Claims:1. A pharmaceutical composition comprising (a) pidotimod or pharmaceutically acceptable salt thereof; (b) an alkalizer; and (c) a pharmaceutically acceptable excipient, wherein the composition is orally administered twice daily for 15 days to a paediatric patient, followed by once daily administration till completion of 2 months therapy for reducing the number of episodes of acute respiratory tract infection.
2. The pharmaceutical composition according to claim 1, wherein the pharmaceutical composition is administered as add-on therapy for reducing the number of episodes of acute respiratory tract infection.
3. The pharmaceutical composition according to claim 2, wherein the add-on therapy is in combination with antibiotic therapy.
4. The pharmaceutical composition according to claim 1, wherein the alkalizer comprises tromethamine or sodium hydroxide or combination thereof.
5. The pharmaceutical composition according to claim 4, wherein the tromethamine is present in an amount ranges from about 0.1% w/v to about 0.15% w/v of the composition.
6. The pharmaceutical composition according to claim 4 wherein the sodium hydroxide is present in an amount ranges from 0.90% w/v to about 0.95% w/v of the composition.
7. A pharmaceutical composition comprising (a) about 5.71 % w/v of pidotimod, (b) an alkalizer containing about 0.1% w/v tromethamine and about 0.95 % w/v sodium hydroxide, and (c) a pharmaceutically acceptable excipient, wherein the composition equivalent to 400 mg dose of pidotimod is orally administered twice daily for 15 days to a paediatric patient, followed by once daily administration till completion of 2 months as add-on therapy for reducing the number of episodes of acute respiratory tract infection.
8. The pharmaceutical composition according to claim 1 and 7 , wherein the pharmaceutically acceptable excipient is selected from the group consisting of sweetener, viscosity modifier, stabilizer, flavouring agent, vehicle or solvent, surfactant, chelating agent or combination thereof.
9. The pharmaceutical composition according to claim 1 and 7 wherein the said pharmaceutical composition is in the form of liquid dosage form.
10. A liquid pharmaceutical composition comprising (a) 5.71% pidotimod or pharmaceutically acceptable salt thereof; (b) 0.1% tromethamine; (c) 0.95% sodium hydroxide; (d) 30% liquid glucose; (e) 5% sorbitol solution; (f) 0.010% disodium edetate; (g) 0.2% sucralose; (h) 0.1% flavouring agent; (i) 50% glycerine and (j) purified water, wherein the composition equivalent to 400 mg dose of pidotimod is orally administered twice daily for 15 days to a paediatric patient, followed by once daily administration till completion of 2 months as add-on therapy to concurrent antibiotic therapy for reducing the number of episodes of acute respiratory tract infection.
, Description:FIELD OF THE INVENTION
The invention relates to a pharmaceutical composition comprising pidotimod or pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient for oral administration in pediatric patient, for reducing the number of episodes of acute respiratory tract infection. The invention also relates to a process of preparation of such composition.
BACKGROUND OF INVENTION
Amongst various infections, acute respiratory tract infections (ARTIs) are common in children especially below 5 years and are major cause of morbidity and mortality. These ARTIs tend to be recurrent in children leading to frequent hospital/out-patient visits. Occurrence of six or more ARTIs in a year is recognized internationally as recurrent respiratory infections (RRIs).
Among various predisposing factors, immune immaturity may be an important contributor to recurrence of ARTIs in young children. It has been reported that abnormalities of neutrophils and macrophage activity as well as dendritic cells, natural killer cells, B-cells and T-cells are associated with RRIs.
Immunotherapy is the treatment of disease by inducing, enhancing or suppressing an immune response. Immunotherapies intended to elicit or increase an immune response are classified as activation immunotherapies, while immunotherapies that suppress immune response are classified as suppression immunotherapies.
Pidotimod is a safe immunomodulant, its chemical structure shows a sulfur ring attached to Piracetam. A piracitam is a cyclic derivative of gamma-aminobutyric acid (GABA). The pidotimod has chemical name (4R)-3-[[(2S)-5-Oxo-2-pyrrolidinyl]carbonyl]-4-thiazolidine carboxylic acid and has the structural formula:

Formula I
Pidotimod is a synthetic dipeptide molecule with immunomodulatory properties.
