FIELD OF THE INVENTION:
The invention relates to a formulation of a nasal solution for topical use in nasal cavity.
The invention specifically related to a Povidone Iodine composition, preparation and
stabilization of aqueous, isotonic, nasal solution.
BACKGROUND OF THE INVENTION:
Nasal formulations are aqueous-based systems that are instilled within or sprayed into
the nasal cavity and are predominantly employed for the treatment of congestion,
allergic rhinitis and infections of nasal cavity.
In addition to providing the required pharmacological activity, nasal formulations
must not interfere with the natural cleansing action of the cilia on the nasal mucosa.
This requirement has led to the avoidance of the use of non-aqueous vehicles for nasal
formulations. Many of the formulation requirements of nasal solutions/sprays are
based on the maintaining of ciliary function.
No Povidone Iodine nasal preparation is available commercially till date in domestic
or in the international market.
The active ingredient in Povidone Iodine Nasal 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
3
use, without substantial loss of antimicrobial efficacy. The incorporation of PVP-I into
products for Nasal preparation is to use for decontamination and microbial
decolonization of nasal mucosa with Bacterial, Viral and Fungal infections. It is also
used for treating irritation and nasal discomfort of rhinitis, sinusitis and common cold.
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.
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).
4
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 constituents of the formula, but also of the material to be disinfected such as
skin, mucous membrane, bacteria, etc.
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.
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.
US 6,165, 494 discloses a method of manufacturing iodine-containing nasal
moisturizing saline solution, for the prevention and/or treatment of sinusitis and
related conditions associated with nasal congestion, an iodine-containing mouthwash
solution and a method for the prevention and/or treatment of sore throats caused by
bacteria and viruses. This nasal moisturizing saline solution is made of water, sodium
chloride, iodine, buffer and a preservative and the mouthwash solution is made of
iodine and a pharmaceutically acceptable carrier.
5
US 5,897,872 disclose an iodine-containing nasal moisturizing saline solution and a
method for the prevention and/or treatment of sinusitis and related conditions
associated with nasal congestion. The nasal moisturizing saline solution is made of
water, sodium chloride, iodine, buffer, and a preservative. The iodine-containing nasal
moisturizing saline solution is buffered and made isotonic. In the method for the
prevention and/or treatment of sinusitis and related conditions associated with nasal
congestion, the nasal moisturizing saline solution is administered to the nostrils of a
patient in need thereof.
US 5,709,851 discloses a method of preparing a stable pharmaceutical aqueous iodine
composition which upon application is substantially non-irritating, which comprises
forming an aqueous solution containing an amount of about 0.1 to about 1.4% of
elemental iodine by weight of the composition and at least one organic substance
selected from the group consisting of iodine solubilizers; iodine complexing polymers,
non-ionic surface active agents, cationic surface active agents and anionic surface
active agents; adding iodate ions in an amount such that the resulting composition
contains from about 0.01% to about and not more that 0.04% iodate ions by weight of
said composition, said iodate ions controlling loss of elemental iodine in said
composition due to a reaction with said organic substance to maintain the germicidal
effective amount of elemental iodine, and providing the resulting composition with a
pH of from about 3 to about 7, such that said resulting composition provides
germicidal action without substantially irritating skin or mucosa when applied
topically to an affected area of skin or mucosa.
US 2017/0165296 A1 describes a method of treating and preventing the common cold
and associated secondary illnesses in a human subject, when the common cold is
caused by viruses. The method comprises applying to the nasal passages of the human
6
subject at ambient temperature, an effective amount of a pharmaceutical preparation
comprising povidone-iodine (PVP-I) at a concentration of greater than 0.10% w/v and
less than 2.5% in which at least 50% of the PVP-I is not associated with liposomes or
other particulate carriers. The pharmaceutical preparation further comprises at least
one pharmaceutically acceptable diluent, excipient or carrier, wherein the diluent,
excipient or carrier is a flavour, sweetener, colouring agent, solvent, buffer, alcohol,
polymer, surfactant or other diluent or excipient designed to optimize the nasal
delivery, intranasal distribution, stability, effectiveness, acceptability, tolerability of
the preparation.
