Claims:1. A solid pharmaceutical composition comprising (a) a core comprising pidotimod or pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient; (b) coating layer over said core comprising ethyl cellulose, and (c) a pharmaceutically acceptable excipient; wherein the composition is orally administered twice daily for 8 days to a subject, followed by once daily administration till completion of 2 months therapy for reducing the number of exacerbations of chronic obstructive pulmonary disease in the subject.
2. The pharmaceutical composition according to claim 1, wherein the composition is administered as add-on therapy for reducing number of exacerbations of chronic obstructive pulmonary disease.
3. The pharmaceutical composition according to claim 1, wherein the add-on therapy concurrent to antibiotic therapy.
4. The pharmaceutical composition according to claim 1, wherein the ethyl cellulose is present in amount ranges from about 1.5% w/w to about 5% w/w of the composition.
5. A solid pharmaceutical composition comprising (a) a core comprising of about 65% w/w to about 75% w/w of pidotimod or pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient; (b) coating layer over said core comprising ethyl cellulose; and (c) a pharmaceutically acceptable excipient, wherein the composition is orally administered twice daily for 8 days to a subject, followed by once daily administration till completion of 2 months as add-on therapy for reducing the number of exacerbations of chronic obstructive pulmonary disease in the subject.
6. The pharmaceutical composition according to claim 1 and 5, wherein the coating layer further comprises hydroxypropyl methylcellulose, diethyl phthalate and a pharmaceutically acceptable excipient.
7. The pharmaceutical composition according to claim 6, wherein the coating layer is present in amount ranges from about 1% w/w to about 7% w/w of the composition.
8. The pharmaceutical composition according to claim 1 and 5, wherein the pharmaceutically acceptable excipient comprises filler or diluent, binder, disintegrant and/or super-disintegrant, sorbent, anti-adherent, lubricant, glidant, preservative, flavoring agent, colouring agent, coating agent, solvent or vehicle or combination thereof.
9. The pharmaceutical composition according to claim 1 and 5, wherein the composition is present in the form of powder, tablet, pellet, capsule, granule or pellets filled in capsule, tablet in capsule, multilayer tablet, bilayer tablet, trilayer tablet, minitablet or premixed powder filled in capsule.
10. A solid pharmaceutical composition comprising (a) a core comprising 72% w/w of pidotimod or pharmaceutically acceptable salt thereof; 10% w/w of microcrystalline cellulose; 1.3% w/w cross carmellose sodium; 1.3% w/w maize starch; 5.45% w/w hydroxypropyl cellulose and a pharmaceutically acceptable excipient; (b) coating layer over said core comprising ethyl cellulose; and (c) a pharmaceutically acceptable excipient, wherein the composition equivalent to 800 mg dose is orally administered twice daily for 8 days to a subject, followed by once daily administration till completion of 2 months as add-on therapy concurrent to antibiotic therapy for reducing the number of exacerbations of chronic obstructive pulmonary disease in the subject.
, Description:FIELD OF THE INVENTION
The invention relates to a solid pharmaceutical composition comprising pidotimod or pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient for oral administration to a subject for reducing the number of exacerbations of chronic obstructive pulmonary disease. The invention also relates to a process of preparation of such composition.
BACKGROUND OF INVENTION
Chronic obstructive pulmonary disease (COPD), the fourth leading cause of death in the world, represents an important public health challenge that is both preventable and treatable. COPD is a major cause of chronic morbidity and mortality throughout the world; many people suffer from this disease for years, and die prematurely from it or its complications. Globally, the COPD burden is projected to increase in coming decades because of continued exposure to COPD risk factors and aging of the population.
A new pharmacological approach explored for prevention of such exacerbation by modulation of the immune function in the COPD patients. Many natural substances like bacterial derivatives, mediators of immune function and thymic hormones were tired for such modulations.
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. 8,263,125 patent relates to a dosage form of combination of high dose high solubility active ingredient like pidotimod as modified release and low dose active ingredient as immediate release suitable for swallowing of dosage form. U.S. Patent No. 5,369,131 patent relates to a liquid pharmaceutical composition of pidotimod which is propellant free. U.S. Patent No. 4,839,387 patent describes pharmaceutical composition of pidotimod.
There exists a need to develop pidotimod composition having better moisture protection to get desired storage stability for reducing the number of exacerbations of COPD in the patients.
Besides standard therapy and preventive measures, immunomodulation with synthetic dipeptide - pidotimod - has been found effective in COPD patients. There is so far no known evidence of pidotimod dosage regimen in the patient with COPD. The inventors of this invention surprisingly found that oral administration of pidotimod composition twice daily for 8 days, followed by once daily administration till completion of 2 months therapy significantly reduced the number of exacerbations in the patients with COPD.
SUMMARY OF THE INVENTION
In one general aspect, there is provided a solid pharmaceutical composition comprising, (a) pidotimod or pharmaceutically acceptable salt thereof; (b) coating layer over said core comprising ethyl cellulose; and (c) a pharmaceutically acceptable excipient.
