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Abstract

Lornoxicam is a potent analgesic non-steroidal anti-inflammatory drug that can be used topically to relieve pain and to reduce inflammation. The objectives of this study were to improve the therapeutic efficacy of lornoxicam by complexation with cyclodextrins and to formulate it in liquid crystalline gel. Lornoxicam and β-cyclodextrin (βCD) or hydroxypropyl-β-cyclodextrin (HPβCD) complexes were prepared using the kneaded method in 1:1, 1:2, 1:3 and 1:4 drug:CD molar ratios. Inclusion complexation in aqueous solution and solid state was evaluated by the ultraviolet, phase solubility diagram, differential scanning calorimetry, X-ray diffractometry and Fourier-transform infrared spectroscopy. The stoichiometry for the inclusion complex was found to be 1:2 drug:CD molar ratio as determined from Job’s plot. This result was confirmed by the in vitro dissolution studies for the prepared complexes. Among all the prepared complexes, the complex prepared with βCD in 1:2 drug:CD molar ratio showed highest improvement in drug dissolution and was chosen to be formulated in a topical preparation. For developing liquid crystalline gel, different ratios of Brij 97, glycerol and oils (liquid paraffin, isopropyl myristate and Miglyol® 812) were prepared. The formula composed of Brij 97 and glycerol in 3:1 weight ratio, 10% Miglyol® 812 and 40% water showed higher drug release compared to the other prepared gels. Moreover, this formula showed low ex vivo permeation on excised pigskin thus it could offer high topical effect with low systematic side effects. This formula showed superior anti-inflammatory activity when applied topically on rats’ skin after induction of burn compared to that of Feldene® gel.

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... Following this principle, several studies included in the present review used cyclodextrins (especially β-CD and HP-β-CD) to improve the water solubility and increase the bioavailability of NSAIDs such as aceclofenac [29], meloxicam [80], flurbiprofen [54], diclofenac [37], and lornoxicam. It is worth mentioning that increased solubility was associated with improved bioavailability [37,54] and anti-inflammatory activity [70]. In general, NSAIDs are acidic lipophilic compounds characterized by the presence of an aromatic ring bearing an acidic moiety and can differ in their lipophilicities based on their aryl structure and substituents. ...
... Grecu and collaborators [68] demonstrated that ketoprofen/β-CD complex presented a stronger anti-inflammatory activity than ketoprofen pure in rat models of paw edema and peritonitis. Similar findings were obtained by Auda [88], Alshehri et al. [123], and Ammar et al. [70] using inclusion complexes of nimesulide-Me-β-CD, flufenamic acid-β-CD, and lornoxicam-β-CD/lornoxicam-HP-β-CD, respectively. The impact of CD incorporation on the anti-inflammatory effects of NSAIDs has been further demonstrated in vitro and was associated with inhibition of inflammatory mediator production [32,83]. ...
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Non-steroidal anti-inflammatory drugs (NSAIDs) are one of the most widely used classes of medicines in the treatment of inflammation, fever, and pain. However, evidence has demonstrated that these drugs can induce significant toxicity. In the search for innovative strategies to overcome NSAID-related problems, the incorporation of drugs into cyclodextrins (CDs) has demonstrated promising results. This study aims to review the impact of cyclodextrin incorporation on the biopharmaceutical and pharmacological properties of non-steroidal anti-inflammatory drugs. A systematic search for papers published between 2010 and 2020 was carried out using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) protocol and the following search terms: “Complexation”; AND “Cyclodextrin”; AND “non-steroidal anti-inflammatory drug”. A total of 24 different NSAIDs, 12 types of CDs, and 60 distinct inclusion complexes were identified, with meloxicam and β-CD appearing in most studies. The results of the present review suggest that CDs are drug delivery systems capable of improving the pharmacological and biopharmaceutical properties of non-steroidal anti-inflammatory drugs.
... The clinical studies demonstrate the effectiveness of CDs in a variety of inflammatory conditions ( Table 4). The pre-clinical studies used complexes with natural products (penducoloside [19], curcumin [20,21], β-glycyrrhetinic acid [22], p-cymene [23], (-)linalool [24], Oleogum resin from Boswellia serrata [25] and Shuang-Qing-Cao extract [26], NSAIDs (indomethacin [27][28][29][30][31], ketoprofen [32][33][34], nimesulide [35], lornoxicam [36], acetyl salicylic acid [37], etodolac [38], flurbiprofen [39,40], ketorolac [41,42], naproxen [43], valdecoxib [44], ibuprofen [45], piroxicam [46]), corticosteroids (dexamethasone [47,48], α-methyl prednisolone [49], prednisolone 21-hemisuccinate [50,51]), anti-ethanol (disulfiram [52]) and antiallergic (Tranilast [53]). These studies used different protocols and there was a better anti-inflammatory effect of CD-complexed drugs when compared with the pure drug ( Table 2). ...
... The results showed that the percent inhibition of edema was higher with the prodrug than the free drug. Ammar et al. [36] demonstrated that topical treatment with lornoxicam coupled to β-CD decreased neutrophil infiltration in the dermis in animals with skin inflammation induced by exposure to ultraviolet radiation, having a better effect than the positive control. Batalova et al. [37] tested acetyl salicylic acid and ibuprofen coupled to β-CD in paw edema induced by formalin and peritonitis induced by silver nitrate. ...
Article
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Background: Anti-inflammatory drugs can be ineffective in treating some inflammatory conditions. Improved drug delivery systems like cyclodextrins (CDs) could enhance their efficacy and safety. Objective: We conducted a systematic review to evaluate the anti-inflammatory activity of compounds complexed in CDs, analyzing whether these complexes improved their pharmacological action. Methods: The search terms 'Anti-inflammatory Agents', 'Cyclodextrins' and 'Drug effects' were used to retrieve articles in SCOPUS, PUBMED, MEDLINE and EMBASE. Results: Forty-four papers were identified. In the in vivo and clinical studies, there was greater efficacy for complexed drugs when compared to control groups or uncomplexed drug, decreasing inflammation and inflammatory mediators. Through a meta-analysis, the preclinical studies demonstrated that the complexed drug had a significantly (p<0.001) greater anti-inflammatory effect than the non-CD-complexed drug. Conclusion: The use of CDs can improve the action of anti-inflammatory compounds and it can also be a way to reduce the side effects, therapeutic doses and toxicity.
... The speed of the apparatus was adjusted to 50 rpm, 29 and the temperature was kept at 35°C. 30 The experiment lasted an hour, with samples taken every 5 minutes. A 5 mL sample was removed from the beaker and replaced with 5 mL of fresh buffer. ...
Article
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Meloxicam (MLX) is a nonsteroidal anti-inflammatory medicine (NSAID) that is used to treat rheumatoid arthritis, osteoarthritis, and other joint conditions. Despite MLX's low toxicity, oral administration is linked to adverse gastrointestinal effects such as perforation and ulceration. As a result, an alternative mode of administration for MLX is required to minimize the drawbacks associated with currently available oral medicines. Drug delivery through the skin could be a suitable option since it allows medications to be delivered directly to the illness site, resulting in maximum local effects with minimal systemic activity. Molding is the most common process for making MLX polymer microneedle (MN) patches. After adding the MLX to the surfactant, different types of polymer (polyvinyl pyrrolidone (PVPK30), polyvinyl alcohol (PVA), sodium alginate (SA), and hydroxymethyl cellulose (HPMC) with different ratios and by using DW as a solvent. Afterward, the effect of type and the ratio of polymer used was studied to make the formulation better. Patches were investigated for needle morphology, drug content, axial fracture force measurement, and drug release, with the optimized formulae also being tested for pH, folding endurance, and ex vivo permeation. The PVA patch with 17.5% solid content, 10% PEG 400, and 0.25 percent glycerin has an axial needle fracture force of 30 N/100MN, which is sufficient for skin penetration. The release was quick, with about all of the medication being released in just 60 minutes. With a steady-state flux of around 3.1 times that of the ordinary patch, permeation was greatly improved. In comparison to a regular patch, MN has a lower lag time. According to the findings, the MLX MN patch could improve medication permeability while allowing for quick and painless administration.
... RDC values were calculated based on a well-known relationship (61)(62)(63)(64)(65). The RDC values calculated for physical mixtures and solid dispersion samples are presented in Table I showed that the degree of ibuprofen crystallinity in the 10% SCF, 20% SCF, and 30% SCF is significantly affected the proportion of the drug. ...