PCT/US2020/041089 discloses a pharmaceutical article that includes a container and
a dilute aqueous PVP-I formulation contained in the container, wherein the container
is made of polyethylene terephthalate (PET) or polypropylene (PP). This
pharmaceutical article provides the aqueous PVP-I formulation with surprisingly
enhanced stability over PVP-I formulations in other pharmaceutical package forms,
without the need of a stabilizing agent in the PVP-I formulations. Invention also
summarizes that dilute PVP-I formulations in PET bottles provide the best stability
than those in amber glass bottles, HDPE bottles and PP bottles.
All the aforementioned patent documents fail to teach a stable aqueous nasal solution
formulation containing diluted PVP-I, most specifically when containing a low
concentration of diluted Povidone Iodine in the range of 0.10% to 1.0%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 documents it recommended to store the aqueous Povidone
Iodine nasal solution at low temperature as it becomes a challenge to store at higher
or accelerated storage conditions (40˚C or higher). Therefore, a robust and stable
7
formulation is required to be developed, which not only can be stored at room
temperature condition of hot humid countries (ICH Zones III, IVa and IVb) using the
product, but also have a suitable shelf-life acceptable commercially.
Hence, referred patent documents do not disclose a stable, standardized, aqueous,
isotonic, nasal solution of PVP-I for topical use in nasal cavity for the management of
nasal irritation and discomfort of rhinitis, sinusitis due to common cold,
decontamination and microbial decolonization of nasal mucosa in bacterial, viral and
fungal infection along with moistening of nasal lining to protect it from dryness and
have better chemical stability during shelf-life along with mild to nasal mucosa with
an effective pH range, iso-tonicity or osmolality of the solution.
OBJECTS OF THE INVENTION:
The principal object of the subject matter is to provide a composition and
manufacturing process thereof for the preparation of stable, standardized, aqueous,
isotonic, nasal solution for topical use in nasal cavity.
The primary object of the subject matter is to provide a simple, aqueous preparation
having unique manufacturing process and a composition for the preparation of
Povidone Iodine Nasal solution.
Another object of the subject matter is to provide a composition containing Povidone
Iodine is in a range of 0.10% to 1.00% w/v (available Iodine 0.01 to 0.1%w/v),
preferably 0.10 to 0.50%w/v (available Iodine 0.01 to 0.05%w/v).
8
Yet another object of the subject matter is to provide a composition and unique process
of manufacturing, where an optimized concentration of suitable buffer, more
preferably a citrate-phosphate buffer, within the pH range of 4.5–7.0 to influences the
rate and extent of drug availability or more specifically effectiveness against various
microorganisms, yet mild in nature to the nasal mucosa.
Yet another object of the subject matter is to provide a composition and unique process
of manufacturing, where selective concentration of tonicity agent to maintain isotonic
formulation or Osmolality of formulation for proper nasal ciliary function, mild to
nasal mucosa and maintain mucosal health.
Yet another object of the subject matter is to provide a composition and unique process
of manufacturing, where humectant is added to minimize irritation to the nasal mucosa
or mild to nasal mucosa.
Yet another object of the subject matter is to also provide a composition and unique
process of manufacturing, whereas selective stabilizer provides a stable nasal
formulation, 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 nasal cavity in the form of drops or spray using suitable dispending
system.
Yet another object of the subject matter is to provide a composition and unique process
of manufacturing of nasal solution effectively use for management of nasal irritation
and discomfort of rhinitis, sinusitis due to common cold.
9
Yet another object of the subject matter is to provide a composition and unique process
of manufacturing of nasal solution use for decontamination and microbial
decolonization of nasal mucosa in bacterial, viral and fungal infection.
