WO2019209229A2

WO2019209229A2 - Topical formulations comprising herbal extracts

Info

Publication number: WO2019209229A2
Application number: PCT/TR2018/050928
Authority: WO
Inventors: Ali TÜRKYILMAZ; Melis YENIDOGAN; Gülay Yelken
Original assignee: Montero Gida Sanayi Ve Ticaret Anonim Sirketi
Priority date: 2017-12-29
Filing date: 2018-12-28
Publication date: 2019-10-31
Also published as: WO2019199260A2; TR201804828A2; WO2019209227A2; WO2019209227A3; WO2019209229A3; TR201722959A2; TR201809956A2; WO2019199260A3

Abstract

The present invention relates to stable topical aqueous formulations comprising pelargonium sidoides extract and propolis extract for providing treatment in various respiratory diseases such as cold, cough, allergic asthma, seasonal allergic rhinitis, bronchitis, pharyngitis, laryngitis and pneumonitis.

Description

TOPICAL FORMULATIONS COMPRISING HERBAL EXTRACTS

Technical Field

Background of Invention

In recent years, the use of various herbs and/or herbal medical products for the prevention and treatment of diseases and alleviating the effects thereof have been gradually increasing in all societies. Throughout the human history, there have been and still are attempts for treating many diseases (diabetes, jaundice, dyspnea, etc.) by using some herbs. According to the records of the World Health Organization (WHO), a large proportion of the world's population (70-80%) make use of herbs for therapeutic or prophylactic purposes. Additionally, around 25% of prescription drugs in developed countries are composed of plant-based active agents (vinblastine, reserpine, quinine, aspirin, etc.).

Particularly following the end of the 1990s, the discovery of new areas of use for medical and aromatic herbs and the increasing demand for natural products have increased the use potential thereof day by day.

Herbal medical products have long been in use for the treatment or prophylaxis of respiratory diseases. In the treatment or prophylaxis of these diseases which are typically caused by viruses, bacteria, and/or fungi, it is quite significant both to eradicate these harmful organisms and to boost the immune system of the affected individual. This is because the immune system is comprised of processes providing protection against diseases, as well as recognizing and eliminating the pathogenic and tumor cells in a living being. The system scans the organism against any kind of foreign substances, entering or contacting the former, from viruses to parasitic worms of a wide variety, and distinguishes them from the organism's own healthy cells and tissues. The immune system can even distinguish substances with very similar features from each other to such an extent that even proteins having a different amino acid can be distinguished from the equivalents thereof. The function of the immune system is primarily to prevent harmful foreign substances from entering the respective organism, or upon entry, to retain the substances at the place of entry, or to prevent or delay their spreading therein.

Propolis is one of the most important bee products. Besides its antibacterial, antifungal, antiviral features, a great number of beneficial biological activities such as anti inflammatory, anti-ulcer, local anesthetic, anti-tumor and immunity stimulant properties popularizes its usage in medicine, apitherapy, health nutrition and biocosmetic fields. It comprises 150 chemical compounds, more than 20 mineral substances, beeswax, resin and pollen. In chemical terms, propolis comprises a wide variety of extremely complex and potent terpenes, benzoic acids, caffeic acids, cinnamic acids, and phenolic acids. It has a high flavonoid content.

Propolis is one of the most powerful antibiotics found in nature. It is rich in terms of amino acids and trace metals, has a very high vitamin content and contains at least 38 valuable bioflavonoids. It is an invaluable antioxidant based on its high bioflavonoid content. It was demonstrated to inactivate at least 21 bacteria species, 9 fungi species, 3 protozoa (including giardia), and a wide spectrum of viruses.

In the studies, a lot of advantages of propolis for health are demonstrated. Some of these studies are: 1 ) A clinical study conducted in Spain in 1988 on 138 individuals has shown that the usage of a propolis based supplement is as effective as the usage of antiprotozoal drug tinidazole which is extensively used in the treatment of infections caused by giardiasis parasite. 2) A study published in Nutrition and Cancer in 2003 has shown that propolis has revitalized apoptosis and provided the tissue decomposition of the lung cancer tumors in mouse. 3) According to the National Institutes of Health, propolis may be used as an effective anti-inflammatory agent against aphtha and other gingiva wounds and peptic ulcer. 4) Blue Shield Complementary and Alternative Health has reported that propolis is two times more effective than acyclovir which is the conventional anti-viral drug in herpes treatment. 5) According to a study published in American Journal of Biochemistry and Biotechnology on February 2004, propolis kills the human breast cancer cells called MCF-7. 13% of the cancer cells of the participants were killed only within 24 hours following the administration of propolis extract.

