15 Propylene glycol 1 % - 60 % q . s . : Sufficient quantity ( to make up the total volume of the formulation to 100 ml) . Glycerin 2 % - 90 % Citric acid monohydrate 0 .01 % - 1 % Sodium citrate dihydrate 0 . 005 % - 0 . 5 % Sorbitol 1 % - 60 % Example 6 Sucralose 0 .01 % - 2 % Ammonium glycyrrhizinate 0 .01 % - 10 % 20 Solvents are stirred in a mixer until a homogeneous Ethanol 0 . 5 % - 30 % Eucalyptus 0 .01 % - 5 % mixture is obtained . Then , inactive ingredients are added Water q . s . and are stirred until a homogeneous mixture is obtained . Finally , Hedera helix extract , Pelargonium sidoides extract, q . s .: Sufficient quantity ( to make up the total volume of the formulation to 100 ml) . Echinacea purpurea extract, and Zingiber officinale extract 25 are respectively added and are stirred at high speed until a Example 4 homogeneous mixture is obtained . The resulting mixture is subjected to filtration and is let to settle . Following the Solvents are stirred in a mixer until a homogeneous settling period , the resulting final product is filled into mixture is obtained . Then , inactive ingredients are added and are stirred until a homogeneous mixture is obtained . 30 suitable bottles. Finally , Hedera helix extract , Pelargonium sidoides extract , Echinacea purpurea extract and Glycyrrhiza glabra extract Ingredients Quantity , % are respectively added and are stirred at high speed until a Pelargonium sidoides extract 0 . 2 % - 15 % homogeneous mixture is obtained . The resulting mixture is Echinacea purpurea extract 0 . 5 % - 40 % subjected to filtration and is let to settle . Following the 35 Zingiber officinale extract 0 . 20 % - 10 % settling period , the resulting final product is filled into Hedera helix extract 0 . 25 % - 10 % suitable bottles . Propylene glycol 10 % - 30 % Glycerin 10 % - 45 % Citric acid monohydrate 0 . 03 % - 0 . 2 % Sodium citrate dihydrate 0 .015 % - 0 . 1 % Ingredients Quantity , % 40 Sorbitol 10 % - 25 % Sucralose 0 . 01 % - 2 % Pelargonium sidoides extract 0 . 2 % - 15 % Ammonium glycyrrhizinate 0 .01 % - 10 % Echinacea purpurea extract 0 .5 % - 40 % Ethanol 1 % - 10 % Glycyrrhiza glabra extract 0 . 10 % - 10 % Eucalyptus 0 .05 % - 2 % Hedera helix extract 0 . 25 % - 10 % Water q . s . Propylene glycol 10 % - 30 % 45 Glycerin 10 % - 45 % Citric acid monohydrate 0 .03 % - 0 . 2 % q. s. : Sufficient quantity ( to make up the total volume of the formulation to 100 ml) . Sodium citrate dihydrate 0 .015 % - 0 . 1 % Sorbitol 10 % - 25 % Sucralose 0 .01 % - 2 % Example 7 Ammonium glycyrrhizinate 0 . 01 % - 10 % Ethanol 1 % - 10 % 50 Solvents are stirred in a mixer until a homogeneous Eucalyptus 0 .05 % - 2 % mixture is obtained . Then , inactive ingredients are added Water q . s . and are stirred until a homogeneous mixture is obtained . q . s. : Sufficient quantity (to make up the total volume of the formulation to 100 ml) . Finally , Hedera helix extract, Pelargonium sidoides extract, Echinacea purpurea extract and Propolis extract are respec 5 tively added and are stirred at high speed until a homoge Example 5 neous mixture is obtained . The resulting mixture is subjected Solvents are stirred in a mixer until a homogeneous to filtration and is let to settle . Following the settling period , mixture is obtained . Then , inactive ingredients are added the resulting final product is filled into suitable bottles . and are stirred until a homogeneous mixture is obtained . 60 Finally , Hedera helix extract, Pelargonium sidoides extract, Ingredients Echinacea purpurea extract, and Zingiber officinale extract Quantity , % Pelargonium sidoides extract 0 . 05 % - 30 % are respectively added and are stirred at high speed until a Echinacea purpurea extract 0 . 1 % - 80 % homogeneous mixture is obtained . The resulting mixture is Propolis extract 0 . 02 % - 30 % subjected to filtration and is let to settle . Following the 65 Hedera helix extract 0 .05 % - 20 % settling period , the resulting final product is filled into Propylene glycol 1 % -60 % suitable bottles . US 9, 913 ,869 B2 21 22 -continued -continued Ingredients Quantity , % Ingredients Quantity , % Glycerin 2 % - 90 % Sorbitol 1 % - 60 % Citric acid monohydrate 0 .01 % - 1 % Sucralose 0 . 