Yet another object of the subject matter is to provide a composition and unique process
of manufacturing of nasal solution that can be used as a nasal irrigation in the
treatment of several acute and chronic sinonasal conditions when consumed and/or
combined with anti-allergic, anti-inflammatory, decongestants or anti-infective drugs.
Still another object of the subject matter is to provide a composition and unique
process of manufacturing of nasal solution for providing a protective layer in nasal
cavity and also helping in moistening of the nasal lining to protect it from dryness.
Still another object of the subject matter is to provide a composition and unique
process of manufacturing of nasal solution containing humectants, an optimized
concentration of buffer and an optimum concentration of tonicity agent which is mild
to nasal mucosa.
Still another object of the subject matter is to provide a composition and unique
process of manufacturing of nasal solution, which improves and maintains povidone
Iodine stability throughout its shelf-life.
Still another object of the subject matter is to provide a composition and unique
process of manufacturing of nasal solution, which is stable, aqueous, isotonic, cost
effective and environmental-friendly also.
10
SUMMARY OF INVENTION
The invention provides for a manufacturing process for a versatile aqueous based
formulation of Povidone Iodine Nasal (isotonic) solution, having predetermined
concentration of free Iodine which is immediately achieved and remains constant with
predictable microbicidal effectiveness for a longer duration of action.
This invention specifically provides for a composition, preparation and stabilization
of aqueous, isotonic, nasal solution of Povidone Iodine for topical use in nasal cavity,
wherein the diluted Povidone Iodine is in a range of 0.10% to 1.0%w/v (available
Iodine 0.01 to 0.1%w/v), an optimized concentration of a suitable buffer citratephosphate, within the pH range of 4.5–7.0 to influence the rate and extent of drug
availability, use of a selective concentration of tonicity agent to maintain isotonic
formulation for proper nasal ciliary function. The invention composition further can
comprise of humectants such as glycerol to minimize irritation to the nasal mucosa
and having a selective stabilizer such as potassium iodate for longer shelf- life. The
composition of invention containing humectants, an optimized concentration of buffer
and an optimum concentration of tonicity agent to provide a composition that is mild
to nasal mucosa.
The invention also provides for a manufacturing process wherein the unique steps and
unique order of mixing of ingredients achieves a stabilized, standardized, predetermined concentration of free iodine, which remains constant with predictable
microbicidal effectiveness for a longer duration of action.
The invention can be effectively use for the management of nasal irritation and
discomfort of rhinitis, sinusitis due to common cold, decontamination and microbial
11
decolonization of nasal mucosa in bacterial, viral and fungal infection; provide a
protective layer in nasal cavity and also help in moistening of nasal lining to protect it
from dryness.
Present invention containing Povidone Iodine provide a stable nasal formulation,
which have better chemical stability , as per ICH guidelines, during shelf life and thus
allowing longer shelf-life particularly when packed in suitable size and shape multi
dose container like Glass container, High-density polyethylene (HDPE) container or
Polyethylene terephthalate (PET) containers.
DESCRIPTION OF THE INVENTION:
The present invention provides a composition and unique manufacturing process for
the preparation of stable, aqueous, isotonic, nasal solution for topical use in the nasal
cavity, wherein the diluted Povidone Iodine is in a range of 0.10% to 1.00% w/v
(available Iodine 0.01 to 0.1%w/v) preferably 0.10 to 0.50%w/v (available Iodine 0.01
to 0.05%w/v, an optimized concentration of suitable buffer, citrate-phosphate, within
the pH range of 4.5–7.0 to influence the rate and extent of availability or more
specifically effectiveness against various microorganisms or mild to nasal mucosa,
uses a selective concentration of tonicity agent to maintain isotonic formulation for
proper nasal ciliary function due to mild to nasal mucosa, containing a chemical or
natural humectants such as glycerol or natural ingredients such as aloe-vera, to
minimize irritation and help in obtaining a preparation which is mild to the nasal
mucosa and having a selective stabilizer such as Potassium Iodate.
