Jannin V.,Gattefosse SAS |
Rodier J.-D.,Gattefosse SAS |
Musakhanian J.,West Corporation
International Journal of Pharmaceutics | Year: 2014
Lipid-based formulations are a viable option to address modern drug delivery challenges such as increasing the oral bioavailability of poorly water-soluble active pharmaceutical ingredients (APIs), or sustaining the drug release of molecules intended for chronic diseases. Esters of fatty acids and glycerol (glycerides) and polyethylene-glycols (polyoxylglycerides) are two main classes of lipid-based excipients used by oral, dermal, rectal, vaginal or parenteral routes. These lipid-based materials are more and more commonly used in pharmaceutical drug products but there is still a lack of understanding of how the manufacturing processes, processing aids, or additives can impact the chemical stability of APIs within the drug product. In that regard, this review summarizes the key parameters to look at when formulating with lipid-based excipients in order to anticipate a possible impact on drug stability or variation of excipient functionality. The introduction presents the chemistry of natural lipids, fatty acids and their properties in relation to the extraction and refinement processes. Then, the key parameters during the manufacturing process influencing the quality of lipid-based excipients are provided. Finally, their critical characteristics are discussed in relation with their intended functionality and ability to interact with APIs and others excipients within the formulation. © 2014 Published by Elsevier B.V.
PubMed | Monash Institute of Pharmaceutical Sciences, Gattefosse SAS and Australian Synchrotron
Type: | Journal: The AAPS journal | Year: 2017
Solid self-microemulsifying drug delivery systems (SMEDDS) have received considerable attention in recent times attempting to overcome the drawbacks of liquid SMEDDS. Earlier literature reports on solid SMEDDS have focussed on formulation development; however, the digestibility and propensity for self-assembly of the digested components with endogenous bile salts and phospholipids are unknown. Therefore, as a starting point, previously reported solid SMEDDS containing Gelucire 44/14 (GEL) and the non-digestible surfactants, Vitamin E TPGS (TPGS) and Lutrol F 127 (F 127), were prepared, and their dispersion and digestion behaviours were studied using an in vitro lipolysis model, coupled with small-angle X-ray scattering (SAXS) to determine the formed colloidal structures during digestion in real time. GEL alone was digested (89%) and formed a lamellar phase (L). When surfactants were added at a 40:60%w/w lipid to surfactants ratio, digestion was inhibited with a significant lag time being evident. However, increasing the fraction of GEL to 50%w/w enabled digestion with reduced lag time. The substitution of the non-digestible surfactants with digestible surfactants, sucrose esters S-1670 (S-1670) and Span 60 (S-60), eliminated the digestion lag time, and the formation of colloidal structures was more similar to that of GEL alone.
Roberts M.,Liverpool John Moores University |
Vellucci D.,Liverpool John Moores University |
Vellucci D.,University of Camerino |
Mostafa S.,Gattefosse UK Ltd |
And 2 more authors.
Drug Development and Industrial Pharmacy | Year: 2012
Context: Sustained-release mini-tablets are a potentially suitable for paediatric drug delivery or as multi-particulate dosage forms. Objective: To evaluate the potential for developing lipophilic matrix mini-tablets and to assess the effects of Compritol® 888 ATO concentration on drug release from differently sized mini-tablets prepared by direct compression. Methods: A formulation comprising theophylline as a model soluble drug, 15% w/w Compritol® 888 ATO as the inert matrix-forming agent, with dibasic dicalcium phosphate anhydrous and lactose as diluents was evaluated by producing 12mm tablets at a range of compression speeds and forces. The same formulation and further formulations with 25, 35 or 45% w/w Compritol® 888 ATO were evaluated by producing 2, 3 and 4mm mini-tablets. Results and Discussion: Drug release from matrix tablets was sustained over a period of 12 hours and release rate varied according to the compression force and speed employed. The rate of drug release from matrix mini-tablets was more rapid and increasing Compritol® 888 ATO concentration resulted in slower release rates. The rate of drug release from matrix mini-tablets was inversely proportional to mini-tablet size (2mm > 3 mm > 4mm). Drug release from the matrix tablets and mini-tablets followed square-root of time kinetics. Conclusion: Tailored drug release from matrix mini-tablets may achieved by altering the size of mini-tablet or level of Compritol® 888 ATO in the formulation and this may have potential in the development of paediatric formulations or multi-particulate dosage forms. © 2012 Informa Healthcare USA, Inc.