Article
Masking the unpleasant taste of the pharmaceutically active ingredients plays a critical role in patient acceptance, particularly for children. This work’s primary objective was the preparation of taste-masked ibuprofen microparticles using cocoa butter with the assistance of supercritical fluid technology. Microparticles were prepared by dissolving ibuprofen in melted cocoa butter at 40 °C. The solution was then introduced into a supercritical fluid unit and processed at 10 MPa CO2 pressure for 30 min. The product was collected after depressurizing the system. The effect of the drug to cocoa butter ratio and the supercritical fluid units’ configuration on product quality was evaluated and compared with the sample prepared by a conventional method. Physicochemical characterization of the prepared product, including particle size, crystallinity, entrapment efficiency, in vitro drug release, and product taste using a human volunteer panel was conducted. The produced microparticles were in the range of 1.42 to 15.28 μm. The entrapment efficiency of the formulated microparticles ranged from 66 to 81%. The drug:polymer ratio, the configuration of the supercritical fluid unit, and the method of preparation were found to have a critical role in the formulation of ibuprofen microparticles. Taste evaluation using human volunteers showed that microparticles containing 20% drug and processed with supercritical fluid technology were capable of masking the bitter taste of ibuprofen. In conclusion, the dispersion of ibuprofen in cocoa butter using supercritical fluid technology is a a promising innovative method to mask the bitter taste of ibuprofen.
... The withdrawn samples were analyzed for LXM. The study continued for 6 hours for 22 mg drug loading (15) . The microneedle patch LXN MN was compared to LXM solution (22mg of LXM in 10 ml composed of phosphate buffer pH7.4 with 5% triethanolamine) and LXM ordinary patch with the same composition of polymers and amount of LXM as that of MN patch. ...
Article
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The objective of the study was to develop microneedle (MN) patch, with suitable properties to ensure the delivery of a therapeutic level of lornoxicam (LXM) in a period suitable to replace parenteral administration in patients, especially those who fear needles. The used polymers were cold water-soluble polyvinyl alcohol (PVA) and polyvinylpyrrolidone (PVP) of low molecular weight with PEG 400 as plasticizer and Tween 80 (to enhance the release) using micro molding technique. Patches were studied for needle morphology, drug content, axial fracture force measurement and drug release while the optimized formulas were further subjected to pH measurement, folding endurance, ex vivo permeation study, histopathology study, stability study and compatibility study. The patch with 11:1 ratio of PVA to PVP, 30% solid content, 5% PEG 400 and 3% Tween 80 resulted in axial needle fracture force value of (1.35 N) which is suitable for skin penetration. The release was fast with almost 100% of drug released in 60 minutes. The permeation was enhanced significantly with a steady state flux of about 3.1 times that of the solution. The lag time of MN is shorter in comparison with ordinary patch. Histopathology studies demonstrated the safety of the formulation, both stability studies and compatibility studies showed the suitability of the formulation. The results indicated that LXM microneedle patch could enhance drug permeation while achieving fast and painless administration. Keywords: Microneedle patch, Polyvinyl alcohol, Polyvinylpyrrolidone, Fracture force, Lornoxicam.
... The DSC thermogram of raloxifene with PLGA as a physical mixture showed a slight shift in the thermal degradation peak of PLGA to 350.88°C with complete absence of the drug's endothermic peak. This disappearance might be because of to two causes: the low concentration of the drug (1% w/v) in the physical mixture or the formation of an amorphous dispersion of the drug in the polymer during melting as a consequence of the supply of thermal energy during the DSC scan (El-Mahrouk et al., 2009;Ammar et al., 2012). ...
Article
Bone injury is very serious in elder people or osteoporotic patients. In-situ forming implants (IFI) for bone rebuilding are usually poly-lactic-co-glycolic acid (PLGA)-based, which have a burst release effect. This study aimed to prepare novel liquid lipid-based PLGA-IFI loaded with raloxifene hydrochloride for prolonged non-surgical treatment of bone injuries by applying solvent-induced phase inversion technique. Labrasol® and Maisine® were added to the selected IFI forming long lasting lipid-based IFI (LLL-IFI). The formulations were characterized by analysing their in-vitro drug release, solidification time, injectability, rheological properties, and DSC in addition to their morphological properties. Results revealed that the LLL-IFI composed of 10%w/v PLGA with a lactide to glycolide ratio of 75:25 with ester terminal and 10% Maisine® possessed the most sustained drug release and lowest burst effect, as well as delayed pore formation compared to its counterpart lacking Maisine®. The selected LLL-IFI and PLGA-IFI formulations were tested for their capability to enhance bone regeneration in bone injuries induced in rats. Both formulations succeeded in healing the bones completely with the superiority of LLL-IFI in the formation of well-organized bone structures lacking fibrous tissues. The results suggest that LLL-IFI and PLGA-IFI are innovative approaches for treating critical and non-critical sized bone injuries.
... Topical formulations of ibuprofen at the maximum amount soluble in 10% HP-b-CyD resulted in a higher degree of skin accumulation and photoprotection, with huge potentials in the management of skin cancers [93]. Also, liquid crystalline gels containing lornoxicam-b-CyD showed a higher reduction in the degree of pain and inflammation ex vivo due to higher skin accumulation and avoidance of systemic absorption [94]. In another study, the coating of topical flurbiprofen PLGA and PLGA-PEG nanospheres with HP-b-CyD resulted in higher in vivo topical anti-inflammatory efficiency despite similar ex vivo skin accumulation data with uncoated nanospheres [95]. ...
... 2-hydroxy propyl-β-CD (HP-β-CD) (Fig 1c), have also attracted growing interest due to their improved complexation efficiency, greater water solubility and less toxicity [3]. Inclusion complex formation with CDs is an approach to improve the aqueous solubility via molecular encapsulation of the drug within the cavity of the more soluble CD molecule [2,21]. Molecular weight and solubility parameters of β-CD and HPβ-CD were given in Table 1. ...
... Moreover, the peak of DFV disappeared completely which may be due to the very low concentration of DFV (0.1%w/w) when compared to other ingredients. Another explanation may be due to the mechanical treatment which led to a highly dispersed, high energy state of DFV, which made it prone to interact with the lipids or Poloxamer Õ 407 especially with the supply of thermal energy during the DSC scan (Ammar et al., 2011b) which leads to amorphous dispersion of the drug in the melted lipid. ...
Article
Context: Topical treatment of skin disease needs to be strategic to ensure high drug concentration in the skin with minimum systemic absorption. Objective: The aim of this study was to produce semisolid nanostructured lipid carrier (NLC) formulations, for topical delivery of the corticosteroid drug, diflucortolone valerate (DFV), with minimum systemic absorption. Method: NLC formulations were developed using a high shear homogenization combined with sonication, using Precirol® ATO5 or Tristearin® as the solid lipid, Capryol™ or isopropyl myristate as the liquid lipid and Poloxamer® 407 as surfactant. The present study addresses the influence of different formulations composition as solid lipid, liquid lipid types and concentrations on the physicochemical properties and drug release profile from NLCs. Results and discussion: DFV-loaded NLC formulations possessed average particle size ranging from 160.40 nm to 743.7 nm with narrow polydispersity index. The encapsulation efficiency was improved by adding the lipid-based surfactants (Labrasol® and Labrafil® M1944CS) to reach 68%. The drug release from the investigated NLC formulations showed a prolonged release up to 12 h. The dermatopharmacokinetic study revealed an improvement in drug deposition in the skin with the optimized DFV-loaded NLC formulation, in contrast to a commercial formulation. Conclusion: NLC provides a promising nanocarrier system that work as reservoir for targeting topical delivery of DFV.
... 2-hydroxy propyl-β-CD (HP-β-CD) (Fig 1c), have also attracted growing interest due to their improved complexation efficiency, greater water solubility and less toxicity [3]. Inclusion complex formation with CDs is an approach to improve the aqueous solubility via molecular encapsulation of the drug within the cavity of the more soluble CD molecule [2,21]. Molecular weight and solubility parameters of β-CD and HPβ-CD were given in Table 1. ...
Article
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Incorporation of cyclodextrins (CDs) into electrospun nanofi brous materials can be considered as potential candidates for functional medical textile applications. Naproxen (NAP) is a type of non-steroidal anti-infl ammatory drug commonly administered for the treatment of pain, infl ammation and fever. Drug–inclusion complex formation with CDs is an approach to improve the aqueous solubility via molecular encapsulation of the drug within the cavity of the more soluble CD molecule. In this study, NAP or different NAP–CD inclusion complexes loaded nanofi bres were successfully produced through electrospinning and characterised. The inclusion complex loaded mats exhibited signifi cantly faster release profi les than NAP-loaded thermoplastic polyurethane (TPU) mats. Overall, NAP–inclusion complex loaded TPU electrospun nanofi bres could be used as drug delivery systems for acute pain treatments since they possess a highly porous structure that can release the drug immediately.