12
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 a prolonged action.
This invention can be effectively used for irritation and nasal discomfort of rhinitis,
sinusitis and common cold, decontamination and microbial decolonization of nasal
mucosa in bacterial, viral and fungal infection; provides a protective layer in nasal
cavity and also helps in moisten of nasal lining to protect it from dryness alone or as
an adjuvant therapy with anti-allergic, anti-inflammatory, decongestants or antiinfective drugs. Present invention containing Povidone Iodine provide a stable nasal
formulation, 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 or Polyethylene terephthalate (PET)
containers to deliver it in nasal cavity in the form of drops or spray using suitable
dispensing system.
Thus, composition and unique manufacturing method so described is simple, efficient,
robust, cost effective, environmental-friendly and has industrial applicability for
commercial production of specialized dosage form as a medicament at large scale.
Table 1: Composition for the preparation of stable, standardized, aqueous, isotonic,
nasal solution for topical use in the nasal cavity in the form of drops or spray
S.
No.
Ingredients Category Preferred embodiments Concentration
range
13
(%w/v)
1. Povidone Iodine (10%)
[PVP-I 10%]
Chemical complex of
polyvinylpyrrolidone and elemental
Iodine (Iodophor)
0.10 to 1.00%w/v
2. Humectants Chemical: Glycerin, Sorbitol,
Mannitol or a combination thereof or
any other ingredients imparting
humectants property
Natural: Vegetable Glycerin’s, Aloe
vera or any other natural substance
imparting humectants property
Preferably Glycerin or Glycerol
0.50 – 5.0% w/v
3. Stabilizers Potassium Iodide, Potassium Iodate or
a combination thereof
Preferably Potassium Iodate
0.01 – 0.20% w/v
4. Buffers Buffer – Sodium Phosphate / Sodium
Citrate, Sodium Hydroxide or a
combination thereof.
Preferably Citrate-phosphate buffer
0.1 – 1.5% w/v
5. Tonicity modifier Sodium Bicarbonate, Dextrose,
Mannitol , Polyethylene Glycol 400,
potassium chloride, Sodium chloride
or a combination thereof.
Preferably Sodium Chloride or
Sodium Bicarbonates
0.5 -1.0% w/v
5. Solvent or carrier Purified Water or sterile water for
Injection.
Preferably Purified Water
100%v/v
(q.s. or up to 100%)
6. Viscosity enhancer Carbomer, Hydroxy propyl cellulose,
Hydroxy propylmethyl cellulose,
Sodium carboxy methyl cellulose,
Poloxomer or any polymer imparting
viscosity of preparation
Any concentration,
as per requirements
7. Other Pharmaceutical
Active Ingredients
Optionally other active
pharmaceutical or saline solution or
any category compounds,
Any concentration,
as per clinical
14
have,additive or synergistic effect or
combination thereof.
relevance /
requirements
Isotonicity/ Osmolality
To maintain physiological ciliary function, preferably the nasal formulations are
formulated to be isotonic. The approach taken to achieve this is by using a suitable
quantity of salt (e.g. sodium chloride).
US FDA suggested that formulations containing an agent to control the tonicity or for
products having a label claim regarding tonicity, the osmolality of the formulation
should be tested and controlled at release.
The data from animal models has shown increased bioavailability for salmon calcitonin
from nasal spray formulations with an osmolality of 100 or 600 mOsmol/Kg compared
to isotonic formulations. Other studies have shown that hypotonic nasal spray
formulations improved drug permeability through the nasal mucosa. Some existing
marketed nasal preparations, containing different Active Pharmaceutical Ingredients
have osmolality in the range of 300-700 mOsmol/Kg.
