RESUMO
Omega-3 polyunsaturated fatty acids (n-3 PUFA) are essential nutrients for human health and have been linked to a variety of health benefits, including reducing the risk of cardiovascular diseases. In this paper, a spray-dried powder formulation based on Pickering emulsions stabilized with cellulose nanocrystals (CNC) and hydroxypropyl methylcellulose (HPMC) has been developed. The formulation was compared in vitro and in vivo to reference emulsions (conventional Self-Emulsifying Drug Delivery System, SEDDS) to formulate n-3 PUFA pharmaceutical products, specifically in free fatty acid form. The results of in vivo studies performed in fasted dogs showed that Pickering emulsions reconstituted from powders are freely available (fast absorption) with a similar level of bioavailability as reference emulsions. In the studies performed with dogs in the fed state, the higher bioavailability combined with slower absorption observed for the Pickering emulsion, compared to the reference, was proposed to be the result of the protection of the n-3 PUFAs (in free fatty acid form) against oxidation in the stomach by the solid particles stabilizing the emulsion. This observation was supported by promising results from short-term studies of chemical stability of powders with n-3 PUFA loads as high as 0.8 g oil/g powder that easily regain the original emulsion drop sizes upon reconstitution. The present work has shown that Pickering emulsions may offer a promising strategy for improving the bioavailability and stability as well as providing an opportunity to produce environmentally friendly (surfactant free) and patient-acceptable solid oral dosage forms of n-3 PUFA in the free fatty acid form.
Assuntos
Ácidos Graxos não Esterificados , Ácidos Graxos Ômega-3 , Humanos , Animais , Cães , Emulsões/química , Pós , Ácidos Graxos Insaturados , Tamanho da PartículaRESUMO
In this work, we set out to better understand how the permeation enhancer sodium caprate (C10) influences the intestinal absorption of macromolecules. FITC-dextran 4000 (FD4) was selected as a model compound and formulated with 50-300 mM C10. Absorption was studied after bolus instillation of liquid formulation to the duodenum of anesthetized rats and intravenously as a reference, whereafter plasma samples were taken and analyzed for FD4 content. It was found that the AUC and Cmax of FD4 increased with increasing C10 concentration. Higher C10 concentrations were associated with an increased and extended absorption but also increased epithelial damage. Depending on the C10 concentration, the intestinal epithelium showed significant recovery already at 60-120 min after administration. At the highest studied C10 concentrations (100 and 300 mM), the absorption of FD4 was not affected by the colloidal structures of C10, with similar absorption obtained when C10 was administered as micelles (pH 8.5) and as vesicles (pH 6.5). In contrast, the FD4 absorption was lower when C10 was administered at 50 mM formulated as micelles as compared to vesicles. Intestinal dilution of C10 and FD4 revealed a trend of decreasing FD4 absorption with increasing intestinal dilution. However, the effect was smaller than that of altering the total administered C10 dose. Absorption was similar when the formulations were prepared in simulated intestinal fluids containing mixed micelles of bile salts and phospholipids and in simple buffer solution. The findings in this study suggest that in order to optimally enhance the absorption of macromolecules, high (≥100 mM) initial intestinal C10 concentrations are likely needed and that both the concentration and total dose of C10 are important parameters.
