Medical notes

Cyclodextrins in ophthalmology

Cyclodextrins were isolated for the first time in 1891 by De Villiers. In 1903, Schardinger identified them as oligosaccharides and named them "dextrins". Around 1948, Freudenberg and Cramer showed that they could form inclusion complexes.

The cyclodextrins are obtained during the enzymatic degradation of starch and consist of a series of cyclic oligosaccharides formed by 6 (α), 7 (β) or 8 (γ) units of α-D- [1,4 ] glucose, which form a rigid toroidal molecular structure with a cavity inside of an specific volume.

Various applications have been patented throughout history as the cyclodextrins have a hydrophilic exterior and an interior hydrophobic cavity where they can host non-polar organic molecules. There are several applications of these within the food industry, in agriculture and in the pharmaceutical industry. For example, the addition of α- or β-cyclodextrin increases the water solubility of several lipophilic substances, such as prostaglandins.

In this way, the cyclodextrins may form crystalline compounds based on organic molecules in solid, liquid and even gaseous state. Consequently, molecules insoluble in water can become completely soluble by being treated with an aqueous solution of cyclodextrin, without any chemical modification in the molecule.

The cyclodextrins increase the solubility and improve absorption and stability; they also reduce the local irritation, and are useful excipients in various ophthalmic formulations. The use of cyclodextrins in Latanoprost is a clear example, which is commercially available, and its effectiveness and benefits against other products without cyclodextrins has been highly proved.

Although cyclodextrins have been known for more than a century, their use in Ophthalmology is very recent. Cyclodextrins are useful excipients for eye drops in a variety of lipophilic drugs that otherwise would not be available for topical use; at the same time they are improving the bioavailability and stability of the encapsulated molecule.

Einar Stefánsson and Thorsteinn Loftsson. Faculty of Pharmacy, University of Iceland. Cyclodextrins in Eye Drop Formulations. Journal of Inclusion Phenomena and Macrocyclic Chemistry, December 2002; 44(1-4):23-27. 

Gerardo Martínez, Marina A. Gómez. Ciclodextrinas: Complejos de inclusión con Polímeros. Rev Iberoam Polim. 2007; 8(4): 300-312.

Miguel Alcalde Galeote. Modificación Química y Estabilización de Glicosiltransferazas: Cilodextrin Glicosiltransferaza y dextransacarasa. Departamento de Bioquímica y Biología molecular. Universidad Complutense de Madrid y araza. 1999.

Non-refrigerated Latanoprost. Fact or myth?

Glaucoma is a disease characterized by damage to the optic nerve, causing gradual and permanent loss of visual acuity. It has been estimated that 66.8 million people worldwide suffer from glaucoma, and 6.7 million have bilateral blindness.
The management of glaucoma remains focused on the control of intraocular pressure (IOP).
In 1933 Goldblatt and Von Euler, independently, discovered some substances that they named prostaglandins (PG), and in 1960 Bergstrom was able to crystallize the prostaglandins PGE and PGF.

The PGs (prostanoic acid) are formed by the transformation of fatty unsaturated monocarboxylic acids of 20 carbons, which are formed by two chains and a ring of five carbons. Many prostaglandins are differentiated only by small changes in the methylation or oxidation of their carbonated chains.

In humans, the most important precursor of prostaglandins is the arachidonic acid. Prostaglandin plays a very important role in the history of medicine and we have, as an example the 0.005% latanoprost, a topical prostaglandin analogue that effectively reduces the IOP with one drop every 24 hrs, that works primarily by increasing the flow the uveoscleral drainage of the aqueous humor.

In recent years, it was developed a Latanoprost containing in its formulation cyclodextrins, which increase the solubility and stability of a wide range of biologically active molecules. Due to these characteristics, this new formulation of latanoprost-cyclodextrins penetrates better into the cornea and does not need to be refrigerated.
The cyclodextrins have been used to optimize topical formulations, including eye drops. The development of this medication (lanatoprost-cyclodextrins: GAAP) by Laboratorios Sophia, Guadalajara, Jalisco, Mexico, has caused a great controversy, as it happens when there are alternatives or progresses in the medical area.

This innovative formula that contains cyclodextrins has been subjected to multiple tests to prove that it is within the international standards of quality. It is also stable, powerful and effective, without being refrigerated, compared against Latanoprost, which does not contain cyclodextrins and needs to be cooled to reach stability.