Delivery of Solution & Packaging:
Nasal sprays are applied to the nasal cavity for local and/or systemic effects. Although
similar in many features to other drug products, some aspects of nasal 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
15
composition. Energy is required for dispersion of the formulation as a spray. This is
typically accomplished by forcing the formulation through the nasal actuator and its
orifice. The formulation and the container closure system (container, closure, pump,
and any protective packaging) collectively constitute the drug product. The design of
the container closure system affects the dosing performance of the drug product
solution. Formulation can be formulated into nasal drops or sprays. Suitable packaging
for nasal spray or solution may be HDPE or PET container with a nasal spray pump non
metered dose pump or metered dose pump type.
The present invention discloses a unique manufacturing process for the preparation of
stable, standardized, aqueous, isotonic, nasal solution for topical use in the nasal cavity
in the form of drops or spray. Figure 1 outlines the steps of manufacturing the
standardized and stable bulk nasal spray solution of PVP-I of the present invention
The unique process of the invention includes the following steps:
i. Transfer Purified Water (20%w/v) to the main manufacturing tank ‘A’. Add
stabilizer (Potassium Iodate) into the main manufacturing tank ‘A’ and continue
the stirring for about 10 minutes to dissolve it completely.
ii. Add Humectants (Glycerin) into the above main manufacturing tank ‘A’ under
stirring and continue the stirring for about 5 minutes or till uniform solution
obtain.
iii. Buffer Solution Preparation: In a separate tank ‘B’, dissolve Dibasic Sodium
Phosphate Anhydrous and Citric Acid Anhydrous in Purified Water under
stirring.
16
iv. Transfer the “Buffer Solution” from Tank ‘B’ to main manufacturing tank ’A’
under stirring and continue stirring for another 5 minutes or till a clear solution
is obtain.
v. Isotonic Solution Preparation: In a separate tank ‘C’, dissolve Sodium Chloride
in purified water under stirring to dissolve it completely.
vi. Transfer “Isotonic Solution” from Tank ‘C’ to main manufacturing tank ‘A’
under stirring and continue stirring for another 5 minutes or till a clear solution
is obtain.
vii. Preparation of PVP-I solution: In a separate tank ‘D’, Take about 40% Purified
Water and dissolve Povidone Iodine under stirring and continue the stirring for
another 30 minutes (A brown color, clear solution of Povidone Iodine solution).
viii. Transfer Povidone Iodine solution from Tank ‘D’ to main Manufacturing Tank
‘A’ under stirring and continue the stirring for another 10 minutes.
ix. Stand or keep the solution for overnight for stabilization, standardization and
obtaining a stable pH.
x. Makeup final volume of the solution with purified water and further stir the
solution for about 15 to 30 minutes to obtain a standardized and stable bulk nasal
solution.
Thus, composition and unique manufacturing method so described is simple, efficient,
robust, cost effective, environmental-friendly and has industrial applicability for
commercial production of pharmaceutical dosage form i.e. as a medicament at large
scale.
The experiments conducted are exemplified herein for sake of explanation and
understanding without limitation.
17
Example 1& 2
COMPOSITION
Table 2
S. No. Ingredients Composition Range
(% W/V)
1. Povidone Iodine 0.1 to 1.0
2. Potassium Iodate 0.010 - 0.150
3. Glycerin 1.0 – 2.0
4. Di Basic Sodium Phosphate
Anhydrous
0.70 - 0.75
5. Citric Acid Anhydrous 0.30 - 0.36
6. Sodium Chloride 0.60 - 0.81
7. Purified Water q.s. to 100.0 v/v
Manufacturing Process
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%.