01 % - 2 % Sodium citrate dihydrate 0 . 005 % - 0 . 5 % Ammonium glycyrrhizinate 0 . 01 % - 10 % Sorbitol 1 % - 60 % Ethanol 0 . 5 % - 30 % Sucralose 0 .01 % - 2 % Eucalyptus 0 . 01 % - 5 % Ammonium glycyrrhizinate 0 .01 % - 10 % Water q . s . Ethanol 0 . 5 % - 30 % Eucalyptus 0 .01 % - 5 % 10 q . s .: Sufficient quantity (to make up the total volume of the formulation to 100 ml) . Water q. s . q . s .: Sufficient quantity ( to make up the total volume of the formulation to 100 ml) . Example 10 Example 8 Solvents are stirred in a mixer until a homogeneous mixture is obtained . Then , inactive ingredients are added Solvents are stirred in a mixer until a homogeneous and are stirred until a homogeneous mixture is obtained . mixture is obtained . Then , inactive ingredients are added Finally , Hedera helix extract, Pelargonium sidoides extract , and are stirred until a homogeneous mixture is obtained . Echinacea purpurea extract , Propolis extract and Zingiber Finally , Hedera helix extract, Pelargonium sidoides extract, 20 officinale extract are respectively added and are stirred at Echinacea purpurea extract and Propolis extract are respec high speed until a homogeneous mixture is obtained . The tively added and are stirred at high speed until a homoge resulting mixture is subjected to filtration and is let to settle . neous mixture is obtained . The resulting mixture is subjected Following the settling period , the resulting final product is to filtration and is let to settle . Following the settling period , filled into suitable bottles . the resulting final product is filled into suitable bottles . 25 Ingredients Quantity , % Ingredients Quantity , % Pelargonium sidoides extract 0 . 2 % - 15 % Echinacea purpurea extract 0 . 5 % - 40 % Pelargonium sidoides extract 0 . 2 % - 15 % 30 Propolis extract 0 . 05 % - 10 % Echinacea purpurea extract 0 . 5 % -40 % Zingiber officinale extract 0 . 20 % - 10 % Propolis extract 0 . 05 % - 10 % Hedera helix extract 0 . 25 % - 10 % Hedera helix extract 0 .25 % - 10 % Propylene glycol 10 % - 30 % Propylene glycol 10 % - 30 % Glycerin 10 % - 45 % Glycerin 10 % - 45 % Citric acid monohydrate 0 .03 % - 0 . 2 % Citric acid monohydrate 0 . 03 % - 0 . 2 % Sodium citrate dihydrate 0 .015 % - 0 . 1 % Sodium citrate dihydrate 0 .015 % - 0 . 1 % 35 Sorbitol 10 % - 25 % Sorbitol 10 % - 25 % Sucralose 0 . 01 % - 2 % Sucralose 0 .01 % - 2 % Ammonium glycyrrhizinate 0 .01 % - 10 % Ammonium glycyrrhizinate 0 .01 % - 10 % Ethanol 1 % - 10 % Ethanol 1 % - 10 % Eucalyptus 0 .05 % - 2 % Eucalyptus 0 .05 % - 2 % Water q . s . Water q . s . 40 q . s. : Sufficient quantity (to make up the total volume of the formulation to 100 ml) . q . s. : Sufficient quantity ( to make up the total volume of the formulation to 100 ml). Example 11 Example 9 45 Solvents are stirred in a mixer until a homogeneous Solvents are stirred in a mixer until a homogeneous mixture is obtained . Then , inactive ingredients are added mixture is obtained . Then , inactive ingredients are added and are stirred until a homogeneous mixture is obtained . and are stirred until a homogeneous mixture is obtained . Finally , Hedera helix extract, Pelargonium sidoides extract , Finally , Hedera helix extract, Pelargonium sidoides extract , Echinacea purpurea extract, Propolis extract, Zingiber offi Echinacea purpurea extract , Propolis extract and Zingiber 30 cinale extract and Glycyrrhiza glabra extract are respec officinale extract are respectively added and are stirred at tively added and are stirred at high speed until a homoge high speed until a homogeneous mixture is obtained . The neous mixture is obtained . The resultingmixture is subjected resulting mixture is subjected to filtration and is let to settle . to filtration and is let to settle . Following the settling period , Following the settling period , the resulting final product is the resulting final product is filled into suitable bottles. filled into suitable bottles . Ingredients Quantity , % Ingredients Quantity , % Pelargonium sidoides extract 0 .05 % - 30 % Pelargonium sidoides extract 0 .05 % - 30 % Echinacea purpurea extract 0 . 