Pass Hepatic Metabolism Research Articles

Sustained Release Microparticles Inhalation for Tuberculosis Treatment: Present Issues and Prospects

Mycobacterium tuberculosis, the primary cause of tuberculosis in humans, is a transmissible airborne disease. One of the most significant medical advances of the 20th century was the development of medications to cure tuberculosis. It makes sense to create strategies for administering antitubercular medications orally, or through the respiratory system. The pulmonary route lowers systemic toxicity, necessitates a lower dose, and has instantaneous drug release, first pass hepatic metabolism, and side effects. Presently, the most prevalent patterns in study aim to offer the optimal dry powders in the appropriate fraction for inhalation, which can release the medication before it is eliminated through natural mechanisms.

A Review Article on Transdermal Drug Delivery System

When compared to more conventional drug delivery methods, transdermal administration has many benefits. High bioavailability, the lack of first pass hepatic metabolism, stable medication plasma concentrations, and the non-invasive nature of therapy are a few of these. The stratum corneum, the skin's topmost layer, is the main barrier to medication molecules penetrating it. The study of how to get beyond this layer and improve transdermal drug delivery (TDD) is therefore of great interest. The purpose of this review article is to offer a remark on the most current developments in TDD enhancement methods. Techniques to increase skin penetration have been developed to boost bioavailability and broaden the range of medications for which topical and transdermal distribution is an effective alternative. These approaches include drug selection, prodrugs and ion pairs, supersaturated drug solutions, eutectic systems, complexation, liposomes, vesicles, and particles. These enhancement strategies are centered on optimizing the interaction between the drug and the vehicle. Enhancement through hydration-induced stratum corneum change, chemical enhancers that affect the stratum corneum's lipid and keratin composition, and effects on partitioning and solubility are also covered. It is discussed how penetration enhancers and retarders work and how they could be used in therapeutic settings.

A Review on Transdermal Drug Delivery System (TDDS)

The transdermal route of administration has numerous advantages over more traditional routes of medicine administration. They contain high bioavailability, lack of first- pass hepatic metabolism, stable tubemedicineconcns., and the fact that the treatment is non-invasive. The biggest hedge to the penetration of medicinalmotes is the external subcaste of the skin, the stratum corneum. therefore, exploration to ameliorate transdermal medicine delivery( TDD) is worthwhile this subcaste is the area of interest. This review composition is written togive content commentary recent advances in TDDS enhancement ways. ways that ameliorate the permeability of the skin have been used developed to ameliorate bioavailability and increase the choice of topical and transdermal medicines is a feasible option. This review describes improvement ways grounded on medicine/ vehicle optimization, e.g selection of medicines, prodrugs and ion dyads, supersaturated medicine results, eutectic systems, complexes, liposomes, vesicles and patches. Strengthening by changing the shell with moisturizing chemical enhancers partitioning and solubility goods affecting crustal lipid and keratin structure bandied Medium of action of penetration enhancers and retarders and they're implicit for clinical use operation is described

Transdermal Drug Delivery System

Abstract: A various non-invasive administration have recently emerged as an alternative toconventional needles. Transdermal drug delivery system is most attractive method. The transdermal as route has numerous advantages over the more traditional drug delivery system and they include high bioavailability, absence offirst pass hepatic metabolism, steady drug plasma concentration. and the fact that therapy is noninvasive. TDDS could be applicable in not only Pharmaceuticals but also in the skin industry, including cosmetics. Transdermal drug delivery has made an important contribution to medical practice such as diabetes, hemo rrhoids arthritis, migraine and Schizophrenia treatment, but yet to fully achieve it’s potential in the treatment of Obesity. The adhesive of the transdermal drug delivery system is critical to the safety, efficacy and quality of product

Nanotechnology-Assisted Metered-Dose Inhalers (MDIs) for High-Performance Pulmonary Drug Delivery Applications.

PurposeRespiratory disorders pose a major threat to the morbidity and mortality to public health. Here we reviewed the nanotechnology based pulmonary drug delivery using metered dose inhalers.MethodsMajor respiratory diseases such as chronic obstructive pulmonary diseases (COPD), asthma, acute lower respiratory tract infections, tuberculosis (TB) and lung cancer. At present, common treatments for respiratory disorders include surgery, radiation, immunotherapy, and chemotherapy or a combination. The major challenge is development of systemic delivery of the chemotherapeutic agents to the respiratory system. Conventional delivery of chemotherapy has various limitation and adverse side effected. Hence, targeted, and systemic delivery need to be developed. Towards this direction nanotechnology, based controlled, targeted, and systemic drug delivery systems are potential candidate to enhance therapeutic efficacy with minimum side effect. Among different route of administration, pulmonary delivery has unique benefits such as circumvents first pass hepatic metabolism and reduces dose and side effects.ResultsRespiratory disorders pose a major threat to the morbidity and mortality to public health globally. Pulmonary delivery can be achieved through various drug delivery devices such as nebulizers, dry powder inhalers, and metered dose inhalers. Among them, metered dose inhalers are the most interesting and first choice of clinician over others. This review focused on nanotechnology based pulmonary drug delivery using metered dose inhalers. This report focused on delivery of various types of therapeutics using nanocarriers such as polymeric nanoparticles and micelles, dendrimers, lipid nanocarriers such as liposomes, solid lipid nanostructures and nanostructured lipid carriers, and other using metered dose inhalers discussed comprehensively. This report provides insight about the effect of parameters of MDI such as co-solvent, propellants, actuators shape, nozzle diameters, and jet lengths, and respiratory flow rate, and particle size of co-suspension of drug on aerodynamics and lung deposition of formulation. This review also provided the insight about various metered dose inhalers market scenario and digital metered dose inhalers.ConclusionThis report concluded the clinical potential of metered dose inhalers, summary of current progress and future perspectives towards the smart digital metered dose inhalers development.