Purified Water (20%w/v) is transferred to the main manufacturing tank ‘A’ and start
the stirring. Potassium Iodate is added into the main Manufacturing Tank and
continues the stirring for about 10 minutes to dissolve it completely. Glycerin is added
in main manufacturing tank under stirring and continues the stirring for 5 minutes or
till uniform solution is obtained. In a separate tank ‘B’, Dibasic Sodium Phosphate
Anhydrous and Citric Acid Anhydrous is dissolved in Purified Water under stirring
(Buffer Solution). “Buffer Solution” is transferred to main manufacturing tank ’A’
under stirring and continues stirring for another 5 minutes or till a clear solution is
obtained. In a separate tank ‘C’, Sodium Chloride is dissolved in purified water under
18
stirring to dissolve it completely (Isotonic Solution). “Isotonic Solution” is transferred
to main manufacturing tank ‘A’ under stirring and continues stirring for another 5
minutes or till a clear solution is obtained. In a separate tank ‘D’, 40% Purified Water
is taken, and Povidone Iodine is dissolved under stirring and continues the stirring for
another 30 minutes. A brown colored, clear solution of Povidone Iodine is transferred
to main manufacturing tank ‘A’ under stirring and continued the stirring for another
10 minutes. Solution is kept as such for 12 hr. to overnight for stabilization and
standardization. Final Volume of the solution is made up with purified water.
The stable, standardized, aqueous, isotonic, nasal solution composition made as per
the above examples (Example-1 and Example 2) were filled in 50 ml and 30 ml clear
PET bottles fitted with nasal spray pump and were subjected to Stress condition at
50°C, standard accelerated condition studies at 40°C and 75% relative humidity and
long-term conditions studies at 30°C and 70% relative humidity.
The analytical data and observations made during stability studies are shown in the
Table – 3, Table – 4, Table – 5 and Table – 6.
Table 3
Physical observations:
Example Pack size Stability
conditions Duration
Physical observations
Description pH
1
30 / 50 ml Initial 0 Month
A clear dark brown liquid
with characteristics odor &
free from foreign matter
5.42
50 ml
50°C 1 Month Complies 5.49
40°C/75%RH
3 Month Complies 5.55
6 Month Complies 5.56
19
30 ml
50°C 1 Month Complies 5.50
40°C/75%RH
3 Month Complies 5.56
6 Month Complies 5.50
Table 4
Analytical Data (Chemical Analysis):
Example Pack size Stability
conditions Duration
Chemical Analysis
Assay
(%w/v)
Related Substance
(%w/v)
Iodate Iodide
1
30 / 50 ml Initial 0 Month 108.0% 0.152 1.710
50 ml
50°C 1 Month 102.0% 0.073 1.798
40°C/75%RH
3 Month 102.0% 0.072 1.819
6 Month 106.0% - -
30 ml
50°C 1 Month 94.0% 0.082 1.820
40°C/75%RH
3 Month 98.0% 0.073 1.893
6 Month 92.0% - -
Table 5
Physical observations:
Example Pack
size
Stability
conditions Duration
Physical observations
Description pH Osmolality
mOsmol/Kg
2 30 ml
Initial
0 Month
A clear dark brown
liquid with
characteristics odor &
free from foreign matter
5.68 539
50°C 1 Month Complies 5.47 563
40°C/75%RH 1 Month Complies 5.59 536
20
2 Month Complies 5.55 541
3 Month Complies 5.61 549
30°C/70%RH
3 Month Complies 5.62 541
6 Month Complies 5.65 537
Table 6
Analytical Data (Chemical Analysis):
Example Pack size Stability
conditions Duration
Chemical Analysis
Assay
(%w/v)
Related Substance
(%w/v)
Iodate Iodide
2 30 ml
Initial 0 Month 108.0% 0.067 1.924
50°C 1 Month 92.0% - -
40°C/75%RH
1 Month 102.0% 0.059 1.850
2 Month 100.0% 0.057 1.792
3 Month 111.0% 0.057 1.807
30°C/70%RH
3 Month 107.0% 0.059 1.790
6 Month 108.0% 0.081 1.825
Above stability data demonstrate that novel Povidone Iodine Nasal Solution, prepared
as per example 1 & 2, and packed in 50 ml and 30 ml clear PET bottles fitted with
nasal spray pump, has good stability 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 also at
long-term conditions at 30°C and 70% relative humidity.
