Dexamethasone formulations

Dexamethasone acetate (Dalalone DP, Forest, Decadron-LA, Merck) and Dexamethasone sodium phosphate (Merck) are available as a suspension or a solution. These dexamethasone formulations contain creatine or creatinine as additives. 

Suspension. If the drug is not sufficiently soluble, it can be formulated as a suspension. A suspension may also be desired to improve stability, bioavailability, or efficacy. The major topical ophthalmic suspensions are the steroid anti-inflammatory agents prednisolone acetate, dexamethasone, fluorometholone, and rimex-olone. Water-soluble salts of prednisolone phosphate and dexamethasone phosphate are available however, they have a lower steroid potency and are poorly absorbed. 

Blepharitis is a topical inflammation of the eyelid margins that should be treated using topical antibacterial agents. Gentamicin eye ointment is preferred to the fusidic acid drops since the ointment is a better formulation to be used where the condition involves the eyelid margins. Chloramphenicol eye drops is the third option since it is an antibiotic with a wider spectrum of activity. A combination of corticosteroid and antibiotic is not recommended because of the side-effects associated with the steroid. The use of oral tablets is not usually recommended since blepharitis can easily be managed with topical drops. The use of dexamethasone eye drops, monotherapy steroid, could clear the inflammation but mask persistence of infection. 

Betamethasone is hardly ever used orally. It has a long duration of activity and can therefore also be used for alternate-day therapy. The parenteral formulation is also the sodium phosphate salt which when given IV or IM has a rapid onset of action. There are many similarities with dexamethasone such as their metabolic pathways and the indications for which both steroids are used, like the prevention of neonatal RDS and reduction of raised intracranial pressure. Combinations of betamethasone acetate and sodium phosphate have, when used for intra-articular and intra-lesional injections, the dual advantage of a rapid onset of action together with the long duration of action of a depot preparation. 

Several groups have investigated the effect of surfactants on emitted droplet size. In the early work performed by Polli et al., the surfactant sorbitan trioleate decreased the MM AD of the CFC dexamethasone suspension when added to the formulation (52). A suspension of terbutaline in a CFC system containing sorbitan trioleate surfactant was shown to have little change in emitted particle size when either 2.8 or 14mg/mL of surfactant was added (53). Interestingly, the surfactant had a significant effect on the obscuration (droplet concentration) of the laser diffraction instrument used to determine particle size. Surfactants may lead to an increase in MMAD due to decreased evaporation rates from aerosol droplets. This may occur because of their tendency to associate at the air liquid interface (54). 

Residue depletion studies indicated that different formulations led to different dexamethasone depletion rates. Studies in cattle and pigs indicated that dexa-methasone residues were quickly eliminated from muscle and milk of cows. Residues did not occur in the free form in fat, whereas the depletion rate in liver was the slowest. Following intramuscular administration of 60 g/kg bw to cows, mean dexamethasone levels in milk declined from 8.4 ppb at the first milking after treatment to below 1 ppb at the sixth milking after treatment (52). 

Hydromorphone Hydrochloride Formulations containing hydromorphone with either minocycline hydrochloride or tetracycline hydrochloride were found incompatible and manifest as a color change from pale yellow to light green. Concentration-dependent incompatibilities are reported in formulations containing hydromorphone hydrochloride with dexamethasone sodium or phosphate,59 and fluorouracil.60 Visual incompatibility, such as haziness or precipitation, developed 4 hours after mixing thiopentone sodium and hydromorphone hydrochloride.61 Dependence, withdrawal, and interactions are similar to those of opioid analgesics. 

The drug particle size plays the most important role in the formulation process of suspensions. Particles greater than 10 pm cause patient discomfort. As they are perceived as foreign substances, they cause reflex tearing in order to eliminate the particles from the ocular surface [176]. A study by Schoenwald and Stewart [177] showed the influence of the particle size of dexamethasone on its bioavailability. The in vivo dissolution rate decreased with increasing particle size to the point when particles were removed from the conjunctival sac before the dissolution was complete. 

Like PVA, the viscosity enhancer hydroxypropyl methyl-cellulose is available in a variety of molecular weights and in formulations with different group substitutions. It has been shown to prolong tear film wetting time and to increase the ability of fluorescein and dexamethasone to penetrate the cornea. Hydroxypropyl methylcellulose 0.5% has been shown to exhibit twice the ocular retention time of 1.4% PVA. 

