A povidone iodine oral solution composition, preparation and stabilization thereof

Abstract

Povidone iodine oral composition / formulation as a solution for use in oral cavity specifically in the form of throat spray. Specifically disclosed is a Povidone Iodine composition, preparation, and stabilization of aqueous or hydro-alcoholic oral solution. The formulation of the invention has long resident time in hard-to-reach areas of the throat, such as pharynx. The process for manufacturing of stabilized and standardized povidone iodine solution.

Description

[0001] A POVIDONE IODINE ORAL SOLUTION COMPOSITION, PREPARATION AND STABILIZATION THEREOF FIELD OF THE INVENTION:

[0002] The invention relates to a formulation of a solution for use in oral cavity specifically in the form of throat spray. The invention specifically relates to a Povidone Iodine composition, preparation, and stabilization of aqueous or hydro-alcoholic oral solution.

[0003] BACKGROUND OF THE INVENTION:

[0004] The natural element Iodine was first discovered by the French chemist Bernard Courtois in 1811 and has been used in the treatment of wounds and for the prevention of infection for the last 150 years; the bactericidal efficacy of iodine was described in detail by Davaine in 1880. Despite the fact, that this new element carried with it numerous unsatisfactory properties such as its lack of stability and highly aggressive action on the eyes, skin and mucous membranes. The value of a new disinfectant was soon recognized and put in use. Lugol’s Solution (aqueous solution containing 5% elemental iodine and 10% potassium iodide) was first made in 1829 and ‘Tincture of Iodine’ was listed in the US Pharmacopoeia.

[0005] Over the last century, scientists have developed a number of iodine compounds and preparations to overcome the adverse side effects of iodine, its painfulness on open wounds and the possibility of allergic reactions. The objective was to avoid such incompatibilities without a significant loss in germicidal efficacy. As a result, Iodophors such as PVP-I was developed and introduced into Anglo-American countries towards the end of the 1960s and have also been used successfully in Germany for about 30 years. In a water-soluble complex, iodine is linked to the synthetic polymer polyvinylpyrrolidone by hydrogen bonding. The difference between a conventional Iodine solution and an Iodophor is that the latter carries practically all the Iodine in complexes form, effectively forming a reservoir of iodine for protracted delivery, so that the concentration of free Iodine in solution is always very low (only about one thousandth of the iodine being released).

[0006] The function of PVP-I is to manage the risk of infection and to provide preservative and anti-infective capacity. The disinfecting characteristics of Iodine arise from its ability to substitute for covalently bound hydrogen in compounds containing -OH, -NH, -SH, or CH functional groups. These groups will not only be part of the solvent or other constituentsof the formula, but also of the material to be disinfected such as skin, mucous membrane, bacteria, etc.

[0007] The exact solution-phase chemistry which yields the germicidal action is not easy to determine owing to the number of the reactions which iodine may undergo in solution.

[0008] PVP-Iodine can be defined as a system in which for every two amide groups complexed with HI, there are an average of seventeen un-complexed vinylpyrrolidone units in the molecule. Therefore approximately 80 mole % of the product is actually unaltered polyvinylpyrrolidone and hence should behave as such. The determining factor for bactericidal activity is not the concentration of the “free iodine” in the solution but instead is the concentration of “free iodine” at the wall of the target bacterium. Polyvinylpyrrolidone itself has no bactericidal effect but owing to its affinity for the cell membranes is able to deliver the active ingredient to the target.

[0009] CN 102631317 B discloses a kind of povidone-iodine oral liquid and a method of preparation for treating digestive tract diseases which are caused by broiler chicken, piglet bacteria, virus and the like and repairing the mucous membranous of the digestive tracts of the broiler chicken and the piglets, wherein the povidone-iodine oral liquid consists of the following components in mass fraction: polyvinylpyrrolidone, smart iodine (0.4 - 1%), glycerol, lactic acid, glucose, vitamin C and distilled water; and the povidone-iodine oral liquid is produced by the steps of preparing the polyvinylpyrrolidone-iodine mixed liquor, preparing the vitamin C-glycerol mixed liquor, mixing above two liquor, further stirring then adding the lactic acid, making up the final volume and packing. The preparation is for oral consumption only even though it is recognized that systemic absorption of iodine has severe negative effects on thyroid functions.

[0010] EP 2015761A2 discloses a methods and composition for treating, soothing or reducing the severity of a sore throat or other irritations of the throat for an extended period of time, especially during sleep, by administering a pharmaceutical composition into the back of the throat (i.e. laryngeal part of the throat). Wherein the active ingredient is selected from the group consisting of an oil; a local anesthetic; an antiseptic agent (PVP-I), and mixtures thereof. The composition comprises an oily vehicle that provides an oily coating to the throat of a subject, and an active ingredient in an amount effective to treat, sooth or reduce the severity of a sore throat. MediSnore™, an active ingredient which is selected from an oil, a local anesthetic and an antiseptic agent, and further comprises an oil selected from the group of oils known to possess calming and / or anti-inflammatory and / or anti-microbial and / or antiviral actions, including but not limited to, turmeric oil, chamomile oil, sage oil, thymol oil, clove oil, lemon oil, peppermint oil and eucalyptus oil. The composition ispreferably administered in the form of a throat spray, and provides relief from sore throat for an extended period of time, preferably overnight. The medicinal preparation proposed in invention is mainly has oil ingredient and has povidone iodine in the range 0.1 -5%w / v in oily vehicle. Higher concentration of essential oil used in the invention can be irritant, sensitizer and allergenic, hence there is need for overcoming these problems.