Clinical Study:
A study was undertaken on 10 subjects having rhinitis and nasal infection, to evaluate
the efficacy of present invention PVP-I Nasal spray (0.5% w/v Povidone Iodine) in
21
patients suffering from severe Rhinitis (3 Nasal symptoms) sneezing, nasal
congestion, rhinorrhea.
Primary endpoint(s) targeted for the study were, Change from Baseline in Total Nasal
Symptom score (TNSS). Total Nasal symptom score of a composite of 3 symptoms
(Sneezing, Nasal Congestion and Rhinorrhea) and analyzing the change in Bacterial
and Viral load in the nasal cavity.
From the study it was observed that, there was 95.24% reduction in TNSS in PVP-I
Nasal spray Povidone Iodine 0.5% in treatment group, whereas placebo group showed
84.13% reduction on/within 3rd day. There was approximately 8.5% reduction in
Cycle Threshold (CT) Value and no viral load detected on 3rd Day in PVP-I Nasal
spray Povidone Iodine 0.5% group, Whereas, in Placebo group the mean CT value
increased to 28 after 2nd day. For bacterial load, 2 (40%) subjects showed scanty
growth, 2 (40%) subject showed moderate growth, 1 (20%) subject showed heavy
growth in PVP-I Nasal spray Povidone Iodine IP 0.5% group. There was no moderate
growth showed by any subjects at 3rd Day, as a bacterial load reduction happened. 4
(80%) subjects showed scanty growth at 3rd day, in placebo group.
Secondary endpoint(s) were considered to evaluate the Safety and Tolerability of
PVP-I Nasal spray 0.5% w/v povidone- Iodine in patients suffering from Rhinitis.
Number of patients with no nasal congestion, ease in breathing as a measure of
Tolerability and Quality of Life was judged by the patients using General Health
Questionnaire (GHQ-12 questionnaire).
Form the study data, it was observed that there was 74.4% improvement in quality of
life in PVP-I Nasal spray Povidone Iodine 0.5% group when compared from 1st day
22
and 3rd day symptoms, Placebo group showed 69% improvement. There was no
adverse event(s) observed in both the groups during entire duration of the trial.
These results provide a strong rationale for the use of PVP-I Nasal spray Povidone
Iodine 0.5%, as effective and safe measure for reduction in symptoms of rhinitis. It
also helped achieving a better post-treatment infection “control” compared to placebo
as both the arms were receiving standard of care. Nasal spray Povidone Iodine 0.5%
was well-tolerated as a sinus irrigation agent as well.
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
invention has 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.

WE CLAIM
1. A povidone iodine nasal 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 selective buffer composition,
- at least one selective tonicity modifier,
- at least one solvent or carrier,
- optionally at least one viscosity enhancers or combination thereof, and
- optionally one or more other pharmaceutically active ingredients,
wherein said the composition is stabilized and standardized for a stable pH, comprising of
optimum concentration of stabilizer, buffer and tonicity modifier, to be mild to nasal
mucosa.
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 0.01to 0.1%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, preferably in a range of 0.50
to 5.0%w/v to minimize irritation to nasal musosa.
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 0.20%w/v.
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6. The composition as claimed in claim 1, wherein said buffer is citrate or phosphate or a
combination citrate-phosphate buffer, in a range of 0.1 to 1.5%w/v to obtain said stable
pH within the range of 4.5 to 7.0.
7. The composition as claimed in claim 6, wherein said selected buffer influences the rate
and extent of available iodine in the solution.
8. The composition as claimed in claim 1, wherein said tonicity modifier is sodium
bicarbonate, dextrose, potassium chloride, mannitol, polyethylene glycol and sodium
chloride or a combination thereof, in a range of 0.1 to 2.5%w/v, preferably in a range of
0.5 to 1.0%w/v.
9. The composition as claimed in claim 1 or 8, wherein said selected tonicity modifier
maintains the reasonable physiological osmolality of solution in the range of 300-700
mOsmol/Kg, for proper nasal ciliary function, it is mild to nasal mucosa and
subsequently helps in maintaining mucosal health.
