Route Of Drug Delivery Research Articles

Temporal Distribution Patterns of Alexa Fluor 647-Conjugated CeNPs in theMouse Retina After a Single Intravitreal Injection.

Intravitreal (IVT) injection of ophthalmic therapeutics is the most widely used drug delivery route to the posterior segment of the eye. We employed this method to deliver our inorganic, catalytic antioxidant, cerium oxide nanoparticles (CeNPs), to rodent models of retinal degeneration. A single IVT of CeNPs delays disease progression. Even though we have shown that our synthesized CeNPs are retained in the retina for over a year, we still do not know which cell types in the retina preferentially take up these nanoparticles. In this study, we examined the temporal and spatial distribution of fluorescently labeled CeNPs in retinal sections after IVT. We detected elevated fluorescent signals in all the layers where retinal neurons and glia reside and retinal pigment epithelium (RPE) up to 90days post injection. Additionally, we found that free fluorochrome accumulated in retinal vasculature instead of retinal cells. These data suggested that CeNP-conjugation mediated the targeting of the fluorochrome to retinal cells. We propose that CeNPs can be deployed as ophthalmic carriers to the retina.

Ultrasound microbubble contrast agent – carried chemotherapeutic drug microbubbles

With the continuous research and development of ultrasound microbubble contrast agent-carried chemotherapeutic drug microbubbles, ultrasound microbubble contrast agent not only facilitates the early detection and early diagnosis of tumors but also provides a new direction and development prospect for the drug delivery route. With a broad development prospect, it is expected to become a new safe, effective and non-invasive treatment. This paper reviews the biological effects and research progress of contrast-enhanced microbubble-loaded chemotherapy drugs in tumor therapy.

A review on herbal transdermal patch for arthritis

In conventional medicine system the oral route is highly taken but does not give effective or desired effect because of systemic circulation, the first pass metabolism taken more time to get bioavailable or give therapeutic effect. So Transdermal drug delivery has made an important contribution to medical practice. It is a medicated patch that delivers a specific amount of medication through the skin into the blood stream. An advantage of a transdermal drug delivery route over other types of medication delivery is that the patch provides a controlled release of the medication into the patient, usually through either a porous membrane covering a reservoir of medication or through body heat melting thin layers of medication embedded in the adhesive. These Formulation consist herbal drugs, now days herbal drugs are more used they are safe because of having less side effects or low cost. And people trust herbal drug more than allopathy. The active drugs which are used to formulate herbal transdermal patches for arthritis are Ginger, Turmeric, Lavender, Katuvera, clove oil, wintergreen, Camphor, Menthol, aloe Vera, turpentine. These herbal drugs are very effective in arthritis and they are potent to formulate transdermal dosage form. Formulated transdermal drug delivery system using different polymeric grades of hydroxyl propyl methyl cellulose and with plastsizer propylene glycol. The Transdermal patches prepared are of matrix diffusion controlled systems. Solvent casting Technique was used to prepare the transdermal patches.

Using macropinocytosis for intracellular delivery of therapeutic nucleic acids to tumour cells.

Nucleic acids are a rapidly emerging therapeutic modality with the potential to become the third major drug modality alongside antibodies and small molecules. Owing to the unfavourable physico-chemical characteristics of nucleic acids, such as large size and negative charge, intracellular delivery remains a fundamental challenge to realizing this potential. Delivery technologies such as lipids, polymers and peptides have been used to facilitate delivery, with many of the most successful technologies using macropinocytosis to gain cellular entry; mostly by default rather than design. Fundamental knowledge of macropinocytosis is rapidly growing, presenting opportunities to better tailor design strategies to target this pathway. Furthermore, certain types of tumour cells have been observed to have high levels of macropinocytic activity and traffic cargo to favourable destinations within the cell for endosomal release, providing unique opportunities to further use this entry route for drug delivery. In this article, we review the delivery systems reported to be taken up by macropinocytosis and what is known about the mechanisms for regulating macropinocytosis in tumour cells. From this analysis, we identify new opportunities for exploiting this pathway for the intracellular delivery of nucleic acids to tumour cells. This article is part of the Theo Murphy meeting issue 'Macropinocytosis'.

