Dosing formulations

For two experimental formulations the data shown in Fig. 4.50 was acquired for each formulation, there exists a lower and a higher dose. Formulation A obviously rapidly disintegrates and in 20 minutes has set the contained drug free, while Formulation B needs at least an additional hour for the last 5-10% (the two tablets might have contained, on average, 102 and 97%-of-nominal, respectively). 

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. 

TABLE 13.6. Desirable Characteristics of a Dosing Formulation and Its Preparation... 

Development of an Application Unrelated to Original Approved Use. After initial approval, drug development may continue with studies of new or modified indications, new dosage regimens, new routes of administration or additional patient populations. If a new dose, formulation, or combination is studied, additional human pharmacology studies may be indicated, necessitating a new development plan. 

The following sections provide an overview of the application of the IPL for the study of drug absorption. Examples are provided to illustrate the use of the IPL to study drug permeability, absorption profiles, transport mechanisms and the effects of inhaled dose formulation on drug disposition. 

Xu, X. Mei, H. Wang, S. Zhou, Q. Wang, G. et ah A study of common discovery dosing formulation components and their potential for causing time-dependent matrix effects in high-performance liquid chromatography tandem mass... 

Figure 3.5 Pl< profile of a compound with hERC inhibition with an IC50 between 20-30 XM. The effective plasma concentration is 10 xM. The single dose produced a spike of over 30 xM plasma concentration, not required for therapeutic effect but for a sufficient level 12 hours after administration. However, the associated with this dose/formulation reached the level when hERG inhibition occurs.

Determination of fluorescent drugs in low-dose formulations in the presence non-fluorescent excipients. 

The dosing formulations should be analyzed for concentration, homogeneity, and stability homogeneity and stability may be established in other studies. 

Kayumba, P. C., Huyghebaert, N., Cordelia, C., Ntawukuliryayo, J. D., Vervaet, C., and Remon, J. P. (2007). Quinine sulphate pellets for flexible pediatric drug dosing Formulation development and evaluation of taste-masking efficiency using the electronic tongue. Eur. J. Pharm. Biophurm. 66,460-465. 

Like the p-interferons, glatiramer reduces the frequency of relapse. A high-dose formulation of interferon-P-la, Rebif, has recently been approved in the United... 

Pancreatic enzyme supplements are well tolerated. The capsules should be swallowed, not chewed, because pancreatic enzymes may cause oropharyngeal mucositis. Excessive doses may cause diarrhea and abdominal pain. The high purine content of pancreas extracts may lead to hyperuricosuria and renal stones. Several cases of colonic strictures were reported in patients with cystic fibrosis who received high doses of pancrelipase with high lipase activity. These high-dose formulations have since been removed from the market. 

Tables 2.2 and 2.3 are examples of repeatability data. Table 2.2 shows good repeatability data. However, note that the data show a slight bias below 100% (all data between 97.5 and 99.1%). This may not be an issue, as the true value of the samples and the variation of the assay may be between 97.5 and 99.1%. Table 2.3 shows two sets of data for a formulation at two dose strengths that were performed using sets of six determinations at 100% test concentration. The data indicate a definite bias and high variability for the low-strength dose formulation. It may call into question the appropriateness of the low-dose samples for the validation experiment.

A liquid formulation is usually comprised of a buffering agent, a stabilizer (which may also serve as a tonicity agent), a surfactant, and an anti-oxidant when protein oxidation is significant. Chelating agents are employed when metal ion catalyzed reactions predominate. A preservative may be included when a multi-dose formulation is desired. 

Preservative For multi-dose formulations only Provides protection against microbial growth in formulation E.g., benzyl alcohol For multi-dose formulations only Provides protection against microbial growth in formulation Is usually included in the reconstitution diluent (e.g., BWFI)... 

Dosage should be individualized according to patient, dosing formulation, and disease state... 

A meta-analysis of epidemiological studies of ovarian cancer showed a summary estimated relative risk of 0.64 for ever-use of combined oral contraceptives, implying a 36% reduction in ovarian cancer risk (130). This protective effect increased with increasing duration of oral contraceptive use and continued for at least 10 years after discontinuation. Although most of the oral contraceptives reported in these studies were older, higher-dose formulations, the Cancer and Steroid Hormone (CASH) study included users of tablets containing ethinylestradiol 35 pg or less, and this subgroup of women had a reduced risk of ovarian cancer (115). 

There are some circumstances in which it is prudent to avoid using oral contraceptives, or in which frequent control of the state of the breasts is essential. These include (a) very long-term use before the first full pregnancy (b) prolonged use of high-dose formulations (c) uninterrupted use in women with a family history of breast cancer or with a personal history of fibroadenoma. 

Jaundice as a result of oral contraceptive treatment has been repeatedly described. Whereas in the Swedish population figures between 1 100 and 1 4000 were published when the early high-dose formulations were still in use (213), the overall incidence was estimated in 1979 at about 1 10 000 (9), and the current incidence is certainly further reduced. When such hepatic symptoms occur, they usually do so within the first month of medication (214), and jaundice may be accompanied by anorexia, malaise, and pruritus. Very few cases arise after the third month of medication and those reported are regarded by some as unlikely to be due to oral contraceptives. Microscopic examination of the liver shows intrahepatic cholestasis. When medication is stopped, symptoms usually disappear rapidly and the reaction does not seem to leave any sequelae (215). Genetic components seem to be important for the development of the reaction women who have experienced jaundice or severe pruritus in late pregnancy seem to be especially susceptible to jaundice or gallbladder disease when using... 

Ascorbic acid (vitamin C) is extensively sulfated in the gastrointestinal mucosa and competes with ethinylestra-diol, which is also extensively sulfated. Plasma ethinyles-tradiol concentrations are increased by ascorbic acid in women, both after a single dose of ethinylestradiol and during long-term oral contraceptive use, but the results are not consistent. On one occasion it was claimed that this effectively transformed a low-dose oral contraceptive into a high-dose formulation (333). It seems very dubious whether ascorbic acid in fact interferes significantly with the effects of oral contraceptives. 

---