[0011] US 2022 / 0000907 Al describe an ethanol free antimicrobial treatment composition, comprising an antimicrobially effective amount of polyvinylpyrrolidone iodine ( PVPI ) ranging from 1.0 % to a dilution - accommodating 3.5 %; an inclusion of at least one room - temperature, water-insoluble, viscous membrane permeation - enhancing essential flavoring oil selected from the group consisting of : menthol in an amount of at least 15 % by weight, spearmint oil in an amount of between 30 % to 55 % by weight, peppermint oil in an amount of at least 10 % by weight, carvone, methyl salicylate, anethole, thymol, eugenol, coolants and cinnamic aldehydes; a Stevia sweetener pre - mixed in a microemulsion solution of dimethylsulfoxide (DMSO); and ion - free distilled water. This invention applies to the prevention, disablement and in some cases the cure of a broad range of respiratory - related diseases often initially of nasopharyngeal origin caused and exacerbated by infectious and pathogenic microbial organisms. This invention contains very high concentration of spearmint flavoring oil between 30 -55%w / w as a major ingredient.

[0012] Essential oils used in high concentrations in oral formulations have limitations. Pure oil is highly irritant to skin and eye and is a potent sensitizer. E.g. Eucalpytus oil extracted from the leaves of the Eucalyptus tree is available as an essential oil that is used as a medicine to treat a variety of common diseases and conditions including nasal congestion, asthma, and as a tick repellant. However, Eucalyptus oil should not be taken by mouth or applied to the skin when pure (concentrated oil). It must be diluted for safety.

[0013] The diluted eucalyptus oil can be taken by mouth for pain and swelling (inflammation) of respiratory tract mucous membranes, coughs, bronchitis, sinus pain and inflammation, asthma, chronic obstructive pulmonary disease (COPD), and respiratory infections. It is also used as an expectorant to loosen coughs, antiseptic, fever reducer, and in vaporizer fluids. Other uses include treatment of wounds, burns, ulcers, and cancer. Diluted Eucalyptus oil is used to ease cold symptoms and provide respiratory health benefits including stimulation of respiration, relieves coughing, helps to expel mucus and relax the respiratory muscles. In overall, low concentration of Eucalyptus Oil are used to silence a cough, clear chest, breathe easy and fresh.Hence, Eucalyptus oil is possibly unsafe when applied directly to the skin without first being diluted. Eucalyptus oil is likely unsafe when it is taken by mouth without first being diluted. Taking 3.5 mL of undiluted oil can be fatal. Signs of eucalyptus poisoning might include stomach pain and burning, dizziness, muscle weakness, small eye pupils, feelings of suffocation, and some others. Eucalyptus oil can also cause nausea, vomiting, and diarrhea.

[0014] Throat sprays, Gargles, mouthwashes or oral rinses are diluted liquid pharmaceutical preparation, which contains medicament(s) along with suitable flavoring agents for its application in the oro- mucosal cavity specially to treat oral infections and / or pain associated due to infections. Any painful sensation arising from the pharynx and its surrounding area is described as sore throat. Causes of sore throat are varied and may be due to infection such as a cold or flu, pharyngitis or tonsillitis, allergic reactions oral irritation in oral cavity. The topical therapy specifically using oral rinses (mouthwash), gargles and sprays or oral sprays acts by direct application to a targeted area and reduces risk of toxicity compared to oral ingestion or through a systemic administration.

[0015] Gargles are aqueous solution, containing medicaments, which are used to prevent or treat infections in the oral cavity and to maintain the oral hygienic condition in routine. The reach of a gargle preparation in the oral cavity is limited to upper pharynx locally. Similarly, Mouthwashes are aqueous solutions with a pleasant taste and odour and are used for cleaning, antisepsis or to de-odor the oral cavity. Various studies have critically observed and concluded that oral rinses are used to treat diseases of the oral cavity, whereas the oral sprays and gargles gave better results for ailments of the oropharynx and a negligible or very low reach to larynx. Additionally, it is also observed and recommended that, oral sprays are much more effective when compared to gargling, because certain technique of gargling is necessary otherwise it is just a rinse instead. Therefore, giving rise to poor treatment or recovery from symptoms. On the contrast, throat sprays are considered to be convenient and most significantly provides direct application of medication into the tonsillar fossa and deeper larynx.

[0016] There is no teaching available for a marketable product of a stable aqueous or hydroalcoholic oral solution formulation, suitable for use in the pharyngeal region, containing diluted PVP-I, most specifically when containing a significantly low concentration of diluted Povidone Iodine in the range of 0.10% to 1.00%w / v. It is well established that, at lower concentrations, PVP-I degrades rapidly resulting in poor concentration of available iodine, which cannot be effectively maintained during shelf-life. In the aforesaid inventions, it is categorically recommended to store the aqueous Povidone Iodine oral solution at low temperature as it becomes a challenge to store at moderate roomtemperature or at accelerated storage conditions (temperature 40°C or higher). Therefore, a robust and stable oral aqueous or hydro- alcoholic liquid formulation is required to be developed, which not only can be stored at room temperature condition of hot humid countries (e.g. ICH Zones II, IVa and IVb), but also have an acceptable shelf-life considering commercial feasibility.

[0017] Hence, referred patent documents do not disclose a stable, standardized, aqueous or hydroalcoholic, oral solution of PVP-I for local use in oral cavity (oro-pharyngeal) especially in the form of throat spray to provide relief from sore throat, minimize bacterial or viral load in oral cavity or other infections of oral cavity and also provide soothing effect over an extended period of time preferably overnight .