Pelargonium sidoides (African Geranium, Umckaloabo) is a plant species widely used in the treatment and prevention of, or in the alleviation and/or elimination of the symptoms of cold and respiratory tract disease (pharyngitis, sinusitis, acute bronchitis, tonsillitis). It was determined to be effective in increasing the generation of natural killer cells and tumor necrosis factor alpha, and to enhance the release of interferon beta. Pelargonium sidoides has antiviral properties strengthening the immune system. It further has both antibacterial effects and antioxidative properties against some bacteria. Apart from that, it was also reported to boost the immune system of the respective organism and to have expectorant action by increasing the ciliary beat frequency of respiratory epithelial cells. In a multicenter study conducted by the Pneumology Department of a German University Hospital (2000) on acute bronchitis patients, including adults, children, and infants, it was determined that an extract of the roots of Pelargonium sidoides reduced the severity of the symptoms after 7 days treatment from 6.3 to 0.9 according to the average bronchitis severity score. A study published in "Acta Paediatrica" in April 2010, showed that preparations extracted from herbal roots were much more effective in the treatment of acute bronchitis as compared to placebo. A study group of children aged 6 to 18 years, taking the herbal extracts experienced less coughing, sputum, and bed rest times versus placebo. By assessing the results of four placebo-controlled clinic trials, the researchers at the Medical Center, the University of Pittsburgh, concluded that a standardized extract of Pelargonium sidoides showed a much better performance in alleviating the bronchitis symptoms versus placebo in a 7-day treatment period.

Ginger (Zingiber officinale) is also called "warming herb" and used for a long time as an important medical herb. It comprises essential oils with ether comprising Zingiberene, Zingiberol, Gingerol and Shogol. The essential oils contained which are mixed with terpenoids give the special taste and scent of ginger. The bitter substances without essential oils which make the mouth feel warm are gingerol and zingeron.

Ginger has a wide area of usage. Ginger is preventive against cancer based on stopping the Epstein-barr virus activity. 6-gingerol and 6-paradol, among the active substances of ginger, are effective in stopping promyelocytic leucaemia by disturbing the DNA synthesis. It also has anti-inflammatory effect, is effective against arthritis and headache, and is bacteriostatic. It is used against nausea, spasm and fever in kids. Based on its antiseptic effect, it is used against stomach and intestine infections and even against food poisoning. It also prevents the coagulation of the blood and has blood thinning effect. It supports the cardiovascular system by making the platelets less adherent, this in turn causes a decrease in the problems of circulation system. It is appetizing and can also be used against constipation. In addition to these, it has a warming and sedative effect in cough, flu, cold and other respiratory system diseases. Echinacea purpurea, the purple coneflower, is a plant species widely used in the prophylaxis and/or treatment of infection, cold, cough, bronchitis, flu, in the treatment of infection of the urinary system, in the treatment of the sore throat and toothache, in boosting the immune system, and externally, in the treatment of snakebite, eczema, psoriazis, acne, wounds and burns. Echinacea purpurea is known to have immunostimulant, anti-inflammatory, antibacterial, antiviral, antifungal, anticancer, cicatrizant activities. The compounds accounting for these activities are thought to be polysaccharides, glycoproteins, alkylamides, and caffeic acid derivatives (cichoric acid, echinacoside). Echinacea purpurea supports the production of interferon, thereby strengthening the defense system of the respective organism. Interferon activates the natural killer cells and induces these cells to bind to and destroy infected cells or tumor bearing cells. Interferon is effective in releasing the enzymes destroying the genetic structure of viruses and inhibiting their reproductive and spreading capabilities.

