Reference formulation

R. E. Ohm, ed.. The Vanderbilt Rubber Handbook, 13th ed., R. T. Vanderbilt Co., Inc., Norwalk, Conn., 1990. Contains general information for novices and practical reference formulations for experienced compounders. 

The reference formulation is used to correct for differences in drug clearance between study populations when data from more than one study are combined. The reference formulation is chosen so that when it is used in deconvolution with the ER formulation, the in vivo drug release or absorption from the ER formulation is obtained. Appropriate reference formula-... 

Including a reference formulation is always recommended, even if a specifically designed IVIVC study is... 

Figure 7 Observed concentration—time data for ISMN from the test extended-release formulations included in the four PK studies. The profile for the reference formulation (a) is represented as an intravenous injection with the same AUC as the reference extended-release formulation (IMDUR) and the literature elimination half-life of 3.77 hr. IVIVC development included the two fast ( ) and one medium (o) batch from Study 194.573 and two slow batches ( ) from Study 372.05/196.638 and external validation included the two medium batches ( ) in Studies 196.581 and 372.02.

Often the first few pilot PK studies in formulation development are not aimed for the specific purpose of IVIVC. However, it is normally in these first studies that the greatest difference in release rates is seen, before settling on a target profile, making them very valuable for IVIVC development. Prospective inclusion of an appropriate reference formulation can allow these valuable data to be used retrospectively for the purpose of IVIVC. 

IVIVC studies normally involve two to four ER formulations and a reference formulation (e.g., IV solution, immediate release, or oral solution). Data analysis involves deconvolution of each ER formulation, using the reference data for each subject. Thus, if a subject drops out of the study prior to the IR arm, none of that subject s data... 

Retrospective IVIVC development, using studies not designed for this purpose, reduces the probability of successful IVIVC development and validation. Normally such studies are compromised by not including a reference formulation and do not have a large enough range of release rates, thereby requiring cross-study comparisons where subjects have different clearance characteristics that could have been accounted for had a reference formulation been incorporated. 

Martin, W., Ring, J., Gaupp, M., Arnold, P., Sennewald, R. Bioavailability investigation of a new tilidine/naloxone liquid formulation compared to a reference formulation, Arzneim.-Forsch./Drug-Res. 1999, 49, 599-607. 

In-process testing and acceptance criteria Finished product testing and acceptance criteria Test method references Formulation... 

The mean plasma anti-factor Xa and anti-factor Ha activities following single 175 IU/kg subcutaneous administration of test and reference formulations is shown graphically in Fig. 8.2 A and B, respectively. The mean maximum plasma anti-Xa activity (Amax) was approximately 0.818 IU/mL at 4 h after tinzaparin injection. Anti-Xa activity fell to undetectable levels by 24—30 h in all subjects. The mean maximum plasma anti-IIa activity was 0.308 IU/mL at 5 h post-dose, and anti-IIa activity fell to undetectable levels by 24 h in all subjects. Inter-subject var-... 

Cross-over study designs are typically employed in bioequivalence trials. Imagine that the new formulation is called N and the existing formulation is called R (the reference formulation). The two order possibilities for receiving the two drug treatments are NR and RN. Typically, healthy male and female adults participate in these studies, and the treatment orders are appropriately controlled and balanced. Pharmacokinetic parameters are used to represent both safety and efficacy. 

Cmai and AUC data for the new formulation N are both too high relative to the reference formulation R. 

An f2 value between 50 and 100 suggests that the two dissolution profiles are similar, indicating the test formulation is bioequivalent to the reference formulation.1 There are a minimum of three timepoints in extended release dosage forms an early timepoint that detects dose dumping, a middle point, and a not-less-than (NLT) 80% point. More points may be added, especially for very long drug release testing periods. 

To characterize the bioavailability of XYZ1234 drug substance (25 mg) as a capsule formulation following a single oral administration in fasting conditions in healthy male adult volunteers, using 10 mg of intravenously administered XYZ1234 as reference formulation. 

To investigate the pharmacokinetics (PK) of an XYZ1234 formulation (200 mg) following topical release in the proximal small bowel, distal small bowel and colon via the Enterion capsule in healthy subjects and to compare to the PKof an XYZ1234 immediate release reference formulation (200 mg). 

The study described here has a very complex design for its exploratory approach. It combines four different extended release formulations, each tested under fasting and non-fasting conditions, and compares the results to the immediate release drug product as the reference formulation. The bilayer tablets combines an immediate release component and an extended release component in one vehicle. In this project a close cooperation between the galenics department and the clinical pharmacokinetic function was mandatory. The in vitro/in vivo correlation was done by means of the deconvolution which is an appropriate surrogate to describe the in vivo dissolution. 

Point estimates and confidence intervals were primarily calculated for the ratio of each ER formulation and the IR reference formulation. Additionally, the ratios fasting/non-fasting for each ER formulation were computed. 

Aubeny, E., Colau, J. C., and Nandeuil, A. (2000), Local spermicidal contraception A comparative study of the acceptability and safety of a new pharmaceutical formulation of benzalkonium chloride, the vaginal capsule, with a reference formulation, the pessary, Eur. J. Contracept. Reprod. Health Care, 5, 61-67. 

In the above equation /2 is the similarity factor, n is the number of time points, Rt is the mean percent drug dissolved of the reference formulation, and Tt is the mean percent drug dissolved of the tested formulation. 

Alcoa s rehydratable CP alumina powders can be used effectively to improve a viable FCC catalyst formulation. Well-formed microspheres which have superior attrition resistance can be fabricated by controlling the pH and viscosity of the FCC slurry. At this time, the preferred formulation uses CP-2 as the free alumina source and a silica sol which has aged at conditions conducive to the formation of chains of polysilicic acid aggregates. The addition of the rehydratable alumina can also have a beneficial effect on the cracking activity of the catalyst. The conversion and selectivity of a CP-2 formulated sample were comparable to a commercial grade catalyst and an experimental reference, which was alumina-free. After heavy metals poisoning, the CP-2 material had activity which was superior to the reference formulation. 

Figure 4 Mean it-verapamil S-verapamil ratio observed following intravenous and oral dosing of racemic verapamil. A, After intravenous administration of a single 15 mg dose in 8 volunteers (personal communication from A. Rasymas, Univ. of Toronto, Canada). B, After oral administration of two different 120-mg immediate release formulations dosed every 8 hr to 22 normal volunteers in a crossover design study and measured at steady state over two dosing intervals (- -, test formulation u, reference formulation). C, After oral administration of two different lots of a 180-mg once daily sustained-release formulation to 48 normal volunteers in a cross-over design study and measured at steady state new manufacturing site n, reference manufacturing site).

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