Bilayer tablets

The manufacture of this system utilizes essentially the same process as the one inherent in the manufacture of OROS. The complicating factors are that a bilayer tablet press is required and the tablet must be oriented during the laser drilling operation to ensure that the drug-containing layer is directed toward the laser beam. 

In addition to the scale-up issues mentioned in the previous case studies, there are scale-up issues specific to bilayered tablets. These specific issues include mixing of the granulation on the die table during compression,... 

During scale-up of a bilayered tablet, it is necessary to determine the range of tamping that can be tolerated for a product. Typically, the tamping force and overall compression force are varied and the tendency to laminate is observed. In addition, the other tablet characteristics are also determined, e.g., hardness, thickness, weight uniformity, disintegration, and dissolution. 

As an example of the additional requirements posed by bilayered tablets during scale-up, a summary of the typical in-process tests is shown in Table 10. 

Figure 28 Dependence of the compression profiles of bilayered tablets on size.

Figure 29 Dependence of bilayered tablet friability on size.

Average first-layer tablet weight (n — 20) Individual first-layer tablet weight (n = 20) Average bilayer-tablet weight (n — 20) Individual bilayer-tablet weight (n — 20) Eirst layer-tablet cylindrical height Action limit 1.1% Tolerance limit 1.7% Action limit 2.0% Tolerance limit 3.0% Action limit 1.1% Tolerance limit 1.7% Action limit 2.0% Tolerance limit 3.0% 2.45-3.00 mm... 

Ozdemir, N., Sefika, 0., and Ozkan, Y. Studies of floating dosage forms of furosemide In vitro and in vivo evaluations of bilayer tablet formulations. Drug Dev. Ind. Pharm. 26 857-866, 2000. 

A fixed combination tablet formulation was developed and studied for the treatment of depression. The formulation consisted of two active ingredients in a bilayer tablet,... 

HPLC method development for the fixed combination tablet formulation became more challenging in the presence of the excipients used in the tablet formulations. HPMC and pregelatinized starch in the sustained release portion of the bilayer tablet caused extraction difficulties and interferences in the HPLC chromatogram. 

Figure 10.4 Representative HPLC chromatograms (a) excipient placebo for the high dose active IR portion of the bilayer tablet (b) excipient placebo for the low-dose active sustained release portion of the bilayer tablet (c) Amicon Ultra-4 filtered fixed combination tablet sample. Annotation 1 = low-dose active ingredient 2 = high-dose active ingredient = pregelatinized starch-related peak = HPMC-related peak = filter-related peaks.

Treatment C 600 mg XYZ1234 in ER formulation (LLL bilayer tablet) under F and NF conditions. 

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. 

The primary objective of the present study was to investigate the pharmacokinetic characteristics of four ER formulations of XYZ1234. Two LLL formulations (matrix and bilayer tablets, Treatments B C respectively), and two KKK formulations (matrix and bilayer tablets, Treatments D E) were compared with the pharmacokinetic characteristics of an IR formulation (Treatment A) in the non-fasting state. The secondary PK objective was to assess the influence of food on the pharmacokinetics of these ER formulations of XYZ1234. 

LLL tablets (Treatments B and C) provided lower Cmax values and lower relative bioavailability compared to the IR formulation (Treatment A). A longer half-life was observed for Treatment B (matrix tablets), under both fasting and non-fasting conditions, but for Treatment C (bilayer tablets) the lower limit of the 90 % confidence was above 100 % only under fasting conditions. 

KKK tablets (Treatments D and E), provided lower Cmax values with similar (though not higher) AUC values for Treatment E (bilayer tablets), and similar AUC for Treatment D - only under nonfasting conditions. Increased half-lives were recorded for Treatments D and E, only under fasting conditions. 

The effect of the IR component within the bilayer tablets on the absorption profile was most markedly observed in the figures describing the hypothetical in vivo dissolution. The increase in amount absorbed was steeper for Treatments C and E, especially under fasting conditions. 

No effect of food was recorded on AUCo-co and MRT values for the bilayer tablets (Treatments C and E), with marginal effect on their rate of absorption and on Cmax values. The absorption rate of matrix tablets, as well as their Cmax values, were more affected. Ci2h values presented food consumption effects for all formulations, however to a larger extent for KKK than for LLL tablets. 

Treatments C and E (the bilayer tablets that contain the IR component) had a steeper amount absorbed profile as compared to the parallel matrix tablets (Treatments B and D). This effect was more pronounced under fasting conditions. Only with Treatment E (KKK bilayer tablets) did the hypothetical in vivo dissolution profiles surpass the 100% absorption, both under fasting and non-fasting conditions. For Treatment C, this occurred only under fasting conditions and for Treatment D only under non-fasting conditions. 

A bilayer tableting technology that combines an immediate-release granulate and a CR hydrophilic matrix complex within the one tablet. 

Bilayer tablet presses employ the same general design concepts as single-sided machines. Typically, a double-sided machine can be converted to a bilayer machine by replacing various cams. The material for each layer is introduced separately into each feeder and is removed from the die table to prevent contamination. 

Inman SJ, Briscoe BJ, Pitt KG. Topographic characterization of cellulose bilayered tablets interfaces. Chem Eng Res Des 2007 85(A7) 1005-1012. 

Three-dimensional printing was used for the production of bilayer tablets. Hydroxypropyl methyl cellulose and poly(acrylic add) were used as a hydrophilic matrix for the formation of a sustained release layer. The drug release is comparable with commercial counterparts. 

In the case of the above-mentioned pharmaceutical bilayer tablets, Korsmeyer-Peppas n values between 0.27 and 0.44 were observed, which indicates a Fickian diffusion governed drug release (60). 

M. ito, T. Suzuki, S. Yada, H. Nakagamib, H. Teramotoc, E. Yonemochia, and K. Terada, Development of a Method for Nondestructive NiR Transmittance spectroscopic Analysis of Acetaminophen and Caffeine Anhydrate in intact Bilayer Tablets, /. Pharm. Biomed. Anal., 53, 396 (2010). 

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