Dissolution Method for Quality Control of Immediate Release Dosage Forms 3611 Dissolution Media

Aqueous test media are generally preferred (USP, 2004 FDA, 1997b). Although the design of a dissolution test used for QC is mainly based upon the physico-chemical properties of the drug substance and the characteristics of the dosage form, it is important to select dissolution media to at least reflect the pH effect in the GI environment. For this reason, the pH of these media should be within the physiologic pH range of 1.2-6.8, where pH 1.2 and pH 6.8 represent the pH values under the gastric...

Secondary Factors Influencing Drug Absorption 441 Biological Factors of Gastrio Intestinal Tract

GI tract plays important roles in secretion, digestion, and absorption. Many biological factors, such as gastric emptying, gastric and intestinal pH, GI content, GI motility, GI surface area, and blood flow (Fleisher et al., 1990) can affect drug absorption. Gastric emptying time refers to the time needed for the stomach to empty the total initial stomach contents. During digestion, gastric emptying depends on the tone of proximal stomach and pylorus, which is under reflex and hormonal control....

PAMPA permeability nmsec

Correlation of PAMPA permeability with Caco-2 cell permeability for 100 internal research compounds from the Bristol-Myers Squibb labs. Each point is the mean of three or more repeats or efflux transporters are involved. And the follow-up studies using more mechanistic models (e.g., cell line with specific transporter expressed, xenopus oocytes, etc.) might be warranted. A combination of PAMPA and Caco-2 cells is often used to assess the permeability of test compounds in the most...

Organic Anion Transporters Oat Slc22A Oatp Slco

Conventional pH-partition hypothesis theory states that ionic agents generally exhibit low passive membrane permeability, resulting in their poor bioavailabil-ity. However, there is evidence demonstrating that the intestinal absorption of numerous ionic agents are mediated by the organic anion (OA) or organic cation (OC) transporter systems (Katsura and Inui, 2003 Sai and Tsuji, 2004 Steffansen et al., 2004), thereby overcoming the passive membrane barriers and significantly increasing the...

Physical Pharmacy Physical Chemical Principles

Physical pharmacy is a term that came into common use in the pharmacy community in the mid-twentieth century, and the field has grown and evolved over the years. Essentially, physical pharmacy is a collection of basic chemistry concepts that are firmly rooted in thermodynamics and chemical kinetics. Scientists in the mid-twentieth century pioneered research in the areas of physical-chemical properties of drugs and their influence on biological performance (Reinstein and Higuchi, 1958 Higuchi,...

Theories of Dissolution

Dissolution is generally defined as a process by which a solid substance is sol-ubilized into the solvent to yield a solution. This process is fundamentally controlled by the affinity between the solid substance and the solvent and consists of two consecutive steps. The first step involves the liberation of molecules from the solid phase to the liquid layer near the solid surface (an interfacial reaction between the solid surface and the solvent). It is followed by the transport of solutes from...

PAMPA and Caco2 Cell Synergies

PAMPA and Caco-2 cell models are often used in combination to evaluate the permeability properties of a large number of compounds at the early drug discovery stage. PAMPA model has been demonstrated in recent years to be an efficient, economical and high-throughput model. Caco-2 cell model, on the other hand, has been the gold standard model for over a decade for permeability screening in drug discovery phase. PAMPA captures the transcellular passive permeability across lipoidal membrane...

Potential Excipient Effect on Tight Junctions

The intercellular tight junction is one of the major barriers to the paracellu-lar transport of macromolecules and polar compounds (Denker and Nigam, 1998). They have two physiological functions first, they constitute the principal barrier to passive movement of fluid, electrolytes, macromolecules, and cells through the paracellular pathway (the gate function), and secondly, they contribute to transepithelial transport of compounds promoting epithelial cell polarity (Madara, 1987 Citi, 1992...

NTrimethyl Chitosan as Absorption Enhancer of Peptide Drugs

TMC was first investigated for permeation enhancing properties and toxicity by Kotze and coworkers (1997,1999), using the Caco-2 cells as a model for intestinal epithelium. Initially a trimethylated chitosan having a degree of trimethylation of 12 (dimethylation 80 ) was tested. This polymer (1.5-2.5 , w v pH 6.7) caused large increases in the transport rate of 14C mannitol (32- to 60-fold), fluorescently labeled dextran 4,400 (167- to 373-fold), and the peptide drug buserelin (28- to 73-fold)....