Beduneau A.,University of Franche Comte |
Tempesta C.,University of Franche Comte |
Fimbel S.,University of Franche Comte |
Pellequer Y.,University of Franche Comte |
And 4 more authors.
European Journal of Pharmaceutics and Biopharmaceutics | Year: 2014
Standard monoculture models utilizing Caco-2 monolayers were extensively used to mimic the permeability of the human intestinal barrier. However, they exhibit numerous limitations such as the lack of mucus layer, an overestimation of the P-gp-mediated efflux and a low paracellular permeability. Here, we suggest a new procedure to set up an in vitro model of intestinal barrier to adjust gradually the properties of the absorption barrier. Mucin-secreting HT29-MTX cells were added to Caco-2 absorptive cells in a Transwell® at different time intervals. Effects of seeding day of HT29-MTX on the paracellular permeability of lucifer yellow (LY) and on the P-gp-mediated efflux of rhodamine 123 were investigated. Apparent permeability of the rhodamine 123 in the secretory direction was highly dependent on the seeding day of goblet cells. Transepithelial electrical resistance values and LY transport across the co-cultures in the apical-to-basolateral direction were intermediary between single Caco-2 and HT29-MTX models. Early seeding days of HT29-MTX allowed increasing the fraction of goblet cells in the co-culture. Co-culture permeability was unchanged between 21 and 30 days after Caco-2 seeding, corresponding to the period of use for Caco-2-based cell models. Thus, the HT29-MTX seeding day was a key factor to set up an in vitro intestinal model with tailor-made barrier properties in terms of P-gp expression and paracellular permeability. © 2014 Elsevier B.V. All rights reserved.
Fernandez S.,Aix - Marseille University |
Fernandez S.,Gattefosse SAS |
Jannin V.,Gattefosse SAS |
Chevrier S.,Gattefosse SAS |
And 3 more authors.
Pharmaceutical Research | Year: 2013
Purpose: Labrasol® is a self-emulsifying excipient used to improve the oral bioavailability of poorly water-soluble drugs. It is a mixture of acylglycerols and PEG esters, these compounds being substrates for digestive lipases. The characterization of Labrasol® gastrointestinal lipolysis is essential for understanding its mode of action. Methods: Labrasol® lipolysis was investigated using either individual enzymes (gastric lipase, pancreatic lipase-related protein 2, pancreatic carboxyl ester hydrolase) or a combination of enzymes under in vitro conditions mimicking first the gastric phase of lipolysis and second the duodenal one. Specific methods for quantifying lipolysis products were established in order to determine which compounds in Labrasol® were preferentially hydrolyzed. Results: Gastric lipase showed a preference for di- and triacylglycerols and the main acylglycerols remaining after gastric lipolysis were monoacylglycerols. PEG-8 diesters were also hydrolyzed to a large extent by gastric lipase. Most of the compounds initially present in Labrasol ® were found to be totally hydrolyzed after the duodenal phase of lipolysis. The rate of Labrasol® hydrolysis by individual lipases was found to vary significantly with the dilution of the excipient in water and the resulting colloidal structures (translucent dispersion; opaque emulsion; transparent microemulsion), each lipase displaying a distinct pattern depending on the particle size. Conclusions: The lipases with distinct substrate specificities used in this study were found to be sensitive probes of phase transitions occurring upon Labrasol® dilution. In addition to their use for developing in vitro digestion models, these enzymes are interesting tools for the characterization of self-emulsifying lipid-based formulations. © 2013 Springer Science+Business Media New York.
Jannin V.,Gattefosse S.A.S. |
Lemagnen G.,University of Bordeaux Segalen |
Gueroult P.,University of Bordeaux Segalen |
Larrouture D.,University of Bordeaux Segalen |
Tuleu C.,University College London
Advanced Drug Delivery Reviews | Year: 2014
The rectal route can be considered a good alternative to the oral route for the paediatric population because these dosage forms are neither to be swallowed nor need to be taste-masked. Rectal forms can also be administered in an emergency to unconscious or vomiting children. Their manufacturing cost is low with excipients generally regarded as safe. Some new formulation strategies, including mucoadhesive gels and suppositories, were introduced to increase patient acceptability. Even if recent paediatric clinical studies have demonstrated the equivalence of the rectal route with others, in order to enable the use of this promising route for the treatment of children in the 21st Century, some effort should be focused on informing and educating parents and care givers. This review is the first ever to address all the aforementioned items, and to list all drugs used in paediatric rectal forms in literature and marketed products in developed countries. © 2014 Elsevier B.V.