Assuntos
Coloides/química , Ácidos Decanoicos/farmacologia , Absorção Intestinal/efeitos dos fármacos , Mucosa Intestinal/efeitos dos fármacos , Animais , Microscopia Crioeletrônica , Ácidos Decanoicos/análise , Ácidos Decanoicos/química , Dextranos/farmacologia , Sinergismo Farmacológico , Fluoresceína-5-Isotiocianato/análogos & derivados , Fluoresceína-5-Isotiocianato/farmacologia , Mucosa Intestinal/química , Masculino , Ratos , Ratos WistarRESUMO
In this work, we studied the intestinal absorption of a peptide with a molecular weight of 4353 Da (MEDI7219) and a protein having a molecular weight of 11â¯740 Da (PEP12210) in the rat intestinal instillation model and compared their absorption to fluorescein isothiocyanate (FITC)-labeled dextrans of similar molecular weights (4 and 10 kDa). To increase the absorption of the compounds, the permeation enhancer sodium caprate (C10) was included in the liquid formulations at concentrations of 50 and 300 mM. All studied compounds displayed an increased absorption rate and extent when delivered together with 50 mM C10 as compared to control formulations not containing C10. The time period during which the macromolecules maintained an increased permeability through the intestinal epithelium was approximately 20 min for all studied compounds at 50 mM C10. For the formulations containing 300 mM C10, it was noted that the dextrans displayed an increased absorption rate (compared to 50 mM C10), and their absorption continued for at least 60 min. The absorption rate of MEDI7219, on the other hand, was similar at both studied C10 concentrations, but the duration of absorption was extended at the higher enhancer concentration, leading to an increase in the overall extent of absorption. The absorption of PEP12210 was similar in terms of the rate and duration at both studied C10 concentrations. This is likely caused by the instability of this molecule in the intestinal lumen. The degradation decreases the luminal concentrations over time, which in turn limits absorption at time points beyond 20 min. The results from this study show that permeation enhancement effects cannot be extrapolated between different types of macromolecules. Furthermore, to maximize the absorption of a macromolecule delivered together with C10, prolonging the duration of absorption appears to be important. In addition, the macromolecule needs to be stable enough in the intestinal lumen to take advantage of the prolonged absorption time window enabled by the permeation enhancer.
Assuntos
Dextranos , Absorção Intestinal , Animais , Fluoresceína-5-Isotiocianato , Mucosa Intestinal/metabolismo , Permeabilidade , RatosRESUMO
Currently, the screening of new drug candidates for intestinal permeation is typically based on in vitro models which give no information regarding regional differences along the gut. When evaluation of intestinal permeability by region is undertaken, two preclinical rat models are commonly used, the Ussing chamber method and single-pass intestinal perfusion (SPIP). To investigate the robustness of in vivo predictions of human intestinal permeability, a set of four model compounds was systematically investigated in both these models, using tissue specimens and segments from the jejunum, ileum, and colon of rats from the same genetic strain. The influence of luminal pH was also determined at two pH levels. Ketoprofen had high and enalaprilat had low effective (Peff) and apparent (Papp) permeability in all three regions and at both pH levels. Metoprolol had high Peff in all regions and at both pHs and high Papp at both pHs and in all regions except the jejunum, where Papp was low. Atenolol had low Peff in all regions and at both pHs, but had high Papp at pH 6.5 and low Papp at pH 7.4. There were good correlations between these rat in situ Peff (SPIP) and human in vivo Peff determined previously for the same compounds by both intestinal perfusion of the jejunum and regional intestinal dosing. The results of this study indicate that both investigated models are suitable for determining the regional permeability of the intestine; however, the SPIP model seems to be the more robust and accurate regional permeability model.