Ginseng root is harvested after a cultivation period of 6 years and this part of the plant is used for therapeutic purposes. It comprises saponins (dammaran and oleanan derivatives; ginsenosites), polyacetylene derivatives and polysaccarides. The effects of Ginseng on the body are not local, and thus, one of the benefits of Ginseng is that it strengthens the entire body and helps in balancing entire body systems. Ginseng is an antioxidant and an important immunity system improver which increases the number of immunity system cells in the body. It is useful in the treatment of bronchitis, asthma and circulation problems. According to a study conducted by American scientists, the flu risk of people who are administered 200mg ginseng root capsules twice a day reduced by 31%. In the laboratory and animal experiments, it is found that it is effective against prostate, stomach, kidney, liver, large intestine, brain and lung cancers. In the animals with prostate cancer, it prevented the development of cancer.

Berberis vulgaris berries are edible and rich in vitamin C. Berberine is the main active alkaloid with a benzyl tetra hydroxy quinoline chemical structure which can be found in all part of berberis vulgaris especially in its fruit (barberry). It is odorless but with a bitter taste powder which is sparingly soluble in methanol, slightly soluble in ethanol and very slightly soluble in water.

Products to be used for medical purposes have to incorporate the elements of quality, efficiency, and reliability. A product can be a "medical" product only by having these elements. In order for a product prepared from a herbal source to be a medical product, it has to be prepared from an efficient and standardized extract, to have established pharmacological, clinical outcomes and toxicological data, and a determined stability. Therefore, it bears great significance to have a good stability for a product, produced from herbal sources, to be used in the treatment and prevention of diseases, or in the alleviation and/or elimination of the symptoms thereof.

Physical, chemical, and microbiological factors play role in the stability of medicaments or other products prepared for medical purposes. The stability issue is not dependent on a simple cause only but emerges as a result of many factors. Factors such as the interaction of active agents contained in a product, the interaction of excipients among themselves or with active agents, pH, light, humidity, and temperature are among many elements which may influence the stability of such products.

Until recently, the researchers deemed considerable importance on the chemical stability of pharmaceutical products rather than the physical stability thereof and conducted many studies accordingly. In many instances, however, they could show how important the changes in the physical structures of products are for the product quality, and for the durability of the technologic, microbiologic, and biopharmaceutical properties thereof. Accordingly, it was shown that primarily the physical stability of a product has to be maintained in order to sustain its quality and other features thereof, and therefore ensuring the physical stability during the development of pharmaceutical products is as important as, or sometimes more important than ensuring the chemical stability thereof.

Additionally, the physical properties are taken into account in the evaluation of the physical stability of a product, particularly the taste, scent, color, clarity, uniformity, etc. of a product, also considerably influence the patient compliance. For this reason, when a novel formulation is developed, besides aiming a formulation of good physical stability, the physical properties of this formulation should be made ideal to provide high patient compliance.

However, it is quite difficult to provide the above described conditions in the formulations comprising herbal substances. Due to some characteristic chemical, biological and physical properties of the herbal substances used in the formulation, some problems are encountered in obtaining a formulation comprising said substances as well as having a good physical stability and ideal physical properties in terms of patient compliance.

The physical properties and the physical stability of a formulation are influenced directly from the characteristic properties of herbal agents contained therein. Some aspects of herbal agents contained in a formulation, such as having a bad taste, a bad scent, a bad color and similar physical properties, becoming easily oxidized, and providing a suitable medium for the reproduction of microorganisms negatively influence the physical properties and physical stability of that formulation. Additionally, in case a formulation comprises a combination of herbal agents, a correct selection of the herbal agents bears great importance, since more than one herbal agent present in the same formulation iscapable to mutually affect their respective properties.

Even if there are formulations comprising herbal extracts prior art, it would be desirable to provide a new formulation, as well as a process for the preparation of this formulation, comprising combinations of herbal agents, being capable to retain the physical stability for a long time, and having ideal physical properties in terms of patient compliance for the treatment of respiratory diseases.

Accordingly, there is a need for topical aqueous formulations comprising herbal extracts, which optimize the delivery of them through the oral mucosal surface.