U.S. Patent No. 5,369,131 relates to a liquid pharmaceutical composition of pidotimod which is propellant free and mechanically foamable. C.N. Patent No. 102525903 relates to an oral liquid preparation of pidotimod and its use to promote the body's immune response. C.N. Patent No. 102525902 relates to a high concentration of pidotimod oral liquid preparations used to promote the body's immune response. C.N. Patent No. 102166183 relates to immunologic stimulant oral syrup compositions comprising pidotimod, sucrose, pH regulator, ethyl hydroxyl benzoate, ethanol, essence and purified water. U.S. Patent No. 8,263,125 relates to a dosage form for high dose-high solubility active ingredients that provides for immediate release and modified release of the active ingredients.
The prior art teaches various dosage forms and process for preparation of pidotimod composition, but still there exist a need to develop a formulation having desired storage stability and precise dosing regimen therapy in pediatric patients for reducing the number of episodes of acute respiratory tract infection.
ARTIs are responsible of 75% of antibiotics prescription in pediatric age and may contribute substantially to the rise in antibiotic resistance. Non-specific enhancement of the antimicrobial immune responses or the innate immunity mechanisms are functional approaches to prevent and treat ARTIs considering the immaturity and naivety of childhood immune system.
Besides standard therapy and preventive measures, immunomodulation with synthetic dipeptide - pidotimod - has been found effective in RRIs. Pidotimod exerts its immunomodulatory effect by different mechanisms involving adaptive and innate immune responses. Pidotimod has been found effective, safe and well tolerated in children suffering from RRIs with or without asthma. There is so far no known evidence of pidotimod dosage regimen in children with ARTIs. The inventors of this invention surprisingly found that oral administration of pidotimod composition twice daily for 15 days, and followed by once daily till completion of 2 months significantly reduced the number of episodes of ARTIs.
SUMMARY OF THE INVENTION
In one general aspect, there is provided a pharmaceutical composition comprising (a) pidotimod or pharmaceutically acceptable salt thereof; (b) an alkalizer; and (c) a pharmaceutically acceptable excipient.
In another aspect, there is provided a pharmaceutical composition comprising (a) pidotimod or pharmaceutically acceptable salt thereof; (b) an alkalizer; and (c) a pharmaceutically acceptable excipient, wherein the composition is orally administered twice daily for 15 days to a pediatric patient, followed by once daily administration till completion of 2 months therapy for reducing the number of episodes of acute respiratory tract infection.
In another aspect, there is provided a pharmaceutical composition; wherein the composition is administered as add-on therapy for reducing the number of episodes of acute respiratory tract infection.
In another aspect, there is provided a pharmaceutical composition; wherein the composition is administered as add-on therapy for reducing the number of episodes of acute respiratory tract infection; and wherein the add-on therapy is concurrent to antibiotic therapy.
In another aspect, there is provided a pharmaceutical composition; wherein pidotimod is present in an amount of 5.71% w/v of the composition.
In another aspect, there is provided a pharmaceutical composition; wherein an alkalizer comprises tromethamine or sodium hydroxide or combination thereof.
In another aspect, there is provided a pharmaceutical composition comprising (a) pidotimod or pharmaceutically acceptable salt thereof; (b) an alkalizer; and (c) a pharmaceutically acceptable excipient, wherein the composition is orally administered twice daily for 15 days to a pediatric patient, followed by once daily administration till completion of 2 months therapy for reducing the number of episodes of acute respiratory tract infection, and wherein the pharmaceutical composition is administered as add-on therapy for reducing the number of episodes of acute respiratory tract infection, and wherein the add-on therapy to concurrent antibiotic therapy, and wherein an alkalizer comprises tromethamine or sodium hydroxide or combination thereof, and wherein the tromethamine is present in an amount ranges from about 0.1% w/v to about 0.15% w/v of the composition, and wherein the sodium hydroxide is present in an amount ranges from 0.90% w/v to about 0.95% w/v of the composition.
In another aspect, there is provided a pharmaceutical composition comprising (a) about 5.71 % w/v of pidotimod, (b) an alkalizer containing about 0.1% w/v tromethamine and about 0.95 % w/v sodium hydroxide, and (c) a pharmaceutically acceptable excipient.