Assuntos
Absorção Fisiológica , Avaliação Pré-Clínica de Medicamentos/métodos , Absorção Intestinal/fisiologia , Modelos Animais , Ratos , Animais , Biofarmácia/métodos , Colo/metabolismo , Concentração de Íons de Hidrogênio , Íleo/metabolismo , Mucosa Intestinal/metabolismo , Jejuno/metabolismo , Masculino , Perfusão/métodos , Permeabilidade , Ratos WistarRESUMO
Over recent decades there has been an increase in the proportion of BCS class II and IV drug candidates in industrial drug development. To overcome the biopharmaceutical challenges associated with the less favorable properties of solubility and/or intestinal permeation of these substances, the development of formulations containing nanosuspensions of the drugs has been suggested. The intestinal absorption of aprepitant from two nanosuspensions (20 µM and 200 µM total concentrations) in phosphate buffer, one nanosuspension (200 µM) in fasted-state simulated intestinal fluid (FaSSIF), and one solution (20 µM) in FaSSIF was investigated in the rat single-pass intestinal perfusion model. The disappearance flux from the lumen (Jdisapp) was faster for formulations containing a total concentration of aprepitant of 200 µM than for those containing 20 µM, but was unaffected by the presence of vesicles. The flux into the systemic circulation (Japp) and, subsequently, the effective diffusion constant (Deff) were calculated using the plasma concentrations. Japp was, like Jdisapp, faster for the formulations containing higher total concentrations of aprepitant, but was also faster for those containing vesicles (ratios of 2 and 1.5). This suggests that aprepitant is retained in the lumen when presented as nanoparticles in the absence of vesicles. In conclusion, increased numbers of nanoparticles and the presence of vesicles increased the rate of transport and availability of aprepitant in plasma. This effect can be attributed to an increased rate of mass transport through the aqueous boundary layer (ABL) adjacent to the gut wall.
Assuntos
Antieméticos/farmacocinética , Absorção Intestinal , Mucosa Intestinal/metabolismo , Morfolinas/farmacocinética , Animais , Antieméticos/química , Aprepitanto , Disponibilidade Biológica , Biofarmácia/métodos , Química Farmacêutica , Masculino , Modelos Animais , Morfolinas/química , Nanopartículas/química , Perfusão/métodos , Ratos , Ratos Wistar , Solubilidade , SuspensõesRESUMO
Currently there are only a limited number of determinations of human Peff in the distal small intestine and none in the large intestine. This has hindered the validation of preclinical models with regard to absorption in the distal parts of the intestinal tract, which can be substantial for BCS class II-IV drugs, and drugs formulated into modified-release (MR) dosage forms. To meet this demand, three model drugs (atenolol, metoprolol, and ketoprofen) were dosed in solution intravenously, and into the jejunum, ileum, and colon of 14 healthy volunteers. The Peff of each model drug was then calculated using a validated deconvolution method. The median Peff of atenolol in the jejunum, ileum, and colon was 0.45, 0.15, and 0.013 × 10(-4) cm/s, respectively. The corresponding values for metoprolol were 1.72, 0.72, and 1.30 × 10(-4) cm/s, and for ketoprofen 8.85, 6.53, and 3.37 × 10(-4) cm/s, respectively. This is the first study where the human Peff of model drugs has been determined in all parts of the human intestinal tract in the same subjects. The jejunal values were similar to directly determined values using intestinal single-pass perfusion, indicating that the deconvolution method is a valid approach for determining regional Peff. The values from this study will be highly useful in the validation of preclinical regional absorption models and in silico tools.
Assuntos
Absorção Intestinal/fisiologia , Mucosa Intestinal/metabolismo , Adolescente , Adulto , Atenolol/metabolismo , Atenolol/farmacocinética , Colo/metabolismo , Feminino , Humanos , Íleo/metabolismo , Intestino Delgado/metabolismo , Jejuno/metabolismo , Cetoprofeno/metabolismo , Cetoprofeno/farmacocinética , Masculino , Metoprolol/metabolismo , Metoprolol/farmacocinética , Pessoa de Meia-Idade , Permeabilidade , Adulto JovemRESUMO
The development of oral modified-release (MR) dosage forms requires an active pharmaceutical ingredient (API) with a sufficiently high absorption rate in both the small and large intestine. Dogs are commonly used in preclinical evaluation of regional intestinal absorption and in the development of novel MR dosage forms. This study determined regional intestinal effective permeability (Peff) in dogs with the aim to improve regional Peff prediction in humans. Four model drugs, atenolol, enalaprilat, metoprolol, and ketoprofen, were intravenously and regionally dosed twice as a solution into the proximal small intestine (P-SI) and large intestine (LI) of three dogs with intestinal stomas. Based on plasma data from two separate study occasions for each dog, regional Peff values were calculated using a validated intestinal deconvolution method. The determined mean Peff values were 0.62, 0.14, 1.06, and 3.66 × 10(-4) cm/s in the P-SI, and 0.13, 0.02, 1.03, and 2.20 × 10(-4) cm/s in the LI, for atenolol, enalaprilat, metoprolol, and ketoprofen, respectively. The determined P-SI Peff values in dog were highly correlated (R(2) = 0.98) to the historically directly determined human jejunal Peff after a single-pass perfusion. The determined dog P-SI Peff values were also successfully implemented in GI-Sim to predict the risk for overestimation of LI absorption of low permeability drugs. We conclude that the dog intestinal stoma model is a useful preclinical tool for determination of regional intestinal permeability. Still, further studies are recommended to evaluate additional APIs, sources of variability, and formulation types, for more accurate determination of the dog model in the drug development process.