In another aspect, there is provided a solid pharmaceutical composition comprising (a) a core comprising pidotimod or pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient; (b) coating layer over said core comprising ethyl cellulose, and (c) a pharmaceutically acceptable excipient; wherein the composition is orally administered twice daily for 8 days to a subject, followed by once daily administration till completion of 2 months therapy for reducing the number of exacerbations of chronic obstructive pulmonary disease in the subject.
In another aspect, there is provided a solid pharmaceutical composition, wherein the composition is administered as add-on therapy for reducing number of exacerbations of chronic obstructive pulmonary disease; and wherein the add-on therapy concurrent to antibiotic therapy.
In another aspect, there is provided a solid pharmaceutical composition; wherein amount of pidotimod present in amount ranges from about 50% w/w to about 80% w/w of the composition.
In another aspect, there is provided a solid pharmaceutical composition comprising (a) a core comprising pidotimod or pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient; (b) coating layer over said core comprising ethyl cellulose, and (c) a pharmaceutically acceptable excipient; wherein the composition is orally administered twice daily for 8 days to a subject, followed by once daily administration till completion of 2 months therapy for reducing the number of exacerbations of chronic obstructive pulmonary disease in the subject; wherein the composition is administered as add-on therapy for reducing number of exacerbations of chronic obstructive pulmonary disease; and wherein the add-on therapy concurrent to antibiotic therapy; wherein amount of pidotimod present in amount ranges from about 50% w/w to about 80% w/w of the composition; wherein the ethyl cellulose is present in amount ranges from about 1.5% w/w to about 5% w/w of the composition.
In another aspect, there is provided a solid pharmaceutical composition comprising (a) a core comprising of about 65% w/w to about 75% w/w of pidotimod or pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient; (b) coating layer over said core comprising ethyl cellulose; and (c) a pharmaceutically acceptable excipient, wherein the composition is orally administered twice daily for 8 days to a subject, followed by once daily administration till completion of 2 months as add-on therapy for reducing the number of exacerbations of chronic obstructive pulmonary disease in the subject.
In another aspect, there is provided a solid pharmaceutical composition; wherein the coating layer further comprises hydroxypropyl methylcellulose, diethyl phthalate and a pharmaceutically acceptable excipient; wherein the coating layer is present in amount ranges from about 1% w/w to about 7% w/w of the composition.
In another aspect, there is provided a solid pharmaceutical composition; wherein a pharmaceutically acceptable excipient comprises filler or diluent, binder, disintegrant and/or super-disintegrant, sorbent, anti-adherent, lubricant, glidant, preservative, flavoring agent, colouring agent, coating agent, solvent or vehicle or combination thereof.
In another aspect, there is provided a solid pharmaceutical composition; wherein the composition is present in the form of powder, tablet, pellet, capsule, granule or pellets filled in capsule, tablet in capsule, multilayer tablet, bilayer tablet, trilayer tablet, minitablet or premixed powder filled in capsule; wherein the composition provides immediate release of pidotimod from the dosage from.
In another aspect, there is provided a solid pharmaceutical composition comprising (a) a core comprising about 70% w/w to about 75% w/w pidotimod, about 8% w/w to about 12% w/w microcrystalline cellulose; about 1% w/w to about 3% w/w cross carmellose sodium; about 1% w/w to about 3% w/w maize starch; and about 3% w/w to about 7% w/w hydroxypropyl cellulose; and (b) a coating layer over said core comprising ethyl cellulose.
In another aspect, there is provided a solid pharmaceutical composition comprising (a) a core comprising about 70% w/w to about 75% w/w pidotimod, about 8% w/w to about 12% w/w microcrystalline cellulose; about 1% w/w to about 3% w/w cross carmellose sodium; about 1% w/w to about 3% w/w maize starch; and about 3% w/w to about 7% w/w hydroxypropyl cellulose; and (b) a coating layer over said core comprising ethyl cellulose, wherein the composition equivalent to 800 mg dose is orally administered twice daily for 8 days to a subject, followed by once daily administration till completion of 2 months as add-on therapy concurrent to antibiotic therapy for reducing the number of exacerbations of chronic obstructive pulmonary disease in the subject.
In another aspect, there is provided a solid pharmaceutical composition comprising (a) a core comprising about 70% w/w to about 75% w/w pidotimod, about 8% w/w to about 12% w/w microcrystalline cellulose; about 1% w/w to about 3% w/w cross carmellose sodium; about 1% w/w to about 3% w/w maize starch; and about 3% w/w to about 7 % w/w hydroxypropyl cellulose; and (b) a coating layer over said core comprising ethyl cellulose, wherein the composition equivalent to 400 mg dose is orally administered twice daily for 8 days to a subject, followed by once daily administration till completion of 2 months as add-on therapy concurrent to antibiotic therapy for reducing the number of exacerbations of chronic obstructive pulmonary disease in the subject.