In another aspect, there is provided a pharmaceutical composition comprising (a) about 5.71 % w/v of pidotimod, (b) an alkalizer containing about 0.1% w/v tromethamine and about 0.95 % w/v sodium hydroxide, and (c) a pharmaceutically acceptable excipient, wherein the composition equivalent to 400 mg dose of pidotimod is orally administered twice daily for 15 days to a pediatric patient, followed by once daily administration till completion of 2 months as add-on therapy to concurrent antibiotic therapy for reducing the number of episodes of acute respiratory tract infection.
In another aspect there is provided a pharmaceutical composition, wherein the a pharmaceutically acceptable excipient is selected from the group consisting of sweetener, viscosity modifier, stabilizer, flavouring agent, vehicle or solvent, surfactant, chelating agent or combination thereof, and wherein the said pharmaceutical composition is in the form of liquid dosage form.
In one general aspect, there is provided a liquid pharmaceutical composition comprising (a) 5.71% pidotimod or pharmaceutically acceptable salt thereof; (b) 0.1% tromethamine; (c) 0.95% sodium hydroxide; (d) 30% liquid glucose; (e) 5% sorbitol solution; (f) 0.010% disodium edetate; (g) 0.2% sucralose; (h) 0.1% flavouring agent; (i) 50% glycerine and (j) purified water, wherein the composition equivalent to 400 mg dose of pidotimod is orally administered twice daily for 15 days to a pediatric patient, followed by once daily administration till completion of 2 months as add-on therapy for reducing the number of episodes of acute respiratory tract infection.
In another aspect, there is provided a stable pharmaceutical composition comprising pidotimod or pharmaceutically acceptable salt thereof, wherein the composition stable when stored at a temperature of 40°C and 75% relative humidity for a period of at least 6 months.
In another aspect, there is provided a pharmaceutical composition comprising pidotimod or pharmaceutically acceptable salt thereof, wherein the composition is in the form of oral liquid dosage form.
In another aspect, there is provided a process for preparing a pharmaceutical composition comprising pidotimod or pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient.
In another aspect, there is provided a process for preparing a pharmaceutical composition comprising pidotimod or pharmaceutically acceptable salt thereof, wherein the process comprises steps such as mixing, dissolving, filtering, stirring, heating.

In another aspect, there is provided a process for preparing a liquid pharmaceutical composition comprising pidotimod or pharmaceutically acceptable salt thereof, wherein the process comprises the steps of:
(a) preparing a solution comprising sweeteners and viscosity modifying agent;
(b) dissolving stabilizer or alkalizer separately in purified water and mixing of these solutions in to solution obtained in step (a) to get solution;
(c) mixing active ingredient to a solution obtained in step (b) and stirring it to obtain clear a solution;
(d) adjusting pH of step (c) solution;
(e) preparing additional sweetener solution in purified water and adding to step (d) solution;
(f) adding flavoring agent to a solution obtained in step (e); and
(g) making up volume to 100 mL and filtering to obtain a liquid pharmaceutical composition.
In another aspect, there is provided a process for preparing liquid pharmaceutical composition comprising pidotimod or pharmaceutically acceptable salt thereof, wherein the process comprises:
(a) preparing a solution comprising liquid glucose, glycerine and sorbitol;
(b) dissolving disodium edetate or tromethamine or sodium hydroxide separately in purified water and mixing of these solutions in to solution obtained in step (a) to get a solution;
(c) mixing of pidotimod to solution obtained in step (b) and stirring it to obtain clear solution;
(d) adjusting pH of the solution obtained in step (c);
(e) preparing additional sucralose solution in purified water and adding it to the solution obtained in step (d);
(h) adding flavoring agent to the solution obtained in step (e), filtering this syrup through 200# nylon cloth and making up volume to 100 mL to obtain a liquid pharmaceutical composition.

DETAILED DESCRIPTION OF THE INVENTION
The term “pharmaceutical composition” or “pharmaceutical formulation” or “pharmaceutical dosage form” can be used interchangeably and refers to the combination of a active ingredients and a excipient.
The term “pharmaceutically acceptable salt” refers to salts derived from a variety of organic and inorganic counter ions well known in the art and includes any pharmaceutically acceptable salt soluble in water to form an aqueous solution.
The term “pidotimod” as used herein refers not only its free form (base) but also refers to its salt, solvate, prodrug, hydrate, enantiomer or polymorph thereof.
The term “pediatric patient” refers to aged 2-10 years with history of 6 or more RRIs in preceding year.