1 % - 80 % Echinacea purpurea extract 0 . 1 % -80 % 60 Propolis extract 0 . 02 % - 30 % Propolis extract 0 .02 % - 30 % Glycyrrhiza glabra extract 0 . 01 % - 20 % Zingiber officinale extract 0 .05 % - 30 % Zingiber officinale extract 0 .05 % - 30 % Hedera helix extract 0 .05 % - 20 % Hedera helix extract 0 .05 % - 20 % Propylene glycol 1 % - 60 % Propylene glycol 1 % - 60 % Glycerin 2 % - 90 % Glycerin 2 % - 90 % Citric acid monohydrate 0 .01 % - 1 % 65 Citric acid monohydrate 0 .01 % - 1 % Sodium citrate dihydrate 0 .005 % - 0 . 5 % Sodium citrate dihydrate 0 .005 % - 0 . 5 % US 9, 913 ,869 B2 23 24 - continued - continued Ingredients Quantity , % Ingredients Quantity , % Sorbitol 1 % - 60 % Propylene glycol 1 % - 60 % Sucralose 0 .01 % - 2 % 5 Glycerin 2 % - 90 % Ammonium glycyrrhizinate 0 .01 % - 10 % Citric acid monohydrate 0 .01 % - 1 % Ethanol 0 . 5 % - 30 % Sodium citrate dihydrate 0 .005 % - 0 . 5 % Eucalyptus 0 .01 % - 5 % Sorbitol 1 % -60 % Water 4 . S . Sucralose 0 .01 % - 2 % Ammonium glycyrrhizinate 0 . 01 % - 10 % q . s. : Sufficient quantity ( to make up the total volume of the formulation to 100 ml). 10 Ethanol 0 . 5 % - 30 % Eucalyptus 0 .01 % - 5 % Example 12 Water q . s . q . s . : Sufficient quantity to make up the total volume of the formulation to 100 ml) . Solvents are stirred in a mixer until a homogeneous 15 mixture is obtained . Then , inactive ingredients are added Example 14 and are stirred until a homogeneous mixture is obtained . Finally , Hedera helix extract, Pelargonium sidoides extract , Solvents are stirred in a mixer until a homogeneous Echinacea purpurea extract, Propolis extract, Zingiber offi - mixture is obtained . Then , inactive ingredients are added cinale extract and Glycyrrhiza glabra extract are respec - 20 and are stirred until a homogeneous mixture is obtained . tively added and are stirred at high speed until a homoge Finally , Hedera helix extract, Pelargonium sidoides extract , neous mixture is obtained . The resulting mixture is subjected Echinacea purpurea extract, Propolis extract, Zingiber offi cinale extract , Glycyrrhiza glabra extract and Ginseng root to filtration and is let to settle . Following the settling period , extract are respectively added and are stirred at high speed the resulting final product is filled into suitable bottles . 25 until a homogeneous mixture is obtained . The resulting mixture is subjected to filtration and is let to settle . Follow Ingredients Quantity , % ing the settling period , the resulting final product is filled into suitable bottles. Pelargonium sidoides extract 0 . 2 % - 15 % Echinacea purpurea extract 0 . 5 % - 40 % Propolis extract 0 .05 % - 10 % 30 Glycyrrhiza glabra extract 0 . 10 % - 10 % Ingredients Quantity, % Zingiber officinale extract 0 .20 % - 10 % Pelargonium sidoides extract Hedera helix extract 0 . 25 % - 10 % 0 . 2 % - 15 % Propylene glycol 10 % - 30 % Echinacea purpurea extract 0 . 5 % - 40 % Glycerin Propolis extract 0 .05 % - 10 % 10 % - 45 % Glycyrrhiza glabra extract 0 . 10 % - 10 % Citric acid monohydrate 0 .03 % - 0 . 2 % 35 Zingiber officinale extract 0 . 20 % - 10 % Sodium citrate dihydrate 0 .015 % - 0 . 1 % Hedera helix extract 0 . 25 % - 10 % Sorbitol 10 % - 25 % Ginseng root extract 0 . 50 % - 40 % Sucralose 0 .01 % - 2 % Propylene glycol 10 % - 30 % Ammonium glycyrrhizinate 0 .01 % - 10 % Glycerin 10 % - 45 % Ethanol 1 % - 10 % Citric acid monohydrate 0 .03 % - 0 . 2 % Eucalyptus 0 .05 % - 2 % 40 Sodium citrate dihydrate 0 .015 % - 0 . 1 % Water q . s . Sorbitol 10 % - 25 % Sucralose 0 .01 % - 2 % q . s .: Sufficient quantity ( to make up the total volume of the formulation to 100 ml) . Ammonium glycyrrhizinate 0 . 01 % - 10 % Ethanol 1 % - 10 % Eucalyptus 0 . 