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The purpose of this work was to investigate the use of the dimethylaminoethyl methacrylate-copolymer Eudragit EPO (EPO) in oral solubility-enabling formulations for anionic lipophilic drugs, aiming to guide optional formulation design and maximize oral bioavailability. We have studied the solubility, the permeability, and their interplay, using the low-solubility nonsteroidal anti-inflammatory drug mefenamic acid as a model drug. Then, we studied the biorelevant solubility enhancement of mefenamic acid from EPO-based formulations throughout the gastrointestinal tract (GIT), using the pH-dilution dissolution method. EPO allowed a profound and linear solubility increase of mefenamic acid, from 10 μg/mL without EPO to 9.41 mg/mL in the presence of 7.5% EPO (∼940-fold; 37 °C); however, a concomitant decrease of the drug permeability was obtained, both in vitro and in vivo in rats, indicating a solubility-permeability trade-off. In the absence of an excipient, the unstirred water layer (UWL) adjacent to the GI membrane was found to hinder the permeability of the drug, accounting for this UWL effect and revealing that the true membrane permeability allowed good prediction of the solubility-permeability trade-off as a function of EPO level using a direct relationship between the increased solubility afforded by a given EPO level and the consequent decreased permeability. Biorelevant dissolution studies revealed that EPO levels of 0.05 and 0.1% were insufficient to dissolve mefenamic acid dose during the entire dissolution time course, whereas 0.5 and 1% EPO allowed complete solubility with no drug precipitation. In conclusion, EPO may serve as a potent solubility-enabling excipient for BCS class II/IV acidic drugs; however, it should be used carefully. It is prudent to use the minimal EPO amounts just sufficient to dissolve the drug dose throughout the GIT and not more than that. Excess amounts of EPO provide no solubility gain and cause further permeability loss, jeopardizing the overall success of the formulation. This work may help the formulator to hit the optimal solubility-permeability balance, maximizing the oral bioavailability afforded by the formulation.

The main factors influencing the absorption of orally administered drugs are solubility and permeability, which are location-dependent and may vary along the gastrointestinal tract (GIT). The purpose of this work was to investigate segmental-dependent intestinal absorption and its role in controlled-release (CR) drug product development. The solubility/dissolution and permeability of carvedilol (vs. metoprolol) were thoroughly studied, in vitro/in vivo (Octanol-buffer distribution coefficients (Log D), parallel artificial membrane permeability assay (PAMPA), rat intestinal perfusion), focusing on location-dependent effects. Carvedilol exhibits changing solubility in different conditions throughout the GIT, attributable to its zwitterionic nature. A biorelevant pH-dilution dissolution study for carvedilol immediate release (IR) vs. CR scenario elucidates that while the IR dose (25 mg) may dissolve in the GIT luminal conditions, higher doses used in CR products would precipitate if administered at once, highlighting the advantage of CR from the solubility/dissolution point of view. Likewise, segmental-dependent permeability was evident, with higher permeability of carvedilol vs. the low/high Peff marker metoprolol throughout the GIT, confirming it as a biopharmaceutical classification system (BCS) class II drug. Theoretical analysis of relevant physicochemical properties confirmed these results as well. A CR product may shift the carvedilol&rsquo, s solubility behavior from class II to I since only a small dose portion needs to be solubilized at a given time point. The permeability of carvedilol surpasses the threshold of metoprolol jejunal permeability throughout the entire GIT, including the colon, establishing it as a suitable candidate for CR product development. Altogether, this work may serve as an analysis model in the decision process of CR formulation development and may increase our biopharmaceutical understanding of a successful CR drug product.

Vitamin E TPGS (TPGS) has both surfactant and P-glycoprotein (P-gp) inhibitory effects. While surfactants were previously found to cause solubility-permeability tradeoff, TPGS P-gp inhibitory effects may change this unfavorable interplay. The purpose of this research was to investigate the solubility-permeability interplay when using TPGS vs. amorphous solid dispersions (ASD) as oral drug delivery systems for the anticancer, P-gp substrate, lipophilic drug etoposide. The concentration-dependent effects of TPGS (0-100mg/mL) vs. ASD on the solubility of etoposide, as well as the in-vitro (PAMPA) vs. in-vivo (intestinal rat perfusion) permeability of the drug were studied, and the resulting solubility-permeability interplay was analyzed. TPGS above CMC (0.3mg/mL) increased etoposide solubility linearly, and ASD allowed significant supersaturation. Etoposide in-vitro PAMPA permeability decreased markedly with increasing TPGS levels, similarly to the solubility-permeability tradeoff previously defined for surfactants. In contrast, the presence of TPGS significantly increased etoposide in-vivo rat permeability, attributable to P-gp inhibition, similarly to the effect of the potent P-gp inhibitor GF120918 (10µg/mL). High supersaturation achieved via ASD increased the drug's in-vivo permeability to the level obtained by TPGS or GF120918, supporting P-gp saturation. In conclusion, unique pattern of solubility-permeability interplay was found, involving concomitant increase of both the solubility and the permeability, as opposed to the previously reported tradeoff for solubilization methods and the unchanged permeability for supersaturation; P-gp inhibition/saturation by TPGS or by supersaturation allows simultaneous increase of both solubility and permeability, representing a significant advantage of such drug delivery approaches when suitable.