The term “add-on therapy” refers to any treatment given to bolster or enhance the effectiveness of a previous one, especially when the first treatment proved not to be fully effective.
The term “acute respiratory tract infections” refers to upper respiratory tract infections or lower respiratory tract infections or infections of the respiratory tract that last for less than 30 days.
The term "pharmaceutically acceptable excipient” as used herein means a component of a pharmaceutical product that is not an active ingredient may include, but are not limited to antioxidants, alkalizers, humectants, defoaming agents, chelating agents, preservatives, solubilizers, buffers, electrolytes, sweeteners, viscosity modifier, syrup base, flavours, colours, solvents such as purified water, co-solvents, taste masking agents and/or mixture thereof. The excipients that are useful in preparing a pharmaceutical composition are preferably safe, non-toxic and neither biologically nor otherwise undesirable, and are acceptable for pharmaceutical use.
In one general embodiment, there is provided a pharmaceutical composition comprising (a) pidotimod or pharmaceutically acceptable salt thereof; (b) an alkalizer; and (c) a pharmaceutically acceptable excipient.
In another embodiment, there is provided a pharmaceutical composition comprising (a) pidotimod or pharmaceutically acceptable salt thereof; (b) an alkalizer; and (c) a pharmaceutically acceptable excipient, wherein the composition is orally administered twice daily for 15 days to a pediatric patient, followed by once daily administration till completion of 2 months therapy for reducing the number of episodes of acute respiratory tract infection.
In another embodiment, there is provided a pharmaceutical composition; wherein the composition is administered as add-on therapy for reducing the number of episodes of acute respiratory tract infection.
In another embodiment, there is provided a pharmaceutical composition; wherein the composition is administered as add-on therapy for reducing the number of episodes of acute respiratory tract infection; and wherein the add-on therapy is concurrent to antibiotic therapy.
In another embodiment, there is provided a pharmaceutical composition; wherein pidotimod is present in an amount of 5.71% w/v of the composition.
In another embodiment, an alkalizer is selected from group comprising of calcium carbonate, calcium hydroxide, magnesium carbonate, magnesium hydroxide, magnesium silicate, magnesium aluminate or aluminum magnesium hydroxide, sodium hydroxide, sodium chloride, tromethamine. Preferably, the alkalizers are sodium chloride, tromethamine.
In another embodiment, there is provided a pharmaceutical composition; wherein an alkalizer comprises tromethamine or sodium hydroxide or combination thereof.
In another embodiment, the tromethamine is present in an amount ranges from about 0.1% w/v to about 0.15% w/v, or about 0.12% w/v to about 0.14%w/v, or about 0.13% w/v of the composition.
In another embodiment, the sodium hydroxide is present in an amount ranges from 0.90% w/v to about 0.95% w/v, or about 0.91% w/v to about 0.94% w/v, or about 0.93% w/v of the composition.
In another embodiment, there is provided a pharmaceutical composition comprising (a) pidotimod or pharmaceutically acceptable salt thereof; (b) an alkalizer; and (c) a pharmaceutically acceptable excipient, wherein the composition is orally administered twice daily for 15 days to a pediatric patient, followed by once daily administration till completion of 2 months therapy for reducing the number of episodes of acute respiratory tract infection, and wherein the pharmaceutical composition is administered as add-on therapy for reducing the number of episodes of acute respiratory tract infection, and wherein the add-on therapy for reducing the number of episodes of acute respiratory tract infection is in combination with antibiotic therapy, and wherein an alkalizer comprises tromethamine or sodium hydroxide or combination thereof, and wherein the tromethamine is present in an amount ranges from about 0.1% w/v to about 0.15% w/v of the composition, and wherein the sodium hydroxide is present in an amount ranges from 0.90% w/v to about 0.95% w/v of the composition.
In another embodiment, there is provided a pharmaceutical composition comprising (a) about 5.71 % w/v of pidotimod, (b) an alkalizer containing about 0.1% w/v tromethamine and about 0.95 % w/v sodium hydroxide, and (c) a pharmaceutically acceptable excipient.
In another embodiment, there is provided a pharmaceutical composition comprising (a) about 5.71 % w/v of pidotimod, (b) an alkalizer containing about 0.1% w/v tromethamine and about 0.95 % w/v sodium hydroxide, and (c) a pharmaceutically acceptable excipient, wherein the composition equivalent to 400 mg dose of pidotimod is orally administered twice daily for 15 days to a pediatric patient, followed by once daily administration till completion of 2 months as add-on therapy to concurrent antibiotic therapy for reducing the number of episodes of acute respiratory tract infection.