Sublingual route for systemic drug delivery

Drug delivery via the oral mucous membrane is considered to be a promising alternative to the oral route. Sublingual route is a rapid onset of action and better patient compliance than orally ingested tablets. Sublingual literally meaning is “under the tongue”, administrating substance via mouth in such a way that the substance is rapidly absorbed via blood vessels under tongue. The portion of drug absorbed through the sublingual blood vessels bypasses the hepatic first‐pass metabolic processes giving acceptable bioavailability. Sublingual technology is convenient for dosing in geriatric, pediatric and psychiatric patients with dysphagia. Sublingual drug delivery shows fast therapeutic action than orally ingested drugs with fewer side effects. This review highlights advantages, disadvantages, different sublingual Gland, sublingual formulation such as tablets, films drops, sprays etc, evaluation parameters.
 Keywords: Sublingual delivery, dysphagia, sublingual gland, improved bioavailability, evaluations.

DEVELOPMENT OF TERMINALIA CHEBULA LOADED ETHOSOMAL GEL FOR TRANSDERMAL DRUG DELIVERY

Objective: Oral route is the usual route of drug delivery which has many advantages such as easy delivery but has disadvantages such as poor bioavailability and tendency to produce rapid blood level spikes, such that there becomes a necessity for higher dose or recurrent dosing which becomes difficult for the patient and also high cost. Keeping all these drawbacks in concern, there arises a necessity for novel development of drug delivery with improved therapeutic efficacy and safety with targeted delivery such that size and number of doses could be reduced. This can be achieved by transdermal delivery which possesses several advantages such as avoids first-pass metabolism, eliminates gastrointestinal irritation reduces frequency of dosing, and rapid termination of drug action.Methods: Dried fruits of Terminalia chebula were extracted and preliminary phytochemical evaluation was performed. Ethosome was prepared by cold method using soya lecithin. Ethosomal gel was prepared using carbopol as gelling agent and was evaluated.Results and Discussion: The prepared gel was evaluated for its pharmaceutical properties and was found to be satisfactory. The in vitro drug diffusion of ethosomal gel showed better release compared with that of the gel with extract. In vitro anti-arthritic activity exhibited significant effect compared to that of the standard diclofenac.Conclusion: Considering all the above-mentioned factors, the present study was aimed to develop a natural drug-loaded ethosomal gel for transdermal drug delivery, thereby permeation of drug can be enhanced compared with conventional dosage forms.

Formulation, Optimization and Evaluation of Rasagiline Mouth Dissolving Films

The oral route is the most preferred route, though preoral administration of drug has disadvantage like hepatic first pass metabolism and enzymatic degradation within the GI tract. Trans-mucosal routes of drug delivery offer distinct advantage over preoral administration. The aim of present investigation was to formulate the fast-dissolving oral films (FDOF) of rasagiline, an anti-Parkinson drug. In the present study, rasagiline fast dissolving films were formulated by solvent-casting method containing HPMC 5cps, 15 cps and 50 cps as polymers and PEG 400 as plasticizer, Crospovidone and SSG as superdisintigrating agents. All films prepared were smooth and elegant in appearance and showed no visible cracks, were even in weight, thickness and drug content. Formulation F16 is considered as the optimized formulation as it showed the faster disintegration time i.e., 8±0.18 sec, good percentage elongation (9.4%), good folding endurance (120±4), and the in vitro drug release is 99.39±5.28% within 9 min. It can be concluded that from the study that the mouth dissolving film can be potential novel drug dosage for treatment of Parkinson’s disease.

Chylomicron mimicking solid lipid nanoemulsions encapsulated enteric minicapsules targeted to colon for immunization against hepatitis B

