Lyophilization improving water solubility of Indomethacin
Indomethacin is a non-steroidal anti-inflammatory drug (NSAID) with anti-inflammatory, analgesic and antipyretic activity. Chemically, it is an indole acetic acid derivative, which acts by inhibiting cyclooxygenase enzyme and thus reducing prostaglandin synthesis. Prostaglandins are known to be the mediators of inflammation, which sensitize the afferent nerves and induce pain response. Inhibition of prostaglandin synthesis in peripheral tissues abolishes pain symptoms.
Mechanism of action - Indomethacin
By considering physicochemical properties, Indomethacin is formulated in to various dosage forms that can be delivered orally including capsules with different strengths (25, 50 and 75 mg) and suspensions (25 mg/5ml). Even, rectal suppositories in strengths of 50 mg and 100 mg are also made available over the years of its clinical applications.
The general indication of these Indomethacin dosage forms includes;
- Moderate to severe rheumatoid arthritis including acute flares of chronic disease.
- Moderate to severe ankylosing spondylitis.
- Moderate to severe osteoarthritis.
- Acute painful shoulder (bursitis and/or tendinitis).
- Acute gouty arthritis.
Apart from these indications of Indomethacin in adults, early Indomethacin treatment may significantly reduce the morbidities in premature infants arising from a persistent patent ductus arteriosus making Indomethacin the drug of choice for this medical disorder.
For such critical situation, intravenous route is the most appropriate route for drug administration in infants and which makes the development of a new injectable dosage form of Indomethacin very important.
However, the major hurdle in the formulation of Indomethacin injection is its limited solubility in water. Indomethacin is available as a crystalline powder, which is practically insoluble in water.
Therefore, lyophilization technique is employed to conquer solubility issues in delivering Indomethacin by intravenous route.
The lyophilization technique results in a freeze-dried solid powder, which is porous and fluffy. The increased surface area and surface free energy enhances rapid dissolution of Indomethacin when reconstituted with sterile saline solution or water for injection.
Through diverse development strategies, Indomethacin is made available as lyophilized powders in single use vials each containing 1 mg of Indomethacin which after reconstitution with preservative free 0.9% saline solution or water for injection can be infused intravenously over 20 to 30 minutes and at 12- to 24-hour intervals.
Therefore, lyophilization technique implicated in formulation of Indomethacin injection profoundly increases its dissolution making it available for delivering through intravenous route in premature infants and considerably reducing morbidities in a critical medical condition.
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