In another embodiment, there is provided a pharmaceutical composition, wherein the a pharmaceutically acceptable excipient is selected from the group consisting of sweetener, viscosity modifier, stabilizer, flavouring agent, vehicle or solvent, surfactant, chelating agent or combination thereof, and wherein the said pharmaceutical composition is in the form of liquid dosage form.
The present oral compositions comprise a sugar and/or other sweetener to provide sweetness and taste masking of pharmaceutical active(s) as well as to provide some body and thickness. Sucrose, glucose or table sugar, often in liquid form, may be used. Alternatively, or additionally if greater sweetening is desired, sugar alcohols such as glycerin, sorbitol, maltitol, and mannitol can be used to provide sweetness. Preferably, the sweetener used is sucralose present in an amount of 0.2% w/v of the composition, liquid glucose and sorbitol solution.
Suitable viscosity modifying agents include but are not limited to chitosan, xanthan, hydroxpropylmethylcellulose (HPMC), hydroxypropylcellulose (HPC), hydroxyethylcellulose (HEC), glycerin, polyvinyl alcohol, glactomannons such as guar, konjac, locust bean gum and mamman, for example, microcrystalline cellulose and combinations thereof. Preferably, the viscosity modifying agent is glycerin present in an amount of 50% w/v of the composition.
Examples of suitable flavoring agents include, but are not limited to, natural and artificial flavors such as mints (i.e., peppermint, etc.), menthol, chocolate, artificial chocolate, bubblegum, both artificial and natural fruit flavors (i.e., cherry, grape, orange, blue berry, strawberry, etc.) and combinations of two or more thereof. Flavoring agents are generally provided as a minor component of the composition in amounts effective to provide palatable flavor to the compositions. Typically, flavoring agents are present in amounts in the range of about 0 grams to about 5 grams per 100 ml of the composition. Preferably menthol, essence mixed fruit VSA S 2535 (IFF) and flavor RSW 786 can be used.
Antioxidants which are effective according to the invention as stabilizers include, but not limited to diamylhydroquinone, di-tert-butylhydroquinone, dicetyl thiodipropionate, digalloyl trioleate, dilauryl thiodipropionate, dimyristyl thiodipropionate, dioleyltocopherylmethylsilanol, disodium rutinyldisulphate, disodium edetate, distearyl thiodipropionate, ditridecyl thiodipropionate, dodecyl gallate, erythorbic acid, ethyl ferulate, ferulic acid, hydroquinone. Preferably, the antioxidant used is disodium edetate present in an amount of 0.01% w/v of the composition.
In yet another embodiment, there is provided a liquid pharmaceutical composition comprising (a) 5.71% pidotimod or pharmaceutically acceptable salt thereof; (b) 0.1% tromethamine; (c) 0.95% sodium hydroxide; (d) 30% liquid glucose; (e) 5% sorbitol solution; (f) 0.010% disodium edetate; (g) 0.2% sucralose; (h) 0.1% flavouring agent; (i) 50% glycerine and (j) purified water, wherein the composition equivalent to 400 mg dose of pidotimod is orally administered twice daily for 15 days to a pediatric patient, followed by once daily administration till completion of 2 months as add-on therapy to concurrent antibiotic therapy for reducing the number of episodes of acute respiratory tract infection.
In another embodiment, there is provided a stable pharmaceutical composition comprising pidotimod or pharmaceutically acceptable salt thereof, wherein the composition stable when stored at a temperature of 40°C and 75% relative humidity for a period of at least 6 months.
In another embodiment, there is provided a pharmaceutical composition comprising pidotimod or pharmaceutically acceptable salt thereof, wherein the composition is in the form of oral liquid dosage form.
In another embodiment, there is provided a process for preparing a pharmaceutical composition comprising pidotimod or pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient.
In another embodiment, there is provided a process for preparing a pharmaceutical composition comprising pidotimod or pharmaceutically acceptable salt thereof, wherein the process comprises steps such as mixing, dissolving, filtering, stirring, heating.