In another aspect, there is provided a solid pharmaceutical composition comprising (a) a core comprising 72% w/w of pidotimod or pharmaceutically acceptable salt thereof; 10% w/w of microcrystalline cellulose; 1.3% w/w cross carmellose sodium; 1.3% w/w maize starch; 5.45% w/w hydroxypropyl cellulose and a pharmaceutically acceptable excipient; (b) coating layer over said core comprising ethyl cellulose; and (c) a pharmaceutically acceptable excipient.
In another aspect, there is provided a solid pharmaceutical composition comprising (a) a core comprising 72% w/w of pidotimod or pharmaceutically acceptable salt thereof; 10% w/w of microcrystalline cellulose; 1.3% w/w cross carmellose sodium; 1.3% w/w maize starch; 5.45% w/w hydroxypropyl cellulose and a pharmaceutically acceptable excipient; (b) coating layer over said core comprising ethyl cellulose; and (c) a pharmaceutically acceptable excipient, wherein the composition equivalent to 800 mg dose is orally administered twice daily for 8 days to a subject, followed by once daily administration till completion of 2 months as add-on therapy concurrent to antibiotic therapy for reducing the number of exacerbations of chronic obstructive pulmonary disease in the subject.
In another aspect, there is provided a solid pharmaceutical composition comprising (a) a core comprising 72% w/w of pidotimod or pharmaceutically acceptable salt thereof; 10% w/w of microcrystalline cellulose; 1.3% w/w cross carmellose sodium; 1.3% w/w maize starch; 5.45% w/w hydroxypropyl cellulose and a pharmaceutically acceptable excipient; (b) coating layer over said core comprising ethyl cellulose; and (c) a pharmaceutically acceptable excipient, wherein the composition equivalent to 400 mg dose is orally administered twice daily for 8 days to a subject, followed by once daily administration till completion of 2 months as add-on therapy concurrent to antibiotic therapy for reducing the number of exacerbations of chronic obstructive pulmonary disease in the subject.
In another aspect, there is provided a solid pharmaceutical composition comprising pidotimod or pharmaceutically acceptable salt thereof, wherein the composition is 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 solid pharmaceutical composition comprising pidotimod or pharmaceutically acceptable salt thereof, wherein the composition is tablet dosage form.
In another aspect, there is provided a process for preparing a solid pharmaceutical composition, which comprising pidotimod or pharmaceutically acceptable salt thereof, wherein process comprises steps of:
a) sifting of active ingredient and excipients and then loading these materials into rapid mixer granulator;
b) preparing binder solution and granulating the ingredients of step (a) by using the solution
c) drying of step (b) material in fluidized bed dryer (FBD);
d) milling of step (c) material;
e) lubricating the step (d) material;
f) compressing the step (e) material to get solid dosage form;
g) coating of dosage unit obtained in step (f) to obtain the solid pharmaceutical composition.

In another aspect, there is provided a process for preparing a solid pharmaceutical composition comprising pidotimod or pharmaceutically acceptable salt thereof, wherein the process comprises steps of:
a) checking the weights and sifting all the intra granular ingredients through #40 sieve and mixing the material in rapid mixer granulator
b) adding hydroxypropyl cellulose-LM to isopropyl alcohol and purified water and mixing under stirring
c) adding the binder solution into the rapid mixer granulator and granulate till mass of suitable consistency formed
d) transferring the binded mass into the bowl of FBD for drying and passing the dried granules through #20 sieve
e) croscarmellose sodium, low substituted hydroxy propyl cellulose and colloidal silicone dioxide sifting through # 40 sieve and blending with dried granules
f) sifting magnesium stearate through # 60 sieve, and mixing with above material
g) compressing the above blend to prepare tablets
h) coating the tablets with hydroxypropyl methylcellulose, diethyl phthalate, ethyl cellulose, talc, and titanium dioxide to obtain the solid pharmaceutical composition.

DETAILED DESCRIPTION OF THE INVENTION
The term "active ingredient" refers to a therapeutically active compound in its free form (base), pharmaceutically acceptable salt, hydrates, solvates and its prodrugs.
The term “pharmaceutical composition” or “pharmaceutical formulation” or “pharmaceutical dosage form” can be used interchangeably and refers to the combination of active ingredients and excipients.
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 “immediate release” is meant that the pharmacologically active ingredient or agent is released from the dosage form immediately such that not less than 80% of the pharmaceutically active agent in the formulation is released within 45 minutes when dissolution is measured according to the USP 31 NF 26 section 711.
The term “subject” refers to an individual who is or becomes a subject in research, either as a recipient of the test article or as a control. A subject may be either a healthy human or a patient of all the age groups.
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 "pharmaceutically acceptable excipient" includes a pharmaceutically acceptable material, vehicle, suitable for administering an active pharmaceutical ingredient. Each excipient should be "acceptable" in the sense of being compatible with the other ingredients of the formulation and not injurious to the patient.
The term “chronic obstructive pulmonary disease” refers to a lung disease characterized by chronic obstruction of lung airflow that interferes with normal breathing and is not fully reversible.
