Lipid-based systems, such as self-microemulsifying systems (SMEDDS) are attracting strong attention as a formulation approach to improve the bioavailability of poorly water-soluble drugs. By applying ...the “spring and parachute” strategy in designing supersaturable SMEDDS, it is possible to maintain the drug in the supersaturated state long enough to allow absorption of the complete dose, thus improving the drug’s bio-availability. As such an approach allows the incorporation of larger amounts of the drug in equal or even lower volumes of SMEDDS, it also enables the production of smaller final dosage forms as well as decreased gastrointestinal irritation, being of particular importance when formulating dosage forms for children or the elderly. In this review, the technological approaches used to prolong the drug supersaturation are discussed regarding the type and concentration of polymers used in liquid and solid SMEDDS formulation. The addition of hypromellose derivatives, vinyl polymers, polyethylene glycol, polyoxyethylene, or polymetacrylate copolymers proved to be effective in inhibiting drug precipitation. Regarding the available literature, hypromellose has been the most commonly used polymeric precipitation inhibitor, added in a concentration of 5 % (
). However, the inhibiting ability is mainly governed not only by the physicochemical properties of the polymer but also by the API, therefore the choice of optimal precipitation inhibitor is recommended to be evaluated on an individual basis.
Display omitted
Biopharmaceuticals are one of the fastest growing areas within the pharmaceutical industry. As protein drugs require parenteral administration, they are commonly formulated as aqueous ...solutions. However, this is not always feasible due to their general instability. In such cases, lyophilised powders for injection are the dosage form of choice, for the preparation of stable products. Lyophilisation is known to be highly time and energy consuming, and hence it is an expensive technological process. Thus, the pharmaceutical industry is increasingly focused on its optimisation. Implementation of aggressive conditions, together with optimisation of formulation parameters, represent the contemporary approach to reduction of the primary drying time. As such, incorporation of drug-specific excipients can contribute significantly to the stability of a biologically active ingredient, and indirectly they can also affect the time needed for lyophilisation. The addition of the most relevant protein stabilisers, surfactants, buffers and bulking agents is therefore crucial. The main aim of the present review is to define the most important groups of biopharmaceutical excipients, based on their roles in formulations and the mechanism(s) through which they support the lyophilisation process, to provide products with the required protein efficiency and product characteristics. The scope of the article is to critically discuss the suitability of novel stabilizers, with higher critical temperatures and bulking agents in terms of implementation of aggressive primary drying. For better assignment of the topic-related challenges, the stabilities of biopharmaceutical drugs and the fundamentals of the lyophilisation process are also briefly described.
The drug delivery potential of liquid crystals (LCs) for ascorbyl palmitate (AP) was assessed, with the emphasis on the AP stability and release profile linked to microstructural rearrangement taking ...place along the dilution line being investigated by a set of complementary techniques. With high AP degradation observed after 56 days, two stabilization approaches, i.e., the addition of vitamin C or increasing AP concentration, were proposed. As a rule, LC samples with the lowest water content resulted in better AP stability (up to 52% of nondegraded AP in LC1 after 28 days) and faster API release (~18% in 8 h) as compared to the most diluted sample (29% of nondegraded AP in LC8 after 28 days, and up to 12% of AP released in 8 h). In addition, LCs exhibited a skin barrier-strengthening effect with up to 1.2-fold lower transepidermal water loss (TEWL) and 1.9-fold higher skin hydration observed in vitro on the porcine skin model. Although the latter cannot be linked to LCs’ composition or specific microstructure, the obtained insight into LCs’ microstructure contributed greatly to our understanding of AP positioning inside the system and its release profile, also influencing the overall LCs’ performance after dermal application.
(Chenopodiaceae) is an under-investigated annual plant that occurs in dry areas stretching from eastern and south-eastern Europe to East Asia. This article presents the botanical characterization and ...examination of proximate parameters, minerals and cytotoxic activity of
that grows wild in Kazakhstan. The results of morphological analysis using a light microscope, based on cross-sections of stems, roots and leaves, provide the necessary data to develop a regulatory document for this herbal substance as a raw material for use in the pharmaceutical, cosmetic and food industries. The investigated proximate characteristics included moisture content (6.8 ± 0.28%), ash (5.9 ± 0.40%), fat (12.5 ± 21.28%) and protein (392.85 ± 25.50). The plant is also rich in minerals (mg/100 g dry weight); Na (20.48 ± 0.29), K (302.73 ± 1.15), Zn (4.45 ± 0.35), Fe (1.18 ± 0.03), Cu (0.11 ± 0.02), Mn (0.76 ± 0.01), Ca (131.23 ± 0.09) and Mg (60.69 ± 0.72). The ethanolic extract of
showed no acute toxicity against the brine shrimp nauplii.