Assuntos
Intestino Grosso/metabolismo , Intestino Delgado/metabolismo , Animais , Atenolol/farmacocinética , Cães , Enalaprilato/farmacocinética , Humanos , Absorção Intestinal , Jejuno/metabolismo , Cetoprofeno/farmacocinética , Masculino , Metoprolol/farmacocinética , PermeabilidadeRESUMO
Selection of excipients for drug formulations requires both intellectual and experimental considerations as many of the used excipients are affected by physiological factors, e.g., they may be digested by pancreatic enzymes in the gastrointestinal tract. In the present paper we have looked systematically into the differences between Kolliphor ELP, EL, and RH40 and how they affect the bioavailability of fenofibrate, through pharmacokinetic studies in rats and in vitro lipolysis studies. The study design was made as simple as possible to avoid confounding factors, for which reason the tested formulations only comprised an aqueous micellar solution of the model drug (fenofibrate) in varying concentrations (2-25% (w/v)) of the three tested surfactants. Increased concentrations of Kolliphor ELP and EL led to increased fenofibrate AUC0-24h values. For the Kolliphor RH40 formulations, an apparent fenofibrate absorption optimum was seen at 15% (w/v) surfactant, displaying both the highest AUC0-24h and Cmax. The reduced absorption of fenofibrate from the formulation containing the highest level of surfactant (25% w/v) was thought to be caused by some degree of trapping within Kolliphor RH40 micelles. In vitro, Kolliphor ELP and EL were found to be more prone to digestion than Kolliphor RH40, though not affecting the in vivo results. The highest fenofibrate bioavailability was attained from formulations with high Kolliphor ELP/EL levels (25% (w/v)), indicating that these surfactants are the better choice for solubilizing fenofibrate in order to increase the absorption upon oral administration. Due to drug dependent effects of the different types of Kolliphor, more studies are recommended in order to understand which type of Kolliphor is best suited for a given drug.
Assuntos
Fenofibrato/administração & dosagem , Polietilenoglicóis/química , Tensoativos/química , Administração Oral , Animais , Área Sob a Curva , Química Farmacêutica/métodos , Cromatografia Líquida de Alta Pressão , Excipientes , Absorção Intestinal , Lipídeos , Lipólise , Masculino , Micelas , Tamanho da Partícula , Veículos Farmacêuticos , Ratos , Ratos Sprague-Dawley , Solubilidade , Óleo de Soja/químicaRESUMO
The use of animal experiments can be minimized with computational models capable of reflecting the simulated environments. One such environment is intestinal fluid and the colloids formed in it. In this study we used molecular dynamics simulations to investigate solubilization patterns for three model drugs (carvedilol, felodipine and probucol) in dog intestinal fluid, a lipid-based formulation, and a mixture of both. We observed morphological transformations that lipids undergo due to the digestion process in the intestinal environment. Further, we evaluated the effect of bile salt concentration and observed the importance of interindividual variability. We applied two methods of estimating solubility enhancement based on the simulated data, of which one was in good qualitative agreement with the experimentally observed solubility enhancement. In addition to the computational simulations, we also measured solubility in i) aspirated dog intestinal fluid samples and ii) simulated canine intestinal fluid in the fasted state, and found there was no statistical difference between the two. Hence, a simplified dissolution medium suitable for in vitro studies provided physiologically relevant data for the systems explored. The computational protocol used in this study, coupled with in vitro studies using simulated intestinal fluids, can serve as a useful prescreening tool in the process of drug delivery strategies development.