... LOR exhibits a short plasma elimination with halflife (3-5 hr). LOR is characterized by lipophilic nature with a poor solubility in the acidic media of the stomach which gives local toxicity on the stomach [6,7]. LOR has a molecular weight of 371.8, partition coefficient of 1.7, and dose of 4 to 8 mg [6], and it is available only in tablet and parenteral forms. ...
Article
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The current study was designed to develop a topical gel formulation for improved skin penetration of lornoxicam (LOR) for enhancement of its analgesic activity. Moreover, the effect of different penetration enhancers on LOR was studied. The LOR gel formulations were prepared by using hydroxylpropyl methylcellulose (HPMC) and carbopol. The carbopol gels in presence of propylene glycol (PG) and ethanol were developed. The formulated gels were characterized for pH, viscosity, and LOR release using Franz diffusion cells. Also, in vitro skin permeation of LOR was conducted. The effect of hydroxypropyl β-cyclodextrin (HP β-CD), beta-cyclodextrin (β-CD), Tween 80, and oleic acid on LOR permeation was evaluated. The optimized LOR gel formulation (LORF8) showed the highest flux (14.31 μg/cm(2)/h) with ER of 18.34 when compared to LORF3. Incorporation of PG and HP β-CD in gel formulation (LORF8) enhanced the permeation of LOR significantly. It was observed that LORF3 and LORF8 show similar analgesic activity compared to marketed LOR injection (Xefo). This work shows that LOR can be formulated into carbopol gel in presence of PG and HP β-CD and may be promising in enhancing permeation.
... Since the transdermal system lessens gastrointestinal problems and has strong points over oral dosage forms and injections, it would be an alternative of lornoxicam to oral delivery. Although lornoxicam topical gel formulation has been reported recently (Ammar et al. 2012), transdermal study has not been seen in the literature. ...
Article
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Transdermal permeation of lornoxicam, one of potent non-steroidal anti-inflammatory drugs, was studied in vitro with various vehicles and fatty acids using hairless mouse dorsal skin and human cadaver full skin. Vehicles used were diethylene glycol monoethyl ether (DGME), propylene glycol monocaprylate, propylene glycol, oleyl alcohol, dimethyl sulfoxide (DMSO) and others. Various fatty acids were employed as enhancers. Among pure vehicles studied, only DMSO showed permeation from saturated solutions. In the case of DMSO–DGME co-solvent, the higher the DGME ratios were, the lower the fluxes were. The addition of fatty acid (3 w/v %) increased the permeation in the rank order of linoleic acid (LOA) ≥ oleic acid ≥ lauric acid > capric acid > caprylic acid. Enhancement ratios ranged from 2 to 37 compared to the flux without fatty acid. Lornoxicam flux decreased in inverse proportion to the concentration of triethanolamine (TEA), which was used as a salt former and solubilizer. However, the flux increased linearly as the donor dose increased even in the presence of TEA. Using human cadaver skin, the permeability of lornoxicam was much lower than that using the hairless mouse skin, but fluxes increased as the concentration of LOA increased. These results indicate the feasibility of lornoxicam transdermal delivery with a combination of fatty acid and TEA in DMSO or DMSO–DGME cosolvents.
... Preparation of amisulpride-c CD inclusion complex and physical mixture Amisulpride and c-CD complex was prepared in a molar ratio of 1:1 by kneading method [16]. The accurately weighed quantity of c-CD (2.594 g) and AMI (0.74 g) were taken in a mortar and kneaded with minimum amount of water and ethanol (1:1 v/v) mixture to form a thick paste. ...
Article
Amisulpride (AMI) is an atypical antipsychotic having poor aqueous solubility and poor oral bioavailability. Inclusion complex between AMI and gamma cyclodextrin (γ-CD) was prepared by kneading method using 1:1 stoichiometry. Solubility of AMI was enhanced by 3.74 times after inclusion complex formation. Amisulpride–γ-cyclodextrin inclusion complex was characterized by FTIR, DSC and XRD techniques. Further sustained release granules of Amisulpride–γ-cyclodextrin inclusion complex (CDSR) were prepared by treating complex with molten stearic acid. Drug release from CDSR granules was sustained up to 12 h with 100 % stearic acid proportion. The integrity of AMI–γ-CD inclusion complex in lipid phase was assessed by XRD study. Finally orodispersible tablets of CDSR granules (OD-CDSR) were prepared using Ac-Di-Sol and microcrystalline cellulose. Disintegration time was assessed by both pharmacopoeial and modified method. Optimized formulation was rapidly disintegrated within 25 s. Thus solubility enhancement and sustained release of AMI was achieved by orodispersion of CDSR granules for improvement of patient compliance.
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Cyclodextrin (CD)–hydrogel hybrids have emerged as versatile and multifunctional drug delivery systems, offering enhanced solubility, controlled drug release, and improved bioavailability. By combining the inclusion complexation properties of CDs with the swelling and retention capabilities of hydrogels, these hybrid systems overcome key challenges in conventional drug formulations. This review explores CD composition, hydrogel polymer selection, fabrication techniques, key drug release factors, and real-world therapeutic applications. Additionally, the latest advancements in stimuli-responsive hydrogels, nanogels, and microneedle-based drug delivery are discussed. While CD–hydrogel systems demonstrate significant potential, scalability, regulatory hurdles, and clinical translation remain key challenges. Future research should focus on smart hydrogels, improved drug loading strategies, and enhanced clinical validation to bridge the gap between laboratory innovations and commercial applications.
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Currently, the development of pharmaceutical science and industry, the introduction and development of evidence-based medicine dictate the need for a voluminous and at the same time careful attitude to the standardization of newly proposed original dosage forms. But any modern instrument variants require the use of a SS – standard capable of confirming the stability and expediency of the developed methodology. Therefore, this article focuses not only on technology and the choice of the optimal composition, but also on analytical support. In this paper, we have studied the possibility of obtaining a rectal dosage form of lornoxicam based on microemulsion by selecting the optimal composition that provides the necessary release of the active substance, as well as solving the issue of standardization of the dosage form using a standard sample.
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Objective The present study was aimed to prepare and characterize new cocrystals of lornoxicam (LORX), a BCS class II drug employing 1,3-dimethyl urea (DMU) as a coformer to improve physicochemical, pharmaceutical, and pharmacokinetic performance. Methods A screening study was conducted by employing three techniques viz. neat grinding, liquid-assisted grinding (LAG), and solvent evaporation (SE) using different drug–coformer molar ratios (1:1, 1:2, and 1:3). Samples were characterized by DSC, PXRD, ATR-FTIR, SEM, intrinsic dissolution rate (IDR) studies, compressional studies, and pharmacokinetic studies. In vitro dissolution and stability studies (25 °C/60%RH and 40 °C/75%RH for three months) were carried out for cocrystal tablets. Results LAG and SE were found successful in ratio 1:3 and IDR showed approximately 28- and 19-fold increase, respectively in 0.1 N HCl (pH 1.2) and buffer (pH 7.4) as compared to pure LORX. The cocrystal exhibited good tabletability and was ∼2.5 times that of LORX at 6000 Psi. Dissolution profiles of tablets of cocrystal increased (56% and 100% at pH 1.2 and 7.4, respectively in contrast to those of physical mixture (PhyMix) (∼35% and ∼10%) and pure LORX (∼17% and ∼7%) within 60 min. The Cmax and AUC0–∞ for the selected cocrystal were significantly increased (p < 0.05) which was 2.4 and 2.5 times, respectively, that of LORX in a single dose oral pharmacokinetic study executed in rabbits. Tablets of cocrystal were found stable at both conditions. Conclusion The study indicates that cocrystallization with DMU can concomitantly improve tabletability, dissolution rate, and in vivo performance of dissolution limited drug LORX.
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The aim of the present research work is to prepare and evaluate topical hydrogel of lornoxicam using different gelling agent for the treatment of inflammation. Lornoxicam is a highly selective cyclooxigenase-1 & cyclooxigenase-2 inhibitor used in the treatment of inflammation, pain and edema, rheumatoid arthritis and so on. Topical gel of Lornoxicam was formulated using triethanolamine (5%) as solvent, carbopol 934p as gelling polymer and various penetration enhancers. Formulated gel was evaluated with respect to different physiochemical parameters such as pH, viscosity, spreadability, gel strength. The in-vitro drug release rate of gel was evaluated using Franz diffusion cell with phosphate buffer 7.4 as the receptor medium. Stability studies carried out at different temperatures and humidity did not show any significant change in drug content, % CDR, viscosities and other parameters at the end of 12 weeks indicating that all the formulations were stable. It was concluded that Physiochemiclly stable and non-irritant Lornoxicam gel was formulated and the drug release increased with increase in concentration of penetration enhancer which is suitable for topical application.