In one general embodiment, there is provided a solid pharmaceutical composition comprising, (a) pidotimod or pharmaceutically acceptable salt thereof; (b) coating layer over said core; and (c) a pharmaceutically acceptable excipient.
In another embodiment, there is provided a solid pharmaceutical composition comprising, (a) pidotimod or pharmaceutically acceptable salt thereof; (b) coating layer over said core comprising ethyl cellulose; and (c) a pharmaceutically acceptable excipient.
In another embodiment, there is provided a solid pharmaceutical composition comprising (a) a core comprising pidotimod or pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient; (b) coating layer over said core comprising ethyl cellulose, and (c) a pharmaceutically acceptable excipient; wherein the composition is orally administered twice daily for 8 days to a subject, followed by once daily administration till completion of 2 months therapy for reducing the number of exacerbations of chronic obstructive pulmonary disease in the subject.
In another embodiment, there is provided a solid pharmaceutical composition, wherein the composition is administered as add-on therapy for reducing number of exacerbations of chronic obstructive pulmonary disease.
In another embodiment, there is provided a solid pharmaceutical composition, wherein the composition is administered as add-on therapy for reducing number of exacerbations of chronic obstructive pulmonary disease; and wherein the add-on therapy concurrent to antibiotic therapy.
In another embodiment, there is provided a solid pharmaceutical composition; wherein amount of pidotimod present in amount ranges from about 50% w/w to about 80% w/w or about 50% w/w to about 55% w/w or about 55% w/w to about 65% w/w or about 65% w/w to about 75% or about 75% w/w to about 80% w/w of the composition. Preferably, pidotimod is 72.7% w/w of the composition.
In another embodiment, there is provided a solid pharmaceutical composition comprising (a) a core comprising pidotimod or pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient; (b) coating layer over said core comprising ethyl cellulose, and (c) a pharmaceutically acceptable excipient; wherein the composition is orally administered twice daily for 8 days to a subject, followed by once daily administration till completion of 2 months therapy for reducing the number of exacerbations of chronic obstructive pulmonary disease in the subject; wherein the composition is administered as add-on therapy for reducing number of exacerbations of chronic obstructive pulmonary disease ; and wherein the add-on therapy concurrent to antibiotic therapy; wherein amount of pidotimod present in amount ranges from about 50% w/w to about 80% w/w of the composition.
Example of coating material use in the composition comprising, but not limited to water-insoluble or water-resistant coating polymers comprising ethyl cellulose, polyvinyl acetates, polyacrylates, polymethacrylates, polyvinyl alcohol, hydroxylpropyl methylcellulose (HPMC) or low viscosity HPMC polymer, diethyl phthalate, talc, titanium dioxide, polyvinylpyrrolidone (PVP), hydroxypropyl cellulose (HPC), hydroxypropyl ethyl cellulose (HPEC), polyethylene glycol (PEG) and hydroxyethyl cellulose (HEC) or combination thereof. Preferably, coating material is ethyl cellulose.
In another embodiment, there is provided a solid pharmaceutical composition; wherein amount of ethyl cellulose present in amount ranges from about 1.5% w/w to about 5% w/w or 1.5% w/w to about 2.0% w/w or about 2.0% w/w to about 3.0% w/w to about 4% w/w or about 4.0% w/w to about 5.0% w/w of the composition. Preferably, ethyl cellulose is 0.262% w/w of the composition.
In another embodiment, there is provided a solid pharmaceutical composition comprising (a) a core comprising pidotimod or pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient; (b) coating layer over said core comprising ethyl cellulose, and (c) a pharmaceutically acceptable excipient; wherein the composition is orally administered twice daily for 8 days to a subject, followed by once daily administration till completion of 2 months therapy for reducing the number of exacerbations of chronic obstructive pulmonary disease in the subject; wherein the composition is administered as add-on therapy for reducing number of exacerbations of chronic obstructive pulmonary disease; and wherein the add-on therapy concurrent to antibiotic therapy; wherein amount of pidotimod present in amount ranges from about 50% w/w to about 80% w/w of the composition; wherein the ethyl cellulose is present in amount ranges from about 1.5% w/w to about 5% w/w of the composition.
In another embodiment, there is provided a solid pharmaceutical composition comprising (a) a core comprising of about 65% w/w to about 75% w/w of pidotimod or pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient; (b) coating layer over said core comprising ethyl cellulose; and (c) a pharmaceutically acceptable excipient, wherein the composition is orally administered twice daily for 8 days to a subject, followed by once daily administration till completion of 2 months as add-on therapy for reducing the number of exacerbations of chronic obstructive pulmonary disease in the subject.
In another embodiment, there is provided a solid pharmaceutical composition; wherein the coating layer further comprises hydroxypropyl methylcellulose, diethyl phthalate and a pharmaceutically acceptable excipient.
In another embodiment, there is provided a solid pharmaceutical composition; wherein the coating layer further comprises hydroxypropyl methylcellulose, present in amount ranges from about 1% w/w to about 7% w/w or about 1% w/w to about 2% w/w or about 2% w/w to about 3% w/w or about 3% w/w to about 4% w/w or about 4% w/w to about 5% w/w or about 5% w/w to about 6% w/w or about 6% w/w to about 7% w/w of the composition. Preferably, hydroxypropyl methylcellulose is 1.45% w/w of the composition.