In another embodiment, there is provided a process for preparing a liquid pharmaceutical composition comprising pidotimod or pharmaceutically acceptable salt thereof, wherein the process comprises the steps of:
(i) preparing a solution comprising sweeteners and viscosity modifying agent;
(j) dissolving stabilizer or alkalizer separately in purified water and mixing of these solutions in to solution obtained in step (a) to get solution;
(k) mixing active ingredient to a solution obtained in step (b) and stirring it to obtain clear a solution;
(l) adjusting pH of step (c) solution;
(m) preparing additional sweetener solution in purified water and adding to step (d) solution;
(n) adding flavoring agent to a solution obtained in step (e); and
(o) making up volume to 100 mL and filtering to obtain a liquid pharmaceutical composition.
In another embodiment, there is provided a process for preparing liquid pharmaceutical composition comprising pidotimod or pharmaceutically acceptable salt thereof, wherein the process comprises:
(f) preparing a solution comprising liquid glucose, glycerine and sorbitol;
(g) dissolving disodium edetate or tromethamine or sodium hydroxide separately in purified water and mixing of these solutions in to solution obtained in step (a) to get a solution;
(h) mixing of pidotimod to solution obtained in step (b) and stirring it to obtain clear solution;
(i) adjusting pH of the solution obtained in step (c);
(j) preparing additional sucralose solution in purified water and adding it to the solution obtained in step (d);
(p) adding flavoring agent to the solution obtained in step (e), filtering this syrup through 200# nylon cloth and making up volume to 100 mL to obtain a liquid pharmaceutical composition.
EXAMPLES
Example 1: Pidotimod composition
Table 1
Sr. No. Ingredients Quantity (% w/v)
1 Pidotimod 5.71
2 Glycerin 44.0
3 Liquid glucose 34.0
4 Sorbitol solution (70%) (Non Crystallizing) 5.5
5 Tromethamine 0.15
6 Sodium Hydroxide 0.90
7 Disodium Edetate 0.01
8 Sucralose 0.15
9 Blue berry FLV 7030 0.10
10 Purified Water q.s to 100 mL
Total quantity (mL) 100

Manufacturing procedure:
1. Glycerin and non- crystallising sorbitol solution (70 %) were transferred to the clean jacketed main manufacturing tank. The mixture was heated under continuous stirring to 50°C to 60°C by circulating steam in the jacket of the tank.
2. Liquid glucose was added to the main manufacturing tank (step 1) and mixed for 15 minutes. The solution was cooled to 40°C to 45°C by circulating cold water in the jacket of the tank.
3. Disodium edetate was dissolved in purified water in mixing tank for 15 minutes. This solution was transferred to main manufacturing tank under continuous stirring. The mixing tank was rinsed with purified water and the rinsing was added to the main manufacturing tank under stirring for 5 minutes.
4. Tromethamine was dissolved in purified water in mixing tank for 15 minutes and the solution was transferred to main manufacturing tank under continuous stirring. The mixing tank was rinsed with purified water and the rinsing was added to the main manufacturing tank under stirring for 5 minutes.
5. Sodium hydroxide was added and mixed in purified water, in mixing tank and the solution was allowed to cool below 40°C and transferred to main manufacturing tank under stirring. The mixing tank was rinsed with purified water and the rinsing was added to the main manufacturing tank under stirring, for 10 minutes.
6. Pidotimod was added slowly in main manufacturing tank under stirring for 30 minute. Above bulk solution pH was adjusted to 5 ± 0.3 using sodium hydroxide solution.
7. Thereafter, sucralose was dissolved in purified water by manual stirring in vessel. The sucralose solution was transferred to main manufacturing tank under constant stirring. The vessel was rinsed with purified water and the rinsing was added to the main manufacturing tank by stirring the solution for 5 minutes.
8. The flavour blue berry FLV 7030 was added to main manufacturing vessel under constant stirring for 10 minutes.
9. The final volume was adjusted with purified water and mixed for 30 minutes, to obtain liquid pharmaceutical composition.