In addition, there is a need in the state of art for a formulation comprising pelargonium sidoides extract and propolis extract, and having ideal physical properties to ensure high patient compliance and good physical stability, as well as to a method for preparing this formulation, which is simple, cost-efficient and time-saving.

Object of the Invention

The main object of the present invention is to provide an oral topical aqueous pharmaceutical formulation of herbal extracts having enhanced taste and absorption from mucosal surface.

An object of the present invention is to obtain formulations which have improved physical stability, comprising pelargonium sidoides extract and propolis extract.

Another object of the present invention is to provide formulations with a significantly improved stability, as well as the excellent long-term stability.

Another object of the present invention is to provide formulations for providing treatment in various respiratory diseases such as cold, cough, allergic asthma, seasonal allergic rhinitis, bronchitis, pharyngitis, laryngitis and pneumonitis.

Another object of the present invention is to provide formulations which have increased quality, reliability, and shelf life as a result of an improved physical stability. Another object of the present invention is to provide formulations comprising pelargonium sidoides extract and propolis extract, which both maintains the physical stability and has improved physical properties as a result of using suitable excipients.

A further object of the present invention is to provide a simple, cost-efficient, and time saving process for preparing formulations comprising pelargonium sidoides extract and propolis extract.

A further object of the present invention is to provide improved topical aqueous formulations of pelargonium sidoides extract and propolis extract.

A further object of the present invention is to provide stable topical aqueous formulations having desired levels of dissolution rate, solubility and having improved taste.

A further object of the present invention is to provide formulations do not cause the staining of the teeth which is an unwanted effect of oral topical aqueous preparations.

Detailed Description of Invention

In order to achieve the aforementioned objects, the present invention discloses a novel, stable, formulations of extracts of pelargonium sidoides and propolis.

According to the present invention, the novel oral topical aqueous pharmaceutical formulations which have desired levels of dissolution rate, solubility, enhanced taste and rapidly absorbed from the oral mucosa are obtained.

In order to fulfill all these requirements described above, a special formulation is needed and therefore the excipients should be selected carefully.

Therefore, the topical aqueous formulation of pelargonium sidoides extract and propolis extract and a process for preparing this formulation are required.

During development of a herbal formulation comprising pelargonium sidoides extract for medical purposes, it is found that in the event of adding another substance, propolis extract, into the formulation, the efficacy of the formulation is improved. The maintenance of the physical stability of a pharmaceutical product can be ensured if no change occurs in the physical structure of that product. Therefore, whether the physical stability is maintained or not is assessed by determining changes in various physical properties of the product during formulation development process. Properties such as the color, scent, taste, pH, clarity, viscosity, homogeneity, density are among the physical properties of a pharmaceutical are the basic physical properties playing role in the assessment of the physical stability thereof. It has been found that adding propolis extract into a herbal formulation comprising pelargonium sidoides extract, improves the physical properties and the stability of the formulation.

According to the present invention, an oral topical aqueous pharmaceutical formulation comprises pelargonium sidoides extract and propolis extract.

According to this embodiment, the amount of pelargonium sidoides extract in the formulation is between 0.05% and 30.00% by weight of the total formulation and the amount of propolis extract in the formulation is between 0.02% and 30.00% by weight of the total formulation.

An acceptable taste which helps to improves patient compliance is obtained by using the extracts of pelargonium sidoides and propolis as described above range.

In one embodiment, the formulation comprises at least one additional herbal extract which is selected from a group comprising glycyrrhiza glabra, echinacea purpurea, panax ginseng, berberis vulgaris, eucalyptus, salvia officinalis, narcissus pseudonarcissus, hamamelis virginiana, althaea officinalis, sambucus nigra, hydrastis canadensis, tilia, zingiber officinale, citrus junos, licorice, hedera helix, ginkgo biloba, turmeric, capsicum, sage, rosemary, maca, rhodiola or combinations thereof.

In one embodiment, the additional herbal extract is glycyrrhiza glabra.

When glycyrrhiza glabra is selected as the additional herbal extract, physical properties of the formulation such as odor and taste, improve since the extract of glycyrrhiza glabra has a characteristic odor and a sweet taste.