In another embodiment, there is provided a solid pharmaceutical composition; wherein the coating layer further comprises hydroxypropyl methylcellulose, diethyl phthalate and a pharmaceutically acceptable excipient; wherein the coating layer is present in amount ranges from about 1% w/w to about 7% w/w of the composition.
In another embodiment, there is provided a solid pharmaceutical composition; wherein the pharmaceutically acceptable excipient comprises filler or diluent, binder, disintegrant and/or super-disintegrant, sorbent, anti-adherent, lubricant, glidant, preservative, flavoring agent, colouring agent, coating agent, solvent or vehicle or combination thereof.
Examples of the disintegrants suitable for use in the composition of the present invention comprises, but are not limited to alginic acid, carboxymethylcellulose calcium, carboxymethylcellulose sodium, colloidal silicon dioxide, crosscarmellose sodium, crospovidone, guar gum, magnesium aluminum silicate, maize starch, methyl cellulose, microcrystalline cellulose, polacrilin potassium, powdered cellulose, pregelatinized starch, sodium alginate, sodium starch glycolate and starch. Preferable disintegrants are crosscarmellose sodium, and maize starch.
Examples of the fillers or diluents suitable for use in the composition of the present invention may comprises but are not limited to starches, such as potato starch, rice starch, maize starch, wheat starch, pregelatinized starch, fully pregelatinized starch, cellulose, such as microcrystalline cellulose or silicified microcrystalline cellulose, mannitol, erythritol, calcium salts, such as calcium hydrogen phosphate dihydrate, anhydrous dibasic calcium phosphate, xylitol, sorbitol, lactose monohydrate, magnesium stearate, mannitol or mixtures thereof. Preferable fillers or diluent is microcrystalline cellulose.
Examples of the binder suitable for use in the composition of the present invention may comprises but are not limited to polyvinyl pyrrolidone (povidone), copolymers of vinylpyrrolidone with other vinylderivatives (copovidone), hydroxypropyl cellulose, low substituted hydroxy propyl cellulose, methylcellulose, hydroxypropyl methylcellulose (hypromellose), powdered acacia, gelatin, guar gum and carbomer such as carbopol, polymethacrylates and starch or mixtures thereof. Preferable binders are hydroxypropyl cellulose and low substituted hydroxy propyl cellulose.
Examples of the lubricant or glidant suitable for use in the composition of the present invention may comprises from group, but are not limited to stearic acid, talc, siliconised talc, colloidal silicone dioxide, micronised talc, sodium stearyl fumarate and magnesium stearate. Preferable lubricants or glidants are magnesium stearate, and colloidal silicone dioxide.
Solvent is a substance that can chemically different liquid, solid or gas. Examples of solvent suitable for use in oral pharmaceutical composition may be comprises, but not limited to purified water, isopropyl alcohol, dichloromethane, glycerol, propylene glycol, ethanol, chlordiazepoxide hydrochloride or mixture thereof. Preferable solvents are purified water, isopropyl alcohol, and dichloromethane.
In another embodiment, the microcrystalline cellulose is present in an amount ranges from about 8% w/w to about 12% w/w or about 8% w/w to about 9% w/w or about 9% w/w to about 10% w/w or about 10% w/w to about 11% w/w or about 11% w/w to about 12% w/w of the composition. Preferably, microcrystalline cellulose is 10% w/w of the composition.
In another embodiment, the cross carmellose sodium is present in an amount ranges from about 1% w/w to about 3% w/w or about 1% w/w to about 2% w/w or about 2% w/w to about 3% w/w of the composition. Preferably, cross carmellose sodium is 1.3% w/w of the composition.
In another embodiment, the maize starch is present in an amount ranges from about 1% w/w to about 3% w/w or about 1% w/w to about 2% w/w or about 2% w/w to about 3% w/w of the composition. Preferably, maize starch is 1.3% w/w of the composition.
In another embodiment, the hydroxypropyl cellulose is present in an amount ranges from about 3% w/w to about 7% w/w or about 3% w/w to about 4% w/w or about 4% w/w to about 5% w/w or about 5% w/w to about 6% w/w or about 6% w/w to about 7% w/w of the composition. Preferably, hydroxypropyl cellulose is 5.45% w/w of the composition.
In another embodiment, there is provided a solid pharmaceutical composition; wherein the composition is present in the form of powder, tablet, pellet, capsule, granule or pellets filled in capsule, tablet in capsule, multilayer tablet, bilayer tablet, trilayer tablet, minitablet or premixed powder filled in capsule; wherein the composition provides immediate release of pidotimod from the dosage from.
In another embodiment, there is provided a solid pharmaceutical composition comprising pidotimod or pharmaceutically acceptable salt thereof, wherein the composition is tablet dosage form.