[0018] OBJECTS OF THE INVENTION:

[0019] The principal object of the subject matter is to provide a composition and manufacturing process thereof for the preparation of stable, standardized, aqueous or hydro-alcoholic, oral solution for use in the oral cavity especially in the form of a throat spray.

[0020] The primary object of the subject matter is to provide a simple, pharmaceutical preparation having unique manufacturing process and a composition for the preparation of Povidone Iodine oral solution.

[0021] Another object of the invention is to provide a PVP-I formulation having long residenttime in hard-to-reach areas of the throat, such as pharynx.

[0022] Another object of the subject matter is to provide a composition and unique process of manufacturing of oral solution, which improves and maintains povidone Iodine stability throughout its in-use and at its shelf-life.

[0023] Another object of the subject matter is to provide a composition containing Povidone Iodine in a range of 0.10% to 1.00% w / v (available Iodine 0.01 to 0.10%w / v), preferably 0.10 to 0.50%w / v (available Iodine 0.01 to 0.05%w / v).

[0024] Yet another object of the subject matter is to provide a composition, where a high concentration of humectant is added to minimize pungent, irritating or burning sensation of povidone iodine in oral cavity and also improve overall viscosity of the solution to allow increased residence time of PVP-I in pharyngeal cavity or site of application. The composition of the invention has self-buffering capabilities.Yet another object of the subject matter is to also provide a composition and unique process of manufacturing, whereas selective stabilizer provides a stable oral formulation with low concentration of related substance iodide or iodate, which has better chemical stability during shelf life when packed in suitable size and shape multi dose containers like Glass container, High-density polyethylene (HDPE) container or Polyethylene terephthalate (PET) container to deliver it in oral cavity in the form of drops or spray using suitable dispensing system, such as elongated nozzle spraying pumps.

[0025] Yet another object of the subject matter is to provide a composition and unique process of manufacturing of oral solution effectively provide relief from sore throat and also provide soothing effect over an extended period of time.

[0026] Yet another object of the subject matter is to provide a composition and unique process of manufacturing of oral solution use for decontamination and microbial decolonization of oral mucosa in bacterial, viral and fungal infection.

[0027] Yet another object of the subject matter is to provide a composition and unique process of manufacturing of oral solution that can be used as a throat spray in the treatment of several acute and chronic bronchial conditions or in Chronic obstructive pulmonary disease (COPD) when consumed and / or combined with anti-allergic, anti-inflammatory or anti-infective drugs.

[0028] Yet another object of the subject matter is to provide the composition of the invention in a dispensing system so as to use the composition as throat spray.

[0029] Still another object of the subject matter is to provide a composition of oral solution for providing a protective layer in oral cavity for soothing effect.

[0030] Still another object of the subject matter is to provide a composition of oral solution containing an optimum concentration of ethanol or ethyl alcohol to reduces oral colonization of harmful bacteria by denaturing bacterial proteins, dissolving and disrupting the bacterial lipid membrane which also helps in oral mucositis.

[0031] Still another object of the subject matter is to provide a composition of oral solution optionally containing an optimized or very low concentration of flavoring agent like diluted eucalyptus oil to improve breathing and clear out mucus from oral cavity.

[0032] Still another object of the subject matter is to provide a composition of oral solution optionally containing an optimized or very low concentration of flavoring agent likementhol to provide a cooling or refreshing sensation, to treat minor sore throat pain or mouth irritation.

[0033] Still another object of the subject matter is to provide a composition and unique process of manufacturing of aqueous or hydro-alcoholic oral solution, which is stable, cost effective, safer and environmental-friendly also.

[0034] SUMMARY OF THE INVENTION

[0035] The present invention provides a pharmaceutical composition and unique manufacturing process for the preparation of stable, standardized, aqueous or hydro-alcoholic, oral solution for use in the oral cavity especially in the form of throat spray to provide relief from sore throat and also provide a local soothing effect over an extended period of time preferably overnight.

[0036] The invention provides for a povidone iodine oral aqueous or hydro-alcoholic solution composition comprising,

[0037] povidone iodine in a range of 0.10% to 1.00% w / v,

[0038] at least one humectant,

[0039] at least one selective stabilizer,

[0040] at least one solvent or carrier or combination thereof,

[0041] optionally at least one selective flavoring agent or combination thereof, optionally at least one viscosity enhancers or combination thereof, and optionally one or more other pharmaceutically active ingredients.

[0042] The preparation have Povidone Iodine concentration in a range of 0.10% to 1.00% w / w (available Iodine 0.01 to 0.10% w / w) preferably 0.10 to 0.50%w / w (available Iodine 0.01 to 0.05%w / w), with a high concentration of chemical or natural humectants such as glycerol or natural ingredients such as aloe-vera, to minimize pungent, irritating or burning sensation of povidone iodine in oral cavity, with an optimum concentration of ethanol or ethyl alcohol to reduces oral colonization of harmful bacteria by denaturing bacterial proteins, dissolving and disrupting the bacterial lipid membrane also help in oral mucositis. Formulation also contains a low concentration of selective stabilizer such as Potassium Iodide to maintain stability of preparation throughout its shelf-life. Formulation may also contain Menthol, to provide a cooling or refreshing sensation, to treat minor sore throat pain or mouth irritation; and also have low concentration or diluted Eucalyptus oil to improve breathing and clear out mucus from oral cavity as an expectorant.

[0043] This invention can be effectively used for cleaning and irrigation of the oral cavity, inhibited oropharyngeal bacterial, viral or fungal growth, treat infections of mouthand throat, such as gingivitis and mouth ulcers or as an adjuvant therapy with anti-allergic, anti-inflammatory or anti-infective drugs or can also be used in combination with other pharmaceutically active agents i.e., by having a fixed dose pharmaceutical composition.