10. The composition as claimed in claim 1, wherein said solvent or carrier is a purified water
or water for injection, to solubilize the components and to make up the volume from
about 80%v/v to 100%v/v.
11. The composition as claimed in claims 1-10, wherein said solution can be packed in
suitable size and shape unit dose or multi dose containers.
12. The composition as claimed in claim 11, wherein said container is attached with a
suitable dispensing system to deliver the solution in the form of drops or spray locally,
inside the nasal cavity.
13. The composition as claimed in claim 1, wherein said composition comprises
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Povidone Iodine (10%) 0.10 to 1.00%w/v
Humectants 0.50 – 5.0% w/v
Stabilizers 0.01 – 0.20% w/v
Buffers 0.1 – 1.5% w/v
Tonicity modifier 0.1 – 2.5 % w/v
Solvent or carrier100%v/v (q.s. or up to 100%)
Viscosity enhancer, as per requirements and
optionally other pharmaceutically active ingredients as required.
14. The composition as claimed in claims 1-13, wherein said composition is used as a nasal
spray medicament for treating nasal infections, rhinitis, common cold, and related
symptoms including sneezing, nasal congestion, nasal irritation, nasal discomfort and
rhinorrhea.
15. The composition as claimed in claims 1-13, wherein said composition is effectively used
for decontamination and microbial decolonization of nasal mucosa in case of bacterial,
viral or fungal infection.
16. The composition as claimed in claims 1, wherein said another active pharmaceutical
ingredient/s having, anti-allergic, anti-inflammatory, decongestive or anti-infective
properties, to effectively use it for nasal application or in treatment of several acute and
chronic sinonasal diseases.
17. The composition as claimed in claims 1-13, wherein said composition is effectively
provides a protective layer over the nasal mucosa.
18. The composition as claimed in claims 1-13, wherein said composition is effectively
moistens the nasal lining to protect it from dryness.
19. The composition as claimed in claims 1-13, wherein said composition is aqueous,
isotonic, stable, cost effective and environmental-friendly.
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20. 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 70% relative
humidity.
21. A process for manufacturing of stabilized and standardized povidone iodine solution for
nasal application comprising
- Solubilization of Stabilizer and humectants, in a main manufacturing tank,
containing solvent or carrier under stirring,
- Separate preparation of ‘buffer solution’ by completely solubilizing buffering
agent in a solvent or carrier under stirring and further adding it in a main
manufacturing tank,
- Separate preparation of ‘isotonic solution’ by completely solubilizing tonicity
agent in a solvent or carrier under stirring and further adding it in a main
manufacturing tank,
- Separate preparation of ‘povidone iodine solution’ by completely solubilizing
povidone iodine in a solvent or carrier under stirring and further adding it in a main
manufacturing tank,
- Standing the above solution for overnight for stabilization and standardization to
achieve a solution having pH in the range of 4.5 to 7.0,
- Making the final volume of solution to prepare the stable povidone iodine solution.
22. The process as claimed in 21, wherein the said stable povidone iodine 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 nasal application.
23. The process as claimed in claim 22, wherein said container is made of glass, high-density
polyethylene or polyethylene terephthalate or polypropylene, preferably polyethylene
terephthalate.
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24. The process as claimed in claim 22, wherein said container is suitable for delivery or
distribution of said stable povidone iodine into nasal cavity in the form of spray or drops.
25. The process as claimed in claim 21, wherein said stable povidone iodine solution
maintains its potency and has improved povidone iodine stability during in-use and
standard accelerated stability conditions respectively.
26. The process as claimed in claims 21-25, wherein said stable povidine iodine solution is
the composition as claimed in claims 1-20
27. The stable povidine iodine solution as prepared by the process of claims 21-25.
28. The process for manufacturing of stabilized povidone iodine solution standardized for
nasal application substantially as herein described with reference to examples and
drawings.
29. The povidone iodine nasal solution composition substantially as herein described with
reference to examples and drawings.