According to this embodiment, the amount of glycyrrhiza glabra in the formulation is between 0.01 -20.00% by weight of the total formulation. In one embodiment, the addition herbal extract is echinacea purpurea.

According to this embodiment, the amount of echinacea purpurea in the formulation is between 0.10-80.00% by weight of the total formulation.

In one embodiment, the addition herbal extract is zingiber officinale.

According to this embodiment, the amount of zingiber officinale extract in the formulation is between 0.05-30.00% by weight of the total formulation.

In one embodiment, the additional herbal extract is panax ginseng.

According to this embodiment, the amount of panax ginseng in the formulation is between 0.05-60.00% by weight of the total formulation.

In one embodiment, the additional herbal extract is berberis vulgaris.

According to this embodiment, the amount of berberis vulgaris in the formulation is between 0.02-20.00% by weight of the total formulation.

In one embodiment, the additional herbal extract is eucalyptus.

According to this embodiment, the amount of eucalyptus in the formulation is between 0.01 -5.00% by weight of the total formulation.

An ideal oral formulation should give a pleasing mouth feel. When eucalyptus is used as the additional herbal extract as said above, it is observed that eucalyptus provided a supportive effect on the action of the formulation based on the refreshing, cooling and smoothening effects of eucalyptus scent, and that patients administered with said formulations feels an instant relief and alleviation of symptoms, thus it helped them to feel better within a relatively shorter period of time. Furthermore, using eucalyptus improves the taste and the clearness of the solution and increases the dissolution rate and solubility.

In one embodiment, the additional herbal extract is salvia officinalis. According to this embodiment, the amount of salvia officinalis in the formulation is between 0.00-20.00% by weight of the total formulation.

In one embodiment, the additional herbal extract is narcissus pseudonarcissus.

According to this embodiment, the amount of narcissus pseudonarcissus in the formulation is between 0.00-80.00% by weight of the total formulation.

In one embodiment, the additional herbal extract is hamamelis virginiana.

According to this embodiment, the amount of hamamelis virginiana in the formulation is between 0.00-80.00% by weight of the total formulation.

In one embodiment, the additional herbal extract is althaea officinalis.

According to this embodiment, the amount of althaea officinalis in the formulation is between 0.00-80.00% by weight of the total formulation.

In one embodiment, the additional herbal extract is sambucus nigra.

According to this embodiment, the amount of sambucus nigra in the formulation is between 0.00-80.00% by weight of the total formulation.

In one embodiment, the additional herbal extract is hydrastis canadensis.

According to this embodiment, the amount of hydrastis canadensis in the formulation is between 0.00 - 20.00% by weight of the total formulation.

According to one embodiment, the oral topical aqueous pharmaceutical formulation further comprises glycyrrhiza glabra extract, echinacea purpurea extract and zingiber officinale extract with pelargonium sidoides extract and propolis extract.

According to another embodiment, the oral topical aqueous pharmceutical formulation further comprises glycyrrhiza glabra extract, echinacea purpurea extract, zingiber officinale extract and panax ginseng extract with pelargonium sidoides extract and propolis extract. According to a further embodiment, said above oral topical aqueous pharmceutical formulations further comprises eucalyptus.

In one embodiment, the formulation is in the form of mouthwash, mouth rinse or spray.

Accordingly, the present invention may be used for treating periodontal diseases and non-specific epidermal and muco-epidermal infections and inflammations.

The oral or buccal mucosa being highly vascularized, drugs can be absorbed directly and can enter the systemic circulation without undergoing first-pass hepatic metabolism. This advantage can be exploited in preparing products with improved oral bioavailability of molecules that undergo first pass effect.

In one embodiment, the formulation further comprises at least one pharmaceutically acceptable excipient which is selected from a group comprising antimicrobial agents, buffering agents, solvents, cosolvents, antioxidants, sweeteners, stabilizers, surfactants, pH adjusters, flavouring agents or mixtures thereof.

In the oral topical aqueous formulations according to the present invention, suitable excipients have to be used which do not degrade during storage and therefore are stable throughout the shelf life, and prevent the bitter taste.

Suitable antimicrobial agents are selected from a group comprising sodium benzoate, propylene glycol, methyl paraben, propyl paraben, polyethylene glycolor mixtures thereof.