The oral route is one of the most convenient routes for drug and/or vaccine delivery. Yet variable nature of gastrointestinal tract due to transient changes in pH, physiology, and flora throughout the gut together with hostile nature of peptide drugs/vaccines when given by this route results in limited success. Colon targeting is a recent area of interest for most of the research among which hard gelatin coated capsules is one such important and useful contrivance. The present study assesses the mucosal immunization with HBsAg loaded lyophilized nanoparticles delivered in the colonic region using enteric coated minicapsules. Designed minicapsules offers better compliance and oral vaccine antigen delivery to the colonic region which involving mucosal exposure thus mimicking the natural pathogen entry in the body. The present study is an extension of our reported work where nanoparticles were administered to the colon through the rectal route. Lyophilized nanoparticles were characterized for particle size, in-vitro release and antigen integrity along with cell uptake study. Particles had ~241 ± 32 nm sizes, flattened yet spherical in morphology. Enteric coated minicapsules were evaluated for size, coating thickness, and dissolution profile. In-vivo immune response assured its immunogenic potential with profound IgG (485 ± 41 mIU/ml) and IgA (885 ± 126 mIU/ml) antibody production as compared to marketed recombinant hepatitis B antigen formulation (Gene Vac-B®) which induce IgG and IgA titer; 1027 ± 62 mIU/ml and 220 ± 11 mIU/ml respectively following well established immunization protocol. Former induced significant mucosal immunity due to the involvement of Common Mucosal Immune System (CMIS). The study supports the workable novel approach for immune protection against hepatitis B.

Cost variation analysis of various brands of topical eye preparations currently available in Indian pharmaceutical market

Background: Ocular drug delivery is a complex drug delivery system, and topical administration being the most frequently employed route of drug delivery in eye diseases. Many topical eye preparations are sold under brand names. The variation in the costs of the same drug and inadequate information on quality and bio-equivalence makes it difficult for the physician to prescribe the most cost-effective treatment. The objective of this study was to analyse the cost variation in different brands of commonly used topical eye preparations in India.Methods: The minimum and the maximum cost in Rupees (INR) of particular topical eye preparations manufactured by various pharmaceutical companies in the same strength were noted. The percentage cost variation and cost ratio were calculated for each brand.Results: The costs of the total of 19 topical eye preparations available in 26 different formulations in India were analysed and a substantial variation in cost was observed. Of 19 drug formulations studied, the percentage cost variation of 10 drug formulations was more than 100% out of which one had more than 1000% variation. Cost ratio was also observed to be very high and 10 drug formulations had this ratio more than two.Conclusions: There is a wide variation in the prices of different brands, so there is an urgent need to raise the awareness of physicians about cost variation to lower the financial burden on patients.

APPLICATION AND CHARACTERIZATION OF IN SITU GEL

Applications of in situ gel have been used for a variety of drug delivery routes, such as oral, ocular, rectal, vaginal and injection. Characterization of in situ gel was determined to ensure that the prepared preparation met the standard and it safe. This review describes every aspects of this novel application and characterization of in situ gel preparations, which present the readers an exhaustive detail and might contribute to research and development. In the chemical evaluation in situ gel determined the diffusion of the active substance of a compound by measuring its concentration. In physical evaluation of isotonic calculated by osmotic pressure, drug release was determined by melting point of the substance polymer, gel strength as measured by rheometer, homogenecity test determined by under the light, and stability test with environmental conditions setting. In microbiology evaluation determine if the preparations was contaminated or not, also be effective and safe. Ocular irritation studies-Draize Test us an animal mice or rabbit and determination of visual appearance, clarity, and pH is required. In situ gels offer the primary requirement of a successful controlled release product that is increasing patient compliance.

Cluster of Differentiation 46 Is the Major Receptor in Human Blood-Brain Barrier Endothelial Cells for Uptake of Exosomes Derived from Brain-Metastatic Melanoma Cells (SK-Mel-28).

Brain metastasis is a frequent complication of cancer and may be mediated, at least in part, by the internalization of cancer-cell-derived exosomes into brain capillary endothelial cells. Clarifying the mechanism(s) of this internalization is of interest because it could help us to develop ways to block brain metastasis, as well as affording a potential new route for drug delivery into the brain. Therefore, the purpose of the present study was to address this issue by identifying the receptors involved in the internalization of exosomes derived from a brain-metastatic cancer cell line (SK-Mel-28) into human blood-brain barrier endothelial cells (hCMEC/D3 cells). The combination of sulfo-SBED-based cross-linking and comprehensive proteomics yielded 20 proteins as exosome receptor candidates in hCMEC/D3 cells. The uptake of PKH67-labeled exosomes by hCMEC/D3 cells measured at 37 °C was significantly reduced by 95.6% at 4 °C and by 15.3% in the presence of 1 mM RGD peptide, an integrin ligand. Therefore, we focused on the identified RGD receptors, integrin α5 and integrin αV, and CD46, which is reported to act as an adenovirus receptor, together with integrin αV. A mixture of neutralizing antibodies against integrin α5 and integrin αV significantly decreased the exosome uptake by 11.8%, while application of CD46 siRNA reduced it by 39.0%. Immunohistochemical analysis confirmed the presence of CD46 in human brain capillary endothelial cells. These results suggest that CD46 is a major receptor for the uptake of SK-Mel-28-derived exosomes by human blood-brain barrier endothelial cells (hCMEC/D3 cells).

