Effect Of Pharmaceutical Excipients Research Articles

Effects of polyvinylpyrrolidone (K90) on membrane permeation via the transcellular route in the rat jejunum

Although pharmaceutical excipients do not affect the membrane permeation of active drugs, some have been shown to influence absorption-regulating factors. However, limited information is currently available on the effects of pharmaceutical excipients on membrane permeation via passive transcellular transport, which is the main membrane permeation route of many drugs. We herein focused on polyvinylpyrrolidone (PVP) (K90), which is used as a diluent and binder in pharmaceutical formulations, and examined its effects on passive transport via the transcellular route in the rat jejunum using the in vitro sac method. The membrane permeation of β-naphthol, a passive transcellular marker, was increased by the co-existence of 0.02 w/v % PVP (K90). However, PVP (K90)-induced increases in membrane permeation were not observed following a pre-incubation with PVP (K90). Therefore, PVP (K90)-induced increases in membrane permeation may be attributed to a drug-excipient interaction, but not a mucosal membrane-excipient interaction. PVP (K90) affected membrane transport via the transcellular route in the rat jejunum. However, since the coexistence of PVP (K90) did not influence membrane protein expression levels or cause membrane lesions, the absorption of active drugs may be regulated by the optimal application of PVP (K90).

Investigating Non-Therapeutic Pharmaceutical Substances for Improving In-Vitro Efficacy of Clindamycin Phosphate Against MRSA and Staphylococcus Epidermidis

The aim of present study was to investigate the effect of pharmaceutical excipients and other active substances on antimicrobial efficacy of standard antibiotic against resistant and susceptible microorganisms. Pharmaceutical excipients (sodium lauryl sulfate [SLS], Tween-80, citric acid, NaOH, NaCl) and active substances (fusidic acid, sorbic acid) were investigated to check in-vitro efficacy and their effect on the efficacy of standard antibiotic. Clindamycin was selected as standard antibiotic. Clindamycin was found to be ineffective against methicillin-resistant Staphylococcus aureus (MRSA). Fusidic acid and SLS showed concentration dependent effect against MRSA. Other tested substances were also ineffective against MRSA, and also failed to improve the susceptibility of MRSA towards clindamycin. The clindamycin + fusidic acid (0.05 µg, 0.1 µg), and clindamycin + SLS (0.5 mg, 1 mg) showed concentration dependent effect on Staphylococcus epidermidis (S. epidermidis). Clindamycin combinations with fusidic acid or SLS showed better inhibition of S. epidermidis, than individual substance. At lower concentration of clindamycin (2 µg), the sorbic acid (25 µg) improves its effectiveness. SLS (0.5 mg, 1 mg) and clindamycin (4 µg, 10 µg) showed almost equal zone of inhibition against S. epidermidis, respectively. Present findings showed that certain pharmaceutical excipients (e.g. SLS) are effective against resistant and susceptible microbes, and suggested that more excipients should be screened for their antimicrobial potential and their ability to improve the efficacy of standard antibiotics.

Evaluation of the Inhibitory Effects of Pharmaceutical Excipients toward the Efficiency of Polymerase Chain Reaction (PCR)

Evaluation of the Inhibitory Effects of Pharmaceutical Excipients toward the Efficiency of Polymerase Chain Reaction (PCR)

Sex-Dependence in the Effect of Pharmaceutical Excipients: Polyoxyethylated Solubilising Excipients Increase Oral Drug Bioavailability in Male but not Female Rats.

It is known that males and females respond differently to medicines and that differences in drug behaviour are due to inter-individual variability and sex specificity. In this work, we have examined the influence of pharmaceutical excipients on drug bioavailability in males and females. Using a rat model, we report that a portfolio of polyoxyethylated solubilising excipients (polyethylene glycol 2000, Cremophor RH 40, Poloxamer 188 and Tween 80) increase ranitidine bioavailability in males but not in females. The in vivo sex and excipient effects were reflected in vitro in intestinal permeability experiments using an Ussing chamber system. The mechanism of such an effect on drug bioavailability is suggested to be due to the interaction between the excipients and the efflux membrane transporter P-glycoprotein (P-gp), whose expression in terms of gene and protein levels were inhibited by the solubilising agents in male but not in female rats. In contrast, the non-polyoxyethylated excipient, Span 20, significantly increased ranitidine bioavailability in both males and females in a non-sex-dependent manner. These findings have significant implications for the use of polyoxyethylated solubilising excipients in drug formulation in light of their sex-specific modulation on the bioavailability of drugs that are P-gp substrates. As such, pharmaceutical research is required to retract from a ‘one size fits all’ approach and to, instead, evaluate the potential impact of the interplay between excipients and sex on drug effect to ensure effective pharmacotherapy.