Assuntos
Felodipino , Simulação de Dinâmica Molecular , Solubilidade , Cães , Animais , Felodipino/administração & dosagem , Felodipino/farmacocinética , Felodipino/química , Probucol/administração & dosagem , Probucol/farmacocinética , Probucol/química , Carvedilol/administração & dosagem , Carvedilol/farmacocinética , Carvedilol/química , Lipídeos/química , Líquidos Corporais/química , Líquidos Corporais/metabolismo , Ácidos e Sais Biliares/química , Masculino , Secreções Intestinais/químicaRESUMO
A Biopharmaceutics Classification System (BCS)-based biowaiver monograph is presented for isavuconazonium sulfate. A BCS-based biowaiver is a regulatory option to substitute appropriate in vitro data for in vivo bioequivalence studies. Isavuconazonium sulfate is the prodrug of isavuconazole, a broad-spectrum azole antifungal indicated for invasive fungal infections. While the prodrug can be classified as a BCS Class III drug with high solubility but low permeability, the parent drug can be classified as a BCS Class II drug with low solubility but high permeability. Interestingly, the in vivo behavior of both is additive and leads isavuconazonium sulfate to act like a BCS class I drug substance after oral administration. In this work, experimental solubility and dissolution data were evaluated and compared with available literature data to investigate whether it is feasible to approve immediate release solid oral dosage forms containing isavuconazonium sulfate according to official guidance from the FDA, EMA and/or ICH. The risks associated with waiving a prodrug according to the BCS-based biowaiver guidelines are reviewed and discussed, noting that current regulations are quite restrictive on this point. Further, results show high solubility but instability of isavuconazonium sulfate in aqueous media. Although experiments on the dissolution of the capsule contents confirmed 'very rapid' dissolution of the active pharmaceutical ingredient (API) isavuconazonium sulfate, its release from the commercial marketed capsule formulation Cresemba is limited by the choice of capsule shell material, providing an additional impediment to approval of generic versions via the BCS-Biowaiver approach.
Assuntos
Nitrilas , Pró-Fármacos , Piridinas , Triazóis , Disponibilidade Biológica , Equivalência Terapêutica , Biofarmácia/métodos , Administração Oral , Solubilidade , Formas de Dosagem , PermeabilidadeRESUMO
Lemborexant is a dual orexin receptor antagonist assigned to class II of the Biopharmaceutics Classification System (BCS). Thus, the ICH M9 Guideline excludes immediate-release (IR) solid oral dosage forms containing lemborexant from BCS-based biowaivers, irrespective of their in vitro dissolution behavior. By contrast, classification of lemborexant according to the refined Developability Classification System (rDCS) falls into class I, indicating few biopharmaceutics risks. Customized rDCS investigations identify dissolution as the main risk factor, in line with clinical data in humans which suggest that the absorption of lemborexant is limited neither by solubility nor by permeability. Instead, any risks lie in dissolution. Analysis by the rDCS coupled with biorelevant dissolution testing thus provides a way forward for manufacturers to mitigate the risks associated with changes in formulation or introduction of a generic version prior to running clinical bioequivalence (BE) studies. As a way forward regarding biowaivers for lemborexant and similar cases, where justifying BE based on the current BCS-based approach is not possible, a four-step pathway towards establishing BE virtually could be adopted as follows: (i) rDCS analysis to identify critical bioavailability attributes, (ii) comparative (biorelevant) dissolution testing, (iii) Physiologically Based Biopharmaceutics Modeling (PBBM), and (iv) virtual BE assessment.