Fractal Model of Transdermal Drug Delivery

Skin, separating the vital organs of a human body, is a desirable route for drug delivery. However, the intact skin is normally permeable only for drug molecules with a low molecular weight. The stratum corneum (SC), being the outermost layer of the skin and the epidermis being the second – more permeable – layer of the skin, play an essential function in transdermal drug delivery. Physical and chemical methods of skin poration are used to enhance transdermal drug delivery. Each poration leads to an irregular system of pores which are connected with a system of micro-capillaries passing through the epidermis. Both the systems by their irregularity form a fractal porous matrix. Drugs administrated by this matrix can be either suspensions and solutions or creams and gels, therefore they have to be modelled as non-Newtonian fluids. To analyse the fluid flow through the porous matrix the model of the epidermis is assumed as gobbet-andmortar with the tortuous mortar of variable thickness and after transition from the mortar to the tube one considered classical and fractal capillary flows of selected non-Newtonian fluids. Fractal expressions for the flow rate, velocity and permeability of fluids flow in a porous matrix are derived based on the fractal properties of the epidermis and capillary model. Each parameter in the proposed expressions does not contain any empirical constant and has a clear physical meaning and the proposed fractal models relate the flow properties of considered fluids with the structural parameters of the epidermis as a porous medium. The presented analytical expressions will help understand some of the physical principles of transdermal drug delivery.

A systematic review of nano formulation of natural products for the treatment of inflammatory bowel disease: drug delivery and pharmacological targets.

Inflammatory bowel diseases (IBD), which is classified into Crohn’s disease and ulcerative colitis, are among chronic gastrointestinal diseases with unknown pathogenesis. Diverse strategies have been applied for the treatment of this chronic disease. However, selective and site-specific routes of drug delivery to the inflamed location of the colon remain of high importance. Consequently, the application and effects of natural products in the form of nanoformulation and stimuli responsive nanoparticles as a novel strategy for the treatment of IBD are discussed in this review article. This approach may potentially overcome some complications that are associated with conventional means of colon drug delivery. Meanwhile, in vitro and in vivo studies pave the way for understanding of the mechanism that lies behind this chronic relapsing disease and potentially more effective treatment. Graphical abstractᅟ

Three-Dimensional Transport Model for Intravitreal and Suprachoroidal Drug Injection.

PurposeQuantitative understanding of the transport of therapeutic macromolecules following intraocular injections is critical for the design of efficient strategies in treating eye diseases, such as neovascular (wet) age-related macular degeneration (AMD) and macular edema (ME). Antiangiogenic treatments, such as neutralizing antibodies against VEGF or recently characterized antiangiogenic peptides, have shown promise in slowing disease progression.MethodsWe developed a comprehensive three-dimensional (3D) transport model for intraocular injections using published data on drug distribution in rabbit eyes following intravitreal and suprachoroidal (SC) injection of sodium fluorescein (SF), bevacizumab, and ranibizumab. The model then was applied to evaluate the distribution of small molecules and antiangiogenic proteins following intravitreal and SC injections in human eyes.ResultsThe model predicts that intravitreally administered molecules are substantially mixed within the vitreous following injection, and that the long-term behavior of the injected drug does not depend on the initial mixing. Ocular pharmacokinetics of different drugs is sensitive to different clearance mechanisms. Effective retinal drug delivery is impacted by RPE permeability. For VEGF antibody, intravitreal injection provides sustained delivery to the retina, whereas SC injection provides more efficient, but short-lived, retinal delivery for smaller-sized molecules. Long-term suppression of neovascularization through SC administration of antiangiogenic drugs necessitates frequent injection or sustained delivery, such as microparticle-based delivery of antiangiogenic peptides.ConclusionsA comprehensive 3D model for intravitreal and SC drug injection is developed to provide a framework and platform for testing drug delivery routes and sustained delivery devices for new and existing drugs.