[0044] The term ‘anti-allergic’ refers to agents that are used for relieving, controlling, or preventing allergic symptoms. An example of suitable anti-allergic includes but is not limited to diphenhydramine, cetirizine, levocetirizine, loratadine, desloratadine and fexofenadine etc., or any other active natural substances.

[0045] The term ‘anti-inflammatory’ refers to agents that are used to reduce inflammations (redness, swelling and pain) caused by various reasons. The examples of suitable antiinflammatory for such preparations may include but is not limited to ibuprofen, naproxen, diclofenac, celecoxib, mefenamic acid, etoricoxib, indomethacin, aspirin etc. or any other natural substances.

[0046] The term ‘anti-infective’ refers to agents that are used to prevent or treat infections; they include anti-bacterials, anti-virals, anti-fungals and anti-parasitic medicaments. The examples of suitable anti-infective drug classes include but is not limited to amebicides, aminoglycosides, anthelmintics, antifungals (azole antifungals, echinocandins, polyenes), antituberculosis agents (aminosalicylates, diarylquinolines), antiviral agents (adamantine), antibiotics (cephalosporin and its generations, glycopeptides, macrolide derivatives, other miscellaneous antibiotics) etc.

[0047] The invention also provides for a unique process for manufacturing of stabilized and standardized povidone iodine solution for oral application comprising steps of:

[0048] Solubilization of Stabilizer, in a main manufacturing tank, containing solvent or carrier under stirring,

[0049] Solubilization of povidone iodine, in a main manufacturing tank, containing above solution under stirring,

[0050] Solubilization of humectants, in a main manufacturing tank, containing above solution under stirring,

[0051] Optional separate preparation of ‘flavor solution’ by completely solubilizing flavors in a solvent or carrier under stirring and further adding it in a main manufacturing tank,

[0052] Standing the above solution for stabilization and standardization to achieve a solution having pH in the range of 1.5 to 4.5,

[0053] Making the final volume of solution to prepare the stable povidone iodine oral solution.The invention further provides for the stable povidone iodine oral solution to be filled in suitable size and shape containers with suitable dispensing device, to prepare a pharmaceutical dosage form of a medicament for oral application especially in the form of throat spray, wherein said container is suitable for delivery or distribution of said stable povidone iodine solution into oral cavity in the form of spray or drops or mist or as liquid.

[0054] BRIEF DESCRIPTION OF THE DRAWINGS

[0055] Figure 1: The manufacturing process as per the preferred embodiments depicted in Examples 5 to 8 is depicted in Figure 1.

[0056] Figure 2: The manufacturing process as per the preferred embodiments depicted in Examples 1 to 4 is depicted in Figure 2.

[0057] DETAILED DESCRIPTION OF THE INVENTION:

[0058] Broadly, the present invention relates to a pharmaceutical composition containing PVP-I in combination with at least one humectant and preferably with one or more pharmaceutically acceptable solvent or carrier. The invention also relates to methods of making said pharmaceutical composition containing at least one excipient or optional excipients, such as one or more flavor, viscosity enhancer or additional pharmaceutically active ingredient. As used herein the term ‘composition’ is used interchangeably with the term ‘formulation’ or ‘preparation’ and is intended to refer to the final oral application product such as solution (mothwash or gargle) or a throat spray.

[0059] The present invention provides a pharmaceutical composition and unique manufacturing process for the preparation of stable, standardized, aqueous or hydro-alcoholic, oral solution for use in the oral cavity especially in the form of throat spray to provide relief from sore throat and also provide soothing effect over an extended period of time preferably overnight. The formulation of the invention has long resident- time in hard-to-reach areas of the throat, such as pharynx.

[0060] Oral throat spray formulations are aqueous or hydro-alcoholic based liquid systems that are sprayed into the oral cavity and are predominantly employed for relief from sore throat and also minimize bacterial or viral colonization in oral cavity and other infections of oral cavity.

[0061] The active ingredient in Povidone Iodine Oral Solution is Povidone Iodine [PVP-I]. PVP-I is a stable chemical complex of polyvinylpyrrolidone and elemental Iodine (Iodophor).In the process of development of Iodophor, PVP-I produces a water-soluble complex that possesses the beneficial antimicrobial effects of Iodine with reduced toxicity and no skin staining. PVP-I have been shown a wide antimicrobial activity and used in both humans and veterinary medicine to kill on contact a wide variety of Bacteria, Viruses, Fungi, Protozoa and Yeast. It is thus safer and easier to use, without substantial loss of antimicrobial efficacy. The incorporation of PVP-I into products for oral throat spray preparation is to use for decontamination and microbial decolonization of oral mucosa with Bacterial, Viral and Fungal infections. It is also used for treating sore throat pain, inflammation of respiratory tract mucous membrane, bronchitis, pharynx discomfort and other throat infections.

[0062] The preparation has Povidone Iodine concentration in a range of 0.10% to 1.00% w / w (available Iodine 0.01 to 0.10% w / w) preferably 0.10 to 0.50%w / w (available Iodine 0.01 to 0.05%w / w), with a high concentration of chemical or natural humectants such as glycerol or natural ingredients (such as aloe-vera) or a combination thereof, in a range of 60.0 to 90.0%w / v, preferably in a range of 80.0 to 90.0 %w / v to minimize pungent, irritating or burning sensation along with and enhanced residence time of povidone iodine in oro - pharyngeal cavity.

