Formulation dose numbers

Many of the major new products reaching the market in the last few years will have had total databases of 5000 or more patients, but when the subtractions are made for formulation, dose and indications that are no longer relevant, then, perhaps, no more than 2500-3500 remain. This is still far short of the number required to make an assessment of safety that would be appropriate for its expected performance when it reaches the market. 

Dose numbers of >20 are by definition related to low soluble and dissolution rate limited substances (see Amidon et al. ). In such cases special formulation approaches are to be considered from the scratch in the formulation strategy. 

When the dose of the active substance does not dissolve in the approximately 250 mL of liquid that is present in the gastrointestinal lumen (a high dose number), the solid fraction of the substance will be unable to permeate across the intestinal mucosa and, consequently, will be eliminated in the faeces. Newly discovered active substances are often very poorly soluble in water, which requires unique formulations in order to achieve therapeutically relevant... 

Pharmaceutical powder aerosols have more stringent requirements placed upon the formulation regarding moisture, particle size, and the valve. For metered-dose inhalers, the dispensed product must be deflvered as a spray having a relatively small (3—6 -lm) particle size so that the particles can be deposited at the proper site in the respiratory system. On the other hand, topical powders must be formulated to minimize the number of particles in the 3—6-p.m range because of the adverse effects on the body if these materials are accidently inhaled. 

Process Rationale. The products of plasma fractionation must be both safe and efftcaceous, having an active component, protein composition, formulation, stabiUty, and dose form appropriate to the intended clinical appHcation. Processing must address a number of specific issues for each product. Different manufacturers may choose a different set or combination of unit operations for this purpose. 

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. 

Concentrated Oral Solutions. Presentation of a drug may be made in the form of a concentrated solution that allows the entire dose to be held within a volume of less than 5 mL (e.g., Intensol Concentrated Oral Solutions, Roxanne). This opens up another means of providing medication to the aged, infants, or any other patients experiencing difficulties swallowing. Such preparations can be mixed with food or drink. Taste and poor solubility are problems that may set limits on the number of successful formulations that can be prepared in this way. Also, small errors in the measurement of such preparations represent large errors in dosing. 

The potential for the metabolites that are formed to have the same masses as other parent compounds is another factor that limits the number of compounds that may be included in the cassette, as does the potential for drug-drug interactions [35]. Other limitations are the total dose that can be administered without saturating important pathways of metabolism or distribution, and the solubility of the compounds in the dosing formulation. However, there is a balance to be achieved as, if the dose of each component given is very low, it is likely that the analytical method will not have sufficient sensitivity to provide an accurate assessment of the pharmacokinetics. 

When the excipient matrix in a formulation is largely amorphous, similar XRPD methods can be used to determine the amount of crystalline drug substance present in a drug product. The principles were established in a study that included a number of solid dose forms [40],... 

Liquid instillation and nebulised aerosols are the most common methods for pulmonary administration to experimental animals [22, 54, 109, 134], The use of pressurised metered dose inhaler (pMDIs) and dry powder inhaler (DPIs) in preclinical studies is limited by the need for formulation development, which often cannot be performed in early drug discovery due to short supply of test materials. A number of alternative techniques for intra-tracheal administration of coarse sprays and powder formulations have been described [9, 15, 21, 36, 71, 80, 99, 138],... 

Number/sex/group age at start of study Animal housing Formulation/vehicle Drug stability/homogeneity Methods Doses... 

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