New Insights on the Mechanism of Fatty Acids as Buccal Permeation Enhancers.

Buccal mucosa has recently received much attention as a potential route for systemic delivery of drugs, including biologics and vaccines. The aim of this work was to gain insight into the mechanism of fatty acids as buccal permeation enhancers, by studying the effect of a series of medium and long chain fatty acids on the permeation of a model high molecular weight and hydrophilic molecule, fluorescein isothiocyanate labelled dextran (FD-4, m.w. 4 kDa) across porcine esophageal epithelium. A parabolic relationship between fatty acid lipophilicity and enhancement was obtained, regardless of the presence and number of double bonds. The relationship, which resembles the well-known relationship between permeability and lipophilicity of transdermal delivery, presents a maximum value in correspondence of C10 (logP approx. 4). This is probably the ideal lipophilicity for the fatty acid to interact with the lipid domains of the mucosa. When the same analysis was performed on skin data, the same trend was observed, although the maximum value was reached for C12 (logP approx. 5), in agreement with the higher lipophilicity of the skin. The results obtained in the present work represent a significant advancement in the understanding of the mechanisms of action of fatty acids as buccal penetration enhancers.

Selective Laser Melting of Integrated Ti6Al4V ELI Permeable Walls for Controlled Drug Delivery of Vancomycin.

Bacteria colonizing the surface of orthopedic implants are responsible for most postoperative periprosthetic joint infections. A possible alternative route for drug delivery is described in this study by utilizing the bulk of the implant itself as a reservoir. Drug release is enabled by manufacturing of integrated permeable structures possessing high porosity through application of selective laser melting technology. The concept was evaluated in two paths, with 400 μm permeable thin walls and with dense reservoirs containing an integrated 950 μm permeable wall. Components were designed and preprocessed as separate parts, allowing for allocation of different settings of laser power and scanning speed. Lowering the energy input into the selective laser melting process to induce intermittent melting of the Ti6Al4V ELI powder produced porous components through which vancomycin was released with differing profiles. Static water contact angle measurements demonstrated a significant effect on the hydrophilicity by permeable wall thickness. Relative porosities of the 400 μm structures were determined with microcomputed tomography analyses. A transition zone of 21.17% porosity was identified where release profiles change from porosity-dependent to near free diffusion. Antimicrobial activity of released vancomycin was confirmed through evaluation against Staphylococcus aureus Xen 36 in two separate agar diffusion assays. The approach is promising for incorporation into the design and manufacturing of next-generation prosthetic implants with controlled release of antibiotics in situ and the subsequent prevention of periprosthetic joint infections.

A preliminary study on plasma concentration achieved following intrapterygomandibular space injection of dexamethasone as a route of drug delivery with lignocaine inferior alveolar nerve block-correlation of clinical effects.

To determine the quantity of dexamethasone plasma concentration achieved following intrapterygomandibular space injection of dexamethasone when co-administered with inferior alveolar nerve block correlating with the clinical effects in the postoperative phase. A preliminary prospective study to evaluate the dexamethasone plasma concentration achieved following intrapterygomandibular space injection of dexamethasone with 2% lignocaine inferior alveolar nerve block to achieve hemi-mandibular anesthesia for minor oral surgical procedures and derive clinical correlations. Dexamethasone is a glucocorticoid, chiefly used for the management of postsurgical sequelae like trismus and swelling in maxillofacial surgical practice. Conventionally, parenteral dexamethasone is administered via intravenous or intramuscular route. Intrapterygomandibular space injection is a novel route of steroid delivery described in literature. For minor oral surgical procedures in maxillofacial surgical practice requiring inferior alveolar nerve block, dexamethasone can be administered along with local anesthetic through a single injection as a mixture (twin mix). Prospective double-blind randomized clinical trial was designed to evaluative plasma concentration of dexamethasone achieved following injection of a freshly prepared mixture of 1.8ml of 2% lignocaine with adrenaline (1:200000) and 1ml (4mg) dexamethasone [2.8ml solution of twin mix] in the pterygomandibular space. The 30 candidates included for the trial were randomly split into three study groups (ten each)-(1) control group (C); (2) intramuscular group (IM); (3) intraspace group (IS). The mean plasma dexamethasone concentration at 30min postinjection in group IM was 226.41 ± 48.67ng/ml and for IS group it was 209.67 ± 88.13ng/ml. Post hoc (Bonferroni-Holm test) intergroup comparison for plasma dexamethasone concentration (IM and IS) was found statistically insignificant (P = 0.605). Intraspace route of drug administration can be utilized to deliver dexamethasonized local anesthetics safely with predictable clinical effects in the patients requiring mandibular minor oral surgery under local anesthesia.

