Oral solutions, bioavailability

Whenever a drug is administered by an extra-vascular route, there is a danger that part of the dose may not reach the blood (i.e., absorption may not be complete). When the intravenous route is used, the drug is placed directly in the blood therefore an IV injection is, by definition, 100% absorbed. The absolute bioavailability of an extravascular dosage form is defined relative to an IV injection. If IV data are not available, the relative bioavailability may be defined relative to a standard dosage form. For example, the bioavailability of a tablet may be defined relative to an oral solution of the drug. 

Comparative bioavailability data are discussed where a number of different dosage forms/routes of administration have been used during the development process, e.g., tablets, capsules, oral solutions, granules, and injections. 

A number of oral solution or suspension products are included in the EPARs. Apart from the usual points of consideration for active ingredients and excipients, particular mention is made of possible precipitation of active ingredient when a solution is in use, the inclusion of excipients having a major impact on bioavailability, the need for flavoring to mask the taste of the active ingredient, relative potency compared with other routes of administration, preservation issues, dosing devices and the precision and accuracy of the dose delivered, and bioequivalence where formulations have been modified during the development process. 

Oral solution/Injectlon The oral bioavailability is maximal when itraconazole oral solution is taken without food. Steady state is reached after 1 to 2 weeks during chronic administration. Peak plasma levels are observed 2 hours (fasting) to 5 hours (with food) following oral administration. Steady-state plasma concentrations are approximately 25% lower when the oral solution is taken with food. 

Amprenavir oral solution was 14% less bioavailable compared to the capsules. 

Absorption/Distribution - Lamivudine is rapidly absorbed after oral administration. Absolute bioavailability as demonstrated in HIV-infected patients is 86% for the tablet and 87% for the oral solution. The solution and tablet may be used interchangeably. The apparent volume of distribution (Vd)... 

Absorption - Abacavir was rapidly and extensively absorbed after oral administration with bioavailability at 83%. Systemic exposure to abacavir was comparable after administration of oral solution and tablets. Therefore, these products may be used interchangeably. 

Bioequivalency Sandimmune capsules and oral solution have decreased bioavailability in comparison with A/eora/capsules, Neoral ora solution, Gengraf capsules, and Gengraf ora solution. Gengraf and Neoral are not bioequivalent to Sandimmune and cannot be used interchangeably without physician supervision. Adjunct therapy Adjunct therapy with adrenal corticosteroids is recommended. P.1163... 

Bioavailability studies for IVIVC development should be performed with enough subjects to characterize adequately the performance of the drug product under study. In prior acceptable data sets, the number of subjects has ranged from 6 to 36. Although crossover studies are preferred, parallel studies or cross-study analyses may be acceptable. The latter may involve normalization with a common reference treatment. The reference product in developing an IVIVC may be an intravenous solution, an aqueous oral solution, or an immediate release product. 

The bioavailability of sustained released formulation of etodolac is about 80% of that of an oral solution in healthy male subjects [18]. Etodolac from tablets and capsules is 100% bioavailable relative to oral solution... 

Bioequivalence or Clinical Study In the patient, the general or systemic circulation is responsible for carrying molecules to different tissues of the body. To assure the expected bioactivity of a product, the amount of drug that reaches the systemic circulation per unit of time is analyzed and is known as bioavailability. Bioequivalence is the comparison of the bioavailability of a product with a reference product. While oral solutions may not always need bioequivalence studies because they are considered self-evidente, suspensions usually require bioequivalence or clinical studies in order to demonstrate effectiveness. However, OTC suspension products such as antacids are exempt from these studies [6]. 

Drug products for which bioavailability is self-evident Drug solution (e.g., parenteral ophthalmic, oral solutions) Drug bioavailability from a true solution is considered self-evident. However, highly viscous solutions may have bioavailability problems... 

The sublingual administration of methyltestosterone was examined by Alkalay et al. The sublingual tablet produced a 50%i higher relative bio availability when compared with the oral tablet or oral solution. The increased bioavailability was attributed to the avoidance of first-pass hepatic metabolism due to absorption from the sublingual vasculature and lymphatics. 

Most oral formulations are solid tablets or capsules, but there are many solution formulations for oral administration that are filled into capsules, or are bulk solutions such as oral solutions, syrups, and elixirs. The reasons for pursuing a solubilized oral formulation include enhancing the oral bioavailability of a poorly water-soluble drug, a drug molecule that is an oil, a low dose drug (i.e., pediatric formulation, a measurable formulation for dose modification, a formulation for patients who cannot swallow tablets... 

Elixirs are sweetened hydroalcoholic oral solutions that are specially formulated for oral use in infants and children. Digoxin, a non-ionizable cardiotonic glycoside, is practically insoluble in water and is solubilized in propylene glycol, 10% ethanol, flavor, sweetener, preservative, and buffers to 50pg/ml in Lanoxin Elixir Pediatric from which the oral bioavailability of digoxin is 70-85%. Phenobarbital, an anticonvulsant and sedative with an intrinsic water solubility of 1 mg/ml, is solubilized in water, 23% ethanol, glucose, sodium saccharin, and flavors to 3.5 mg/ml in Donnatal Elixir. 

Itraconazole, a weakly basic (pKa 3.7) water-insoluble antifungal drug, is solubilized to lOmg/ml using a combination of 40% hydroxypropyl-p-cyclo-dextrin (i.e., 400mg/ml) in water and pH adjustment to approximately 2 in Sporanox oral solution. The relative oral bioavailability of itraconazole from the oral solution is 149%i 68%i compared to capsules from which the oral bioavailability is 55%). Therefore, the oral bioavailability of itraconazole from the oral solution can be estimated to be 45-82%i. The dose of Sporanox oral solution is up to 20 ml once a day, which is 8.0 g of hydroxypropyl-p-cyclodextrin per dose representing the estimated maximum amount administered orally per dose. 

Kaukonen AM, Lennemas H, Mannermaa JP. Water-soluble beta-cyclodextrins in paediatric oral solutions of spironolactone preclinical evaluation of spironolactone bioavailability from solutions of beta-cyclodextrin derivatives in rats. ] Pharm Pharmacol 1998 50(6) 611-619. 

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