Erythromycin A A Pharmaceutics Victory

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Erythromycin A A Pharmaceutics Victory

• Gene Fiese, Ph.D.
• Pharmaceutics Consultant
• Ledyard, CT

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Ilo Ilo Island, Philippines
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Macrolide Antibiotic Erythromycin A
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Acidic Solution Decay of Erythromycin
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Erythromycin Stability at pH 2.0 / 37C

• t 10 3.7 seconds
• Eact 15.6 kcal/mole
• Mechanism Intramolecular dehydration

Fiese, E.F. and S.H. Steffen (1990). Comparison
of the acid stability of azithromycin and
erythromycin A. J. Antimicrobial Chemotherapy
25, Suppl. A, 39-47.
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Early Clinical Evidence of Acid Decay
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Range of pH Values in Human GI Tract

• GI Area pH Value
• Stomach 1.0-3.5
• Duodenum 6.5-7.6
• Jejunum 6.3-7.3
• Ileum 7.6
• Colon 7.9-8.0
• Rectum 7.8

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Physical Properties of Erythromycin Salts

• Salt Water Relative
• Form m.pt. Solubility Bitterness
• Sulfamate 192 gt20,000 5
• Formate 164 gt20,000 5
• Phosphate 151 gt20,000 5
• Laurate 105 571 4
• Lauryl Sulfate 128 320 3
• Stearate 103 182 3
• Stearyl Sulfamate 115 316 2
• Stearyl Sulfate 125 108 1
• Solubility in ug/mL at 25 C
• Bitterness Scale 5very bitter, 1tasteless

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Enteric Tablet vs. Insoluble Salt
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Salts and Prodrugs of Erythromycin
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Salts and Prodrugs of Erythromycin
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Prodrugs of Erythromycin

• Relative Serum
• Analog Bioactivity Half-Life
• Erythro. A 100
• 2 Propionate 5 93 minutes
• 2 Ethylsuccinate 10 54 minutes

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Enteric Granules vs. ESS Prodrug
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Making Enteric Polymers
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Cellulose Acetate Phthalate - CAP
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Other Enteric Possibilities
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pH Sensitivity of Polymer Coatings
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Enteric Effect on Erythromycin Bioavailability
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Enteric Granules (?) vs. Tablet (?)
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Enteric Granules (o) vs. ESS Prodrug Powder (?)
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PK Model for Erythromycin
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IV Pharmacokinetics of Erythromycin
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Erythromycin Formulation History

• Year Dosage Form Concept Bioavial.
• 1952 Erythromycin discovered
• 1953 Plain Tablet None 15
• 1953 Coated Tablet Easy to Swallow 15
• 1953 Tablet Antacid Neutralize Acid 31
• 1962 Erythro. Stearate Insoluble in Salt
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• 1968 Erythro. Estolate Prodrug 43
• 1970 Erythro. Ethylsuccinate Prodrug 15
• 1980 E-Mycin Enteric Tablet 55
• 1982 Eryc Enteric Granules 73
• Bioavailability based on AUC comparison to an
  equivalent IV dose

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Eryc
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Goal Acid Stable Macrolide Antiobiotic

• 1983 Discovery that Helicobacter pylori bacterium
  (H. pylori) was the main cause of peptic ulcers.
  
• One in three people over 40 are infected with
  this bacteria in Australia
• H. pylori is susceptible to treatment with
  macrolide antibiotics such as Erythromycin

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Azithromycin Decay Mechanism
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Fiese, E.F. and S.H. Steffen (1990). Comparison
of the acid stability of azithromycin and
erythromycin A. J. Antimicrobial Chemotherapy
25, Suppl. A, 39-47.
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PK Tissue and Plasma Concentrations
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Azithromycin PK Summary
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2006 Ulcer Treatment

• Up to 20 doses per day.
• Antibiotics
• H2 blockers
• Proton pump inhibitors
• Stomach-lining protector

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2006 Ulcer Treatment

• Up to 20 doses per day.
• Antibiotics metronidazole, tetracycline,
  clarithromycin, amoxicillin
• H2 blockers cimetidine, ranitidine, famotidine,
  nizatidine
• Proton pump inhibitors omeprazole, lansoprazole,
  rabeprazole, esomeprazole, pantoprozole
• Stomach-lining protector bismuth subsalicylate

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