This literature mini-review focuses on glaucoma drugs in respect of mode of action and different analytical techniques used for their determination either alone or in combination with other drugs in different pharmaceutical and biological matrices. Only two drugs are cited in the mini-review which are timolol and latanoprost.

Mini-review; Glaucoma; Analytical techniques; Timolol; Latanoprost

Glaucoma is a condition of increased intraocular pressure that causes damage to eye's optic nerve and gets worse over time. It’s a worldwide main cause of irreversible loss of vision. It’s asymptomatic and that’s why its diagnosis is delayed. The increased intraocular pressure can happen when eye fluid isn't circulating normally in the front part of the eye. Normally, this fluid which is called aqueous humor flows out of the eye through a mesh-like channel. If this channel becomes blocked, fluid builds up causing glaucoma. Most treatments for glaucoma are designed to lower and/or control intraocular pressure. There are several different types of glaucoma. They can be classically divided into primary or secondary categories and open-angle or closed-angle glaucoma. Primary glaucoma is usually associated with a direct disturbance of eye fluids outflow, while secondary glaucoma arises from a number of diseases or of trauma. Chronic open-angle glaucoma occurs due to blockage in drainage of intra-ocular fluids which leads to gradual increase in intra-ocular pressure. This condition is usually asymptomatic until well advanced and severe damage has occurred. Usually, both eyes are affected and risk factors include old age and diabetes patients. Closed-angle glaucoma usually occurs as an acute emergency. Due to the fast rise in intra-ocular pressure, patients feel symptoms of a painful red eye, sweating, nausea and vomiting. This can result from blockage of the flow of aqueous humour into the anterior chamber. The resulting rise in intra-ocular pressure bows the iris against the trabecular meshwork, restricting outflow and thereby further raising intra-ocular pressure. Glaucoma affects more than 70 million people worldwide with approximately 10% becoming totally blind. The main goals of glaucoma treatments are to delay the progression of the disease and preserve patient’s quality of life. Most of drugs used in treatment regimens are used topically to decrease the intra-ocular pressure by various mechanisms. Treatment categories include topical beta blockers, prostaglandin analogues, parasympathomimetic miotics, alpha2-adrenoceptors agonists and carbonic anhydrase inhibitors. In severe cases intravenous osmotic diuretics can produce marked reduction in the intra-ocular pressure [1-3].

Molecular formula: C₁₃H₂₄N₄O₃S.

Molecular weight: 316.42 g/mol.

IUPAC name: (Z)-but-2-enedioic acid;(2S)-1-(tert-butylamino)-3-[(4-morpholin-4-yl-1,2,5-thiadiazol-3-yl)oxy]propan-2-ol (Figure 1). 

Figure 1: Timolol chemical structure

Physical properties

Timolol is a white or almost white, crystalline powder or colorless crystals. It’s soluble in water and in alcohol. A 2% solution in water has a pH of 3.8 to 4.3. pKa value is 9.21.

Mechanism of action

TIM is a non-selective beta-blocker that works by decreasing fluid (aqueous) production in the eye. It possesses a relatively high degree of lipid solubility. The exact mechanism whereby TIM reduces ocular pressure is still not known. The most likely action is by decreasing the secretion of aqueous humor.

Literature review

TIM is official in the British pharmacopoeia (BP) and in the United States pharmacopoeia (USP). BP describes the determination of TIM by non-aqueous titration in the pure raw material monograph and UV-spectrophotometric method in the eye drops monograph. BP describes another separate RP-HPLC method for the impurity profile. USP describes stability indicating LC-methods for determination of TIM using gradient elution/reversed phase methods. Literature survey reveals that there are several methods for determination of TIM alone or in combination with other drugs using HPLC, high performance thin layer chromatography (HPTLC) and spectrophotometry [5-10]

Molecular formula: C₂₆H₄₀O₅.

Molecular weight: 432.6 g/mol.

IUPAC name: Isopropyl (Z)-7-((1R,2R,3R,5S)-3,5-dihydroxy-2-((3R)-3-hydroxy-5-phenylpentyl)cyclopentyl)-5-heptenoate (Figure 2). 

Figure 2: Latanoprost chemical structure.

Physical properties 

LTN is a colorless viscous solution. It has water solubility of 8mg/mL.

Mechanism of action

LTN is a synthetic analogue of prostaglandin that is used to reduce intra-ocular pressure in patients with open-angle glaucoma. LTN works by relaxing muscles in the eye's interior structure to allow better outflow of fluids, thus reducing buildup of eye pressure.

Literature review

LTN is non-official in BP, but official in USP. USP describes stability indicating HPLC-method for determination of LTN individually using isocratic elution/normal phase method. Few papers were reported for LTN determination individually in pharmaceutical dosage forms using HPLC and one other method in combination with two more prostaglandin analogues. LTN isomers were determined by LC using amino column in only one reported method [5-15].

TIM and LTN combination is common in eye drops and often have the best user compliance because they are required only once daily. Organic impurities found in any synthetic or semi-synthetic active pharmaceutical ingredient (API) can arise from the manufacturing process (e.g. starting materials or intermediates) and/or can be a degradation product arising from storage of API. The impurity profile of any API in its crude raw material form and after being manufactured in the final dosage form is very crucial. Hence, analytical procedures validated for APIs quantification must be able to separate and identify such impurities. LTN combination with TIM is not official in both BP and USP. Literature review revealed that only four papers were published for simultaneous determination of LTN and TIM using three HPLC and one using UV spectrophotometry. The three LC methods were described only for fast separation and quantification of the APIs. Only one was a stability indicating method revealing the impurity profile for the APIs, but at longer elution time and without considering the separation of TIM labeled impurities or LTN C3-epimer [1,11,16-21].

Conclusion

This literature mini-review is introducing brief summary about glaucoma drugs specifically timolol and latanoprost. It shed the light on mode of action and different analytical techniques used for their determination either alone or in combination with other drugs in different pharmaceutical and biological samples.

Corresponding Author: Mahmoud M. Sebaiy, Faculty of Pharmacy, Zagazig University, Zagazig, Egypt. 

Copyright: © 2021 All copyrights are reserved by Mahmoud M. Sebaiy, published by Coalesce Research Group. This work is licensed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution and reproduction in any medium, provided the original author and source are credited.