Breast Cancer Resistance Protein Bcrp Abcg2

The ABC transporter BCRP was first cloned from a doxorubicin-resistant MCF7 breast cancer cell line (MCF-7 AdrVp) by Doyle et al. (1998). Subsequently, other groups cloned the BCRP cDNA sequence from other sources and designated the gene either MXR (mitoxantrone resistance protein) or ABCP (placental ABC protein) (Allikmets et al., 1998 Maliepaard et al., 1999). Since structural and sequence homology revealed that BCRP belongs to the ABCG gene subfamily, the Human Genome Nomenclature Committee...

Monocarboxylate Transporters Mct Slc16A

Many endogenous and exogenous short chain anionic compounds, such as lactic acid, pyruvate, acetoacetate, p-hydroxybutyrate, acetate, propionate, and butyrate, are all good substrates for a family of proton-coupled transporter proteins, termed the monocarboxylate transporter family (MCT SLC16) (Price et al., 1998). Although investigation of MCT activity was studied biochemically in earlier literature, it was not until the first identified member of the MCT family, MCT1, was cloned in CHO cells...

Potential Excipient Effect on Bioavailability

The Biopharmaceutics Classification System (BCS) (Amidon et al., 1995) allows waivers of in vivo bioequivalence for rapidly dissolving immediate-release (IR) formulations of drugs with high solubility and high permeability. One potential issue in possibly extending BCS biowaivers to low-permeability drugs is the potential for excipients to modulate the intestinal permeability of the drug. Rege et al. (2001) investigated the effects of common excipients on Caco-2 transport of such...

Enzyme Inhibitory Effects of Polyacrylates

LueBen and coworkers (1996a) have studied the potency of mucoadhesive excipients to inhibit intestinal proteases. Among the different mucoadhesive polymers investigated, uniquely the poly(acrylates) polycarbophil and carbomer 934P were able to inhibit the activities of trypsin, a-chymotrypsin, carboxypeptidase A, and cytosolic leucine aminopeptidase. However, they failed to inhibit microso-mal leucine aminopeptidase and pyroglutamyl aminopeptidase. Carbomer was found to be more efficient to...

Evaluation of Oral Drug Absorption in Human 451 Drug Absorption Assessment Using In Vivo Data

4.5.1.1 Estimation of Fraction of Drug Absorbed Using Experimental Intestinal Permeability In Vivo An in vivo method has been successfully established to measure human intestinal permeability by in situ intestinal perfusion (Lennernas et al., 1997 Sun et al., 2002, 2002 Cao et al., 2006). A perfusion tube, as illustrated in Fig. 4.8, is placed in the human jejunum to allow drug passage through a 10-cm intestinal segment. The drug concentration is measured at the inlet and outlet of the...

PAMPA and Caco2 Cell Caveats

5.4.4.1 Transporter- and Paracellular-Mediated Absorption PAMPA is a high-throughput, non-cell-based permeability model that provides estimates of the passive transcellular permeability property. The lack of any functional drug transporters and paracellular pores in PAMPA makes it an inappropriate model for compounds that are absorbed via transporter- and pore-mediated processes. However, the lack of transporter- and pore-mediated permeability might be an advantage of the PAMPA model. Because...

Importance of Biopharmaceutics in the Overall Development Process

Biopharmaceutics is an integral component of the overall development cycle of a drug. Evaluation begins during the drug discovery process, proceeds through compound selection, preclinical efficacy and safety testing, formulation development, clinical efficacy studies, and postapproval stages. At each stage, biopharmaceuti-cal scientists interface with colleagues in multiple disciplines including discovery chemistry and biology, drug safety assessment, clinical development, pharmaceutical...

References

Aguiar A.J., Krc J., Kindel A.W., and Samyn J.C., 1967. Effect of polymorphism on the absorption of chloramphenicol from chloramphenicol palmitate. J. Pharm. Sci., 56, 847-853. Amidon G.L., Lennernas H., Shah V.P., and Crison J.R., 1995. A theoretical basis for a biopharmaceutic drug classification the correlation of in vitro drug product dissolution and in vivo bioavailability. Pharm. Res., 12(3), 413-420. Avdeef A., 2001. High throughput measurements of solubility profiles. In...