Suitable sweeteners are selected from a group comprising sodium saccharin, honey, xylose, ribose, glucose, sucrose, maltose, stevioside, fructose, thaumatin, mogroside, sucralose, erythritol, inulin, calcium saccharin, cyclamete salts, acesulfame-K aspartame, sorbitol, mannitol, isomalt, maltitol, neotame, sucralose, alitame or mixtures thereof.

In one preferred embodiment, the sweetener is honey or sodium saccharin.

The selection of the sweetener has surprisingly provided the oral formulations having a taste which is not unpleasant.

Suitable buffering agents are selected from a group comprising citric acid monohydrate, sodium citrate dihydrate or mixtures thereof. Suitable pH adjusters are selected from a group comprising sodium hydroxide, calcium hydroxide, diethanolamine, monoethanolamine, potassium bicarbonate, potassium citrate, potassium hydroxide, sodium bicarbonate, sodium borate, sodium carbonate, sodium citrate dehydrate, triethanolamine and mixtures thereof.

In one preferred embodiment, the pH adjuster is sodium hydroxide.

Suitable flavouring agents are selected from a group comprising eucalyptol, menthol, peppermint, cinnamon, chocolate, vanilla, cocoa, coffee, chocolate, citrus, and fruit essences such as apple, raspberry, pineapple, cherry, orange, strawberry, grape, tutti frutti or mixtures thereof.

Suitable surfactants are selected from a group comprising sodium lauryl sulfate, polysorbate, benzalkonium chloride, benzthonium chloride, poloxamer or mixtures thereof.

In one preferred embodiment, the surfactant is sodium lauryl sulfate.

Suitable antioxidants are selected from a group comprising butylhydroxytoluene, butylhydroxyanisole or mixtures thereof.

In one embodiment, the antioxidant is the mixture of butylhydroxytoluene and butylhydroxyanisole.

In one embodiment, the stabilizer is sorbitol 70%.

Suitable solvents or cosolvents may comprise but not limited to ethyl alcohol, glycerin, polyethylene glycol, propylene glycol, isopropyl alcohol, sorbitol, purified water and mixtures thereof.

In one embodiment, the solvent is ethyl alcohol.

In one embodiment, the cosolvent is glycerin. In one embodiment, the formulation comprises;

• 0.05% to 30.00% by weight of pelargonium sidoides extract

• 0.02% to 30.00% by weight of propolis extract

• 0.01% to 20.00% by weight of glycyrrhiza glabra extract

• 0.10% to 80.00% by weight of echinacea purpurea extract

• 0.05% to 30.00% by weight of zingiber officinale extract

In another embodiment, the formulation comprises;

• 0.05% to 30.00% by weight of pelargonium sidoides extract

• 0.02% to 30.00% by weight of propolis extract

• 0.01% to 0.00% by weight of glycyrrhiza glabra extract

• 0.10% to 80.00% by weight of echinacea purpurea extract

• 0.05% to 30.00% by weight of zingiber officinale extract

• 0.05% to 60.00% by weight of panax ginseng extract

In a further embodiment, the formulation comprises;

• 0.05% to 30.00% by weight of pelargonium sidoides extract

• 0.02% to 30.00% by weight of propolis extract

• 0.01% to 20.00% by weight of glycyrrhiza glabra extract

• 0.10% to 80.00% by weight of echinacea purpurea extract

• 0.05% to 30.00% by weight of zingiber officinale

• 0.00% to 60.00% by weight of panax ginseng extract

• 0.00% to 20.00% by weight of berberis vulgaris extract

• 0.01% to 5.00% by weight of eucalyptus

• 0.00% to 20.00% by weight of salvia officinalis extract

• 0.00% to 80.00% by weight of narcissus pseudonarcissus extract

• 0.00% to 80.00% by weight of hamamelis virginiana extract

• 0.00% to 80.00% by weight of althaea officinalis extract

• 0.00% to 80.00% by weight of sambucus nigra extract

• 0.00% to 20.00% by weight of hydrastis canadensis extract

• 0.00% to 20.00% by weight of sodium benzoate

• 0.00% to 20.00% by weight of citric acid monohydrate

• 0.00% to 20.00% by weight of sodium citrate dihydrate

• 0.00% to 50.00% by weight of glyceryn

• 0.00% to 2.00% by weight of butyl hydroxy anisole

• 0.00% to 2.00% by weight of butyl hydroxy toluene • 0.00% to 30.00% by weight of ethanol

