Drugs for the Treatment of Skin Disorders

This synthetic route had several demerits regarding commercial feasibility. Additionally, the product obtained was a waxy low-melting solid that proved to be difficult to work with because of its instability to light, heat, and moisture. More significantly, it was difficult to formulate and speculation centered on its intrinsic instability, especially when hydroxylic solvents were used in formulations. It was therefore imperative to develop alternative procedures for synthesis and formulations. 

Replacing 2-iodoethanol with 2-bromoethanol further modified the preparation of 245, as the latter was nearly one-sixth as expensive and the 0-aIkylated product (244) was obtained in higher yields. Compound 245 on reaction with methanesulfonyl chloride and triethylamine in methylene chloride gave a mesylate (246), which was further reacted with 

0-alkylated product 250 in 76% yield. Reaction of compound 250 with p-chlorothiophenol (238) and sodium methoxide powder in THF gave the -alkylated derivative (250) in 72% yield. On heating with cuprous cyanide in DMF, compound 250 afforded a cyano compound (19) in 72% yield. 

Acetophenone (252) was converted into the vinyl ketone (232) by the procedure of Girotra et al. Mannich reaction of compound 252 with AA -dimethylamine hydrochloride and p-formaldehyde in refluxing isopropyl alcohol in the presence of a catalytic amount of HCl resulted in formation of the Mannich base (254) in 77% yield. Subsequently, treatment of 254 with aqueous NaOH and methyl iodide in ethyl acetate gave a quaternary salt (255) in 83% yield. On heating in a H20-EtOAc biphasic system, compound 255 underwent a 

och3 H3C0., Jv och3 H3C0., 0CH3 H3C0.  

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The widespread applicability of di-O-methylisosorbide as a medium for chemical reactions or as a solvent for pharmaceutical formulations is well documented. In some cases, an additive synergism of the solvent and the solute was observed. Some typical examples mentioned include that it acts as a solvent for muscle-relaxant drugs, which are otherwise difficultly soluble,226 and is used for topical and other types of pharmaceutical formulations,227,228 transdermal controlled-release films229 and tapes,230 anthelmintic solutions,231 antimycotic emulsions,232 and for the treatment of skin disorders, such as eczema.233... 

An understanding of the factors which influence cutaneous and percutaneous absorption, together with advances in polymer technology, have led to the possibility of providing optimal drug therapy for the treatment of systemic disorders — acute or chronic — by means of controlled, unattended administration of a drug to the skin surface, for prolonged, predetermined periods of time (5). ... 

For the treatment of various skin disorders, local application of drugs in the form of cream, ointment, gel etc., appears to be the ideal and convenient form of management. However, in severe conditions different drugs can also be given by oral routes. The different agents used in various skin disorders are classified as in table 13.2.1. 

In summary, a classic liposomes remain confined to the upper skin layers, resulting in the formation of drug reservoir mainly in the horny strata and generally do not penetrate into the deeper layers of the skin. Thus, the liposomal carriers could be efficient in local treatment of skin disorders and for cosmetic uses. 

Leflxmomide is a disease-modifying antirheumatic drug which was approved in August 1998 by the US FDA for the treatment of rheumatoid arthritis. It inhibits dihydroorotate dehydrogenase (DHODH) and as a consequence it blocks the de novo pathway of pyrimidine nucleotide synthesis, which is crucial for T cell activation and proliferation. The tolerability of leflxmomide is rather poor, as up to 50% of rheumatoid arthritis patients withdrew from leflxmomide xvithin the first year mostly due to adverse effects such as GI disorders (dyspepsia, diarrhoea, nausea and vomiting or abdominal pain), increased level of liver enzymes, alopecia, skin rashes, infections and hypertension. 

A number of clinical implications of drug reservoir formation in the upper skin layers by delivery from liposomes have been reported [4-6,13], From these studies it appears that the efficiency of liposomal-incorporated drugs was superior to other formulations in the treatment of disorders, which do not affect the deep layers of the skin. For example, in a doubleblind, randomized paired study on patients suffering from atopic eczema or psoriasis vulgaris, a liposomal betamethasone dipropionate was more efficient than a nonliposomal preparation in eczematous but not in psoriatic patients [6],... 

In the work by Forsatz and Snow, three APIs and one excipient were determined by HPLC-UV and HPLC-CAD .22 The APIs were mometasone furorate, a moderately potent glucocorticoid steroid used in the treatment of inflammatory skin disorders, albuterol, a short-acting /32-adrenergic receptor agonist used for the relief of bronchospasm in conditions such as asthma, and Loratadine, a drug used to treat allergies. The excipient evaluated was lactose. In this work, the signal-to-noise ratio was compared at 10 ng for each of the APIs. Sensitivity was comparable for both albuterol and loratadine when compared to HPLC-UV, while CAD offered... 

Amiodarone, for example (Fig. 1.12), was introduced as a coronary dilator for angina, but concern about comeal deposits, discoloration of skin exposed to sunlight and thyroid disorders led to the withdrawal of the drug in 1967. However, in 1974 amiodarone was found to be highly effective in the treatment of a rare type of arrhythmia known as the Wolff-Parkinson-White syndrome. Accordingly, amiodarone was reintroduced specifically for that purpose [22]. 

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