Traditionally, the colon is considered a secondary intestinal segment in the drug absorption process. However, in many cases the role of colonic drug permeability cannot be overlooked. The purpose of this research was to compare colon permeability data obtained using two different rat perfusion methods the single-pass intestinal perfusion (SPIP) approach and the closed-loop (Doluisio) perfusion model. A list of 14 structurally diverse model drugs was constructed, and their rat colon permeability was studied using the two methods. The two sets of results were compared to each other, and were evaluated vs. in-vitro, ex-vivo, and in-vivo literature values. The SPIP and the Doluisio results exhibited good correlation between them (R2=0.81). The best correlation of both sets was obtained with transport studies across Caco-2 monolayers (R2∼0.9), as well as the sigmoidal fit vs. human fraction of dose absorbed (Fabs) data. On the other hand, Ussing chambers data, as well as lipophilicity (Log P) data, resulted in weak correlation to the in-situ results. In conclusion, the single-pass intestinal perfusion (SPIP) and the Doluisio (closed-loop) perfusion models were found to be equally convenient and useful for obtaining validated colon permeability values, although more human colonic Fabs data are needed for a better understanding of colonic drug permeability and absorption.

The purpose of this work was to investigate key factors dictating the success/failure of cyclodextrin-based solubility-enabling formulations for oral delivery of low-solubility drugs. We have studied the solubility, the permeability, and the solubility–permeability interplay, of the highly lipophilic drug danazol, formulated with different levels (8.5, 10, 20, and 30%) of the commonly used hydroxypropyl-β-cyclodextrin (HPβCD), accounting for the biorelevant solubilization of the drug along the gastrointestinal tract (GIT), the unstirred water layer (UWL) adjacent to the GI membrane, and the overall absorption. HPβCD significantly increased danazol solubility, and decreased the drugs’ permeability, in a concentration-dependent manner. These Peff results were in good correlation (R2 = 0.977) to literature rat AUC data of the same formulations. Unlike vehicle without HPβCD, formulations containing 8.5% HPβCD and above were shown to successfully dissolve the drug dose during the entire biorelevant dissolution...

Injectable-to-oral conversions for anticancer drugs represent an important trend. The goal of this research was to investigate the suitability of formulation approaches for anticancer oral drug delivery, aiming to reveal mechanistic insights that may guide oral chemotherapy development. TPGS vs. PEG-400 were studied as oral formulations for the anticancer drug etoposide, accounting for drug solubility, biorelevant dissolution, permeability, solubility-permeability interplay, and overall bioavailability. Increased etoposide solubility was demonstrated with both excipients. Biorelevant dissolution revealed that TPGS or PEG-400, but not aqueous suspension, allowed complete dissolution of the entire drug dose. Both TPGS and PEG-400 resulted in decreased in-vitro etoposide permeability across artificial membrane, i.e. solubility-permeability tradeoff. While PEG-400 resulted in the same solubility-permeability tradeoff also in-vivo, TPGS showed the opposite trend: the in-vivo permeability of etoposide was markedly increased in the presence of TPGS. This increased permeability was similar to the drug permeability under P-gp inhibition. Rat PK study demonstrated significantly higher etoposide bioavailability from TPGS vs. PEG-400 or suspension (AUC of 72, 41, and 26 µg·min/mL, respectively). All in all, TPGS-based delivery system allows overcoming the solubility-permeability tradeoff, increasing systemic etoposide exposure. Since poor solubility and strong efflux are common to many anticancer agents, this work can aid in the development of better oral delivery approach for chemotherapeutic drugs.

Bariatric surgery is the most effective solution for severe obesity and obesity with comorbidities, and the number of patients going through bariatric surgery is rapidly and constantly growing. The modified gastrointestinal anatomy of the patient may lead to significant pharmacokinetic alterations in the oral absorption of drugs after the surgery; however, because of insufficient available literature and inadequate awareness of the medical team, bariatric surgery patients may be discharged from the hospital with insufficient instructions regarding their medication therapy. In this article, we aim to present the various mechanisms by which bariatric surgery may influence oral drug absorption, to provide an overview of the currently available literature on the subject, and to draw guidelines for the recommendations bariatric surgery patients should be instructed before leaving the hospital. To date, and until more robust data are published, it is essential to follow and monitor patients closely for safety and efficacy of their medication therapies, both in the immediate and distant time post-surgery.