TRANSFEROSOME: A RECENT APPROACH FOR TRANSDERMAL DRUG DELIVERY

Novel drug delivery systems are now a day is creating a new interest in development of drug deliveries. The transdermal route of drug delivery has gained great interest of pharmaceutical research, as it circumvents number of problems associated with oral route of drug administration. Transferosomes are capable of transdermal delivery of low as well as high molecular weight drugs. This offers several potential advantages over conventional routes like avoidance of first pass metabolism, predictable and extended duration of activity, minimizing undesirable side effects, utility of short half life drugs, improving physiological and pharmacological response and have been applied to increases the efficiency of the material transfer across the intact skin, by the use of penetration enhancers and non-ionic surfactant vesicles. It is suitable for controlled and targeted drug delivery and it can accommodate drug molecules with wide range of solubility. Due to its high deformability it gives better penetration of intact vesicles. Transferosome possess an infrastructure consisting of hydrophobic and hydrophilic moieties together and as a result can accommodate drug molecules with wide range of solubility. They are biocompatible and biodegradable as they are made from natural phospholipids and have high entrapment efficiency. In this review, we have focused on transferosome with discussions on novel drug delivery systems for targeted delivery of therapeutics and important issues and challenges for future clinical applications.
 Keywords: Novel drug delivery systems, Transferosomes, Transdermal drug delivery, Targeted drug delivery

The efficacy of oral piroxicam fast-dissolving tablets versus sublingual fentanyl in incident breakthrough pain due to bone metastases: a double-blinded randomized study.

Breakthrough pain (BTP) is a transient exacerbation of pain occurring in a patient with chronic, persistent pain. The most common type is incident pain that is mostly related to bone metastases. The oral mucosa is an attractive route for drug delivery. Sublingual fentanyl preparations are a very attractive agent in controlling attacks of BTP due to its rapid absorption through the oral mucosa. Non-steroidal anti-inflammatory drugs (NSAIDs) play a key role as a first step in treatment of cancer pain; piroxicam sublingual formulations could be a useful alternative in controlling incident pain. Our study hypothesis is to evaluate the efficacy of sublingual fentanyl versus oral piroxicam fast-dissolving tablets in patients with incident pain and its impact on functional status. A cohort of 100 adults of both genders suffering from bone metastases. Patients were assigned to receive either sublingual fentanyl tablet (group 1) or oral piroxicam fast-dissolving tablets (group 2). The pain intensity reduction on a 0-10 visual analog scale (VAS), frequency of BTP attacks, and onset of pain relief. Secondary end points included the functional interference items of the Brief Pain Inventory (BPI). There is no significant difference between the two groups regarding the patients' demographics. Significant decline of the VAS in each group in comparison to the pretreatment values (p = 0.001). Non-significant changes of the VAS, duration of pain attacks, and number of rescue doses in comparing both groups were measured. There was significant reduction in group 2 BPI regarding the relation with others, sleep pattern and enjoyment of life parameters at 2 and 4weeks (p = 0.001). Our study demonstrated that oral piroxicam fast-dissolving tablet is an analgesic alternative to sublingual fentanyl in patients with bone metastasis to control incidental BTP attacks with more favorable cost-benefit values.

Targeted Ocular Drug Delivery with Pharmacokinetic/Pharmacodynamic Considerations.

The development of ophthalmic drug delivery systems is a long and comprehensive process including research, nonclinical, and clinical development stages. It is critical to understand the similarity and differences between animal models and patients. There are many anatomically and physiologically important parameters for targeted drug delivery into eyes. This paper reviews the constraints to various routes of ocular drug delivery and discusses the respective pharmacokinetic considerations, to lay the foundation for formulation approaches pharmaceutical scientists can use to maximize successful drug delivery for each route. The overall goal is to give both researchers and drug developers a better understanding of ocular drug delivery and offer tools to successfully develop new medicines that will fulfil unmet medical needs and improve patients' quality of life.