RESUMO
The present monograph discusses the possibility of BCS-based biowaivers for immediate release pharmaceutical products containing raltegravir potassium, which is used to treat human immunodeficiency virus (HIV) infections. Raltegravir potassium can be assigned to BCS class II or IV since this compound has low solubility and uncertain permeability. Therefore, according to the ICH M9 guideline, it is not recommended to apply BCS-based biowaiver to approval of immediate release solid dosage forms of raltegravir potassium, either for new generic versions or when moderate to major changes in composition and/or the manufacturing method of the product are made.
RESUMO
In this monograph, the potential use of methods based on the Biopharmaceutics Classification System (BCS) framework to evaluate the bioequivalence of solid immediate-release (IR) oral dosage forms containing fexofenadine hydrochloride as a substitute for a pharmacokinetic study in human volunteers is investigated. We assessed the solubility, permeability, dissolution, pharmacokinetics, pharmacodynamics, therapeutic index, bioavailability, drug-excipient interaction, and other properties using BCS recommendations from the ICH, FDA and EMA. The findings unequivocally support fexofenadine's classification to BCS Class IV as it is neither highly soluble nor highly permeable. Further impeding the approval of generic equivalents through the BCS-biowaiver pathway is the reference product's inability to release ≥ 85 % of the drug substance within 30 min in pH 1.2 and pH 4.5 media. According to ICH rules, BCS class IV drugs do not qualify for waiving clinical bioequivalence studies based on the BCS, even though fexofenadine has behaved more like a BCS class I/III than a class IV molecule in pharmacokinetic studies to date and has a wide therapeutic index.
Assuntos
Disponibilidade Biológica , Solubilidade , Terfenadina , Equivalência Terapêutica , Terfenadina/análogos & derivados , Terfenadina/farmacocinética , Terfenadina/administração & dosagem , Terfenadina/química , Humanos , Administração Oral , Excipientes/química , Biofarmácia/métodos , PermeabilidadeRESUMO
PURPOSE: To investigate the effect of increasing the loading level of the poorly soluble drug cinnarizine in a self-nanoemulsifying drug delivery system (SNEDDS) both in vitro and in vivo. METHODS: A fixed dose of cinnarizine was administered orally to dogs in solution in different amounts of SNEDDS vehicle. Furthermore, the SNEDDSs were characterised using the dynamic in vitro lipolysis model. RESULTS: Statistical differences in bioavailability were not obtained between the different amounts of SNEDDS vehicle, in spite of differences in the tendency of cinnarizine to precipitate during in vitro lipolysis of the treatments. Use of the SNEDDS concept decreased the variation in cinnarizine exposure observed between dogs as compared to administering cinnarizine in an aqueous suspension. CONCLUSIONS: Optimization of SNEDDSs towards keeping the drug compound in solution upon in vitro lipolysis of the SNEDDSs may not be as important as previously suggested.