Vithani K.,University of Greenwich |
Maniruzzaman M.,University of Greenwich |
Slipper I.J.,University of Greenwich |
Mostafa S.,Gattefosse Arc House |
And 4 more authors.
Colloids and Surfaces B: Biointerfaces | Year: 2013
The aim of this work was to develop sustained release solid lipid matrices of diclofenac sodium (Df-Na) processed by hot melt extrusion (HME) and subsequent compression into tablets. Different extrusion processing approaches such as "cold", "hot" and pre-mixed formulations were used to develop the Compritol® 888 ATO lipid matrices by altering the extrusion temperatures, drug loading and formulation composition. The extrudates were characterized via a range of techniques such as differential scanning calorimetry (DSC), hot stage microscopy (HSM) and X-ray powder diffraction (XRPD) to identify the drug state within the lipid matrix. Df-Na was found to be either in crystalline or amorphous state depending on the processing conditions. Energy dispersive X-ray (EDX) microanalysis demonstrated excellent drug distribution of Df-Na on the surface of the compressed tablets. The lipid matrices developed by HME provided sustained release of pre-mixed formulations for 12h mainly controlled by diffusion. © 2013 Elsevier B.V.
Jannin V.,Gattefosse SAS |
Rosiaux Y.,Gattefosse SAS |
Doucet J.,Joseph Fourier University
Journal of Controlled Release | Year: 2015
Lipid excipients are more and more commonly used in the pharmaceutical industry as sustained drug delivery agents. However, their development may still be hindered by the well-known polymorphism of lipids which is perceived as a disadvantage with possible impact on drug release upon storage. In order to explore the eventual link between drug release modification and lipid polymorphism, we used a synchrotron radiation-based micro X-ray diffraction that allows probing the crystalline structures of the lipid matrix-forming excipient at a local scale and scanning it across the whole tablet. This technique demonstrated that only one polymorph of Compritol® 888 ATO is present in each tablet. This polymorph is identical whatever the compression force applied during the manufacturing is, and stays the same after storage at 40°C for 45 days, even if these tablets exhibit different drug release profiles. Hence modification of drug release observed after storage is not due to lipid polymorphism. Implementation of post-compression thermal treatments generates another lipid polymorph. Again drug release is not linked with polymorphism because two different polymorphs of Compritol® 888 ATO lead to exactly the same dissolution profile. Variation of drug release observed during storage in accelerated conditions could be attributed to an altered distribution of the lipid component within the matrix structure. The lipid may flow within the matrix structure and increase the hydrophobicity of tablets. © 2014 Elsevier B.V. All rights reserved.
Rosiaux Y.,Gattefosse S.A.S. |
Jannin V.,Gattefosse S.A.S. |
Hughes S.,Gattefosse S.A.S. |
Marchaud D.,Gattefosse S.A.S.
Journal of Controlled Release | Year: 2014
Lipid excipients are attracting interest from drug developers due to their performance, ease of use, versatility and their potential to generate intellectual property through innovation in drug delivery particularly in the case of modifying drug release systems. Many articles have described the use of lipid excipients to develop matrix modified release dosage forms in a range of processing techniques, therefore a comprehensive review is timely to collect together and analyze key information. This review article focuses on the utility of lipid excipients in solid sustained drug delivery systems with emphasis on the efficiency and robustness of these systems with respect to: (i) the choice of the manufacturing process and impact on drug release, (ii) the fundamental drug release mechanisms, (iii) resistance of the drug formulation under physiological conditions and (iv) long-term stability. Understanding the functionality of these versatile excipients in formulation is elementary for the development of highly robust lipid-based sustained release medicines. © 2014 Elsevier B.V.
Gattefosse Sas | Date: 2012-02-17
Cell culture process includes seeding a suitable culture medium with enterocytes and then, after a delay, seeding the medium containing the enterocytes that have begun to proliferate, with goblet cells.