Mr. Pankaj Kusum Ramdas Khuspe

Dapsone - Overview

History In the early 20th century, the German chemist Paul Ehrlich was

developing theories of selective toxicity based largely on the ability of certain dyes to kill microbes.

Gerhard Domagk, who would later win a Nobel Prize for his efforts, made a major breakthrough in 1932 with the discovery of the antibacterial prontosil red (sulfonamidochrysoidine).

Further investigation into the involved chemicals opened the way to sulfa drug and sulfone therapy, first with the discovery of sulfanilamide, the active agent of prontosil, by Daniel Bovet and his team at Pasteur Institute (1935).

History Then with of Dapsone independently by Ernest Fourneau in

France and Gladwin Buttle in United-Kingdom. Dapsone (diamino-diphenyl sulfone) is a medication most

commonly used in combination with rifampicin and clofazimine as multidrug therapy (MDT) for the treatment of Mycobacterium leprae infections (leprosy).

Official in IP, BP, USP.

Structure and IUPAC

4,4’-diaminodiphenylsulfone

QSAR Substitution of aromatic ring with acetyl group results

in decreased activity, increased solubility in water and decreased G.I irritation.

Replacement of 1 amino group with nitro,hydroxy or hydroxylamine results in decreased activity.

Replacement of both amino groups gives inactive product(with above).

QSAR Replacement of both amino groups

with aldehyde results in prodrug formation(eg.glucosulfone sodium).

Replacement of one of benzene rings with thiazole resulted in decreased activity.

Synthesis

Synthesis

Pharmacokinetics1. Absorption It is completely absorbed after oral administration

2. Distribution Approximately 70% bound to plasma protein. The

main metabolite, monoacetyl dapsone, is nearly 100% protein bound.

4 . EliminationThe plasma t1/2 is variable, though often>24hrsElimination takes 1-2 weeks or longerMetabolites are excreted in bile & urine

3. Metabolism Dapsone is acetylated in the liver, the degree of which

is genetically determined.

Pharmacokinetics

Adverse Action Mild haemolytic anaemia Gastric intolerance-nausea & anorexia methaemoglobinaemia, headache, paresthesias,

mental symptoms & drug fever allergic rashes, fixed drug eruption, hypermelanosis,

phototoxicity& rarely exfoliative dermatitis Hepatitis & agranulocytosis Dapsone reaction/sulfone syndrome

Dapsone Reaction Hypersensitivity

more frequent in patients receiving multiple-drug therapy.

The reaction involves a rash and may also include fever, jaundice, and eosinophilia.

In general, these symptoms will occur within the first six weeks of therapy or not at all, and may be treated by corticosteroid therapy.

USES

1. Mycobacterium leprae infections (leprosy)./hansen’s disease

2. Acne.3. Pneumocystis pneumonia.4. Dermatitis Herpetiformis.5. Toxoplasmosis - Prophylaxis

DOSE DISEASE ADULT CHILDREN DAYS

Leprosy - Lepromatous 50-100

mg/day 6-10 mg/day 2-5 years

Leprosy - Tuberculoid 100

mg/day NA 6 months

Dermatitis Herpetiformis 50-300

mg/day NA Life long basis

Pneumocystis Pneumonia 100

mg/day 2 mg/kg/day 14-21 days

Pneumocystis Pneumonia Prophylaxis

100 mg/day 2 mg/kg/day Life long basis

Toxoplasmosis - Prophylaxis

100 mg/day 2 mg/kg/day Life long basis

Administered transdermally As a gel 5% topical acne medication available in 3-, 30-, and 60-gram tubes. In normal use, 0.5 grams should be administered

to the face per application twice a day.

Transdermal Dose

Physicochemical PropertiesMolecular Formula (C6H4NH2) 2SO2

Molecular weight 248.30 g/mol

Synonyms 4,4-Sulfonyldianiline; 4,4'-Sulfonylbisbenzenamine; 4-Aminophenyl sulfone; Sulfonyldianiline.

Physical state white crystalline powder.

Melting point 175 - 180 deg C

Odor NA

Specific gravity NA

Solubility insoluble in water , soluble in alcohol.

Vapors density 8.3 mg/ml

Stability Stable under ordinary conditions.

Drug InteractionsBefore using this medication, consult with

your doctor or pharmacist of all prescription and nonprescription/herbal products you may use, especially of: folic acid antagonists (such as pyrimethamine), nitrofurantoin, primaquine.

This medication may decrease the effectiveness of combination-type birth control pills.

This can result in pregnancy.

Analytical MethodA reversed-phase high performance liquid

chromatography method is developed to simultaneously estimate serum concentrations of dapsone (DDS)

Mobile phase-mixture of n-heptane , ethyl acetate ,methanol,strong ammonia solution

Stationary phase-silica gel

Spectrophotometric determination of dapsone is also described

PH-6.98 λmax=525nm

Recent Development The need for a more reliable route of administration

led to investigation the possibility of an I.M. dapsone depot injection.

To achieve effective blood levels for 3-4 weeks, suspensions of large dapsone particles in an aqueous vehicle were made.

Studies in the rat revealed that dapsone-dependent methaemoglobinaemia could be greatly diminished by the co-administration of metabolic inhibitors(eg-cimetidine).

Recent Development The need for a more reliable route of administration

led to investigation the possibility of an I.M. dapsone depot injection.

To achieve effective blood levels for 3-4 weeks, suspensions of large dapsone particles in an aqueous vehicle were made.

Studies in the rat revealed that dapsone-dependent methaemoglobinaemia could be greatly diminished by the co-administration of metabolic inhibitors(eg-cimetidine).

STRENGTH VOLUME PRESENTATION PRICE( Rs.)Aczone Gel

5%w/w30g Aczone Gel 46.00

Marketed Products

STRENGTH VOLUME PRESENTATION

Dapsone 25mg 1000 Dapsone TAB(IP)

Dapsone 50mg 1000 Dapsone TAB(IP)

Dapsone 100mg 1000 Dapsone TAB(IP)

REFRENCES1. https://en.wikipedia.org/wiki/Dapsone#History2. Williams D.et al ,Foye's principles of medicinal chemistry, fifth

edition, Lippincott's Williams & Wilkins3. John H.et al ,Wilson & Gisvolds textbook of organic medical &

pharmaceutical chemistry , eleventh edition ,Lippincott's Williams & Wilkins

4. Indian Pharmacopoeia, 1996,Volume I, 1162-11635. United states Pharmacopoeia,2009,Volume II, 2059-20606. Moncrief J. Journal of Chromatography B: Biomedical Sciences

and ApplicationsVolume 654, Issue 1, 18 March 1994, 103:110.

7. http://www.rxlist.com8. http:// www.medicinenet.com9. http://www.leprosy-information.org10. http://onlinelibrary.wiley.com