• 0.00% to 80.00% by weight of honey

• 0.00% to 30.00% by weight of propylene glycol

• 0.00% to 1.00% by weight of methyl paraben

· 0.00% to 1.00% by weight of propyl paraben

• 0.00% to 2.00% by weight of sodium saccharin

• 0.00% to 80.00% by weight of polyethylene glycol

• 0.00% to 10.00% by weight of sodium lauryl sulfate

• 0.00% to 60.00% by weight of sorbitol

· sodium hydroxide q.s^*.

• hydrochloric acid q.s^*.

^*q.s.: quantity sufficient The present invention is described in the following examples in more details. These examples are not limiting the scope of the present invention and should be considered under the light of the foregoing detailed disclosure.

Example 1 : Spray/Mouthwash

Example 2: Spray/Mouthwash

Example 3: Spray/Mouthwash

Example 4: Spray/Mouthwash

Example 5: Spray/Mouthwash

Example 6: Spray/Mouthwash

Example 7: Spray/Mouthwash

Example 8: Spray/Mouthwash

Example 9: Spray/Mouthwash

Example 10: Spray/Mouthwash

The formulations mentioned above is prepared by following these steps:

• adding herbal extracts and excipients to the process tank comprising solvent and/or cosolvent and mixing them until homogenous mixture is obtained,

• filtration of the mixture and then mixture is rested,

• after resting, mixture is filled to the bottles.

Claims

1. An oral topical aqueous pharmaceutical formulation comprising pelargonium sidoides extract and propolis extract.

2. The formulation according to claim 1 , wherein the amount of pelargonium sidoides extract in the formulation is between 0.05% and 30.00% by weight of the total formulation.

3. The formulation according to claim 1 , wherein the amount of propolis extract in the formulation is between 0.02% and 30.00% by weight of the total formulation.

4. The formulation according to claim 1 , wherein the formulation further comprising at least one additional herbal extract which is selected from a group comprising glycyrrhiza glabra, echinacea purpurea, panax ginseng, berberis vulgaris, eucalyptus, salvia officinalis, narcissus pseudonarcissus, hamamelis virginiana, althaea officinalis, sambucus nigra, hydrastis canadensis, tilia, zingiber officinale, citrus junos, licorice, hedera helix, ginkgo biloba, turmeric, capsicum, sage, rosemary, maca, rhodiola or combinations thereof.

5. The formulation according to claim 4, wherein said at least one additional herbal extract is glycyrrhiza glabra.

6. The formulation according to claim 4, wherein said at least one additional herbal extract is zingiber officinale.

7. The formulation according to claim 4, wherein said at least one additional herbal extract is echinacea purpurea

8. The formulation according to claim 4, wherein said at least one additional herbal extract is berberis vulgaris.

9. The formulation according to claim 4, wherein said at least one additional herbal extract is panax ginseng.

10. The formulation according to claim 4, wherein said at least one additional herbal extract is eucalyptus.

1 1. The formulation according to claim 4, wherein said at least one additional herbal extract is salvia officinalis.

12. The formulation according to claim 4, wherein said at least one additional herbal extract is narcissus pseudonarcissus.

13. The formulation according to claim 4, wherein said at least one additional herbal extract is hamamelis virginiana.

14. The formulation according to claim 4, wherein said at least one additional herbal extract is althaea officinalis.

15. The formulation according to claim 4, wherein said at least one additional herbal extract is sambucus nigra.

16. The formulation according to claim 4, wherein said at least one additional herbal extract is hydrastis canadensis.

17. The formulation according to claim 1 , further comprising glycyrrhiza glabra extract, echinacea purpurea extract, zingiber officinale extract.

18. The formulation according to claim 1 , further comprising glycyrrhiza glabra extract, echinacea purpurea extract, zingiber officinale extract, panax ginseng extract.