Example 2: Pidotimod composition
Table 2
Sr. No. Ingredients Quantity (% w/v)
1 Pidotimod 5.71
2 Glycerin 54.0
3 Liquid glucose 27.0
4 Sorbitol solution (70%) (Non Crystallizing) 4.0
5 Tromethamine 0.10
6 Sodium Hydroxide 0.95
7 Disodium Edetate 0.01
8 Sucralose 0.15
9 Blue berry FLV 7030 0.10
10 Purified Water q.s to 100 mL
Total quantity (mL) 100

Manufacturing Procedure:
1. Glycerin and non- crystallising sorbitol solution (70 %) were transferred to the clean jacketed main manufacturing tank. The mixture was heated under continuous stirring to 50°C to 60°C by circulating steam in the jacket of the tank.
2. Liquid glucose was added to the main manufacturing tank (step 1) and mixed for 15 minutes. The solution was cooled to 40°C to 45°C by circulating cold water in the jacket of the tank.
3. Disodium edetate was dissolved in purified water in mixing tank for 15 minutes. This solution was transferred to main manufacturing tank under continuous stirring. The mixing tank was rinsed with purified water and the rinsing was added to the main manufacturing tank under stirring for 5 minutes.
4. Tromethamine was dissolved in purified water in mixing tank for 15 minutes and the solution was transferred to main manufacturing tank under continuous stirring. The mixing tank was rinsed with purified water and the rinsing was added to the main manufacturing tank under stirring for 5 minutes.
5. Sodium hydroxide was added and mixed in purified water, in mixing tank and the solution was allowed to cool below 40°C and transferred to main manufacturing tank under stirring. The mixing tank was rinsed with purified water and the rinsing was added to the main manufacturing tank under stirring, for 10 minutes.
6. Pidotimod was added slowly in main manufacturing tank under stirring for 30 minute. Above bulk solution pH was adjusted to 5 ± 0.3 using sodium hydroxide solution.
7. Thereafter, sucralose was dissolved in purified water by manual stirring in vessel. The sucralose solution was transferred to main manufacturing tank under constant stirring. The vessel was rinsed with purified water and the rinsing was added to the main manufacturing tank by stirring the solution for 5 minutes.
8. The flavour blue berry FLV 7030 was added to main manufacturing vessel under constant stirring for 10 minutes.
9. The final volume was adjusted with purified water and mixed for 30 minutes, to obtain liquid pharmaceutical composition.
Example 3: Pidotimod composition
Table 3
Sr. No. Ingredients Qty/ 7 mL (mg) % Formula (w/v)
1 Pidotimod 400 5.71
2 Glycerine IP 3500 50
3 Liquid glucose NF 2100 30
4 Sorbitol solution (70 %)
(Non- Crystallizing) IP 350 5
5 Tromethamine USP 7 0.10
6 Sodium Hydroxide IP 66.5 0.95
7 Disodium Edetate IP 0.70 0.01
8 Sucralose IP 14 0.2
9 Blue berry FLV 7030 7 0.1
10 Purified Water IP q.s. to 7 mL q.s. to 100 mL

Manufacturing Procedure:
1. Glycerin and non- crystallising sorbitol solution (70 %) were transferred to the clean jacketed main manufacturing tank. The mixture was heated under continuous stirring to 50°C to 60°C by circulating steam in the jacket of the tank.
2. Liquid glucose was added to the main manufacturing tank (step 1) and mixed for 15 minutes. The solution was cooled to 40°C to 45°C by circulating cold water in the jacket of the tank.
3. Disodium edetate was dissolved in purified water in mixing tank for 15 minutes. This solution was transferred to main manufacturing tank under continuous stirring. The mixing tank was rinsed with purified water and the rinsing was added to the main manufacturing tank under stirring for 5 minutes.
4. Tromethamine was dissolved in purified water in mixing tank for 15 minutes and the solution was transferred to main manufacturing tank under continuous stirring. The mixing tank was rinsed with purified water and the rinsing was added to the main manufacturing tank under stirring for 5 minutes.
5. Sodium hydroxide was added and mixed in purified water, in mixing tank and the solution was allowed to cool below 40°C and transferred to main manufacturing tank under stirring. The mixing tank was rinsed with purified water and the rinsing was added to the main manufacturing tank under stirring, for 10 minutes.
6. Pidotimod was added slowly in main manufacturing tank under stirring for 30 minute. Above bulk solution pH was adjusted to 5 ± 0.3 using sodium hydroxide solution.
7. Thereafter, sucralose was dissolved in purified water by manual stirring in vessel. The sucralose solution was transferred to main manufacturing tank under constant stirring. The vessel was rinsed with purified water and the rinsing was added to the main manufacturing tank by stirring the solution for 5 minutes.