The purpose of this research was to investigate drug dose, solubility, permeability, and their interplay, as key factors in oral formulation development for lipophilic drugs. A PEG400-based formulation was studied for five doses of the lipophilic drug carbamazepine, accounting for biorelevant dissolution of the dose in the GIT, and in-vivo bioavailability in rats. With the three lower doses (10, 25 and 50 mg/kg), complete in-vitro dissolution was achieved and maintained throughout the experiment with this formulation, while significant precipitation was obtained with higher doses (100 and 200 mg/kg). Likewise, the studied formulation allowed complete bioavailability in-vivo with the three lower doses, while the same formulation allowed only 76% and 42% bioavailability for the 100 and 200 mg/kg doses, respectively. There was good correlation between the in-vitro and in-vivo results. In conclusion, this work demonstrates that the dose is a crucial factor in formulation development; while a given formulation may be optimal for a certain drug dose, it may no longer be optimal for higher doses of the same drug. Hence, the solubility, the permeability, and their interplay, have to be considered in light of the drug dose intended to be administered in order to achieve successful oral formulation development.

Oral drug bioavailability may be significantly altered after laparoscopic sleeve gastrectomy (LSG), the most popular bariatric procedure worldwide. Paracetamol (acetaminophen) is the post-bariatric analgesic/antipyretic drug of choice. In this work we studied and analyzed the LSG effects on systemic bioavailability and pharmacokinetics of paracetamol after oral administration of solid vs. liquid dosage form. A 4-armed, pharmacokinetic, crossover trial was performed in patients enrolled for LSG. Single paracetamol dose (500 mg), as caplet (n = 7) or syrup (n = 5), was administered before vs. 4&ndash, 6 months post-LSG. Bioavailability was enhanced after LSG, in the caplet groups, average AUC0&ndash, t increased from 9.1 to 18.6 &micro, g&middot, h/mL with AUC0&ndash, t difference of 9.5 &micro, h/mL (95% CI 4.6&ndash, 14.5, p = 0.003). Cmax increased from 1.8 (95% CI 1.2&ndash, 2.5) to 4.2 &micro, g/mL (3.6&ndash, 4.8) after LSG (p = 0.032). In the syrup groups, AUC0&ndash, t increased from 13.4 to 25.6 &micro, h/mL, with AUC0&ndash, t difference of 12.2 &micro, h/mL (95% CI 0.9&ndash, 23.5, p = 0.049). Cmax changed from 5.4 (95% CI 2.5&ndash, 8.4) to 7.8 &micro, g/mL (6.1&ndash, 9.6), and systemic bioavailability was complete (102%) after the surgery. Overall, decreased paracetamol exposure in obesity, with recovery to normal drug levels (caplet) or even higher (syrup) post-LSG, was revealed. In conclusion, attention to paracetamol effectiveness/safety in obesity, and after bariatric surgery, is prudent.

Background Bariatric surgery can lead to changes in the oral absorption of many drugs. Levothyroxine is a narrow therapeutic drug for hypothyroidism, a common condition among patients with obesity. Objective The purpose of this work was to provide a mechanistic overview of levothyroxine absorption, and to thoroughly analyze the expected effects of bariatric surgery on oral levothyroxine therapy. Methods We performed a systematic review of the relevant literature reporting the effects of bariatric surgery on oral levothyroxine absorption and postoperative thyroid function. A PubMed search for relevant keywords resulted in a total of 14 articles reporting levothyroxine status before versus after bariatric surgery. Results Different mechanisms may support opposing trends as to levothyroxine dose adjustment postsurgery. On the one hand, based on impaired drug solubility/dissolution attributable to higher gastric pH as well as reduced gastric volume, compromised levothyroxine absorption is expected. On the other hand, the great weight loss, and altered set-point of thyroid hormone homeostasis with decreased thyroid-stimulating hormone after the surgery, may result in a decreased dose requirement. Conclusions For patients after bariatric surgery, close monitoring of both the clinical presentation and plasma thyroid-stimulating hormone and T4 levels is strongly advised. Better understanding and awareness of the science presented in this article may help to avoid preventable complications and provide optimal patient care.