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PurposeOndansetron hydrochloride (OND) suffers from rapid elimination (t1/2 = 3–4 h), moderate bioavailability (60%) and inconvenience following oral administration in emetic patients. As an alternative convenient approach, the current work explored the potential of high-frequency ultrasound (HFU) waves to promote transdermal delivery of OND via bilosomal gel systems (BGS) in an attempt to increase OND bioavailability and achieve a rapid onset of action in patients suffering from emesis.MethodsOND-loaded BGS were prepared and characterized for pH and rheologic properties. The variables influencing HFU were optimized, viz. bilosomal system: coupling-gel ratio (1:2 or 1:3), application period (5, 10 or 15 min) and (iii) ultrasound intensity (medium or high), mode (continuous or pulsed) & duty cycle (20, 50 or 100%). Ex-vivo permeation and confocal laser scanning microscopy (CLSM) studies were conducted. The best achieved BGS (BGS10-HFU) was subjected to histopathologic and pharmacokinetic studies in rats.ResultsOND-loaded BGS were shear thinning systems having tolerable pH values for skin application. The optimized HFU variables involved the utilization of a bilosomal system: coupling-gel ratio of 1:3 and the application of high intensity, continuous and 100% duty cycle ultrasound waves for 10 min. Ex-vivo permeation and CLSM studies revealed the superiority of BGS10 following HFU-pretreatment. BGS10-HFU exhibited minor histopathologic changes. Compared to an oral OND solution, BGS10-HFU system had significantly (P < 0.05) higher AUC0–24 and AUC 0–∞values. Non-significant differences between Cmax and tmax values were revealed.Conclusion The best achieved system (BGS10-HFU) can increase OND bioavailability and initiate a rapid onset of action.
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Background Nanostructured lipid carriers (NLCs) are emerging as attractive drug carriers in transdermal drug delivery. The surface modification of NLCs with cell-penetrating peptides (CPPs) can enhance the skin permeation of drugs. Purpose The objective of the current study was to evaluate the ability of the cell-penetrating peptide (CPP) polyarginine to translocate NLCs loaded with lornoxicam (LN) into the skin layers and to evaluate its anti-inflammatory effect. Methods The NLCs were prepared using an emulsion evaporation and low temperature solidification technique using glyceryl monostearates, triglycerides, DOGS-NTA-Ni lipids and surfactants, and then six histidine-tagged polyarginine containing 11 arginine (R11) peptides was modified on the surface of NLCs. Results The developed NLCs formulated with LN and R11 (LN-NLC-R11) were incorporated into 2% HPMC gels. NLCs were prepared with a particle size of (121.81±3.61)–(145.72±4.78) nm, and the zeta potential decreased from (−30.30±2.07) to (−14.66±0.74) mV after the modification of R11 peptides. The encapsulation efficiency and drug loading were (74.61±1.13) % and (7.92±0.33) %, respectively, regardless of the surface modification. Cellular uptake assays using HaCaT cells suggested that the NLC modified with R11 (0.02%, w/w) significantly enhanced the cell internalization of nanoparticles relative to unmodified NLCs (P<0.05 or P<0.01). An in vitro skin permeation study showed better permeation-enhancing ability of R11 (0.02%, w/w) than that of other content (0.01% or 0.04%). In carrageenan-induced rat paw edema models, LN-NLC-R11 gels inhibited rat paw edema and the production of inflammatory cytokines compared with LN-NLC gels and LN gels (P<0.01). Conclusion In our investigation, it was strongly demonstrated that the surface modification of NLC with R11 enhanced the translocation of LN across the skin, thereby alleviating inflammation.
Article
Cyclodextrins are valuable natural or synthetically modified cyclic oligosaccharides that are widely used for ameliorating properties of biologically active compounds such as food additives and ingredients or medicinal compounds. They protect these compounds against light and oxidative degradation and provide host–guest supramolecular complexes having controlled release properties by molecular encapsulation, enhancing the water solubility and bioavailability. Among many characterization methods that are applicable in both solution and solid state, thermal techniques were widely used for analysis and stability evaluation of cyclodextrins and cyclodextrin complexes. This updated review deals with the use of thermal methods for analysis of cyclodextrins and cyclodextrin complexes. Classical and modern thermal techniques used for evaluation of inclusion compound formation were reviewed. Special attention was gave for thermogravimetry–differential thermogravimetry, differential thermal analysis, differential scanning calorimetry, hot stage microscopy, as well as for the more recent techniques thermogravimetry–mass spectrometry, gas chromatography-time-of-flight-mass spectrometry and isothermal titration calorimetry. In order to evaluate the cyclodextrin complexation capability by thermal methods, we grouped for the first time the guest compound as drugs by anatomical therapeutic chemical classification (ATC), as well as odorants, essential oils and vegetable extracts, antioxidants, fatty acids, oils, fatty acid-based derivatives, other organic, organometallic and inorganic compounds. The formation of cyclodextrin inclusion complexes was emphasized by disappearance of the signal corresponding to the melting or boiling points of the guest compound and the behavior of the hydration water molecules in the complex in comparison with the raw host and guest compounds. The thermal stability of the guest compound after cyclodextrin complexation was also discussed. It was emphasized that thermal methods are some of the most valuable techniques for analyzing cyclodextrin complexes and together with other methods can complete the information related to the host–guest molecular inclusion process and the specific properties of these cyclodextrin complexes.
Chapter
Human health is the most important issue in the society. There are many compounds such as food additives and ingredients or medicinal compounds that can alter human health. Cyclodextrins can protect these compounds against light and oxidative degradation by molecular encapsulation. Moreover, cyclodextrins can also enhance properties of biologically active compounds such as better water solubility and bioavailability, and controlled release. Cyclodextrins are cyclic oligosaccharides comprising of six to eight α-(1→4)-linked d-glucopyranose units corresponding to the natural α-, β- and γ-cyclodextrin, respectively. Cyclodextrins have a truncated cone-like structure, with a hydrophobic inner cavity and highly hydrophilic exterior. This property allows molecular encapsulating of geometrically compatible hydrophobic compounds for obtaining host-guest supramolecular systems. Among many characterization methods that are applicable in both solution and solid state, thermal techniques were widely used for analysis and stability evaluation of cyclodextrin complexes.
Article
The objective of present study was to formulate hydrogel thickened Lornoxicam transdermal formulation. Eutectic mixture of camphor and menthol was chosen as oily phase (maximum 10%), solvent for Lornoxicam and powerful penetration enhancer. Tween 80, ethanol and Carbopol 934p, HPMC K-15M and Xanthan gum were selected as surfactant, co-surfactant and hydrogel thickening agent respectively. Ternary phase diagrams were constructed to obtain the concentration range of oil phase, surfactant and co-surfactant for microemulsion formulation. Hydrogel thickened microemulsions were characterized for pH, viscosity, spreadability, in vitro drug transport study with excised rat skins and invivo anti inflammatory activity. The average drug transport rate of optimized hydrogel thickened microemulsion containing 1 % w/w Lornoxicam, 10 % w/w oily phase of camphor and menthol, 30 % w/w tween 80, ethanol (2:1), 57 % w/w water, 1.5 % w/w Carbopol 934p and 0.5 % w/w Triethanolamine through rat skin was 2.02 μg/cm2/h . The percentage in vitro drug release of optimized hydrogel thickened microemulsion was 78.91 %. pH, viscosity and spreadability of optimizes batch was 6.4, 5291 cps and 5.98 gcm/sec.
Article
The construction and performance characteristics of new sensitive and selective sensors based on funcntiolized multi-walled carbon nanotubes/[small beta]-cyclodextrin nanocomposite (FMWCNTs/[small beta]-CD) was demonstrated for potentiometric determination of different anti-inflammatory agents including lornoxicam, meloxicam, piroxicam and tenoxicam. Screen printed sensors (SPEs) modified with FMWCNTs/[small beta]-CD composite, hyamine (Hy) and 2-fluorophenyl 2-nitrophenyl ether (f-PNPE) showed proper electroanalytical performances with Nernstian compliance range between 61.2 to 52.6 mV decade-1 activity and detection limit 6.0[times]10-7 mol L-1 for different oxicam derivatives. Modification with carbon nanotubes composite as sensing material remarkably improved the potential stability and lifetime of the fabricated sensors. The proposed sensors offer a simple analytical tools for determination of different oxicam derivatives in their pharmaceutical formulations under batch and flow injection analysis (FIA) conditions.