In another embodiment, there is provided a solid pharmaceutical composition comprising (a) a core comprising about 70% w/w to about 75% w/w pidotimod, about 8% w/w to about 12% w/w microcrystalline cellulose; about 1% w/w to about 3% w/w cross carmellose sodium; about 1% w/w to about 3% w/w maize starch; and about 3% w/w to about 7% w/w hydroxypropyl cellulose; and (b) a coating layer over said core comprising ethyl cellulose.
In another embodiment, there is provided a solid pharmaceutical composition comprising (a) a core comprising about 70% w/w to about 75% w/w pidotimod, about 8% w/w to about 12% w/w microcrystalline cellulose; about 1% w/w to about 3% w/w cross carmellose sodium; about 1% w/w to about 3% w/w maize starch; and about 3% w/w to about 7% w/w hydroxypropyl cellulose; and (b) a coating layer over said core comprising ethyl cellulose, wherein the composition equivalent to 800 mg dose is orally administered twice daily for 8 days to a subject, followed by once daily administration till completion of 2 months as add-on therapy concurrent to antibiotic therapy for reducing the number of exacerbations of chronic obstructive pulmonary disease in the subject.
In another embodiment, there is provided a solid pharmaceutical composition comprising (a) a core comprising about 70% w/w to about 75% w/w pidotimod, about 8% w/w to about 12% w/w microcrystalline cellulose; about 1% w/w to about 3% w/w cross carmellose sodium; about 1% w/w to about 3% w/w maize starch; and about 3% w/w to about 7% w/w hydroxypropyl cellulose; and (b) a coating layer over said core comprising ethyl cellulose, wherein the composition equivalent to 400 mg dose is orally administered twice daily for 8 days to a subject, followed by once daily administration till completion of 2 months as add-on therapy concurrent to antibiotic therapy for reducing the number of exacerbations of chronic obstructive pulmonary disease in the subject.
In another embodiment, there is provided a solid pharmaceutical composition comprising (a) a core comprising 72% w/w of pidotimod or pharmaceutically acceptable salt thereof; 10% w/w of microcrystalline cellulose; 1.3% w/w cross carmellose sodium; 1.3% w/w maize starch; 5.45% w/w hydroxypropyl cellulose and a pharmaceutically acceptable excipient; (b) coating layer over said core comprising ethyl cellulose; and (c) a pharmaceutically acceptable excipient.
In another embodiment, there is provided a solid pharmaceutical composition comprising (a) a core comprising 72% w/w of pidotimod or pharmaceutically acceptable salt thereof; 10% w/w of microcrystalline cellulose; 1.3% w/w cross carmellose sodium; 1.3% w/w maize starch; 5.45% w/w hydroxypropyl cellulose and a pharmaceutically acceptable excipient; (b) coating layer over said core comprising ethyl cellulose; and (c) a pharmaceutically acceptable excipient, wherein the composition equivalent to 800 mg dose is orally administered twice daily for 8 days to a subject, followed by once daily administration till completion of 2 months as add-on therapy concurrent to antibiotic therapy for reducing the number of exacerbations of chronic obstructive pulmonary disease in the subject.
In another embodiment, there is provided a solid pharmaceutical composition comprising (a) a core comprising 72% w/w of pidotimod or pharmaceutically acceptable salt thereof; 10% w/w of microcrystalline cellulose; 1.3% w/w cross carmellose sodium; 1.3% w/w maize starch; 5.45% w/w hydroxypropyl cellulose and a pharmaceutically acceptable excipient; (b) coating layer over said core comprising ethyl cellulose; and (c) a pharmaceutically acceptable excipient, wherein the composition equivalent to 400 mg dose is orally administered twice daily for 8 days to a subject, followed by once daily administration till completion of 2 months as add-on therapy concurrent to antibiotic therapy for reducing the number of exacerbations of chronic obstructive pulmonary disease in the subject.
In another embodiment, there is provided a solid pharmaceutical composition comprising pidotimod or pharmaceutically acceptable salt thereof, wherein the composition is 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 process for preparing a solid pharmaceutical composition, which comprising pidotimod or pharmaceutically acceptable salt thereof, wherein process comprises steps of:
a) sifting of active ingredient and excipients and then loading these materials into rapid mixer granulator;
b) preparing binder solution and granulating the ingredients of step (a) by using the solution
c) drying of step (b) material in fluidized bed dryer (FBD);
d) milling of step (c) material;
e) lubricating the step (d) material;
f) compressing the step (e) material to get solid dosage form;
g) coating of dosage unit obtained in step (f) to obtain the solid pharmaceutical composition.

