Prednisolone formulations

In Older to improve the poor oral absorption of carbenicillin [4697-36-3] a bpophilic rndanyl ester has been formulated, Geocillin [33331-88-3] (5). Prednisolone [30-24-8] a steroid, is derivatized to its C-21 hemisuccinate sodium salt (6) to make it extremely water-soluble (108). 

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. 

Benzoic acids substituted with a basic side chain also are also of interest as pro-moieties whose physicochemical properties and rates of enzymatic hydrolysis can readily be modulated. A number of drugs have been converted to prodrugs with this type of pro-moiety, e.g., hydrocortisone, prednisolone, acyclovir, chloramphenicol, and paracetamol [148] [149], These prodrugs appear well suited as parenteral formulations, being water-soluble, stable in slightly acidic solution, and readily hydrolyzed enzymatically. As examples, we consider here the hydrolysis in human plasma of a number of (aminomethyl)ben-zoates of metronidazole (8.109-8.115, Sect. 8.5.5.1, Table 8.9) [138], These prodrugs are very rapidly activated, which may be beneficial for parenteral administration. However, this type of pro-moiety may be cleaved too rapidly after oral administration to be of interest for poorly absorbed drugs. 

FIGURE 7.1 Atomic force microscopy image of prednisolone-loaded Compritol nanoparticles produced by cold homogenization. Imaging was performed by using the noncontact mode. The formulation is composed of 5% Compritol, 1% prednisolone, 2.5% poloxamer 188, and 92.5% water. (From zur Miihlen, A. and Mehnert, W., Pharmazie, 53, 552-55, 1998. With permission.)... 

Prednisone, which in the body is converted to the active form prednisolone, is the most widely used corticosteroid. Maximal activity occurs mostly within 1-2 hours after oral administration, and the effects last up to 36 hours. For patients with colitis localized in the lower part of the colon prednisolone sodium phosphate is formulated for rectal administration as an enema. 

The mineralocorticosteroid activity of methyl-prednisolone is even less than that of prednisone/ prednisolone. It has a comparable duration of action. It is less suitable for substitution therapy in patients with adrenal hypofunctional states. Methyl-prednisolone sodium succinate is formulated for parental administration while methylprednisolone acetate is used for intra-articularly or peri-articularly injections. It can also be administered IM and then has prolonged systemic effects, lasting 1 weeks as the acetate is absorbed slowly from the site of injection. Oral absorption is rapid with peak effects within 1-2 hours. The duration of action is then about 1.5 days. 

Budesonide is a potent synthetic analog of prednisolone that has high affinity for the glucocorticoid receptor but is subject to rapid first-pass hepatic metabolism (in part by CYP3A4), resulting in low oral bioavailability. A controlled-release oral formulation of budesonide (Entocort) is available that releases the drug in the distal ileum and colon, where it is absorbed. The bioavailability of controlled-release budesonide capsules is approximately 10%. 

Neomycin is administered orally for treatment of bacterial infections of cattle, sheep, pigs, goats, and poultry at a dosage of 10 mg/kg bw. It is also used as a feed additive for growth-promoting purposes. Neomycin is further available alone or in combination with other drugs such as oxytetracycline, oleandomycin, lincomycin, and prednisolone, in intramammary formulations for treatment of mastitis. There has been relatively little clinical use of neomycin parenterally in animals because of the compound s reported nephrotoxicity and ototoxicity. 

The most commonly described USP procedure for quantification is the scrap and elution approach. Low analyte recoveries can occur but can be minimized by using polar organic solvents such as methanol, ethanol, or acetone. Generally, analytes with high-Rf values can be desorbed with high recoveries by using the mobile phase. One example of this procedure is the USP assay procedure of the steroid methyl prednisolone acetate in cream formulation. This steroid is separated from its excipients by TLC, extracted from the sorbent, derivatized, and measured spectrophotometrically. 

Other ophthalmic emulsions have been used to formulate prednisolone, piroxicam and amphotericin B emulsion. Although emulsions can produce sustained therapeutic effects and reduced irritancy of drag, their application in ophthalmology have been limited due to problems of stability. 

Fatouros, D. G, and Antimisiaris, S. G. (2002), Effect of amphiphilic drugs on the stability and zeta-potential of their liposome formulations A study with prednisolone, diazepam and griseofulvin, J. Coll. Interf. Sci., 251, 271-277. 

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. 

In more severe disease corticosteroids are needed to induce remission (prednisolone 60 mg/day until remission induced, tailing the dose by 5 mg/week). Approximately 75% of patients respond. Budesonide, a potent topically active corticosteroid, is an alternative which can be administered either orally or as an enema. The oral preparation is presented as a delayed release formulation which delivers drug to the terminal ileum and ascending colon. Extensive first pass metabolism in the liver limits its systemic availability and potential for adverse effects. Budesonide is also useful as maintenance therapy of the 30% of patients with Crohn s disease who are steroid dependent. 

The therapeutic effectiveness of topically applied corticosteroids is attributed primarily to their antiinflammatory activity. The relative efficacy of topical corticosteroids appears to be in the following order hydrocortisone, prednisolone, betamethasone < hydrocortisone valerate or butyrate, betamethasone valerate, triamcinolone acetonide, flucinolone acetonide < betamethasone dipropionate, fluocino-nide. In addition to the nature of the corticosteroid, its solubility, and, to a lesser extent, the concentration used, clinical efficacy is influenced by the formulation of the preparation. Glucocorticoids appear to have greater efficacy when formulated in ointment bases than in cream or lotion vehicles. This could be attributed to the occlusive effect provided by ointments. The application of an occlusive dressing further enhances penetration and persistence of the steroid (reservoir effect) in the stratum corneum. " ... 

A 40-year-old Afro-American woman developed an exfoliative rash and blistering and swelling of the tongue (12). A diagnosis of Stevens-Johnson syndrome was made. She had not taken any medications other than two doses of a formulation that contained G. biloba. Her condition responded to treatment with prednisolone, clotrimazole, and famotidine. G. biloba was withdrawn and no further events occurred. However, 5 months later she still had tenderness in the soles of the feet, peeling of the nails, and discoloration of the skin. 

The ocular bioavailability of topical glucocorticoid formulations varies significantly. Lipid-soluble alcohol and ester preparations penetrate intact conjunctival and corneal epithelium readily and rapidly reach therapeutic levels in the anterior chamber of the normal eye. Water-soluble phosphate preparations are retarded by intact corneal epithelium in the normal eye and are generally used in the management of ocular surface disease. However, it has been shown in experimental animals that the intraocular levels of topically applied prednisolone phosphate exceed that of the acetate preparation in the acutely inflamed eye. 

Due to the nature of the final formulation and its end use, the prednisolone Z-butylacetate monohydrate had to be recrystallized under sterile conditions. To provide the sterile bulk, the prednisolone t-butylacetate monohydrate was dissolved in A, 7V-di methyl acetamide (DMAC), filtered under sterile conditions, and crystallized with sterilized water. Experiments had shown that the solid phase in contact with the saturated solution was indeed the monohydrate. The material was filtered, washed with... 

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