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In general, the complexation efficiency of cyclodextrins is rather low, and thus relatively large amounts of cyclodextrins are needed to complex small amounts of a drug. In addition, various pharmaceutical additives decrease the efficiency even further. Meanwhile, due to toxicological considerations, formulation bulk and production cost, it is important to use as little cyclodextrin as possible in pharmaceutical preparations. Several different methods, which can be applied in order to enhance the complexation efficiency of cyclodextrins, were evaluated. A sugaring-in effect could not be observed in aqueous cyclodextrin solutions. Polymers, and other rheological agents, increase the complexation efficiency by increasing the apparent stability constant of the drug/cyclodextrin complex. Ionization of a drug molecule sometimes increases the complexation efficiency by increasing the intrinsic solubility of the drug. Finally, enhanced complexation efficacy can be obtained by forming a more water-soluble drug derivative of a water- insoluble drug (i.e. prodrug with higher intrinsic solubility than the parent drug).
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The purpose of this chapter is two-fold and includes approaches for identifying potentially problematic drug candidates with regard to formulation, in general, and for the preparation of toxicology vehicles, in particular. In addition, an attempt is made to provide insight as to what oral and parenteral excipients are appropriate for early human testing and, by extension, which of these materials can reasonably be used in GLP toxicology evaluation intended to support these Phase I human assessments. These considerations are becoming more visible in the drug development arena as evidenced by a number of recent symposia and congresses (Liu 2005; Van Gelder, 2006).
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The purpose of the work is physicochemical characterization of nimesulide (NI) and meloxicam (ME)–hydroxypropyl-β-cyclodextrin (HP-β-CD) binary systems both in solution and solid states and to improve the pharmaceutical properties of NI and ME via inclusion complexation with HP-β-CD. Binary systems of NI and ME with HP-β-CD have been characterized both in solution and solid state by different physicochemical methods. Three types of drug–HP-β-CD binary systems, namely physical mixtures (PM), kneaded systems (KS) and co evaporated systems (CS) in 1:1 and 1:2 molar ratios (1:1 and 1:2M) were prepared. Phase solubility and 1H-NMR spectroscopic studies in solution state revealed 1:1M complexation of NI and ME with HP-β-CD. A partial inclusion of NI with HP-β-CD at both molar ratios of kneaded and co evaporated systems and a true inclusion of ME with HP-β-CD at both molar ratios of co evaporated systems in solid state was confirmed by differential scanning calorimetry (DSC), powder X-ray diffractometry (powder X-RD) and scanning electron microscopy (SEM) studies. Dissolution properties of NI and ME–HP-β-CD binary systems were superior when compared to corresponding pure drugs. The aqueous solubility and dissolution properties of NI and ME can be improved by inclusion complexation with HP-β-CD.
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Cytokines produced by keratinocytes play an essential role in the induction of immune suppression following ultraviolet (UV) exposure. Using antibodies specific for either interleukin-10 (IL-10) or tumor necrosis factor alpha (TNF-alpha), we present evidence indicating that IL-10 suppresses delayed-type hypersensitivity (DTH) but not contact hypersensitivity (CHS), whereas TNF-alpha suppresses CHS but not DTH following UV exposure. UV exposure also activates antigen-specific suppressor T cells. To determine whether the antigen-specific CD4+ T cells that transfer suppression in this system mediate their suppressive effect by releasing IL-4 or IL-10, we transferred UV Ts into normal mice that were then injected with either anti-IL-4 or anti-IL-10 antibody. Both anti-IL-4 and anti-IL-10 blocked the ability of UV Ts cells to suppress DTH in the recipient animals. When UV Ts that suppress CHS were transferred into normal recipients, however, neither antibody was able to block the UV Ts activity. These findings suggest that UV Ts suppress DTH by secreting IL-4 and IL-10 and appear to act like Th2 cells. Because anti-IL-4 and anti-IL-10 did not block the activity of the UV Ts that regulate contact hypersensitivity, their effects appear to be mediated by a different mechanism.
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Cyclodextrins are cyclic oligosaccharides which have recently been recognized as useful pharmaceutical excipients. The molecular structure of these glucose derivatives, which approximates a truncated cone or torus, generates a hydrophilic exterior surface and a nonpolar cavity interior. As such, cyclodextrins can interact with appropriately sized molecules to result in the formation of inclusion complexes. These noncovalent complexes offer a variety of physicochemical advantages over the unmanipulated drugs including the possibility for increased water solubility and solution stability. Further, chemical modification to the parent cyclodextrin can result in an increase in the extent of drug complexation and interaction. In this short review, the effects of substitution on various cyclodextrin properties and the forces involved in the drug-cyclodextrin complex formation are discussed. Some general observations are made predicting drug solubilization by cyclodextrins. In addition, methods which are useful in the optimization of complexation efficacy are reviewed. Finally, the stabilizing/destabilizing effects of cyclodextrins on chemically labile drugs are evaluated.
Article
Cyclodextrins are macrocyclic compounds consisting of a varying number of D(+) glucopiranose residues linked through α(1-4) bonds. The most widely used are α-, β-, γ-cyclodextrins containing respectively 6,7 and 8 glucose units. In spite of their high aqueous solubility, the inner cyclodextrin cavity is non-polar and they can form complexes with many types of molecules placed inside this cavity. Most industrial applications of cyclodextrins aim at improving certain properties of finished products (solubility, organoleptic properties, stability). In this article several applications of cyclodextrins to pharmaceutical industry and chemical catalysis are reviewed. Analytical applications are also considered, since cyclodextrin inclusion improves the sensitivity and selectivity of most analytical methods.
Article
Inclusion complexes of drugs (acetaminophen, indomethacin, piroxicam and warfarin) with β-cyclodextrin were experimentally prepared by using a spray-drying technique. The spray-dried products were evaluated by X-ray diffractometry, differential scanning calorimetry and IR spectroscopy. The micromeritic properties and dissolution behaviour of spray-dried products were examined. It was found that the spray-drying technique could be used to prepare the amorphous state of drug inclusion complexes. The flowability and compressibility of the spray-dried products were poor, due to the small particle size formed by the spray drying process. However, the dissolution rates of drugs from tablets made by the spray-dried products were faster than those of the pure drug and the physical mixture of drug and β-cyclodextrin. The enhanced dissolution rate of spray-dried products might be attributed to the decreased particle size, the high-energetic amorphous state and inclusion complex formation.
Article
The interactions between Carbopol and β-cyclodextrin (BCD) or hydroxypropyl-β-cyclodextrin (HPBCD) were studied by differential scanning calorimetry (DSC) and FTIR spectroscopy. Aqueous solutions of both components were desiccated by freeze-drying or heating in an oven (films) at various temperatures. The use of different drying procedures allowed their influence on the interactions to be studied. The evolution of the Carbopol glass-transition was also evaluated by DSC using first heating runs up to different temperatures. Disappearance of the Carbopol glass-transition was observed in the freeze-dried systems prepared with either of the cyclodextrins and in the films that contained HPBCD. The changes in the FTIR band of Carbopol at 1700 cm-1 confirmed the existence of interactions with both cyclodextrins, especially with HPBCD. This information may be useful for optimising the solubilizing capacity and controlled release performance of aqueous Carbopol-cyclodextrin systems.
Conference Paper
Papers presented in Volume 1 are concerned with miscellar systems, kinetics of micellization, and micelles in nonaqueous media. A separate abstract was prepared for each of three papers. (JRD)
Article
Solid complexes between gliclazide and β-cyclodextrin (β-CD) were prepared by kneading, coprecipitation, neutralization, co-grinding and spray-drying. Characterization of gliclazide-β-CD inclusion complexes was performed using X-ray diffractometry and cross polarizing/magic angle spinning 13C-nuclear magnetic resonance spectroscopy. These techniques have clearly demonstrated the existence of solid-state inclusion compound formation. The complexes, obtained by neutralization and spray-drying methods, showed enhanced dissolution rates of gliclazide.
Article
The phase solubility profiles with HPCD of thesodium salt of the NSAIDs(non-steriodal anti-inflammatory drugs) ibuprofen anddiflunisal were studied. Theslopes of the phase solubility diagrams were determinedfor the sodium salt of ibuprofenat pH 6.1, 6.3 and 6.7, and for the sodium salt ofdiflunisal at pH 6.1 and 8.4. In allcases the slope of the phase solubility diagram wasgreater than unity. These resultssuggested that the stoichiometry of the complex formedwas greater than unity withrespect to the drug. However molecular modeling, NMRand UV studies clearlyshowed that the complex stoichiometry was 1:1. Theseconflicting results can beexplained by applying the theory developed for micellarforming compounds. Thusthe solubilization of the drugs is due partially frominclusion complex formation andpartially from solubilization by aggregation. Wehave therefore demonstrated that thesolubility of drugs in a cyclodextrin solution isexplained not only by inclusioncomplex formation but also by non-inclusion associationof the uncomplexed drugwith the complex.