The Effects of Pharmaceutical Excipients on Gastrointestinal Tract Metabolic Enzymes and Transporters-an Update.

Accumulating evidence from the last decade has shown that many pharmaceutical excipients are not pharmacologically inert but instead have effects on metabolic enzymes and/or drug transporters. Hence, the absorption, distribution, metabolism, and elimination (ADME) of active pharmaceutical ingredients (APIs) may be altered due to the modulation of their metabolism and transport by excipients. The impact of excipients is a potential concern for Biopharmaceutics Classification System (BCS)-based biowaivers, particularly as the BCS-based biowaivers have been extended to class 3 drugs in certain dosage forms. The presence of different excipients or varying amounts of excipients between formulations may result in bio-inequivalence. The excipient impact may lead to significant variations in clinical outcomes as well. The aim of this paper is to review the recent findings of excipient effects on gastrointestinal (GI) absorption, focusing on their interactions with the metabolic enzymes and transporters in the GI tract. A wide range of commonly used excipients such as binders, diluents, fillers, solvents, and surfactants are discussed here. We summarized the reported effects of those excipients on GI tract phase I and phase II enzymes, uptake and efflux transporters, and relevant clinical significance. This information can enhance our understanding of excipient influence on drug absorption and is useful in designing pharmacokinetic studies and evaluating the resultant data.

Effect of pharmaceutical excipients on the permeability of P-glycoprotein substrate

Present investigation evaluated permeability enhancing potential of pharmaceutical excipients (HPMC, PVP, Tween-80, Cremophor EL, Cremophor RH40, Transcutol, Labrasol and pluronics F-68) on the intestinal permeability of a P-glycoprotein substrate (domperidone). Everted and non-everted rat gut sacs were used for permeability studies. The investigation revealed that serosal to mucosal (S-M) transport of domperidone was greater than the mucosal to serosal (M-S) transport, which indicates that net movement of domperidone was towards lumen. Further, it was observed that S-M flux of domperidone was reduced by surfactant such as Tween-80, Cremophor EL, Cremophor RH40, Transcutol, Labrasol and pluronics F-68. Pluronics F-68 showed inhibitory effect at higher concentration (0.8 % w/v), but no significant inhibition was observed at lower concentrations. Polymers like HPMC and PVP did not produce any remarkable effect on the permeability of domperidone. The findings suggested that some of the excipients may be used to increase the permeability and absorption of P-gp substrates. However, their role should be confirmed at molecular level and clinical relevance of these findings should be evaluated.

Effects of pharmaceutical excipients on membrane permeability in rat small intestine

Pharmaceutical excipients should not disturb the effects of drug therapy. In recent years, however, it has been reported that excipients induce some changes to the tight junction (TJ) and P-glycoprotein (P-gp), which can affect drug disposition. In this study, we examined the effects of 20 common pharmaceutical excipients from different classes on mucosal membrane and the differences of such effects among regions of the small intestine. We used the in vitro sac method in rat jejunum and ileum to study the effects of excipients on the membrane permeation of 5(6)-carboxyfluorescein (5-CF). 5-CF was used as a model of water-soluble compounds. In some dosage conditions of methyl-β-cyclodextrin, the membrane permeability of 5-CF was significantly increased in the jejunum, but such change was not observed in the ileum. Similarly, in the cases of sodium carboxymethyl starch, low-substituted hydroxypropyl cellulose and croscarmellose sodium, the membrane permeability of 5-CF was significantly increased in the jejunum, but no change was observed in the ileum. On the other hand, in both the jejunum and the ileum, the membrane permeation of 5-CF was decreased with 0.02% (w/v) hydroxypropyl cellulose, but significantly increased with it at 0.20% (w/v). It was shown that excipients affected the membrane permeability of water-soluble compounds via the paracellular route, and these effects on absorption differed among regions of the small intestine. Moreover, in the case of 20 excipients, not only an increase in membrane permeability but also a decrease was observed. Therefore, it was suggested that a more effective formulation could be designed by changing the combination of excipients.

Phase behavior study of amphiphilic drugs: Effect of pharmaceutical excipients

Effect of various additives, like conventional as well as gemini cationic surfactants, non-ionic surfactants, hydrotropes, bile salts, fatty acid salts and β-cyclodextrin on the cloud point (CP) of two amphiphilic drugs promethazine (PMT) and promazine (PMZ) hydrochlorides was investigated. These additives are generally used as pharmaceutical excipients. The CP variation with the additive concentration has been determined and the energetic parameters of the process have been estimated. All the surfactants increase the CP, while hydrotropes, bile salts and fatty acid salts, when added in low concentrations, increase or decrease, depending the added concentration, increase or decrease the CP. β-cyclodextrin is found to decrease the CP of the drug solutions.