8. The flavour blue berry FLV 7030 was added to main manufacturing vessel under constant stirring for 10 minutes.
9. The final volume was adjusted with purified water and mixed for 30 minutes, to obtain liquid pharmaceutical composition.
Example 4: Clinical Study
Example 4A: Baseline characteristics in two groups
Table 4
Characteristic Pidotimod (n=43) Control
(n=20) P value

Age (years) Mean±SD 5.3±1.9 5.7±1.5 0.335
Known Asthma 19 (44.2) 5 (25.0) -
Age groups (years)
<5 16 (37.2) 5 (25.0) 0.319
5 to 7 20 (46.5) 12 (60.0) -
>7 7 (16.3) 3 (15.0) -
RTI episodes (per year)
Overall 7.40±0.95 7.48±0.84 0.933
In asthmatic patients 7.26±0.87 7.50±1.12 0.665

Sixty-three patients enrolled in to the study, 43 received pidotimod 400 mg twice daily for 15 days, followed by once daily administration till completion of 2 months therapy and 20 were controls. Mean age of patients did not differ in two groups (p=0.335). 44.2% patients in pidotimod group and 25% in placebo group had asthma. Mean number of RTI episodes in previous year were similar in two groups (7.40±0.95 in pidotimod and 7.48±0.84 in controls, p=0.933) as shown in table 4. Also, the mean number of episodes did not differ in patients with asthma in two groups (7.26±0.87 in pidotimod and 7.50±1.12 in controls, p=0.665).

Example 4B: Number of RTI’s in 6-months follow-up in two groups
Table 5
Assessments
timeline Overall population Asthmatic patient
Pidotimod
(n=43) Control
(n=20) P value Pidotimod
(n=19) Control
(n=5) P value
1 month 0.07±0.26 0.45±0.51 0.003 0.05±0.23 0.40±0.55 0.187
2 month 0.02±0.15 0.55±0.51 0.001 0 0.80±0.45 0.001
3 month 0 0.70±0.47 0.001 0 0.60±0.55 0.023
4month 0 0.45±0.51 0.001 0 0.80±0.45 0.001
5 month 0 0.35±0.49 0.002 0 0.20±0.45 0.331
6month 0 0.40±0.50 0.001 0 0.60±0.55 0.023
Total 0.09±0.29 2.90±0.64 0.001 0.05±0.23 3.40±0.55 0.001

Compared to control, mean number of RTI episodes were significantly reduced in pidotimod 400 mg twice daily for 15 days, followed by once daily administration till completion of 2 months therapy in a 6-months follow-up period which was evident from first month (p=0.003). At 3rd month of follow-up, there were no further RTI episodes in pidotimod group and the difference compared to control was significant as shown in table 5. Total number of RTI episodes were significantly lower with pidotimod than in controls (0.09±0.29 Vs. 2.90±0.64, p=0.001). Similar results were evident in patients who had asthma (0.05±0.23 in pidotimod vs. 3.40±0.55 in control, p=0.001).

Example 4C: Change in number of RTI’s in pre- and post- treatment period
Table 6
Assessments
timeline Overall population Asthmatic patient
Pidotimod
(n=43) Control
(n=20) P value Pidotimod
(n=19) Control
(n=5) P value
Pre-treatment
(1 year) 7.40±0.95 7.48±0.84 0.933 7.26±0.87 7.50±1.12 0.665
Post-treatment
(6 months) 0.09±0.29 2.90±0.64 0.001 0.05±0.23 3.40±0.55 0.001
Mean diff.
(Pre-post) -7.31±0.96 -4.48±1.09 0.001 -7.31±0.96 -4.48±1.09 0.001

When compared to pre-treatment frequency of RTIs, mean difference after treatment with pidotimod 400 mg twice daily for 15 days, followed by once daily administration till completion of 2 months therapy versus controls was significant in overall population (mean difference -7.31±0.96 Vs. - 4.48±1.09 respectively, p=0.001) and asthmatic patients (mean difference -7.31±0.96 Vs. -4.48±1.09 respectively, p=0.001) as shown in table 6. Reduction in mean number of RTIs at 6 months was 98.8% with pidotimod and 61.2% in control group in overall population whereas it was 99.3% and 54.7% respectively in asthmatic patients.