19. The formulation according to claim 17 or 18, further comprising eucalyptus.

20. The formulation according to claim 1 , wherein the formulation is in the form of mouthwash, mouth rinse or spray.

21. The formulation according to claim 1 , wherein the formulation further comprising at least one pharmaceutically acceptable excipient which is selected from a group comprising antimicrobial agents, buffering agents, solvents, cosolvents, antioxidants, sweeteners, stabilizers, surfactants, pH adjusters, flavouring agents or mixtures thereof.

22. The film formulation according to claim 21 , wherein the sweetener or a mixture of sweeteners is selected from a group comprising sodium saccharin, honey, xylose, ribose, glucose, sucrose, maltose, stevioside, fructose, thaumatin, mogroside, sucralose, erythritol, inulin, calcium saccharin, cyclamete salts, acesulfame-K aspartame, sorbitol, mannitol, isomalt, maltitol, neotame, sucralose, alitame or mixtures thereof.

23. The formulation according to claim 21 , wherein the surfactant is selected from a group comprising sodium lauryl sulfate, polysorbate, benzalkonium chloride, benzthonium chloride, poloxamer or mixtures thereof.

24. The formulation according to claim 17, wherein the formulation comprising;

• 0.05% to 30.00% by weight of pelargonium sidoides extract

• 0.02% to 30.00% by weight of propolis extract

• 0.01% to 20.00% by weight of glycyrrhiza glabra extract

• 0.10% to 80.00% by weight of echinacea purpurea extract

• 0.05% to 30.00% by weight of zingiber officinale extract

25. The formulation according to claim 18, wherein the formulation comprising;

• 0.05% to 30.00% by weight of pelargonium sidoides extract

• 0.02% to 30.00% by weight of propolis extract

• 0.01% to 20.00% by weight of glycyrrhiza glabra extract

• 0.10% to 80.00% by weight of echinacea purpurea extract

• 0.05% to 30.00% by weight of zingiber officinale extract

• 0.05% to 60.00% by weight of panax ginseng extract

26. The formulation according to claim 24 or 25, wherein further comprising eucalyptus and the amount of eucalyptus in the formulation is between 0.01 -5.00% by weight of the total formulation.

27. The formulation according to any of the preceding claims, wherein the formulation comprising;

• 0.05% to 30.00% by weight of pelargonium sidoides extract

• 0.02% to 30.00% by weight of propolis extract

• 0.01 % to 20.00% by weight of glycyrrhiza glabra extract

• 0.10% to 80.00% by weight of echinacea purpurea extract

• 0.00% to 60.00% by weight of panax ginseng extract

• 0.00% to 20.00% by weight of berberis vulgaris extract

• 0.01 % to 5.00% by weight of eucalyptus

• 0.00% to 20.00% by weight of salvia officinalis extract

• 0.00% to 80.00% by weight of narcissus pseudonarcissus extract

• 0.00% to 80.00% by weight of hamamelis virginiana extract

• 0.00% to 80.00% by weight of althaea officinalis extract

• 0.00% to 80.00% by weight of sambucus nigra extract

• 0.00% to 20.00% by weight of hydrastis canadensis extract

• 0.00% to 20.00% by weight of sodium benzoate

• 0.00% to 20.00% by weight of citric acid monohydrate

• 0.00% to 20.00% by weight of sodium citrate dihydrate

• 0.00% to 50.00% by weight of glyceryn

• 0.00% to 2.00% by weight of butyl hydroxy anisole

• 0.00% to 2.00% by weight of butyl hydroxy toluene

• 0.00% to 30.00% by weight of ethanol

• 0.00% to 80.00% by weight of honey

• 0.00% to 30.00% by weight of propylene glycol

• 0.00% to 1 .00% by weight of methyl paraben

• 0.00% to 1 .00% by weight of propyl paraben

• 0.0% to 2.00% by weight of sodium saccharin

• 0.00% to 80.00% by weight of polyethylene glycol

• 0.00% to 10.00% by weight of sodium lauryl sulfate

• 0.00% to 60.00% by weight of sorbitol

• sodium hydroxide