Unlike prednisolone and dexamethasone, which are structurally related to cortisol, fluorometholone is a fluo-rinated structural analogue of progesterone. Formulated both as an alcohol and acetate derivative, fluorometholone has proven to be an effective agent in external ocular inflammations, with relatively low potential for elevating lOP. 

There are three aerosolized corticosteroid preparatioias available in MDI formulation for administration to horses via the Equine AeroMask beclometasone dipropionate, fluticasone propionate and flunisolide (Table 16.2). In terms of the relative potency, fluticasone is more potent than beclometasone, which is more potent than flunisolide, which is equipotent to triamcinolone. Using dexamethasone as the standard (1.0), the relative glucocorticoid receptor affinity of the common corticosteroids is flunisolide 1.9, triamcinolone 2.0, beclometasone (active metabolite) 13.5 and fluticasone propionate 22.0 (Barnes et al 1998). The pulmonary residence time of the aerosolized corticosteroids is determined by the lipophilicity of each drug. Flunisolide has intermediate water solubility (lOmg/ml), simitar to... 

Fialho and Silva-Cunha [127] recently reported formulation of dexamethasone loaded microemulsion based on Cremophore EL, propylene glycol and IPM. The tolerability of the microemulsions was established and it did not cause any significant alteration to eyelids, conjuctiva, cornea and iris. The pharmacokinetics of the dexamethasone from microemulsions was compared to the marketed formulation in rabbit eye. The microemulsion formulation acted faster as well as for the longer period of time (Fig. 9.6 and Table 9.7). 

Figure 9.6 Concentration of dexamethasone (Qex) in the aqueous humour after administration of the microemulsion and conventional formulation. The microemulsion was superior to the conventional formulation (P < 0.05). (Figure redrawn with data from Ref. [127], reprinted with permission of Blackwell Synergy.)...

Table 9.7 Ocular pharmacokinetics of dexamethasone in various formulations...

A selective CZE microassay was developed for the determination of dexa-methasone phosphate and its major metabolite, dexamethasone, in tears (325). An internal standard, indoprofen, was used for quantitation. The limits of detection and quantification were 0.5 and 2.0 pg/mL, respectively. The quantitative method was essential for the in-vivo determination of the dexamethasone concentration-time profiles in tears after the application of the anti-inflammatory drug. Two examples of rapid and simple drug analysis in pharmaceutical formulations using capillary electrophoresis can be found in the methods described for the separation of naphazoline, dexamethasone, and benzalkonium in nose drops (326). 

K Raith, E Althoff, J Banse, H Neidhardt, RH Neuber. Two examples of rapid and simple drug analysis in pharmaceutical formulations using capillary electrophoresis Naphazoline, dexamethasone and benzalkonium in nose drops and nystatin in an oily suspension. Electrophoresis 19 2907-2911, 1998. 

Qin, Y Liang, D. Zeng, J. Mao, W. [Determination of hydrocortisone and methylprednisolone in plasma by reversed-phase HPLC]. Hua Hsi I Ko Ta Hsueh Hsueh Poo, 1991, 22, 270-273 Shalaby, A. Shalyahan, M. Improved high performance liquid chromatographic method for the determination of some corticosteroids. J.Liq.Chromatogr., 1991, 14, 1267—1274 [formulations ointment lotion tablets iiyections simultaneous dexamethasone, prednisolone]... 

Paclitaxel has very limited solubility and must be administered in a vehicle of 50% ethanol and 50% polyethoxylated castor oil (CREMOPHOR EL), a formation likely responsible for a high rate of hypersensitivity reactions. Patients receiving this formulation are protected by pretreatment with a histamine Hj receptor antagonist such as diphenhydramine, an receptor antagonist such as cimetidine fsee Chapter 24), and a glucocorticoid such as dexamethasone (see Chapter 59). Docetaxel, which is somewhat more soluble, is administered in polysorbate 80 and causes a lower incidence of hypersensitivity reactions. Pretreatment with dexamethasone is required to prevent progressive, and often disabling, fluid retention. 

Stability of Dexamethasone - The following reported stability Information is entirely consistent with the potential reactivity discussed above. Dexamethasone solid is reported to be stable in air but should be protected from light. Solutions of dexamethasone lose about 50% of the C-17 a-ketol side chain within 5-8 minutes in the presence of a base catalyst.Excellent stability is shown by dexamethasone in a variety of marketed pharmaceutical dosage forms. Wahba has compared the thermal stability of dexamethasone in four different tablet formulations. ... 

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