Article
Inclusion complexation of heptakis (2,6-di-O-methyl)--cyclodextrin (DM--CyD) with -tocopheryl acetate and -tocopheryl nicotinate in aqueous solution was studied by the solubility method. The aqueous solubilities of the esters were about 105 times increased by DM--CyD complexation. The phase-solubility diagram of the tocopheryl ester-DM--CyD systems showed a typicalA p type, and the stability constants (K) of high-order complexes were estimated by analyzing the upward curvature of the diagrams. The solid complex of -tocopheryl nicotinate with DM--CyD in a molar ratio of 12 was prepared by the kneading method. The dissolution rate of the solid complex was much greater than that of the drug itself, and the rapidly dissolving form of -tocopheryl nicotinate, as an example, showed a markedly increased bioavailability (about 70-fold) after oral administration to fasted dogs.
Article
Hydroxylpropyl-β-cyclodextrins (HP-β-CDs), hydroxyalkyl derivatives of β-CD, used in a broad range of applications in food, pharmaceutical, agriculture and bioremediation of soil because of their specific chemical properties. The possibility of varying the biodegradation rate of HP-β-CDs by changing the DS and substitution pattern makes HP-β-CDs suitable for various applications. Therefore, their biodegradation fate has been of great concern. In this study, the biodegradation of various HP-β -CDs, which have different degrees and patterns of substitution in different soil ecosystems, was investigated. The degree and pattern of substitution of HP-β-CDs were determined by the reductive-cleavage method and methylation analysis. Two common soils and a contaminated soil were used in the biodegradation test. All CDs were found to be more or less biodegradable. Increasing the degree of substitution (DS) had negative effect on the biodegradation rate of HP-β-CDs. The substitution pattern affected the biodegradation, too. The biodegradation rates of CDs in the contaminated soil were higher than that obtained in the uncontaminated soils. The contamination removing ability of CDs was highly affected by their own biodegradation fate in soil.
Article
Conditions for condensation of β-cyclodextrin with propylene oxide were found which give preparations of hydroxypropyl-β-cyclodextrin with a narrow and symmetrical distribution of the degree of substitution. Furthermore, methods for purification of hydroxypropyl-β-cyclodextrins from the contaminating oligopropylene glycols were developed. Preparations of hydroxypropyl-β-cyclodextrin with low degrees of substitution ( < 8) were found to have optimal solubilization properties for drugs and also these preparations could be transformed into non-hygroscopic powders; the preparations with higher degrees of substitution (12–14) were semi-solids of lower solubilization power. The solubilities of 32 drugs in concentrated aqueous solutions of hydroxypropyl-β-cyclo-dextrins (40–50%) were measured; some of these were improved by three orders of magnitude over the corresponding solubilities in water.
Article
A dissolution test procedure using an adaptation of the FDA paddle method (USP Apparatus 2) has been developed for the purpose of assuring uniform batch to batch release. The patch is held in position in the dissolution vessel by sandwiching it between a watchglass and an aluminum wire screen. The dissolution profiles of the three marketed brands (10 dosage forms) of transdermal nitroglycerin patches were determined over a 24-h period. All samples, were analyzed by HPLC. The results of patches manufactured by each firm indicate dose proportional release. While there is a qualitative difference in the dissolution pattern among manufacturers, the dissolution procedure was found to be simple, reliable and reproducible, suggesting this technique can be used as a quality control tool for assuring product uniformity.
Article
Complex formation of oxazepam and β-cyclodextrin in solution was studied by phase solubility and spectral shift methods. The value of the apparent stability constant, Kc, calculated using these techniques, was 205 and 498 M−1, respectively. Solid complexes of oxazepam and β-CD were prepared using the kneading and spray-drying methods. These complexes led to an improvement in the dissolution rate over free oxazepam, spray-drying being the most efficient technique. These complexes were characterized by differential scanning calorimetry (DSC), scanning electron microscopy (SEM) and X-ray diffraction.
Article
Cyclodextrins are a family of cyclic oligosaccharides composed of α-(1,4) linked glucopyranose subunits. Cyclodextrins are useful molecular chelating agents. They possess a cage-like supramolecular structure, which is the same as the structures formed from cryptands, calixarenes, cyclophanes, spherands and crown ethers. These compounds having supramolecular structures carry out chemical reactions that involve intramolecular interactions where covalent bonds are not formed between interacting molecules, ions or radicals. The majority of all these reactions are of ‘host–guest’ type. Compared to all the supramolecular hosts mentioned above, cyclodextrins are most important. Because of their inclusion complex forming capability, the properties of the materials with which they complex can be modified significantly. As a result of molecular complexation phenomena CDs are widely used in many industrial products, technologies and analytical methods. The negligible cytotoxic effects of CDs are an important attribute in applications such as rug carrier, food and flavours, cosmetics, packing, textiles, separation processes, environment protection, fermentation and catalysis.
Article
Most ocular diseases are treated by topical drug application in the form of aqueous eye drop solutions. Recent studies have shown that cyclodextrins are useful additives in ophthalmic formulations for increasing the aqueous solubility, aqueous stability and bioavailability of ophthalmic drugs, and to decrease drug irritation. However, these studies have also shown that there are some basic differences between ophthalmic administration of cyclodextrins and administration of cyclodextrins via other routes. These differences have induced some limitations in the ophthalmic application of these most recently developed pharmaceutical excipients. The objective of this review is to summarize recent findings and applications of various cyclodextrins in ophthalmic drug delivery. Their mechanism of action in aqueous eye drop formulations is also discussed. Finally, the formulation of a couple of cyclodextrin containing eye drop solutions is described.
Article
Inclusion complexes of indomethacin in β-cyclodextrin and hydroxypropyl-β-cyclodextrin were prepared and evaluated in vivo. With respect to the gastrointestinal tolerance assessed in the rat, it appears that the inclusion of indomethacin in these cyclodextrins results in a decrease in its irritation power, confirming that this undesirable effect has at least a local origin. With respect to the dermal anti-inflammatory activity assessed on healthy volunteers by the methyl nicotinate test, the results seem to demonstrate that inclusions in either of the cyclodextrins investigated have a higher activity than free indomethacin.
Article
The aim of this work was to investigate the inclusion complexation between tadalafil, a practically insoluble selective phosphodiesterase-5 inhibitor (PDE5), and two chemically modified beta-cyclodextrins: hydroxypropyl-beta-cyclodextrin (HP-beta-CD) and heptakis-[2,6-di-O-methyl]-beta-cyclodextrin (DM-beta-CD), in comparison with the natural beta-cyclodextrin (beta-CD) in order to improve the solubility and the dissolution rate of the drug in an attempt to enhance its bioavailability. Inclusion complexation was investigated in both the solution and the solid state. The UV spectral shift method indicated guest-host complex formation between tadalafil and the three cyclodextrins (CDs). The phase solubility profiles with all the used CDs were classified as A(p)-type, indicating the formation of higher order complexes. The complexation efficiency values (CE), which reflect the solubilizing power of the CDs towards the drug, could be arranged in the following order: DM-beta-CD>HP-beta-CD>beta-CD. Solid binary systems of tadalafil with CDs were prepared by kneading and freeze-drying techniques at molar ratios of 1:1, 1:3 and 1:5 (drug to CD). Physical mixtures were prepared in the same molar ratios for comparison. Physicochemical characterization of the prepared systems at molar ratio of 1:5 was studied using differential scanning calorimetry (DSC), X-ray diffractometry (XRD), and Fourier-transform infrared spectroscopy (FTIR). The results showed the formation of true inclusion complexes between the drug and both HP-beta-CD and DM-beta-CD using the freeze-drying method at molar ratio of 1:5. In contrast, crystalline drug was detectable in all other products. The dissolution of tadalafil from all the prepared binary systems was carried out to determine the most appropriate CD type, molar ratio, and preparation technique to prepare inclusion complexes to be used in the development of tablet formulation for oral delivery of tadalafil. The dissolution enhancement was increased on increasing the CD proportion in all the prepared systems. Both the CD type and the preparation technique played an important role in the performance of the system. Irrespective of the preparation technique, the systems prepared using HP-beta-CD and DM-beta-CD yielded better performance than the corresponding ones prepared using beta-CD. In addition, the freeze-drying technique showed superior dissolution enhancement than other methods especially when combined with the beta-CD derivatives.