In another embodiment, there is provided a process for preparing a solid pharmaceutical composition comprising pidotimod or pharmaceutically acceptable salt thereof, wherein the process comprises steps of:
a) checking the weights and sifting all the intra granular ingredients through #40 sieve and mixing the material in rapid mixer granulator
b) adding hydroxypropyl cellulose-LM to isopropyl alcohol and mixing under stirring
c) adding the binder solution into the rapid mixer granulator and granulate till mass of suitable consistency formed
d) transferring the binded mass into the bowl of FBD for drying and passing the dried granules through #20 sieve
e) croscarmellose sodium, low substituted hydroxy propyl cellulose and colloidal silicone dioxide sifting through # 40 sieve and blending with dried granules
f) sifting magnesium stearate through # 60 sieve, and mixing with above material
g) compressing the above blend to prepare tablet
h) coating tablet with hydroxypropyl methylcellulose, diethyl phthalate, ethyl cellulose, talc, and titanium dioxide to obtain the solid pharmaceutical composition
EXAMPLES
Example 1: Pidotimod composition
Table 1
S. No Ingredients Qty/Tablet (% w/w)
Intragranular
1. Pidotimod 70.61
2. Micro Crystalline Cellulose 8.0
3. Cross Carmellose Sodium 1.6
4. Maize Starch 0.7
Binder
5. Hydroxy Propyl cellulose 6.5
6. IPA: Water (80:20) q.s.
Extra Granular
7. Cross Carmellose Sodium 4.0
8. Low Substituted Hydroxy Propyl Cellulose 0.9
9. Colloidal Silicone Dioxide 0.65
10. Magnesium Stearate 1.05
Coating
11. Hydroxypropyl Methylcellulose 1.456
12. Diethyl Phthalate 0.349
13. Ethyl Cellulose 0.262
14. Talc 0.116
15. Titanium Dioxide 0.728
16. Isopropyl Alcohol q.s.
17. Dichloromethane q.s.
Total 100

Manufacturing Process:
a) All intragranular ingredients were sifted through sieve and loaded into rapid
mixer granulator (RMG);
b) Binder solution was prepared by adding hydroxypropyl cellulose to isopropyl
alcohol (IPA), water mixture under stirring and material from step (a) was
granulated by using this solution;
c) Granulated material of step (b) was loaded into fluidized bed dryer (FBD) and
dried at 55°C till loss on drying (LOD) obtained not more than 1.5%;
d) Dried granular material of step (c) was passed through sieve and retained
material was milled using multi mill;
e) All extragranular material except magnesium stearate were passed through
sieve and blended with dried material;
f) Magnesium stearate was passed through sieve, added to step (e) blend;
g) Above blend was compressed to obtain tablets;
h) Coating solution was prepared by the addition of coating material (hydroxypropyl methylcellulose, diethyl phthalate, ethyl cellulose, talc, and titanium dioxide to IPA under stirring followed by dichloromethane; and
i) Compressed tablets of step (g) were coated using the coating solution till 3.0%
weight gain was achieved.

Example 2: Pidotimod composition
Table 2
S. No Ingredients Qty/Tablet (% w/w)
Intragranular
1. Pidotimod 70.61
2. Micro Crystalline Cellulose 10.5
3. Cross Carmellose Sodium 0.7
4. Maize Starch 1.6
Binder
5. Hydroxy Propyl cellulose 2.9
6. IPA: Water (80:20) q.s.
Extra Granular
7. Cross Carmellose Sodium 7.5
8. Low Substituted Hydroxy Propyl Cellulose 1.9
9. Colloidal Silicone Dioxide 0.30
10. Magnesium Stearate 0.50
Coating
11. Hydroxypropyl Methylcellulose 1.456
12. Diethyl Phthalate 0.349
13. Ethyl Cellulose 0.262
14. Talc 0.116
15. Titanium Dioxide 0.728
16. Isopropyl Alcohol q.s.
17. Dichloromethane q.s.
Total 100

Manufacturing Process:
a) All intragranular ingredients were sifted through sieve and loaded into rapid mixer granulator (RMG);
b) Binder solution was prepared by adding hydroxypropyl cellulose to isopropyl alcohol (IPA), water mixture under stirring and material from step (a) was granulated by using this solution;
c) Granulated material of step (b) was loaded into fluidized bed dryer (FBD) and dried at 55°C till loss on drying (LOD) obtained not more than 1.5%;
d) Dried granular material of step (c) was passed through sieve and retained material was milled using multi mill;
e) All extragranular material except magnesium stearate were passed through sieve and blended with dried material;
f) Magnesium stearate was passed through sieve, added to step (e) blend;
g) Above blend was compressed to obtain tablets;
h) Coating solution was prepared by the addition of coating material (hydroxypropyl methylcellulose, diethyl phthalate, ethyl cellulose, talc, and titanium dioxide) to IPA under stirring followed by dichloromethane; and
i) Compressed tablets of step (g) were coated using the coating solution till 3.0% weight gain was achieved.