Mesoporous carriers are a convenient choice for the solidification of self-microemulsifying drug delivery systems (SMEDDS) designed to improve the solubility of poorly water-soluble drugs. They are ...known for high liquid load capacity and the ability to maintain characteristics of dry, free-flowing powders. Therefore, five different mesoporous carriers were used for the preparation of carvedilol-loaded SMEDDS granules by wet granulation methods—in paten (manually) and using a high-shear (HS) granulator. Granules with the highest SMEDDS content (63% and 66% of total granules mass, respectively) and suitable flow properties were obtained by Syloid® 244FP and Neusilin® US2. SMEDDS loaded granules produced by HS granulation showed superior flow characteristics compared to those obtained manually. All SMEDDS granules exhibited fast in vitro release, with 93% of carvedilol releasing from Syloid® 244FP-based granules in 5 min. Upon compaction into self-microemulsifying tablets, suitable tablet hardness and very fast disintegration time were achieved, thus producing orodispersible tablets. The compaction slightly slowed down the carvedilol release rate; nevertheless, upon 1 h (at pH 1.2) or 4 h (at pH 6.8) of in vitro dissolution testing, the amount of released drug was comparable with granules, confirming the suitability of orodispersible tablets for the production of the SMEDDS loaded single unit oral dosage form.
•Incorporation of higher molecular weight binders results in slower in vitro drug release from solid SMEDDS.•High binder concentration is related to faster in vitro drug release from solid ...SMEDDS.•Higher binder amount has favorable effect on flow properties, although flowability of all SMEDDS granules is good for further tableting.•Both high-shear granulation and tableting have a (slight) negative effect on drug release rate.•SMEDDS granules and tablets preserved self-microemulsifying properties.•Povidone K30 is the best polymeric binder candidate for further research.
Self-microemulsifying drug delivery systems (SMEDDS) are lipid-based formulations, designed to improve the solubility of poorly-water soluble drugs. Mesoporous silica is frequently used for SMEDDS solidification by various techniques. One of them is wet granulation, which enables achieving both high SMEDDS load and good flow properties. This study investigated the effect of six polymeric binders’ addition to granulation dispersion (GD) (povidone K30, povidone K90, copovidone, Pharmacoat® 603, Pharmacoat® 615 and MethocelTM K100 Premium LV) on characteristics of produced SMEDDS granules, prepared by wet granulation. By incorporation of polymer in GD, it was possible to produce mesoporous silica-based free-flowing granules, with preserved self-microemulsifying properties, responsible for improved in vitro release of carvedilol. The incorporation of higher molecular weight binders resulted in slower in vitro release, while high binder concentration was related to faster drug release. The highest release rate was achieved with povidone K30 at 7.45 % binder concentration, as corresponding granules exhibited complete drug release already in 5 minutes. Granulation method (manual vs. high-shear) influenced the release rate of carvedilol as it was released slower from SMEDDS granules prepared using the granulator.
Finally, SMEDDS tablet formulation was optimized to achieve maximum granule content and adequate tablet hardness. Increased granule content found to negatively influence tablet hardness, as maximum granule content of 25 % was needed to obtain appropriate hardness. Such tablets exhibited short disintegration time, so this final prototype can be considered as orodispersible tablet.
Display omitted
Display omitted
The purpose of this study was to develop self-microemulsifying (SME-) tablets to improve resveratrol solubility whilst delivering resveratrol in a preferred tablet dosage form. ...Resveratrol was dissolved in liquid self-microemulsifying drug delivery system (SMEDDS) (10% w/w) and solidified through adsorption on several different solid carriers. Two ranges of synthetic amorphous silica (Sylysia® 290, 350, 470, 580; Syloid® 244FP, AL-1FP) as well as granulated magnesium aluminometasilicate (Neusilin® US2) were screened for their SMEDDS adsorbent capacity. The most efficient carrier from every range was chosen for further SME-tablet development. To counteract the high ratio of liquid in SME-tablets, additional dry binders (microcrystalline cellulose, copovidone) were added to the tableting mixture, as well as superdisintegrant (croscarmellose sodium) and lubricant (magnesium stearate). Finally, approx. 600 mg tablets were directly pressed using 12 mm flat face punch, containing 41.75% SMEDDS. Overall, all tablets exhibited sufficient hardness (>50 N), although it was negatively affected by higher compression force. Tablets with Neusilin® US2 proved to have highest hardness, as granulated structure of Neusilin® US2 provided best compaction properties needed for successful direct compression of tablets. All prepared SME tablet formulations disintegrated in under 10 min and formed microemulsions (droplet size < 100 nm) upon dilution with water, with Neusilin® US2 tablets exhibiting the lowest droplet size (<30 nm). While conventional dissolution test indicated incomplete resveratrol release from solid carriers in both pH 1.2 and 6.8 media, no difference fatty acid amount titrated during fasted state in vitro lipolysis between liquid and solid SMEDDS was observed. Moreover, accelerated stability tests confirmed over 90% of trans-resveratrol remained in solid SMEDDS following 90 days at 40 °C, with no crystallization of resveratrol observed during that time. To sum up, through adsorption on solid carriers, in particular Neusilin® US2, SMEDDS was successfully transformed into a directly compressible mixture and tableted without the loss of its self-microemulsifying ability.