Article
Although parabens have several features of ideal preservatives, different studies have shown that they may affect human health due to their estrogenic activity. Therefore, various strategies have been applied to reduce their skin penetration. However, the effect of paraben combinations on transdermal permeation has not yet been investigated. Thus, the objective of this study was to evaluate paraben permeation in pig ear skin using a Franz diffusion cell system with capillary electrophoresis detection, in order to identify which paraben combinations (defined by a factorial design) have the lowest skin permeation. The permeation of isolated parabens was also evaluated and the permeation characteristics, obtained by the Moser model, confirmed that lipophilicity and molecular weight may influence the systemic absorption of these compounds. In previous tests using isolated parabens, methyl and ethyl parabens presented greater retention in the epidermis compared to the dermis, while propyl and butyl parabens had similar retention profiles in these layers. An increase in ethanol concentration and experimental time promoted greater parabens retention in the dermis compared to the epidermis. The binary combinations of methyl and ethyl parabens as well as of methyl and propyl parabens (added to several cosmetic products in order to increase the antimicrobial spectrum) reduced significantly their permeation rates through pig ear skin (with the exception of EP), probably due to the high retention of these parabens in the epidermis and dermis.
Article
Ultraviolet (UV) light is intricately linked to the functional status of the cutaneous immune system. In susceptible individuals, UV radiation can ignite pathogenic inflammatory pathways leading to allergy or autoimmunity. In others, this same UV radiation can be used as a phototherapy to suppress pathogenic cutaneous immune responses. These vastly different properties are a direct result of UV light's ability to ionize molecules in the skin and thereby chemically alter them. Sometimes these UV-induced chemical reactions are essential, the formation of pre-vitamin D(3) from 7-dehydrocholesterol, for example. In other instances they can be potentially detrimental. UV radiation can ionize a cell's DNA causing adjacent pyrimidine bases to chemically bond to each other. To prevent malignant transformation, a cell may respond to this UV-induced DNA damage by undergoing apoptosis. Although this pathway prevents skin cancer it also has the potential of inducing or exacerbating autoreactive immune responses by exposing the cell's nuclear antigens. Ultraviolet-induced chemical reactions can activate the immune system by a variety of other mechanisms as well. In response to UV irradiation keratinocytes secrete cytokines and chemokines, which activate and recruit leukocytes to the skin. In some individuals UV-induced chemical reactions can synthesize novel antigens resulting in a photoallergy. Alternatively, photosensitizing molecules can damage cells by initiating sunburn-like phototoxic reactions. Herein we review all types of UV-induced skin reactions, especially those involving the immune system.
Article
Topical application of a 2.5 per cent indomethacin (IM) solution to the sunburned skin of humans and guinea pigs resulted in a marked decrease in ultraviolet light (UVL) -induced erythema. In humans, a decrease in skin temperatute and hyperalgesia to near normal levels was also observed. Epidermal responses to UVL injury such as keratinocyte cell death and altered DNA synthesis proceeded unmodified by IM. Repeated applications of IM in the 48-hr period following UVL exposure did not improve upon the results obtained following a single treatment. Guinea-pig skin provides a relevant model system for evaluating the effects of topical nosteroidal anti-inflammatory agents on sunburn.
Article
Albino hairless mice (Skh:HR-1) exposed chronically to suberythemal doses of ultraviolet (UV) radiation display visible and histological alterations in the skin. One alteration is an increase in dermal cellularity, including inflammatory cells. This suggested a role for inflammation in chronic photodamage. We evaluated the photoprotective effect of topical hydrocortisone, ibuprofen, and naproxen against photodamage. All 3 agents protected against UVB radiation-induced visible wrinkling, tumor formation, and histological alterations. Hydrocortisone and naproxen were also evaluated for protection against UVA radiation-induced visible skin sagging and histological alterations. Both were very effective. These data indicate that chronic topical application of anti-inflammatory agents provides broad solar UV spectrum photoprotection.
Article
The responses of normal skin to ultraviolet (UV) irradiation are an example of inflammation. The chromophores initiating the reaction are unknown. Characteristic clinical findings are erythema, heat, swelling, and pain. Histopathologic changes include epidermal keratinocyte damage with Langerhans cell depletion and dermal edema, endothelial swelling, mast cell degranulation, and cellular infiltration with neutrophils and monocytes. Biochemical changes include release of histamine, cyclo-oxygenase, and lipoxygenase-derived products of arachidonic acid, kinins, and cytokines, probably from a range of epidermal and dermal cell types. These substances very likely assist in mediation of the reaction. The response is more pronounced in young subjects. UVB (280 to 315 nm) and UVA (315 to 400 nm) radiation both produce inflammation, but with marked qualitative and quantitative differences. UVB having more effect on the epidermis, UVA more on the dermis.
Article
The present study describes the application of differential scanning calorimetry (DSC) to ascertain the crystalline state of a drug with a melting point of approximately 53 degrees C after dispersion on hydrophilic carriers by either simple mixing or by fusion. The carriers examined include polyethylene glycol 6000 and colloidal silicon dioxides. The most interesting of the systems investigated, in which the drug is gradually transformed from the crystalline to the amorphous state at room temperature, are physical mixtures of the drug and colloidal silicon dioxides. The crystalline transformation is manifested by the gradual decrease in the endothermic transition energy of the physical mixture with time. The crystalline transformation is characteristically biphasic with initially fast first-order kinetics, followed by a slow conversion process. The rate of transformation is dependent on the drug-silicon dioxide ratio, temperature, and certain physical properties of the silicon dioxides. An inverse relationship exists between transition energy and the in vitro dissolution rate of the drug in the physical mixtures with silicon dioxide. This suggests that DSC may provide a useful method for evaluating the effects of formulation variables upon dissolution rate.
Article
A rapid, quantitative X-ray diffraction method to monitor the relative degree of crystallinity of lyophilized materials is described. The method was applied to determine the degree of crystallinity of imipenem [(5 R, 6 S)-3-[[2(formimidoylamino)ethyl]thio]-6-[(R)-1- hydroxyethyl]-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid] in 60 process related samples of the combination product of imipenem and amorphous cilastatin sodium (sodium (Z)-7-[[(R)-2-amino-2-carboxyethyl]thio]-2-[(S)-2,2- dimethylcyclopropanecarboxamido]-2-heptenoate). This assured optimizing process conditions which affect the improvement of crystallinity.
Article
We have investigated the effect of ultraviolet-B (UVB) irradiation on the density of epidermal ATPase-positive Langerhans cells, and the modulation of this effect by indomethacin (IND). Depilated backs of albino guinea pigs were exposed to varying doses of UVB (10–550 mJ/cm²). Skin biopsies were taken serially. There was an UVB dose-dependent decrease in the density of dendritic epidermal Langerhans cells, as identified by their membrane ATPase activity. This was accompanied by thinning and shortening, or disappearance of dendritic processes. Such changes were followed by a gradual recovery of the cell density to preirradiation level by day 21. Despite the high doses of UVB given, the maximal decrease in the density of ATPase-positive cells was only 58%. Topical application of IND, a prostaglandin-synthetase inhibitor, after irradiation resulted in a decrease of the erythema; however, the decrease in the density of ATPase-positive cells was still observed. In contrast, guinea pigs that received IND topically prior to irradiation showed a decreased erythemal response, but failed to show any decrease in the density of ATPase-positive cells. Administration of IND orally for 3 days prior to UVB exposure did not prevent the decrease in the cell density. The protective effect of topical IND, applied prior to irradiation, may be explained by its in vitro absorbance at both the UVB and UVA ranges. Topical application of IND 20 min prior to exposure to UVB in 2 human subjects resulted in an increase in the minimal erythema dose, giving a sun protection factor of 1.6, which is comparable to that produced by an equimolar concentration of para-aminobenzoic acid solution. The sun-protective property of IND, together with its activity as a prostaglandin synthetase inhibitor, indicate that it potentially could be a useful sunscreen agent. Its clinical safety and efficacy, however, remain to be determined.