05 % - 2 % Example 13 45 Water q. s. Solvents are stirred in a mixer until a homogeneous q . s . : Sufficient quantity ( to make up the total volume of the formulation to 100 ml) . mixture is obtained . Then , inactive ingredients are added and are stirred until a homogeneous mixture is obtained . The invention claimed is : Finally, Hedera helix extract , Pelargonium sidoides extract , 50 1 . A formulation comprising therapeutically effective Echinacea purpurea extract, Propolis extract, Zingiber offi amounts of extracts of Hedera helix and Pelargonium cinale extract , Glycyrrhiza glabra extract and Ginseng root sidoides , wherein the formulation further comprises an extract are respectively added and are stirred at high speed extract of Echinacea purpurea in an amount effective to until a homogeneous mixture is obtained . The resulting improve the physical stability of the formulation . mixture is subjected to filtration and is let to settle . Follow - 55 2 . The formulation according to claim 1 , wherein the ing the settling period , the resulting final product is filled percentage amount of the Echinacea purpurea extract is into suitable bottles . below 80 % (w / v ) , based on the total volume of the formu lation . 3 . The formulation according to claim 1 , wherein the ratio Ingredients Quantity, % 60 by weight of the Echinacea purpurea extract to the Pelar Pelargonium sidoides extract 0 .05 % - 30 % gonium sidoides extract is between 1 : 0 . 1 and 1 : 35 . Echinacea purpurea extract 0 . 1 % - 80 % 4 . The formulation according to claim 1 , wherein the ratio Propolis extract 0 .02 % - 30 % Glycyrrhiza glabra extract 0 .01 % - 20 % by weight of the Hedera helix extract to the Pelargonium Zingiber officinale extract 0 .05 % - 30 % sidoides extract is between 1 : 0 . 1 and 1 : 45 . Hedera helix extract 0 .05 % - 20 % 65 5 . The formulation according to claim 1 , wherein said Ginseng root extract 0 .05 % - 60 % formulation is administered by an oral, parenteral, ocular , nasal, buccal, sublingual , or topical route . US 9 ,913 ,869 B2 25 26 6 . The formulation according to claim 5 , wherein said 15 . The formulation according to claim 12 , wherein the route is oral and the formulation is presented in a liquid oral formulation comprises no preservative . dosage form . 16 . The formulation according to claim 12 , wherein the 7 . The formulation according to claim 1 further compris - aromatic agent is selected from the group consisting of fruit ing at least one of the Propolis , Glycyrrhiza glabra , Zingiber 5 aromas selected from orange , cherry, strawberry , banana , officinale and Ginseng root extracts . sourcherry, lemon ; aromas of cardamom , anis , mint, men 8 . The formulation according to claim 7 , wherein the formulation further comprises Propolis extract and the per thol, eucalyptus , vanillin , and ethyl vanillin , and mixtures centage amount of the Propolis extract is between 0 . 02 % thereof, and optionally when the aromatic agent is eucalyp and 30 % ( w / v ), based on the total volume of the formulation . 10 tus , the percentage amount of eucalyptus is between 0 .01 % 9 . The formulation according to claim 7 , further compris 10 and 5 % ( w / v ) , based on the total volume of the formulation . ing Propolis extract and Zingiber officinale extract , and 17 . The formulation according to claim 12 , wherein the optionally the percentage amount of the Propolis extract is sweetener is selected from the group consisting of sucralose , between 0 . 02 % and 30 % ( w / v ) , based on the total volume of ammonium glycyrrhizinate, acesulfame- K , aspartame, sac the formulation , whereas the percentage amount of thehe 15is charinecha or sodium and calcium salts of saccharine , sodium Zingiber officinale extract is between 0 .05 % and 30 % ( w / v ) , cyclamate , sucrose , fructose , glucose , sorbitol and mixtures based on the total volume of the formulation . thereof, and optionally the percentage amount of the sweet 10 . The formulation according to claim 7 , further com - ener is between 0 .005 % and 20 % ( w / v ) , based on the total prising Propolis extract, Zingiber officinale extract and volume of the formulation . Glycyrrhiza glabra extract , and optionally : the percentage 20 18 . The formulation according to claim 12 , wherein the amount of the Propolis extract is between 0 .02 % and 30 % solvent is