Studies have shown that the molecule of latanoprost is stable up to 40 °C. This is gratifying for the patient since it is not necessary to keep it in cold chain and they can take it with them without any risk, knowing that it is a first-line drug, effective for the treatment of their condition.

Jaime R. Glez, MD, Leopoldo Baiza-Duran, MD et al. Comparison of The Stability, Efficacy, and Adverse Effect Profile of the Innovator 0.005% Latanoprost Ophthalmic Solution and a Novel Cyclodextrin-containing Formulation. J. C. Pharmacol.2006; 46: 1-6.
J. R. González, L. Baiza-Durán, M. M. González- Lomelí et al. Pilot Study of a New Latanoprost Ophthalmic Solution. 6th International Symposium on Ocular Pharmacology and Therapeutics, Berlin, Germany, March 30-April 2, 2006:111-114.
Jóhannes Kári Kristinsson, et al. Dexamethasone – Cyclodextrin- Polymer Co-complexes in Aqueous Eye Drops. Investigative Ophthalmology and Visual Science, May 1996; 37(6): 1199-1203.

Dry Eye and immunomodulation

In recent years, the evidence that the inflammation and apoptosis of the ocular surface have a key role in the development of dry eye has grown. It is believed that the Dry Eye Syndrome is a complex inflammatory disease characterized by instability of the tear film, damage of the ocular surface epithelium, lacrimal gland inflammation and secretory dysfunction. There are symptoms like discomfort, ocular dryness, burning, pain, itching and feeling of foreign body. It is a problem of global distribution which corresponds to 25% of the daily consultation.

The lacrimal gland is extremely important in the production of the aqueous component of the tear film. The main causes of ocular morbidity are the decrease of the glandular secretion due to an autoimmune process and a dysfunction related to age.

Immunopathological Studies of the lacrimal gland in patients with Sjögren Syndrome show a progressive infiltration of lymphocytes, mainly T CD4 lymphocytes, and B lymphocytes. This lymphocytic infiltration, as well as the substances secreted by them – such as cytokines and auto-antibodies – seems to be responsible for the glandular destruction and, therefore, from the alteration of the normal secretory function of the gland.

This immune inflammatory response is the result of the imbalance between the release of the pro-inflammatory cytokines in the cells of the ocular surface and the decrease in the production of anti-inflammatory factors.

It has been found that, in the Dry Eye Syndrome that non-related with Sjögren's syndrome, the tear hyperosmolarity that results from the glandular dysfunction contributes to the release of inflammatory cytokines such as interleukins (IL) IL-1α, IL-6, IL-8, tumor necrosis factor-α (TNF-α) and matrix metalloproteinase-9 (MMP).

The activation of certain markers such as the HLA-DR, the intracellular adhesion molecule-1 (ICAM-1) and CD11 are also increased, which supports the immune role in the development of the pathology of this disease.

This has led to a search of immunomodulatory substances to be used in ophthalmology, such as cyclosporine-A. This molecule is a not ribosomal cyclical peptide of 11 amino acids, produced by the fungus Tolypocladium inflatum Gams, initially isolated from a sample of Norwegian floor. The immunosuppressive effect of cyclosporine was discovered on January 31st, 1972, in Basel, Switzerland by Hartmann F. Stähelin. The first time it was topically used in ophthalmology to inhibit the rejection of corneal transplant in the 1980s. Today is approved by the FDA and is used on a regular basis.

Cyclosporin has receptors in the immunocompetent lymphocytes and T lymphocytes; it was then designed to bind to the cytosolic protein cyclophilin (a cytoplasmic immunophilin) of those cells. This cyclosporine and cyclophilin complex inhibits the track of the calcineurin, which under normal circumstances is responsible for activating the transcription of the gene of IL-2, IL-3, the Granulocyte Macrophage Colony-Stimulating Factor (GM-CSF) and TNF-α, which are necessary to enable the proliferation of T-lymphocytes. This is why the production inhibition is the main mechanism of cyclosporine-A immunosuppression

It has been reported that cyclosporine-A improves tear production, increases the Globet cells and has therapeutic effects in several diseases of the ocular surface.

It has been recently found that the cyclosporin-A may also have an important neuroprotective effect by inhibiting apoptosis. This is done by preventing the release of cytochrome C, a potent stimulator of program cell death

Therefore, based on the available evidence and current literature, we support the efficacy of topical immunomodulators, specially  the cyclosporine-A in pathologies of the surface including Dry Eye Syndrome.