Effect of pharmaceutical excipients on the stability of angiotensin-converting enzyme inhibitors in their solid dosage formulations

Context: The compatibility studies of moexipril hydrochloride (MOXL), imidapril hydrochloride (IMD), enalapril maleate, (ENA) and lisinopril (LIS) in solid state with magnesium stearate and glyceryl behenate were performed.Objective: The aim of this study was to detect any possible drug–excipient interactions in order to optimize technological process conditions by the selection of the most adequate lubricant.Materials and methods: Reversed-phase high-performance liquid chromatography was employed for studying drug–excipient binary mixtures in 1:1 ratio and pure drugs under forced ageing test conditions: temperature 318K (45°C) and relative humidity range of 50.9%–75.4%. The method had been revalidated prior to use. The degradation rate constants for the binary mixtures and pure substances were calculated.Results: The experimental results evidenced that moexipril and enalapril degradation accorded with autocatalytic-second-order kinetics, imidapril degradation followed first-order reaction mechanism, and LIS followed reversible first-order reaction mechanism. A degradation pathway for each substance was proposed to account for the observed decomposition products. It was determined that moexipril stability decreased threefold in the presence of magnesium stearate indicating an incompatibility − (4.15 ± 0.12) 10−3 compared to (1.43 ± 0.32) 10−6 for moexipril in pure. No interaction between magnesium stearate and the remaining studied compounds was observed. The stability studies of MOXL–glyceryl behenate binary mixture revealed no interaction.Conclusion: Magnesium stearate and increased relative humidity induce MOXL instability, while glyceryl behenate is an optimal lubricant, and therefore, it is recommended for moexipril-containing solid formulations. However, for the formulations containing moexipril and magnesium stearate, it is suggested to minimize the humidity level during storage.

Effects of pharmaceutical excipients on cloud points of amphiphilic drugs

The clouding behavior, i.e., formation of phase separation at elevated temperature (the temperature being known as cloud point (CP)), of three amphiphilic drugs, amitriptyline (AMT), clomipramine (CLP) and imipramine (IMP) hydrochlorides in the presence of various additives, like cationic surfactants (conventional and gemini), nonionic surfactants, bile salts, anionic hydrotropes, sodium salts of fatty acids and cyclodextrin has been investigated. These additives are generally used as drug delivery systems. The drugs used are tricyclic antidepressants. All the surfactants increase the CP of mixed micelles formed by cationic (conventional and gemini) and nonionic surfactants. Hydrotropes, bile salts and fatty acid salts, when added in low concentrations, increase the CP, whereas at high concentrations, they decrease it. β-Cyclodextrin behaves as simple sugar and decreases the CP of the drug solutions.

The role of excipients in determining the pharmaceutical and therapeutic properties of medicinal agents (Review)

The effects of pharmaceutical excipients on the quality of medicinal products are discussed. It is emphasized that excipients must be studied before the development of a product starts, including compliance with production standards, investigations of their influences on the physical, pharmacological, and microbiological characteristics of products, and influences on the therapeutic efficacy and safety of medicinal formulations (release of active ingredient, bioavailability, etc.). Aspects considered in the present review indicate the need for a wide approach to assessment of the roles of excipients in determining the required pharmaceutical and therapeutic properties of medicinal products.

Effect of pharmaceutical excipients on aqueous stability of rabeprazole sodium

The chemical stability of a proton-pump inhibitor, rabeprazole sodium, was evaluated in simulated intestinal fluid (pH 6.8) containing various ‘Generally Recognized As Safe (GRAS)’-listed excipients, including Brij ® 58, Poloxamer 188, Cremophor RH40, Gelucire 44/14 and PEG 6000. After incubation at 37 and 60 °C, the amounts of rabeprazole and its degradation product, thioether-rabeprazole, were quantitated by HPLC analysis. The main degradation product was separated and characterized by LC/MS. The degradation of rabeprazole followed first-order kinetics. In the absence of any excipients, the rate constants ( k) obtained at 37 and 60 °C were 0.75 and 2.78 h −1, respectively. In contrast, the addition of excipients improved its stability. Among several excipients tested in this study, Brij ® 58 displayed the greatest stabilizing effect. For instance, at 37 and 60 °C, Brij ® 58 reduced the k values to 0.22 and 0.53 h −1, respectively. The stabilizing mechanisms of these hydrophilic polymeric excipients with optimal HLB values could be partially explained in terms of their solubilizing efficiency and micellar formation for thioether-rabeprazole. In conclusion, rabeprazole formulations that contain suitable excipients would improve its stability in the intestinal tract, thereby maximizing bioavailability.