[0063] The preparation has low concentration of selective stabilizer such as Potassium Iodide to maintain stability of preparation throughout its shelf-life. The selective stabilizer is in a range of 0.01 to 0.50%w / v and most preferably is in a range of 0.20 to 0.50%w / v. Optionally use of low concentration of flavoring agent like Menthol and / or diluted Eucalyptus oil to improve breathing and clear out mucus from oral cavity is also disclosed. The preparation or composition of the present invention can also have an optimum concentration of ethanol or ethyl alcohol.

[0064] This invention involves unique manufacturing steps, order of mixing of ingredients to achieve a stabilized, standardized, pre-determined concentration of free iodine, which remains constant with predictable microbicidal effectiveness for longer duration of action throughout in oral cavity, pharynx and esophagus.

[0065] This invention can be effectively used for cleaning and irrigation of the oral cavity, inhibiting oropharyngeal bacterial, viral or fungal growth, treating infections of mouth and throat, such as gingivitis and mouth ulcers or as an adjuvant therapy with antiallergic, anti-inflammatory or anti-infective drugs or can also be used to develop fixed dose combination products. The composition of the invention can be used as an aqueous or hydro-alcoholic oral solution medicament for providing relief from a sore throat, mouth irritation, local soothing effect in throat or to improve breathing or use as an expectorantor to treat oral mucositis or as fixed dose combination product to effectively use it for oral application or in treatment of several acute and chronic oro-pharyngeal diseases. The composition can also be effectively used for decontamination and microbial decolonization of oral mucosa in case of upper respiratory bacterial, viral or fungal infections.

[0066] Present invention containing Povidone Iodine provide a stable throat spray formulation for oral cavity, when studied as per ICH guidelines “ stability testing of new drug substance and products Q1A(R2) and Q1F for Zone II and Zone IV, which have better chemical stability during shelf life and thus allowing improved shelf-life particularly when packed in suitable size and shape multi dose container like Glass container, High-density polyethylene (HDPE) container, polypropylene (PP) or Polyethylene terephthalate (PET) containers to deliver it in oral cavity in the form of drops or spray using suitable dispensing system. The composition of the invention is stable for at least up to 1 month at stress conditions at 50°C and at least up to 6 months at accelerated condition at 40°C and 75% relative humidity and at long-term conditions at 30°C and 75% relative humidity.

[0067] Thus, composition and unique manufacturing method so described is simple, efficient, robust, cost effective, safer, effective, and environmental-friendly having industrial applicability for commercial production of specialized dosage form at large scale.

[0068] The composition for the preparation of stable, standardized, aqueous or hydro- alcoholic oral solution for use in the oral cavity especially in the form of throat spray are as per following (Table- 1):

[0069] Table -1

[0070]

[0071]

[0072] Delivery System and Packaging:

[0073] Throat sprays are applied in the deeper part of the oral cavity for local and / or systemic effects. Although similar in many features to other drug products, some aspects of Throat sprays may be unique (e.g. container closure system). Spray producing (e.g., orifice, nozzle, jet) pump mechanisms and components are used for reproducible delivery of drug formulation using or through a device such as metered dose pumps and these can be constructed of many parts of different design that are precisely controlled in terms of dimensions and compositions.

[0074] Energy is required for dispersion of the formulation as a spray. This is typically accomplished by forcing the formulation through the oral actuator and its orifice. The formulation and the container closure system (container, closure, pump, and any protective packaging) collectivelyconstitute the drug product presentation. The design of the container closure system affects the dosing performance of the drug product solution (i.e. metered or simple spray). Formulation can be delivered as oral drops or sprays. Suitable packaging for solution may be HDPE or PET container with a throat spray pump, non metered dose pump or metered dose pump type.

[0075] The present invention discloses a unique manufacturing process for the preparation of stable, standardized, aqueous or hydro- alcoholic, oral solution for use in the oral cavity especially in the form of throat spray.

[0076] The process for manufacturing of stabilized and standardized povidone iodine solution comprises the steps of ( • ) Solubilization of Stabilizer, in a main manufacturing tank, containing solvent or carrier under stirring, ( • ) Solubilization of povidone iodine, in a main manufacturing tank, containing above solution under stirring, and ( • ) Solubilization of humectants, in a main manufacturing tank, containing above solution under stirring, ( • ) Standing the above solution for stabilization and standardization to achieve a solution preferred pH in the range of 1.5 to 4.5 and finally making the final volume of solution to prepare the stable povidone iodine oral solution. The process optionally comprises the step of separate preparation of ‘flavor solution’ by completely solubilizing flavors in a solvent or carrier under stirring and further adding it in a main manufacturing tank before standing for its stabilization and standardization

[0077] The final stable povidone iodine solution / composition is filled in suitable size and shape containers with suitable dispensing device, to prepare a pharmaceutical dosage form of a medicament of stabilized and standardized povidone iodine solution for oral application especially in the form of throat spray. The stable povidone iodine oral solution maintains its potency and has improved povidone iodine stability during in-use and standard accelerated stability conditions respectively. The containers are such that they are suitable for delivery or distribution of said stable povidone iodine solution into oral cavity in the form of spray or drops or mist or as liquid. The container can be made of glass, high-density or low-density polyethylene or polyethylene terephthalate or polypropylene, preferably high-density polyethylene.

[0078] The preferred embodiments of the unique process of the invention are depicted in Figures 1 and 2 and comprise of the following steps:

[0079] i. Transfer Purified Water (10%v / v) to the main Manufacturing Tank ‘A’. Add Stabilizer in to the main Manufacturing Tank ‘A’ and continue the stirring to dissolve it completely.ii. Add Povidone Iodine in to the above main Manufacturing Tank ‘A’ under stirring and continue the stirring till uniform, clear, lump free solution is obtained.