selected from the group consisting of a combina ( w / v ) , based on the total volume of the formulation ; the tion of propylene glycol, glycerin , water , and ethanol; or percentage amount of the Zingiber officinale extract is propylene glycol, glycerin , water , ethanol, isopropyl alcohol between 0 .05 % and 30 % ( w /v ) , based on the total volume of and similar water - soluble polar and water - insoluble non the formulation ; and the percentage amount of the Glycyr- 25 polar solvents or a mixture thereof; or propylene glycol, rhiza glabra extract is between 0 .01 % and 20 % ( w / v ), based glycerin , water, or ethanol, or a mixture thereof, wherein on the total volume of the formulation . optionally ethanol is used as a solvent in a percentage 11 . The formulation according to claim 7 , further com prising Propolis extract, Zingiber officinale extract , Glycyr amount between 0 . 5 % and 30 % ( w / v ) , based on the total rhiza glabra extract and Ginseng root extract , and option - 30 volume of the formulation , or optionally wherein a mixture ally : the percentage amount of the Propolis extract is of propylene glycol, glycerin , water and ethanol is used as between 0 .02 % and 30 % ( w / v ), based on the total volume of a solvent, wherein the percentage amount of ethanol is the formulation , the percentage amount of the Zingiber between 0 . 5 % and 30 % ( w / v ) , based on the total volume of officinale extract is between 0 .05 % and 30 % ( w / v ) , based on the formulation , and wherein the ratio by weight of propyl the total volume of the formulation ; the percentage amountunt 3525 ene glycol to glycerin is between 100 : 1 and 1 : 90 . of the Glycyrrhiza glabra extract is between 0 .01 % and 20 % 19 . The formulation according to claim 2 , wherein the ( w / v ) , based on the total volume of the formulation : and the percentage amount of the Echinacea purpurea extract is percentage amount of the Ginseng root extract is between below 60 % ( w / v ) , based on the total volume of the formu 0 .05 % and 60 % ( w / v ) , based on the total volume of the lation . formulation . 40 20 . The formulation according to claim 19 , wherein the 12 . The formulation according to claim 1 , further com - percentage amount of the Echinacea purpurea extract is prising at least one pharmaceutically acceptable excipient between 0 .5 % and 40 % (w /v ) , based on the total volume of selected from the group consisting of fillers , solvents , pH the formulation . regulating agents , sweeteners , aromatic agents and preser- 21 . The formulation according to claim 3 , wherein the vatives ; or wherein said formulation comprises each of the 45 ratio by weight of the Echinacea purpurea extract to the following pharmaceutically acceptable excipients: a filler, a Pelargonium sidoides extract is between 1 : 0 . 2 and 1 : 25 . solvent, a pH regulating agent, a sweetener , and an aromatic 22 . The formulation according to claim 21 , wherein the agent, and , optionally a preservative . ratio by weight of the Echinacea purpurea extract to the 13 . The formulation according to claim 12 , wherein ( a ) Pelargonium sidoides extract is between 1 : 0 . 6 and 1 : 18 . the filler is selected from the group consisting of sucrose , 50 23 . The formulation according to claim 4 , wherein the sorbitol, Xylitol, dextrose , fructose , maltitol, sugar potas - ratio by weight of the Hedera helix extract to the Pelargo sium , aspartame, saccharine , saccharine sodium , spray dried nium sidoides extract is between 1 : 0 . 25 and 1 : 25 . or anhydrous lactose , mannitol, starch , cellulose and mix - 24 . The formulation according to claim 23 , wherein the tures thereof, and optionally when the filler is sorbitol, the ratio by weight of the Hedera helix extract to the Pelargo percentage amount of sorbitol is between 1 % and 60 % 55 nium sidoides extract is between 1 : 0 . 5 and 1 : 15. ( w / v ) , based on the total volume of the formulation . 