Drug Absorption Assessment Using In Vitro Data

When MAD is estimated with in vivo data, either the in vivo absorption rate constant, or the drug in vivo intestinal permeability is required for the calculation. However, during early stages of drug discovery and development, in vivo data are usually unavailable. The challenge is to optimize the process for selecting compounds to evaluate in vivo human studies based on in vitro data. Fortunately, drug permeability in Caco-2 cells and drug solubility are routinely screened in the pharmaceutical...

Proton Oligopeptide Transporters Pot Slc15A

With the elucidation of the human genome, and advances in molecular biology and cloning, it should be of no surprise that peptidomimetic drugs are increasingly utilized as therapeutic agents for the treatment of numerous disorders. Peptide-like agents have a broad range of clinical applications in the treatment of many disorders including AIDS, hypertension, and cancer. The currently known peptide transporters include the Peptide Transporters 1 and 2, PepT1 (SLC15A1) and PepT2 (SLC15A2) the...

Organic Cation Transporters Oct Octn Slc22A

A significant number of the current therapeutic agents including antihistamines, skeletal muscle relaxants, antiarrhymics, and p-adreno receptor blocking agents, as well as endogenous bioactive amines (e.g., catecholamines, dopamine, hista-mine, and choline) are organic cations (OC). Based on the fact that many of these organic cations are polar and positively charged at physiological pH, membrane bound transporters are required to enhance their intestinal uptake and absorption in an acidic...

The Importance ofBCS on Biorelevant Dissolution Testing

The BCS, which was proposed by Amidon et al. 1995 , emphasizes the contribution of three fundamental factors, dissolution, solubility, and intestinal permeability, to the rate and extent of drug absorption for solid oral dosage forms. The BCS identifies three dimensionless numbers as key parameters including absorption number An , dissolution number Dn , and dose number Do to represent the effects of dissolution, solubility and intestinal permeability on the absorption process. These three...

Discovery and Preclinical Development Candidate Selection

The preclinical development stage encompasses aspects of both drug discovery and drug development. The process to identify a potential drug candidate is an iterative one, as discovery scientists strive to synthesize candidate compounds with appropriate activity and maximal potency at the intended target, maximal safety profile, and desirable ADME properties. The definition of desirable properties will be variable considering the therapeutic target and class of compounds, but typical goals are...

Ent Slc29a

Kinetic studies assessing the transport affinities of both hENT1 and hENT2, the first SLC29 family members identified, have been quite extensive. Earlier research identified hENT1 as the es transport system, while hENT2 was identified as the ei system, where the es system bound NMBPR with high affinity Kd 1-10 nM and the ei system was not affected at nanomolar concentrations, but was affected at higher concentrations gt 10 M Kong et al., 2004 . In fact, since ENT transport is mediated via a...

B

10 100 Caco-2 cell permeability nm sec 10 100 Caco-2 cell permeability nm sec Figure 5.2. Correlation of a PAMPA permeability and b Caco-2 cell permeability with the extent of absorption in humans for marketed drugs. These drugs are known to be primarily absorbed via passive diffusive pathway. Each point is the mean of three or more repeats. The dotted line represents a cut-off of 100 nm s 5. Evaluation of Permeability and P-glycoprotein Interactions 119 Table 5.3. PAMPA and Caco-2 cell...

Biorelevant Dissolution Methods

Unlike dissolution methods used for QC in which their design is primarily based upon drug substance physicochemical properties and formulation principles, biorelevant dissolution methods are designed to closely simulate physiological conditions in the GI tract. However, it should be noted that the physico-chemical properties of the drug substance e.g., solubility and its formulation e.g., immediate- or extended-release dosage forms play a key role in selecting an appropriate type of biorelevant...

PGlycoprotein Pgp ABCB1

Influencing drug transport in mammalian tumor cells, P-glycoprotein P-gp was originally identified as a xenobiotic efflux pump by Juliano and Ling 1976 providing a mechanism for multidrug resistance. Subsequent studies confirmed that P-gp was a 170-180 kDa, ATP-dependent transmembrane glycoprotein, which is formed by the posttranslational glycosylation of a 140 kDa pro-P-gp protein Kramer et al., 1995 . Topological analyses of P-gp showed that the protein comprised four major domains two...