[0080] iii. Add humectant in to the above main Manufacturing Tank ‘A’ under stirring and continue the stirring till uniform solution obtain.

[0081] iv. Flavor Solution Preparation (optional) : In a separate tank ‘B’, transfer Ethanol 95%.

[0082] Add the Eucalyptus Oil and / or Menthol in it, under gentle stirring to dissolve it completely. Label it as “Flavor Solution”.

[0083] Transfer the “Flavor Solution” to Manufacturing Tank ‘A’ under gentle stirring, continue till uniform solution is obtained.

[0084] v. Stand or keep the solution for stabilization, standardization and obtaining a stable pH in the range of 1.5 to 4.5.

[0085] vi. Makeup final volume of the solution with purified water and further stir the solution to obtain a standardized and stable final bulk solution.

[0086] Thus, composition and unique manufacturing method so described is simple, efficient, robust, reproducible, cost effective, environmental-friendly and has industrial applicability for commercial scale production of pharmaceutical dosage form.

[0087] The experiments conducted are exemplified herein for sake of explanation and understanding without limitation.

[0088] Examples 1& 2

[0089] COMPOSITION

[0090] Table 2

[0091]

[0092]

[0093] Manufacturing Process

[0094] All the manufacturing steps are carried out in a controlled environmental condition, temperature not more than 27 °C and Relative humidity not more than 60%.

[0095] Purified Water (10%w / v) is transferred to the main Manufacturing Tank ‘A’ and start the stirring. Potassium Iodide is added in to the main Manufacturing Tank and continues the stirring for about 10 minutes to dissolve it completely. Povidone iodine is added in main Manufacturing Tank under stirring and continues the stirring for 30 minutes or till uniform solution is obtained. Further, Glycerin is added in main Manufacturing Tank under stirring and continues the stirring for 30 minutes or till uniform solution is obtained. In a separate tank ‘B’, Eucalyptus Oil & Menthol are dissolved in Ethanol under stirring (Flavor Solution). “Flavor Solution” is transferred to main Manufacturing Tank ’A’ under stirring and continues stirring for another 5 minutes or till a uniform solution is obtained. Solution is kept as such for overnight for stabilization and standardization. Final Volume of the solution is made up with purified water. The process is illustrated in Figure 2 for ease of understanding.

[0096] The stable, standardized, aqueous or hydro- alcoholic, oral solution for use in the oral cavity especially in the form of throat spray, composition made as per the above examples (Example- 1 and Example -2) were filled in 50 ml & 20 ml opaque HDPE bottles fitted with throat spray pump and were subjected to standard accelerated condition studies at 40°C and 75% relative humidity and long-term conditions at 30°C and 75% relative humidity.

[0097] The physical observations and analytical data made during stability studies are shown in the Table - 3, 4, 5 and 6.

[0098] Table-3

[0099] Physical observations:

[0100]

[0101]

[0102] Table-4

[0103] Physical observations:

[0104]

[0105]

[0106] Table -5

[0107] Analytical Data (Chemical Analysis):

[0108]

[0109]

[0110] Table -6

[0111] Analytical Data (Chemical Analysis):

[0112]

[0113]

[0114] Above stability data demonstrate that novel Povidone Iodine Oral Solution for use in oral cavity, when prepared as per Examples 1 & 2; and packed in 50 ml and 20 ml opaque, round, HDPE bottles fitted with throat spray pump, has good physical and chemical stability up to 6 months at accelerated condition (40°C and 75% relative humidity) and also observed to be stable up to 12 months at long-term conditions (30°C and 75% relative humidity). Furthermore, Povidone iodine oral solution has a very low content of iodine related impurity components like iodide content and iodate content throughout its shelf-life, which is safer for an oral throat spray preparations.

[0115] Example 3

[0116] The composition and manufacturing process was as per the above examples (Example- 1 and Example -2). The final bulk solution was filled in 100 ml clear PET bottles fitted with polypropylene (PP) cap and were subjected to stress condition (at 50°C) and standard accelerated condition at 40°C and 75% relative humidity.

[0117] The physical observations and analytical data made during stability studies are shown in the Table - 7.

[0118] Table -7

[0119]

[0120]

[0121] Stability data demonstrate that novel Povidone Iodine Oral Solution for use in oral cavity, prepared as per example- 3 and packed in 100 ml clear PET bottles with no delivery device or spray pump, has good stability for 1 month at stress conditions at 50°C and up to 3 months at accelerated condition at 40°C and 75% relative humidity with very low content of iodide and iodate.

[0122] Example -4

[0123] The composition and manufacturing process was as per the above examples (Example- 1 and Example -2). The final bulk solution was filled in 20 ml amber PET bottles fitted with polypropylene (PP) cap and were subjected to stress condition (at 50°C) and standard accelerated condition at 40°C and 75% relative humidity.

[0124] The physical observations and analytical data made during stability studies are shown in the Table - 8.

[0125] Table -8

[0126]

[0127]

[0128] Stability data demonstrates that novel Povidone Iodine Oral Solution for use in oral cavity, prepared as per example-4 and packed in 20 ml amber, round, PET fitted without delivery device or spray pump, has good physical and chemical stability for 1 month at stress conditions (at 50°C) and up to 6 months at accelerated conditions (at 40°C and 75% relative humidity).

[0129] Furthermore, Povidone iodine oral solution has a very low content of iodine related impurity components like iodide content and iodate content throughout its shelf-life, which is safer for an oral throat spray preparation.