Formulation, release characteristics and bioavailability of novel monolithic hydroxypropylmethylcellulose matrix tablets containing acetaminophen

Effect of incorporating pharmaceutical excipients on the in vitro release profiles and the release mechanism of monolithic hydroxypropylmethylcellulose (4000 cps) matrix tablets (m-HPMC tablets) in terms of mimicking the dual drug release character of bi-layered Tylenol® ER tablets was studied. We also compared the in vitro release profiles of optimized m-HPMC matrix tablet and Tylenol® ER tablet in water, pH 1.2 gastric fluid, and pH 6.8 intestinal fluid, and in vivo drug bioavailabilities in healthy human volunteers. Acetaminophen was used as the model drug. The m-HPMC tablets were prepared using a wet granulation method followed by direct compression. Release profiles and swelling rates of m-HPMC tablets were found to be highly influenced by the types and amounts of pharmaceutical excipients incorporated. Starch 1500 (Prejel®) and sodium lauryl sulfate (SLS) played a key role in determining the dissolution rate of m-HPMC tablets. Additional excipients, i.e., microcrystalline cellulose (Avicel® PH101) and NaH2PO4 were used to tune the release profiles of m-HPMC tablets. The effect of pharmaceutical excipients on drug release from HPMC-based matrix tablets was found to be mainly due to a change in hydrophilic gel expansion and on physical interactions between the drug and HPMC. The optimized m-HPMC tablet with a balanced ratio of Prejel®, SLS, Avicel® PH101, and NaH2PO4 in the formulation showed dual release profiles in water, pH 1.2 gastric fluid, and pH 6.8 intestinal fluid in vitro. Dual release was defined as immediate drug release within few minutes followed by extended release over 8 h. The similarity factors of m-HPMC tablets and bi-layered Tylenol® ER tablets were 79.8, 66.1, and 82.7 in water, gastric fluid and intestinal fluid, respectively, indicating the equivalence of the two release profiles. No significant in vivo bioavailability differences were observed in healthy human volunteers. The developed m-HPMC tablet with dual release characteristics can be easily prepared using a conventional high-speed tablet machine and could provide an alternative to commercially available bilayered Tylenol® ER tablets.

The effects of pharmaceutical excipients on small intestinal transit.

1. The effect of three iso-osmotic pharmaceutical excipient solutions on gastrointestinal transit were investigated in eight healthy male volunteers. Each subject received 200 ml radiolabelled purified water, or a 200 ml solution of sodium acid pyrophosphate ((SAPP) 1.1 g/200 ml), mannitol (2.264 g/200 ml) or sucrose (4.08 g/200 ml) in a four way cross over design. On each of the study days the volunteers also received five 6 mm diameter non-disintegrating tablets. Dual isotope gamma scintigraphy was used to assess the transit behaviour of the tablets and solutions. 2. There were no significant differences between the gastric emptying times of the four solution formulations. Rapid gastric emptying was observed in all cases (mean t 50% varied from 11-14 min). 3. Small intestinal transit (SIT) times for the SAPP and mannitol solutions were reduced by 39 and 34%, respectively, when compared with the control solution (purified water = 240 min; SAPP = 147 min; mannitol = 158 min). The 95% confidence limits for the mean differences in SIT time between the control and SAPP solutions was 39-94-149 min, and 40-82-124 min between the mannitol and the control. Intestinal transit for the sucrose solution was similar to that for the control solution (sucrose = 229 min). 4. There were no significant differences in the transit times of the non-disintegrating tablet preparations, when co-administered with each solution.(ABSTRACT TRUNCATED AT 250 WORDS)

Assessment of pharmaceutical excipient-induced gastrointestinal mucosal damage in rats in vivo by measuring the permeation of phenolsulfonphthalein.

The effect of pharmaceutical excipients on the gastrointestinal mucosa in rats was examined by measuring the permeation of phenosulfonphthalein (phenol red), a poorly absorbed drug. The urinary recovery after oral administration of phenol red was significantly increased by pretreatment with sodium lauryl sulfate and Triton X-100 in rats. However, pretreatment with polysorbate 80, lactose, fructose, mannitol, calcium citrate, acacia, or polyethylene glycol 4000 had no apparent effect.