Assuntos
Bloqueadores dos Canais de Cálcio/administração & dosagem , Cinarizina/administração & dosagem , Portadores de Fármacos/metabolismo , Emulsões/metabolismo , Lipólise , Administração Oral , Animais , Disponibilidade Biológica , Células CACO-2 , Bloqueadores dos Canais de Cálcio/química , Bloqueadores dos Canais de Cálcio/farmacocinética , Cinarizina/química , Cinarizina/farmacocinética , Cães , Portadores de Fármacos/química , Emulsões/química , Humanos , Lipídeos/química , Masculino , SolubilidadeRESUMO
Levocetirizine, a histamine H1-receptor antagonist, is prescribed to treat uncomplicated skin rashes associated with chronic idiopathic urticaria as well as the symptoms of both seasonal and continual allergic rhinitis. In this monograph, the practicality of using Biopharmaceutics Classification System (BCS) based methodologies as a substitute for pharmacokinetic studies in human volunteers to appraise the bioequivalence of immediate-release (IR) oral, solid dosage forms containing levocetirizine dihydrochloride was investigated, using data from the literature and in-house testing. Levocetirizine's solubility and permeability properties, as well as its dissolution from commercial products, its therapeutic uses, therapeutic index, pharmacokinetics and pharmacodynamic traits, were reviewed in accordance with the BCS, along with any reports in the literature about failure to meet bioequivalence (BE) requirements, bioavailability issues, drug-excipient interactions as well as other relevant information. The data presented in this monograph unequivocally point to classification of levocetirizine in BCS Class 1. For products that are somewhat supra-equivalent or somewhat sub-equivalent, clinical risks are expected to be insignificant in light of levocetirizine's wide therapeutic index and unlikelihood of severe adverse effects. After careful consideration of all the information available, it was concluded that the BCS-based biowaiver can be implemented for products which contain levocetirizine dihydrochloride, provided (a) the test product comprises excipients that are typically found in IR oral, solid drug products that have been approved by a country belonging to or associated with ICH and are used in quantities that are typical for such products, (b) data supporting the BCS-based biowaiver are gathered using ICH-recommended methods, and (c) all in vitro dissolution requirements specified in the ICH guidance are met by both the test and comparator products (in this case, the comparator is the innovator product).
Assuntos
Biofarmácia , Cetirizina , Humanos , Equivalência Terapêutica , Disponibilidade Biológica , Biofarmácia/métodos , Administração Oral , Solubilidade , Formas de Dosagem , PermeabilidadeRESUMO
This work describes the potential applicability of the BCS-based Biowaiver to oral solid dosage forms containing Levamisole hydrochloride, an anthelmintic drug on the WHO List of Essential Medicines. Solubility and permeability data of levamisole hydrochloride were searched in the literature and/or measured experimentally. Levamisole hydrochloride is a highly soluble drug, but there is no clear evidence of high permeability in humans, indicating that it should provisionally be assigned to BCS class III. The biowaiver procedure would thus be applicable for solid oral dosage forms containing levamisole hydrochloride as the only active ingredient. Due to the lack of data in the literature regarding excipient effects on the bioequivalence of products containing levamisole, it is currently recommended that the products comply with the ICH and WHO guidelines: the test formulation should have the same qualitative composition as the comparator, contain very similar quantities of those excipients, and be very rapidly dissolving at pH 1.2, 4.5, and 6.8. However, for certain well-studied excipients, there appears to be opportunity for additional regulatory relief in future versions of the ICH BCS Guidance M9, such as not requiring that the quantities of these common excipients in the test and comparator be the same.
Assuntos
Biofarmácia , Levamisol , Humanos , Disponibilidade Biológica , Biofarmácia/métodos , Excipientes/química , Equivalência Terapêutica , Solubilidade , Permeabilidade , Formas de Dosagem , Administração OralRESUMO
The bioavailability of peptides co-delivered with permeation enhancers following oral administration remains low and highly variable. Two factors that may contribute to this are the dilution of the permeation enhancer in the intestinal fluid, as well as spreading of the released permeation enhancer and peptide in the lumen by intestinal motility. In this work we evaluated an Intestinal Administration Device (IAD) designed to reduce the luminal dilution of drug and permeation enhancer, and to minimize movement of the dosage form in the intestinal lumen. To achieve this, the IAD utilizes an expanding design that holds immediate release mini tablets and places these in contact with the intestinal epithelium, where unidirectional drug release can occur. The expanding conformation limits movement of the IAD in the intestinal tract, thereby enabling drug release at a single focal point in the intestine. A pig model was selected to study the ability of the IAD to promote intestinal absorption of the peptide MEDI7219 formulated together with the permeation enhancer sodium caprate. We compared the IAD to intestinally administered enteric coated capsules and an intestinally administered solution. The IAD restricted movement of the immediate release tablets in the small intestine and histological evaluation of the mucosa indicated that high concentrations of sodium caprate were achieved. Despite significant effect of the permeation enhancer on the integrity of the intestinal epithelium, the bioavailability of MEDI7219 was of the same order of magnitude as that achieved with the solution and enteric coated capsule formulations (2.5-3.8%). The variability in plasma concentrations of MEDI7219 were however lower when delivered using the IAD as compared to the solution and enteric coated capsule formulations. This suggests that dosage forms that can limit intestinal dilution and control the position of drug release can be a way to reduce the absorptive variability of peptides delivered with permeation enhancers but do not offer significant benefits in terms of increasing bioavailability.
