Cromoglicic Acid - Mast Cell Stabilizer CAS 16110-51-3

Cromoglicic Acid: From Khellin to Prophylaxis of Allergic Asthma

1. Introduction

Cromoglicic acid (cromolyn sodium, disodium cromoglycate) is a chromone derivative that acts as a mast cell stabilizer, preventing the release of inflammatory mediators such as histamine, leukotrienes, and slow-reacting substance of anaphylaxis (SRS-A) from sensitized mast cells. It is used prophylactically for the management of bronchial asthma, allergic rhinitis, allergic conjunctivitis, and systemic mast cell disease. Unlike bronchodilators or antihistamines, cromoglicic acid does not relieve acute symptoms but prevents allergic reactions when administered before allergen exposure.

2. Chemical and Physical Properties

Cromoglicic acid (CAS 16110-51-3) has the molecular formula C₂₃H₁₆O₁₁ and a molecular weight of 468.37 g/mol. The compound appears as white to off-white crystalline powder. Key physicochemical properties include:

• Melting Point: 241–242°C (decomposes)

• Boiling Point: 752.3°C at 760 mmHg (predicted)

• Density: 1.623 g/cm³

• Flash Point: 263.9°C

• pKa: 2.0 (uncertain)

• Solubility: Cromoglicic acid is poorly water-soluble (0.1 g/100 mL); the sodium salt (cromolyn sodium) is highly water-soluble (>200 g/L), making it suitable for aqueous formulations.

The sodium salt form, disodium cromoglycate, is the clinically used variant with the molecular formula C₂₃H₁₄Na₂O₁₁ and a molecular weight of 512.34 g/mol.

3. Mechanism of Action

Cromoglicic acid exerts its anti‑allergic effects primarily through mast cell stabilization. In vitro and in vivo studies have shown that cromolyn sodium inhibits the degranulation of sensitized mast cells following antigen exposure. It prevents the release of histamine, leukotrienes (SRS-A), and other inflammatory mediators from mast cells. The exact molecular mechanism involves:

• Inhibition of calcium ion (Ca²⁺) influx into mast cells, thereby preventing degranulation

• Phosphorylation inhibition of FcεRI‑associated proteins

• Reduction of leukotriene C₄ (LTC₄) and prostaglandin D₂ (PGD₂) synthesis

Recent research suggests that cromolyn may also exert anti‑inflammatory effects by acting on anti‑inflammatory features of mast cells, rather than solely through membrane stabilization. Additionally, cromoglicic acid has been identified as a calcium channel blocker.

4. Pharmacokinetics

Cromoglicic acid is poorly absorbed systemically, which contributes to its favorable safety profile:

• Bioavailability: Approximately 1% after oral administration; approximately 10% after inhalation; approximately 0.03% after ophthalmic administration

• Half‑life: 1.3 hours (intravenous)

• Plasma Protein Binding: Approximately 65% (reversible)

• Metabolism: Not metabolized in humans; excreted unchanged

• Excretion: 50% excreted unchanged in urine

5. Clinical Applications

Cromoglicic acid is indicated for prophylactic treatment of:

• Bronchial Asthma: Prophylaxis of mild to moderate allergic and exercise‑induced asthma. Administered via inhalation (metered‑dose inhaler or nebulizer solution), typically 20 mg four times daily. Does not relieve acute bronchospasm.

• Allergic Rhinitis: Seasonal and perennial allergic rhinitis. Administered as intranasal spray (2–4% solution).

• Allergic Conjunctivitis: Vernal keratoconjunctivitis, vernal conjunctivitis, and vernal keratitis. Administered as ophthalmic solution (4%).

• Systemic Mast Cell Disease: Oral administration for mastocytosis, including diarrhea, flushing, and abdominal pain.

• Other: Topical application for atopic dermatitis and other allergic skin conditions.

6. Historical Development

Cromoglicic acid was discovered by Roger Altounyan in 1965 while investigating khellin, an active ingredient from the traditional Middle Eastern remedy khella (Ammi visnaga). Altounyan, an asthmatic physician, conducted experiments on himself to identify the compound's anti‑asthmatic properties. In 1967, the sodium salt (disodium cromoglycate) was introduced as Intal® by Fisons Pharmaceuticals. The first clinical trials were led by John Bernard Lloyd Howell. Intal was approved by the UK Committee on Safety of Drugs in 1968 and launched that same year. Ophthalmic formulations became available in 1973, and powder DPI formulations were introduced in 1996.

7. Safety and Adverse Effects

Cromoglicic acid has a well‑established safety profile with minimal systemic toxicity:

• Adverse Effects (Inhalation): Cough (approximately 5%), throat irritation (approximately 8%), bronchospasm (rare).

• Adverse Effects (Ophthalmic): Transient stinging or burning upon instillation.

• Adverse Effects (Oral): Diarrhea, nausea, skin rash (rare).

• Pregnancy: FDA Pregnancy Category B. Animal studies in mice, rats, and rabbits at doses up to 540 mg/kg showed no evidence of fetal malformations. Cumulative clinical experience suggests no adverse effects on fetal development.

• Lactation: It is not known whether cromoglicic acid is excreted in human breast milk.

8. Storage and Handling

Cromoglicic acid should be stored in tightly sealed containers at 2–8°C (refrigerated). Protect from light and moisture. Inhalation solutions and ophthalmic solutions should be used within the specified period after opening and should not be used if discolored or containing particulate matter. Use appropriate personal protective equipment (gloves, safety goggles) when handling the raw material.

9. Conclusion

Cromoglicic acid remains a safe and effective prophylactic agent for allergic asthma, allergic rhinitis, and allergic conjunctivitis. Its unique mechanism of action—stabilizing mast cells and preventing mediator release—distinguishes it from bronchodilators and antihistamines. Despite competition from corticosteroids, cromoglicic acid continues to hold a valuable place in allergy management, particularly in pediatric patients and for long-term prophylactic use where a favorable safety profile is paramount. Ongoing research into novel delivery systems and expanded clinical applications continues to explore its full therapeutic potential.