Excipient oral formulations

The simplest lipid-based formulations contain only one excipient such as Gelucire 44/14, oleic acid, o -tocopherol, corn oil, peanut oil, sesame oil, medium-chain triglyceride, or medium-chain mono- and diglycerides. There are at least 10 commercially available one-lipid excipient oral formulations, and they all happen to be in soft capsules. 

An inert substance is frequently added to increase the bulk of a tablet for processing and handling. The lower weight limit for formulation of a tablet is usually 50 mg. Ideally, diluents should be chemically inert, nonhygroscopic, and hydrophilic. Having an acceptable taste is important for oral formulations, and cost is always a significant factor in excipient selection. 

IVIVCs are often indicated only for obtaining oral formulations. Various data have been presented in the cases of less-classical formulations such as intrauterine devices, chewing gums, ocular inserts, suppositories, etc. For example, for suppositories two main types of formulations exist one based on hydrophilic excipients and the second on lipophilic excipients. The first step is the dissolution of the mass. This means a fusion of the lipophilic base at human body temperature (36-39.5°C) or dissolution for the water-soluble base (even with a high melting point) in the rectal fluid. 

Established excipients pose some issues for regulatory consideration. Such issues include the use of a well known excipient by an unapproved route, for example, inhalation of a material that has been used in oral formulations. In these cases, some preliminary toxicity studies may be necessary. Additionally, a well designed scientific review of safety data on the excipient will be necessary, with old findings fully evaluated. 

Excipients such as mannitol can affect small intestinal transit, which in turn can affect the absorption of certain drugs. Oral solutions are rarely likely to fall short of bioequivalence relative to solid oral formulations, although during the development of a ranitidine effervescent oral solution dosage form containing sodium acid pyrophosphate (SAPP), a marked decrease in absorption was observed in the extent of ranitidine absorption from the liquid formulation relative to the conventional oral tablet. The formulation contained 150 mg ranitidine with 1132 mg SAPP together with 1.5 MBq hndium chloride solutions. Small intestinal transit time was decreased to 56% in the presence of the excipient. The rapid small intestinal transit associated with an excipient of a solution dosage form resulted in a decreased extent of ranitidine absorption. " ... 

Eorster, A. Rades, T. Hempenstall, J. Selection of suitable drugs and excipient candidates to prepare glass solutions by melt extrusion for immediate release oral formulations. Pharm. Tech. Eur. 2002, 27-57. 

Table 2 Solubilizing excipients used in commercially available solubilized oral formulations...

Table 3 Estimated maximum amount of selected excipients administered from oral formulations...

Ceratonia is generally regarded as an essentially noncarcino-genic, nontoxic and nonirritant material. Therapeutically, it has been used in oral formulations for the control of vomiting and diarrhea in adults and children 20—40 g daily in adults has been used dispersed in liquid. As an excipient, ceratonia is used in oral controlled-release formulations approved in Europe and the USA. 

Docusate salts are used in oral formulations as therapeutic agents for their fecal softening and laxative properties. As a laxative in adults, up to 500 mg of docusate sodium is administered daily in divided doses in children over 6 months old, up to 75 mg in divided doses is used. The quantity of docusate sodium used as an excipient in oral formulations should therefore be controlled to avoid unintended laxative effects.Adverse effects associated with docusate sodium include diarrhea, nausea, vomiting, abdominal cramps, and skin rashes. As with the chronic use of laxatives, the excessive use of docusate sodium may produce hypomagnesemia. ... 

Activity may be improved by using combinations of parabens, as additive effects occur. Propylparaben has been used with methylparaben in parenteral preparations, and is used in combination with other parabens in topical and oral formulations. Activity has also been reported to he improved by the addition of other excipients see Methylparaben. 

Excessive administration of phosphate, particularly intravenously, rectally, or in patients with renal failure, can cause hyperphosphatemia that may lead to hypocalcemia or other severe electrolyte imbalances. Adverse effects occur less frequently following oral consumption, although phosphates act as mild saline laxatives when administered orally or rectally. Consequently, gastrointestinal disturbances including diarrhea, nausea, and vomiting may occur following the use of dibasic sodium phosphate as an excipient in oral formulations. However, the level of dibasic sodium phosphate used as an excipient in a pharmaceutical formulation is not usually associated with adverse effects. 

The range of complexity of solubilized oral formulations filled into a capsule varies from a simple one-excipient formulation such as PEG 400 or a long-chain triglyceride, to complex microemulsion preconcentrates which contain oil, cosolvent, and surfactant excipients. The preferred water-soluble organic solvents... 

Molecule (s)/ trade name/ company/ indication Chemical structure Dose Commercial oral formulation Excipients Estimated maximum amoimt of excipient adrninistered Storage... 

As a guide to solubilized oral formulation drug development, the following examples illustrate the formulation philosophy of simple to complex . Starting with one-excipient formulations to complex microemulsion preconcentrates. 

The next level of complexity in lipid-based formulations is those that contain two excipients. Some typical combinations are sesame oil with a-tocopherol, medium-chain triglyceride with ethanol, and propylene glycol esters of fatty acids with glyceryl monooleate. There are at least 6 commercially available oral formulations with two lipid excipients. 

The next level of complexity of lipid-based formulations currently marketed contain mixtures of four excipients, which can be SEDDS formulations or mixtures such as beeswax, soybean oil, hydrogenated vegetable oils and hydrogenated soybean oil. There are at least two commercially available four-excipient lipid-based oral formulations and both are delivered in soft gelatin capsules. Aptivus soft gelatin capsule (tipranavir) is a SEDDS formulation with ethanol and PG as the polar solvents, cremophor EL as the surfactant, and medium-chain mono-and-diglycerides as the oily phase. 

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