Example 3: Pidotimod composition
Table 3
S. No. Ingredients Qty per Tablet (mg) Qty per Tablet (mg)
Intra Granular
1. Pidotimod 400.00 800.00
2. Microcrystalline Cellulose IP (Chemicel PH 101) 55.00 110.00
3. Croscarmellose Sodium IP (Cellosol) 7.50 15.00
4. Maize Starch IP 7.50 15.00
Binder
5. Hydroxypropyl Cellulose IP
(HPC LM) 30.00 60.00
6. Isopropyl Alcohol IP 144.00 288.00
7. Purified water IP 36.00 72.00
Extragranular
8. Croscarmellose sodium IP 35.00 70.00
9. Low Substituted Hydroxy Propyl Cellulose IP (LHPC LP11) 7.50 15.00
10. Colloidal Silicone Dioxide IP
(Cab-O-Sil M5P) 2.50 5.00
11. Magnesium stearate IP 5.00 10.00
Film Coating
12. Hydroxypropyl Methylcellulose 8.25 16.50
13. Diethyl Phthalate 1.97 3.95
14. Ethyl Cellulose 1.48 2.97
15. Talc 0.65 1.31
16. Titanium Dioxide 4.12 8.25
17. Isopropyl alcohol IP 125.40 250.80
18. Dichloromethane IP 188.10 376.20

Manufacturing Process:
a) All the intra granular ingredients were weighted and sifted through #40 sieve, then transferred to rapid mixer granulator and mixed for 5 minutes.
b) Hydroxypropyl cellulose-LM was mixed with 90% isopropyl alcohol, and purified water.
c) Above step b) binder solution was added into the rapid mixer granulator and granulated till mass of suitable consistency was formed.
d) Thereafter, the binded mass was dried by using FBD.
e) The dried granules were passed through #20 sieve.
f) Croscarmellose sodium, low substituted hydroxy propyl cellulose and colloidal silicone dioxide were sifted through # 40 sieve.
g) Dried granules were blended with step f) material in blender for 10 minutes.
h) Magnesium stearate was sifted through # 60 sieve, and mixed with blended material of step g) and lubricated it for 3 minutes
i) 400 and 800 mg tablets were compressed by using standard concave, round punches, with plain ob both side, and adjusts for the specified weight, hardness and thickness
j) Coating solution was prepared by dissolving hydroxypropyl methylcellulose, diethyl phthalate, ethyl cellulose, talc and titanium dioxide into required quantity of isopropyl alcohol.
k) Required quantity of dichloromethane was added to step j) coating solution
l) Film coating solution was sprayed on uncoated tablets at bed temperature of 38-40 ºC. Tablets were coated till desired weight gain achieved.

Example 3: Clinical Study
In, an open label, single arm study, efficacy of pidotimod tablet was studied in the patients with chronic obstructive pulmonary disease. Pidotimod tablet was orally administered twice daily for 8 days to a subject, followed by once daily administration till completion of 2 months therapy. There were total five visits in this surveillance 1) visit 1: day -7 to day 0: screening 2) visit 2: day 1: enrolment 3) visit 3: end of month 2±7 days – follow up at end of pidotimod treatment 4) visit 4: end of month 6 ±7 days – follow up visit 5) visit 5: end of month 12±7 days – follow up visit.
A total of 114 subjects were enrolled in the study, 3 subjects were withdrawn because of lost to follow up and 111 subjects completed the study successfully. Analysis of efficacy parameters were performed for subjects in whom complete data was available for the respective parameter. Thus, the data for 111 subjects was analyzed.
Example 3A: Overall demographical data of the 114 subjects
Table 4
Parameters Total
No. of Cases 114
Age (years)
Mean±SD 59.51±08.66
Range 38.00–73.00
Gender (%)
Male 77 (67.5%)
Female 37 (32.5%)
Smoking History (No. of packs, N = 31)
Mean±SD 07.61±08.65
Range 01.00–40.00
Years of smoking years (N = 30)
Mean±SD 20.57±11.88
Range 01.00–50.00

Example 3B: Pidotimod efficacy study in patients with chronic obstructive pulmonary disease
Table 5
Duration (Months) N Mean Number of AECB
Episodes
(Mean±SD) Mean No. of Episodes Antibiotics Prescribed
(Mean±SD) Mean Duration of Antibiotics
(Days, Mean±SD)
Baseline 111 2.12±0.50 2.08±0.56 5.58±1.21
2 01 1.00±0.00 1.00±0.00 5.00±0.00
6 01 1.00±0.00 1.00±0.00 5.00±0.00
12 0 0 0 0

As shown in table 5, mean number of acute exacerbations of chronic bronchitis (AECB) episodes at baseline was 2.12 episodes. However, after 2 months of treatment and 6 months follow up, mean number of AECB episodes showed by 1 patient, which was 1 episode. There were no episodes observed in all the study cases at the end of 12 months follow up. As shown in table 5, mean number of episodes of antibiotics prescribed and mean duration (days) at baseline were 2.08 and 5.58, respectively. After 2 months of treatment, for one patient 1 antibiotic was prescribed for one episode for 5 days, which was continued for 6 months follow up period too. There were no episodes after 12 months of follow up period.

Example 3C: Pidotimod efficacy measured by MMRC score in patients with chronic obstructive pulmonary disease
Table 6
Duration (Months) N Mean MMRC Score
(Mean±SD)
Baseline 111 2.81±0.60
2 106 2.65±0.97
6 99 2.46±0.73*
12 91 2.47±0.67*
By Student t Test * Significant