25 . The formulation according to claim 6 , wherein the 14 . The formulation according to claim 12 , wherein the liquid oral dosage form is in the form of a syrup . pH regulating agent is selected from the group consisting of 26 . The formulation according to claim 25 , wherein the ascorbic acid , acetic acid , tartaric acid , citric acid , sodium percentage amount of Hedera helix extract in the formula citrate , citric acid and sodium citrate , potassium citrate , 60 tion is between 0 .05 % and 20 % ( w / v ) , based on the total sodium phosphate , tricalcium phosphate , calcium carbonate , volume of the formulation , and the percentage amount of sodium bicarbonate, calcium phosphates , carbonated cal- Pelargonium sidoides extract in the formulation is between cium phosphates, magnesium hydroxide and hydrates 0 .05 % and 30 % ( w / v ), based on the total volume of the thereof, and mixtures thereof, and optionally when the pH formulation . regulating agent is citric acid monohydrate and sodium 65 27 . The formulation according to claim 8 , wherein the citrate dihydrate , the weight ratio of sodium citrate dihydrate percentage amount of the Propolis extract is between 0 .05 % to citric acid monohydrate is 1 : 2 . and 25 % ( w / v ) ,based on the total volume of the formulation . US 9 , 913 , 869 B2 28 28 . The formulation according to claim 27 , wherein the k . 1 % to 10 % by weight of ethanol, and percentage amount of the Propolis extract is between 0 .05 % 1. 0 .05 % to 2 % by weight of eucalyptus. and 10 % (w /v ), based on the total volume of the formulation . 31 . The formulation according to claim 1 , wherein the 29 . The formulation according to claim 1 , comprising the improved physical stability is characterized by a feature following: selected from the group consisting of maintenance of pH a . 0 .05 % to 20 % by weight of Hedera helix extract, value , maintenance of density , maintenance of viscosity , b . 0 .05 % to 30 % by weight of Pelargonium sidoides reduction in precipitation , maintenance of color, mainte extract , c . 0 . 1 % to 80 % by weight of Echinacea purpurea extract, nance of smell , and maintenance of photostability . d . 1 % to 60 % by weight of propylene glycol, 32 . A method for preparing a formulation according to e . 2 % to 90 % by weight of glycerin , claim 1 , comprising the following steps: f. 0 .01 % to 1 % by weight of citric acid monohydrate , a . adding all solvents to a production container and g . 0 . 005 % to 0 . 5 % by weight of sodium citrate dihydrate , stirring the resulting mixture until a homogeneous h . 1 % to 60 % by weight of sorbitol, mixture is obtained ( mixture A ) , i. 0 .01 % to 2 % by weight of sucralose , 15 b . adding inactive ingredients to the container containing j . 0 .01 % to 10 % by weight of ammonium glycyrrhizinate , the mixture A and stirring the resulting mixture until a k . 0 . 5 % to 30 % by weight of ethanol, and homogeneous mixture is obtained (mixture B ) , 1. 0 .01 % to 5 % by weight of eucalyptus. c . adding the herbal extracts successively to mixture B 30 . The formulation according to claim 29 , comprising obtained in the preceding step and stirring the resulting the following: 20 mixture until a homogeneous mixture is obtained (mix a . 0 .25 % to 10 % by weight of Hedera helix extract , ture C ), b . 0 . 2 % to 15 % by weight of Pelargonium sidoides d . converting the mixture C obtained into a suitable extract , dosage form and filling into packages , or subjecting the c . 0 . 5 % to 40 % by weight of Echinacea purpurea extract, resulting mixture C to filtration and letting to settle , and d . 10 % to 30 % by weight of propylene glycol , 25 following the settling period , filling the resulting final e . 10 % to 45 % by weight of glycerin , product into suitable bottles . f . 0 . 03 % to 0 . 2 % by weight of citric acid monohydrate , 33 . A method of treating or preventing a respiratory tract g . 0 .015 % to 0 . 1 % by weight of sodium citrate dihydrate , disease in a subject, or alleviating or eliminating a symptom h . 10 % to 25 % by weight of sorbitol, thereof , the method comprising administering a formulation i. 0 .01 % to 2 % by weight of sucralose , of claim 1 to the subject. j . 0 .01 % to 10 % by weight of ammonium glycyrrhizinate , * * * * *