[0130] Examples -5, 6, 7& 8

[0131] COMPOSITION

[0132] Table 9

[0133]

[0134] Manufacturing Process

[0135] All the manufacturing steps were carried out in controlled environmental condition, temperature not more than 27 °C and Relative humidity not more than 60%. Themanufacturing process is same as that of Examples 1 & 2 excluding the flavor components (Menthol, Eucalyptus Oil and Ethanol) addition step as depicted in Figure 1.

[0136] The stable, standardized, aqueous or hydro- alcoholic, oral solution for use in the oral cavity especially in the form of throat spray, composition made as per the above examples (Example-5, 6, 7 and Example -8) were filled in 50 ml & 20 ml opaque HDPE bottles fitted with throat spray pump.

[0137] Comparative Study:

[0138] Pharmaceutical preparation prepared using the composition as disclosed in the present invention were compared with market available PVP-I oral compositions available as gargle solutions. There was no PVP-I containing throat spray available to public, in India, to compare.

[0139] There are numerous mouthwashes and gargle preparations already available in the market containing PVP-I, having 0.1 to 0.2% w / v concentration of available iodine. Their effectiveness is clinically proven. However, as detailed herein, treatment of lower / deep down larynx is a challenge. To appreciate the advantages of the novel preparation disclosed in this invention, a comparative evaluation of throat spray of the invention with respect to commercially available PVP-I containing gargles in Indian market is presented in Table- 10.

[0140] Table- 10: A Comparative evaluation of Povidone Iodine Gargle 2%w / v (Samples A & B are commercially available gargle products) Vs Povidone Iodine Throat spray 0.01 to 1.0% w / v (Example -2 of present invention).

[0141] Table 10

[0142]

[0143]

[0144] ND- not detected; Ace -Accelerated Conditions (40°C / 75%RH);

[0145] Ex. -2 - Example -2 (Throat spray); RT-Room Temperature (25°C / 60%RH).

[0146] From the above data it is evident that the gargle preparation A and B have pH range varying between 3 - 5 values, suggesting that these are mildly acidic; and that they have density (weight / ml) and viscosity closer to water. The chemical stability is above 90%w / v of the initial strength over one month and three-month time.

[0147] The Throat spray preparation of the invention has much higher viscosity, contributing to its adherence to application site in the throat thereby having improved residence time in oro - pharyngeal cavity. The drug content is stable over a period of 6 month at accelerated conditions and has controlled impurity levels.

[0148] Clinical Study:

[0149] Pharmaceutical preparation prepared using the composition as disclosed in the present invention were subjected to safety and efficacy study on human volunteers. The detail of the study design and significant outcomes are provided to show that the drug product is effective and safe.

[0150] A study was undertaken on 10 subjects to evaluate the efficacy of present invention PVP- I Throat Spray in patients suffering from severe throat infection.

[0151] Primary endpoint(s) targeted for the study were Changes in the reduction of symptoms such as sore throat, pharynx discomfort, swelling, redness, pain in swallowing, hoarseness of voice and foreign object sensation in the throat were evaluated on a 5 -point Likert Scale during visit 1 (at treatment initiation), visit 2 (day 3, at 48 hours of product use) and visit 3 (day 5, at 96 hours of product use) and by analysing the change in bacterial and viral loadin the throat done by oropharyngeal swab collection followed by quantitation by real time - polymerase chain reaction (RT-PCR).

[0152] From the study it was observed that, there was 93.75% reduction in symptoms on a 5 point Likert scale in PVP-I Throat spray in treatment group, whereas placebo group showed 85.7% reduction on / within 3rd visit.

[0153] For viral load reduction, PVPI Throat Spray caused 100% reduction in Cycle Threshold (CT) value when compared within visit 1 and visit 3. No viral load was detected at visit 2 and visit 3 by RT-PCR techniques. Placebo showed 65.22% reduction of viral load in the same time interval, as viral load is known to decrease during disease, regardless of the intervention.

[0154] These studies were conducted using the very sensitive RT-PCR techniques. This confirms the ability of PVPI Throat Spray to completely wipe-off the causative viruses in patients.

[0155] For bacterial load reduction, no pathogenic bacteria were isolated in the treated group. However normal bacterial flora was isolated in all subjects at all visit times for both treated as well as placebo groups, indicating that the results were real.

[0156] Secondary endpoint(s) were considered to evaluate the Safety and Tolerability of PVP-I Throat spray in patients. Tolerability and Quality of Life was judged by the patients using Sore Throat Quality of Life (STQoL) questionnaire. Complete remission of main complains was observed in all (100%) the patients using PVPI Throat Spray within visit 3 (day 5).

[0157] Overall, from the study data, it was observed that improvement in symptoms as well as quality of life in PVP-I Throat Spray group was significant when compared with placebo group on visit 2 (Day 3) and visit 3 (Day 5). The product was very well tolerated, and no adverse health event was reported in the study.

[0158] Therefore, the PVP-I Throat Spray of the instant invention is effective and safe measure for reduction in symptoms of throat infections. The Throat Spray also helped achieving a better post-treatment infection “control” compared to placebo as both the arms were receiving standard of care.

[0159] In the specification, there has been disclosed preferred embodiments of the invention. Although specific terms are employed, they are used in a generic and descriptive sense only and not for purposes of limitation of the scope of the invention. Although the inventionhas been described with reference to specific embodiments, this description is not meant to be construed in a limiting sense. Various modifications of the disclosed embodiments, as well as alternate embodiments of the invention, will become apparent to persons skilled in the art upon reference to the description of the invention. It is therefore, contemplated that such modifications can be made without departing from the spirit or scope of the present invention as defined.