The goal of this work was to develop an in silico model that allows predicting segmental-dependent permeability throughout the small intestine (SI). In vivo permeability of 11 model drugs in 3 SI segments (jejunum, mid-SI, ileum) was studied in rats, creating a data set that reflects the conditions throughout the SI. Then, a predictive model was developed, combining physicochemical drug properties influencing the underlying mechanism of passive permeability: Log p, polar surface area, MW, H-bond count, and Log fu, with microenvironmental SI conditions. Excellent correlation was evident between the predicted and experimental data (R2 = 0.914), with similar predictability in each SI segment. Log p and Log fu were identified as the major determinants of permeability, with similar contribution. Total H-bond count was also a significant determinant, followed by polar surface area and MW. Leaving out any of the model parameters decreased its predictability. The model was validated against 5 external drugs, with excellent predictability. Notably, the model was able to predict the segmental-dependent permeability of all drugs showing this trend experimentally. Model predictability was better in the high-permeability versus low-permeability range. Overall, our approach of constructing a straightforward in silico model allowed reliable predictions of segmental-dependent intestinal permeability, providing new insights into relative effects of drug-related factors and gastrointestinal environment on permeability.

The effective rat intestinal permeability (P eff ) was deconvolved using a biophysical model based on parameterized paracellular, aqueous boundary layer, transcellular permeabilities, and the villus-fold surface area expansion factor. Four types of rat intestinal perfusion data were considered: single-pass intestinal perfusion (SPIP) in the jejunum (n = 40), and colon (n = 15), closed-loop (Doluisio type) in the small intestine (n = 78), and colon (n = 74). Moreover, in vitro Caco-2 permeability values were used to predict rat in vivo values in the rat data studied. Comparable number of molecules permeate via paracellular water channels as by the lipoidal transcellular route in the SPIP method, although in the closed-loop method, the paracellular route appears dominant in the colon. The aqueous boundary layer thickness in the small intestine is comparable to that found in unstirred in vitro monolayer assays; it is thinner in the colon. The mucosal surface area in anaesthetized rats is 0.96–1.4 times the smooth cylinder calculated value in the colon, and it is 3.1–3.6 times in the small intestine. The paracellular permeability of the intestine appeared to be greater in rat than human, with the colon showing more leakiness (higher P para ) than the small intestine. Based on log intrinsic permeability values, the correlations between the in vitro and in vivo models ranged from r2 0.82 to 0.92. The SPIP-Doluisio method comparison indicated identical log permeability selectivity trend with negligible bias.

Rifaximin is a BCS class IV (low-solubility, low-permeability) drug and also a P-gp substrate. The aims of this work were to assess the efficiency of different rifaximin amorphous solid dispersion (ASDs) formulations in achieving and maintaining supersaturation and to investigate the consequent solubility-permeability interplay. Spray-dried rifaximin ASDs were prepared with different hydrophilic polymers and their ability to achieve and maintain supersaturation was assessed. Then, rifaximin’s apparent intestinal permeability was investigated as a function of increasing supersaturation both in vitro using the parallel artificial membrane permeability assay (PAMPA) and in vivo using the single-pass rat intestinal perfusion (SPIP) model. The efficiency of the different ASDs to achieve and maintain supersaturation of rifaximin was found to be highly polymer dependent, and the copovidone/HPC-SL formulation was found to be superior to the other two, allowing supersaturation of 200× that of the crystalline solubility for 20 h. In vitro, rifaximin flux was increased and the apparent permeability was constant as a function of increasing supersaturation level. In vivo, on the other hand, absorption rate coefficient (k a) was first constant as a function of increasing supersaturation, but at 250×, the crystalline solubility k a was doubled, similar to the k a in the presence of the strong P-gp inhibitor GF120918. In conclusion, a new and favorable nature of solubility-permeability interplay was revealed in this work: delivering high supersaturation level of the BCS class IV drug rifaximin via ASD, thereby saturating the drugs’ P-gp-mediated efflux transport, led to the favorable unique win-win situation, where both the solubility and the permeability increased simultaneously.

Bariatric surgery is the most effective solution for severe obesity and obesity with comorbidities, and the number of patients going through bariatric surgery is rapidly and constantly growing. The modified gastrointestinal anatomy of the patient may lead to significant pharmacokinetic alterations in the oral absorption of drugs after the surgery; however, because of insufficient available literature and inadequate awareness of the medical team, bariatric surgery patients may be discharged from the hospital with insufficient instructions regarding their medication therapy. In this article, we aim to present the various mechanisms by which bariatric surgery may influence oral drug absorption, to provide an overview of the currently available literature on the subject, and to draw guidelines for the recommendations bariatric surgery patients should be instructed before leaving the hospital. To date, and until more robust data are published, it is essential to follow and monitor patients closely for safety and efficacy of their medication therapies, both in the immediate and distant time post-surgery.