Assuntos
Mucosa Intestinal , Intestinos , Animais , Suínos , Mucosa Intestinal/metabolismo , Peptídeos/química , Absorção Intestinal , Administração Oral , Comprimidos , Disponibilidade BiológicaRESUMO
Dissolution models require, at their core, an accurate diffusion model. The accuracy of the model for diffusion-dominated dissolution is particularly important with the trend toward micro- and nanoscale drug particles. Often such models are based on the concept of a "diffusion layer." Here a framework is developed for diffusion-dominated dissolution models, and we discuss the inadequacy of classical models that are based on an unphysical constant diffusion layer thickness assumption, or do not correctly modify dissolution rate due to "confinement effects": (1) the increase in bulk concentration from confinement of the dissolution process, (2) the modification of the flux model (the Sherwood number) by confinement. We derive the exact mathematical solution for a spherical particle in a confined fluid with impermeable boundaries. Using this solution, we analyze the accuracy of a time-dependent "infinite domain model" (IDM) and "quasi steady-state model" (QSM), both formally derived for infinite domains but which can be applied in approximate fashion to confined dissolution with proper adjustment of a concentration parameter. We show that dissolution rate is sensitive to the degree of confinement or, equivalently, to the total concentration C(tot). The most practical model, the QSM, is shown to be very accurate for most applications and, consequently, can be used with confidence in design-level dissolution models so long as confinement is accurately treated. The QSM predicts the ratio of diffusion layer thickness to particle radius (the Sherwood number) as a constant plus a correction that depends on the degree of confinement. The QSM also predicts that the time required for complete saturation or dissolution in diffusion-controlled dissolution experiments is singular (i.e., infinite) when total concentration equals the solubility. Using the QSM, we show that measured differences in dissolution rate in a diffusion-controlled dissolution experiment are a result of differences in the degree of confinement on the increase in bulk concentration independent of container geometry and polydisperse vs single particle dissolution. We conclude that the constant diffusion-layer thickness assumption is incorrect in principle and should be replaced by the QSM with accurate treatment of confinement in models of diffusion-controlled dissolution.
Assuntos
Modelos Teóricos , Difusão , SolubilidadeRESUMO
The purpose of this study was to investigate in vivo intestinal precipitation of a model drug mebendazole, a basic BCS class II drug, using dogs with intestinal stomas for administration or sampling. After oral administration of a solution with an expected intestinal supersaturation of approximately 20 times the solubility, the measured supersaturation in dog intestinal fluid (DIF) was up to 10 times and, on average, only 11% of the given dose was retrieved as solid drug in the collected fluid from the stoma. The drug was rapidly absorbed with >90% of the total systemic exposure reached within three hours after duodenal administration of a solution. In silico absorption modeling showed that in vivo data were reasonably well described by a nonprecipitating solution. An in vitro model of precipitation in DIF predicted that the intestinal concentration of dissolved mebendazole would be less than 1/5 of the initial concentration within 10 min at concentrations comparable to in vivo. It was concluded that intestinal precipitation did not have any major influence on mebendazole absorption. The extent of precipitation was overpredicted in vitro given the in vivo absorption rate, and further work is needed to identify in vitro factors that could enable more accurate in vivo predictions of intestinal precipitation from solutions.