Claims

WE CLAIM1. A povidone iodine oral aqueous or hydro-alcoholic solution composition comprising,povidone iodine in a range of 0.10% to 1.00% w / v,at least one humectant,at least one selective stabilizer,at least one solvent or carrier or combination thereof,optionally at least one selective flavoring agent or combination thereof, optionally at least one viscosity enhancers or combination thereof, and optionally one or more other pharmaceutically active ingredients.wherein the said composition is stabilized and standardized for use as throat spray.

2. The composition as claimed in claim 1 , wherein said povidone iodine is in a range of 0.10 to 0.50%w / v.

3. The composition as claimed in claim 1 or 2, wherein said composition has predetermined available iodine concentration in a range of 0.01 to 0.10%w / v, and most preferably is in a range of 0.01 to 0.05%w / v.

4. The composition as claimed in claim 1 , wherein said humectant is selected form a group of chemical or natural humectant or a combination thereof, in a range of 60.0 to 90.0%w / v, preferably in a range of 80.0 to 90.0 %w / v to minimize pungent, irritating or burning sensation along with and enhanced residence time of povidone iodine in oro - pharyngeal cavity.

5. The composition as claimed in claim 1, wherein said selective stabilizer is potassium iodide or potassium iodate or a combination thereof, in a range of 0.01 to 0.50%w / v and most preferably is in a range of 0.20 to 0.50%w / v.

6. The composition as claimed in claim 1 , wherein said flavoring agent is menthol or diluted eucalyptus oil or a combination thereof, in a range of 0.01 to 0.50%w / v, preferably 0.20 to 0.50%w / v to provide refreshing sensation, improve breathing and act as an expectorant.

7. The composition as claimed in claim 1 , wherein said solvent or carrier is a purified water or ethanol or a combination thereof, to solubilize the components and to make up the volume from about 10%v / v to 40%v / v.

8. The composition as claimed in claims 1-7, wherein said composition comprises ofPovidone Iodine 0.10 to 1.00%w / vHumectants 60.0 - 90.0% w / vStabilizers 0.01 - 0.50% w / vFlavoring agents 0.00 - 0.50% w / vSolvents or carriers 10.0 - 40.0%v / v (q.s. or up to 100%), Optionally also contains quantity of viscosity enhancer and other optional pharmaceutically active ingredients in effective required concentration.

9. The composition as claimed in claims 1-8, wherein said composition is used as an aqueous or hydro- alcoholic oral solution medicament for providing relief from a sore throat, mouth irritation, local soothing effect in throat or to improve breathing or use as an expectorant.

10. The composition as claimed in claims 1-8, wherein said composition is effectively used for decontamination and microbial decolonization of oral mucosa in case of upper respiratory bacterial, viral or fungal infections.

11. The composition as claimed in claims 1-8, wherein said optional other active pharmaceutical ingredient / s having, anti-allergic, anti-inflammatory or anti- infective properties, to effectively use it for oral application or in treatment of several acute and chronic oro-pharyngeal diseases such as oral mucositis.

12. The composition as claimed in claims 1-11, wherein said composition is aqueous or hydro-alcoholic, stable, safer, cost effective and environmental-friendly.

13. The composition as claimed in claims 1-12, wherein said composition effectively provides a protective layer over the application area to improve overall residence time of povidone iodine, preferably reaching hard-to-reach areas of the throat, such as pharynx.

14. The composition as claimed in claims 1-13, wherein said composition is stable for 1 month at stress conditions at 50°C and up to 6 months at accelerated condition at 40°C and 75% relative humidity and at long-term conditions at 30°C and 75% relative humidity.

15. The composition as claimed in claims 1-14, wherein said oral solution is packed in a unit dose or multi dose container.

16. The composition as claimed in claim 15, wherein said container has a suitable dispensing system to locally deliver the solution in the form of drops or spray or liquid or to deliver inside the oral cavity.

17. A drug product presentation comprising a container comprising the composition as claimed in claims 1-14, a closure and a dispensing system.

18. A process for manufacturing of stabilized and standardized povidone iodine solution for oral application comprising:Solubilization of Stabilizer, in a main manufacturing tank, containing solvent or carrier under stirring,Solubilization of povidone iodine, in a main manufacturing tank, containing above solution under stirring,Solubilization of humectants, in a main manufacturing tank, containing above solution under stirring,Optional separate preparation of ‘flavor solution’ by completely solubilizing flavors in a solvent or carrier under stirring and further adding it in a main manufacturing tank,Standing the above solution for stabilization and standardization to achieve a solution having pH in the range of 1.5 to 4.5,Making the final volume of solution to prepare the stable povidone iodine oral solution.

19. The process as claimed in 18, wherein the said stable povidone iodine oral solution is filled in suitable size and shape containers with suitable dispensing device, to prepare a pharmaceutical dosage form of a medicament of stabilized and standardized povidone iodine solution for oral application especially in the form of throat spray.

20. The process as claimed in claim 19, wherein said container is suitable for delivery or distribution of said stable povidone iodine solution into oral cavity in the form of spray or drops or mist or as liquid,21. The process as claimed in claim 19, wherein said container is made of glass, high- density or low-density polyethylene or polyethylene terephthalate or polypropylene, preferably high-density polyethylene.

22. The process as claimed in claim 18, wherein said stable povidone iodine oral solution maintains its potency and has improved povidone iodine stability during in-use and standard accelerated stability conditions respectively.

23. The process as claimed in claims 18-22, wherein said stable povidone iodine oral solution is the composition as claimed in claims 1-14.

24. The stable povidone iodine solution as prepared by the process of claims 18.

25. The process for manufacturing of stabilized povidone iodine solution standardized for oral cavity local application substantially as herein described with reference to examples and drawings.

26. The povidone iodine oral solution composition substantially as herein described with reference to examples and drawings.

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