Article
Immunological unresponsiveness can be initiated by exposure of mice to UV radiation, followed by the introduction of certain antigens. These antigens include epicutaneously applied chemicals that induce contact hypersensitivity (CHS), and antigens that occur on skin cancers induced by UV radiation. Mice exposed repeatedly to high doses of UV radiation during UV carcinogenesis develop immunological unresponsiveness to UV radiation-induced skin cancers, which are highly antigenic. This unresponsiveness is associated with the appearance of suppressor T lymphocytes that are specific for tumors induced by UV radiation, even though these tumors express individually specific transplantation rejection antigens. Thus, the occurrence of suppressor cells with specificity for a set of non-cross-reacting tumors suggests that a common, UV-associated regulatory antigen or determinant may be present on UV-induced skin cancers. Suppression of CHS in mice by UV radiation can be induced by two different procedures. One involves applying the sensitizer directly on skin exposed to low doses of UV-B radiation and is thought to result from a direct effect of UV radiation on cutaneous Langerhans cells. The second involves application of the sensitizer to the unirradiated skin of mice or guinea pigs exposed several days earlier to a higher dose of UV-B radiation. The mechanism of the latter phenomenon is not well understood, but there is evidence that it results from an alteration of antigen presentation by splenic macrophages. Both forms of suppression are associated with the appearance of antigen-specific suppressor lymphocytes in the animals' spleens, which prevent the induction of CHS upon transfer to a normal recipient. Either or both of these pathways could be responsible for the formation of the suppressor cells involved in UV carcinogenesis. Recent studies suggest that UV radiation may also affect immunological responsiveness in humans as well as in animals. However, the extent of such alterations and the mechanisms by which they occur are still unknown.
Article
The incidence of skin cancer is increasing at an alarming rate. To discuss current epidemiologic data concerning the incidence, morbidity, environmental influences, predisposing, host conditions, precursor lesions, and prevention of melanoma and nonmelanoma (basal and squamous cell) skin cancer. The current literature was reviewed in order to provide current epidemiologic data for melanoma, basal cell carcinoma (BCC), and squamous cell carcinoma (SCC). Skin cancer is exceedingly common and the incidence is rising rapidly. Although the mortality rate for nonmelanoma skin cancer (NMSC) is decreasing, that of melanoma is increasing. Both NMSC and melanoma are associated with significant morbidity. Whereas chronic sun exposure is the main cause of NMSC, the development of melanoma appears to be related to intense, intermittent sun exposure. Ozone depletion has contributed to rising incidence rates of both NMSC and melanoma. In contrast to NMSC, there is not a direct relationship between ultraviolet radiation and melanoma. Genetic susceptibility significantly increases the lifetime risk of acquiring melanoma. There is no precursor lesion for BCC. Precursor lesions for invasive SCC include actinic keratoses and SCC in situ. Melanoma may arise from benign nevi and dysplastic nevi. Prevention of melanoma and NMSC is extremely important since prognosis improves with early detection. Prevention may be achieved by educating patients and physicians how to detect skin cancers early and by decreasing or eliminating exposure to ultraviolet light. The incidence of skin cancer has reached epidemic proportions. Only through heroic efforts by health care professionals and the general public to prevent the development or progression of skin cancer will this epidemic be abated.
Article
The objective of this Review is to summarize and critique recent findings and applications of both unmodified and modified cyclodextrins for in vivo drug delivery. This review focuses on the use of cyclodextrins for parenteral, oral, ophthalmic, and nasal drug delivery. Other routes including dermal, rectal, and pulmonary delivery are also briefly addressed. This Review primarily focuses on newer findings concerning cyclodextrin derivatives which are likely to receive regulatory acceptance due to improved aqueous solubility and safety profiles as compared to the unmodified cyclodextrins. Many of the applications reviewed involve the use of hydroxypropyl-beta-cyclodextrins (HP-beta-CDs) and sulfobutylether-beta-cyclodextrins (SBE-beta-CDs) which show promise of greater safety while maintaining the ability to form inclusion complexes. The advantages and limitations of HP-beta-CD, SBE-beta-CD, and other cyclodextrins are addressed.
Article
Lornoxicam is a new non-steroidal anti-inflammatory drug of the oxicam class. This randomised, double-blind, placebo controlled trial compared the analgesic efficacy and tolerability of intramuscular (IM) injections of lornoxicam (4, 8, 16 and 20 mg) with morphine (10 and 20 mg) and placebo in 252 patients with mainly moderate to severe pain following surgical removal of an impacted mandibular third molar. Patients treated with lornoxicam or morphine experienced a significantly greater cumulative pain relief over the 4-h post-injection period (TOTPAR0-4) than placebo recipients. This effect appeared to be dose-dependent, with patients in the lornoxicam 4 mg or morphine 10 mg groups recording significantly lower TOTPAR0-4 scores than patients in the higher dosage groups of these drugs. No significant difference was detected between the morphine 20 mg group and the lornoxicam 8, 16 and 20 mg groups. Lornoxicam was well tolerated at all doses and was associated with a significantly lower incidence of adverse events than morphine 10 or 20 mg. Thus, the analgesic efficacy of IM lornoxicam at doses > or = 4 mg is superior to placebo, and doses > or = 8 mg are at least as effective as IM morphine 20 mg. Furthermore, lornoxicam possesses a more favourable tolerability profile than morphine and thus represents an attractive alternative for the treatment of moderate to severe acute pain.
Article
The objective of this review is to summarize recent findings on the safety profiles of three natural cyclodextrins (alpha-, beta- and gamma-CDs) and several chemically modified CDs. To demonstrate the potential of CDs in pharmaceutical formulations, their stability against non-enzymatic and enzymatic degradations in various body fluids and tissue homogenates and their pharmacokinetics via parenteral, oral, transmucosal, and dermal routes of administration are outlined. Furthermore, the bioadaptabilities of CDs, including in vitro cellular interactions and in vivo safety profiles, via a variety of administration routes are addressed. Finally, the therapeutic potentials of CDs are discussed on the basis of their ability to interact with various endogenous and exogenous lipophiles or, especially for sulfated CDs, their effects on cellular processes mediated by heparin binding growth factors.
Article
Cyclodextrins (CDs) complex hydrophobic drugs, increasing their aqueous solubility and stability. CD complexation enables the creation of formulations for water-insoluble drugs that are difficult to deliver with more traditional formulations. Currently, 10 pharmaceutical products are marketed as CD formulations. A CD-based formulation, like any other, is evaluated for quality and safety. The 6 CDs currently available for use in pharmaceutical products are alpha-, beta-, and gamma-CD and the methyl (M), hydroxypropyl (HP), and sulfobutylether (SBE) derivatives of beta-CD. The structural features of these CDs are evaluated for their affect on complexation performance. Optimal specifications, quality production, and safety of each CD is presented. The current and future regulatory process facing excipients is summarized, and the current regulatory status of the CDs in Japan, the United States, and Europe is presented.
Article
Two of the major cutaneous consequences of ultraviolet (UV) radiation exposure are immunosuppression and the development of skin cancer. This study examined whether these effects are genetically determined. Suppression of contact hypersensitivity by local, low-dose UV radiation was examined in what have been termed "UV-susceptible" and "UV-resistant" strains of mice. C3H/HeJ mice ("UV resistant") were resistant to the adverse effects of low-dose UV radiation when normal doses of hapten were applied to UV-irradiated skin; however, they were sensitive when the amount of hapten used for sensitization was reduced. A similar effect was observed in BALB/c mice ("UV resistant") and when the hapten was dimethylbenz(a)anthracene, thus indicating that the genetic variation was not strain or hapten specific. Despite the fact that some strains were sensitive and some were resistant to low-dose UV radiation when high doses of hapten were employed, all strains initially sensitized to hapten through UV-irradiated skin were found to be unresponsive when rechallenged on normal skin, no matter what the initial sensitizing dose of hapten was. To determine whether other biologic effects of UV also exhibited genetic variation, C3H/HeN and C3H/HeJ mice were compared for susceptibility to UVB-induced skin cancer formation. C3H/HeJ mice developed significantly more tumors than C3H/HeN mice when subjected to a single dose of UV radiation followed by repeated exposure to the tumor promoter 12-O-tetradecanoyl-phorbol-13-acetate. These studies provide strong evidence that genetic factors influence individual susceptibility to the biologic effects of UV radiation.
Article
Lornoxicam (chlorotenoxicam) is a nonsteroidal anti-inflammatory drug (NSAID) of the oxicam class. Unlike other oxicams, lornoxicam has a relatively short plasma half-life (3 to 5 hours). Lornoxicam is eliminated following biotransformation to 5′-hydroxy-lornoxicam, which does not undergo enterohepatic recirculation. Glucoroconjugated metabolites are excreted in urine and faeces with a half-life of about 11 hours. Lornoxicam and its metabolites bind extensively to plasma albumin. Substantial concentrations of lornoxicam are attained in synovial fluid, the proposed site of action in chronic inflammatory arthropathies. The effects of lornoxicam concentration on its therapeutic and toxicological properties have not yet been extensively reported. Lornoxicam, like other NSAIDs, appears to interact with warfarin, sulphonylureas, digoxin and furosemide.