The delivery of probiotics to different sites of action within the human body might help to prevent and treat several diseases. Here, we describe a microcapsule-based system for delivery of probiotic ...bacteria, as vegetative cells or spores, which promotes their prolonged survival and efficient revival, and successful colonisation of the target surface. This system is proposed for local delivery into periodontal pockets. Encapsulation of the probiotic bacteria was based on alginate crosslinking with calcium ions. This was performed by prilling the polymer dispersion supplemented with the probiotic using membrane vibration technology, followed by chitosan coating by polyelectrolyte complexation. The microcapsules were 120–150 μm in diameter, and were dried by lyophilisation. The chitosan coating increased the specific surface area and improved the bioadhesion potential, with no negative impact on viability and growth kinetics of the probiotic bacteria. Chitosan represents a barrier, which promotes sustained release of the probiotic bacteria. Vegetative bacteria were encapsulated at 2 × 108 CFU/g dry microcapsules, which represented ~5% of the prepared microcapsules, with stable viability for at least 2 months. Encapsulation of bacterial spores was greater, at 2 × 1010 CFU/g dry microcapsules, achieving 100% of microcapsules with incorporated revivable spores.
Display omitted
Antioxidant vitamins have been proven to be highly efficient in treatment of skin impaired by oxidative stress, but challenges regarding stability and skin penetration limit their therapeutic effect. ...Lipid-based drug delivery systems offer great potential for overcoming these drawbacks. This work aimed to identify the most promising system for combined antioxidant therapy. A comparative assessment of several systems, containing the same ingredients but differing in their microstructure, was therefore performed. Namely, microemulsions (MEs) of both types (W/O and O/W) and lyotropic liquid crystals (LLCs), simultaneously loaded with vitamin C or ascorbyl palmitate and vitamin E, were assessed. Stability, antioxidant capacity (DPPH assay), and release (Franz diffusion cells) of the vitamins incorporated was examined. The results obtained were supported with the systems' thermal and rheological (rotational and oscillatory tests) evaluation. In addition, biological acceptability (MTS assay) of the systems studied was investigated. The findings demonstrate that the microstructure of MEs and LLCs studied has a decisive impact on the stability, antioxidant activity, and release of the vitamins incorporated. The highest stability was preserved in LLCs for both pairings, with vitamins C and E being a more stable combination. LLCs also provided suitable vitamins' antioxidant activity and release characteristics. In addition, the system exhibited preferable rheological features for dermal administration. Furthermore, cytotoxicity studies on a keratinocyte cell line demonstrated the highest biocompatibility for LCCs with the cell proliferation being greater than 85%. In conclusion, LLCs were confirmed as the most favorable lipid-based drug delivery system for combined antioxidant treatment.
Low oral bioavailability as a consequence of low water solubility of drugs is a growing challenge to the development of new pharmaceutical products. One of the most popular approaches of oral ...bioavailability and solubility enhancement is the utilization of lipid-based drug delivery systems. Their use in product development is growing due to the versatility of pharmaceutical lipid excipients and drug formulations, and their compatibility with liquid, semi-solid, and solid dosage forms. Lipid formulations, such as self-emulsifying (SEDDS), self-microemulsifying SMEDDS) and self- -nanoemulsifying drug delivery systems (SNEDDS) were explored in many studies as an efficient approach for improving the bioavailability and dissolution rate of poorly water-soluble drugs. One of the greatest advantages of incorporating poorly soluble drugs into such formulations is their spontaneous emulsification and formation of an emulsion, microemulsion or nanoemulsion in aqueous media. This review article focuses on the following topics. First, it presents a classification overview of lipid-based drug delivery systems and mechanisms involved in improving the solubility and bioavailability of poorly water-soluble drugs. Second, the article reviews components of lipid-based drug delivery systems for oral use with their characteristics. Third, it brings a detailed description of SEDDS, SMEDDS and SNEDDS, which are very often misused in literature, with special emphasis on the comparison between microemulsions and nanoemulsions.
PDF