Nanoparticles with dense poly(ethylene glycol) coatings with near neutral charge are maximally transported across lymphatics and to the lymph nodes

Lymphatic vessels have recently been shown to effectively deliver immune modulatory therapies to the lymph nodes, which enhances their therapeutic efficacy. Prior work has shown that lymphatics transport 10–250 nm nanoparticles from peripheral tissues to the lymph node. However, the surface chemistry required to maximize this transport is poorly understood. Here, we determined the effect of surface poly(ethylene glycol) (PEG) density and size on nanoparticle transport across lymphatic endothelial cells (LECs) by differentially PEGylated model polystyrene nanoparticles. Using an established in-vitro lymphatic transport model, we found PEGylation improved the transport of 100 and 40 nm nanoparticles across LECs 50-fold compared to the unmodified nanoparticles and that transport is maximized when the PEG is in a dense brush conformation or high grafting density (Rf/D = 4.9). We also determined that these trends are not size-dependent. PEGylating 40 nm nanoparticles improved transport efficiency across LECs 68-fold compared to unmodified nanoparticles. We also found that PEGylated 100 nm and 40 nm nanoparticles accumulate in lymph nodes within 4 h after intradermal injection, while unmodified nanoparticles accumulated minimally. Densely PEGylated nanoparticles traveled the furthest distance from the injection site and densely PEGylated 40 nm nanoparticles had maximum accumulation in the lymph nodes compared to low density PEGylated and unmodified nanoparticles. Finally, we determined that nanoparticles are transported via both paracellular and transcellular mechanisms, and that PEG conformation modulates the cellular transport mechanisms. Our results suggest that PEG conformation is crucial to maximize nanoparticle transport across LECs and into lymphatic vessels, making PEG density a crucial design. Optimizing PEG density on nanoparticle formulations has the potential to enhance immunotherapeutic and vaccine outcomes. Statement of significanceLymphatic vessels are an emerging target for drug delivery both in the context of modulating immune responses and enhancing bioavailability by avoiding first pass hepatic metabolism after oral delivery. Lymphatic vessels are the natural conduits from peripheral tissues to the lymph nodes, where the adaptive immune response is shaped, and eventually to systemic circulation via the thoracic duct. Lymphatics can be targeted via nanoparticles, but the surface chemistry required to maximize nanoparticle transport by lymphatics vessels remains poorly understood. Here, we demonstrate that coating nanoparticles with hydrophilic polyethylene glycol (PEG) effectively enhances their transport across lymphatic endothelial cells in vitro and in vivo and that both paracellular and micropinocytosis mechanisms underly this transport. We found that dense PEG coatings maximize lymphatic transport of nanoparticles, thus providing new material design criteria for lymphatic targeted drug delivery.

FORMULATION DEVELOPMENT AND CHARACTERIZATION OF CLOTRIMAZOLE TRANSFERSOMAL GEL FOR EFFECTIVE TREATMENT OF FUNGAL DISEASE

Transdermal delivery system generally shows better regulation of blood levels, decreased occurrence of systemic toxicity, no first pass hepatic metabolism, and higher compliance as compared with conventional formulations. Transdermal treatment systems are characterized as self containing and discrete dosage types, which supply the medication with a regulated rate of systemic circulation through the skin if applied to the intact skin. The aim of present work to develop transdermal drug delivery system, transfersomes incorporated gel of Clotrimazole for effective treatment of Candidiasis. Prepared formulations of Transfersomes were optimized on basis of vesicle size, shape, surface charge and entrapment efficiency. Average vesicle and zeta potential of optimized formulation F-12 was found 145.58nm and -38.25 mV respectively. Prepared gel was prepared and evaluated for viscosity, % assay, extrudability, spreadability and drug release study. It was found that viscosity of prepared gel was 3150±12 cps, % assay was 99.45±0.12, Extrudability was 175g and Spreadibility (g.cm/sec) was found that 12.32±0.42 (g.cm/sec) respectively. In vitro drug release from Transfersomes was carried out using Franz diffusion cell method and found 98.12% in 10 hr. In first 30 min., it was 182±4 drug release which is slightly high. It was due to the release of free drug present in bag after leaching from transfersomes. Drug release from transferosomal formulation was found in very sustained and controlled manner.

Comparison of the frequency of preterm births in patients treated with oral versus intramuscular progesterone with history of previous preterm birth

Background: Globally, it has proven that preterm birth is associated with perinatal mortality to the extent of >75%, and >50% of perinatal and long term morbidity. Oral progesterone are easy to take but are less effective because of first pass hepatic metabolism leading to variable plasma levels while intramuscular progesterone carries the risk of swelling and bruising at injection site. The aim was to find out frequency of preterm birth in patients treated with oral versus intramuscular progesterone.Methods: Randomized controlled trial conducted in the department of obstetrics and gynecology, Sir Ganga Ram hospital Lahore, Pakistan conducted from 5 October 2017 to 4 April 2018. This study involved 530 pregnant women with history of at least 1 previous preterm delivery presenting in antenatal clinic between 16-20 weeks of gestation. Group I received oral progesterone 10 mg tablet duphaston BD from 20 weeks till 37 weeks. Group II received intramuscular progesterone injection proluton depot 250 mg IM weekly from 16-20 weeks till 37 weeks.Results: The mean age of the patients was 27.52±4.57 years while the mean gestational age was 17.39±1.38 weeks. 47.5% of the patients were para 2 followed by para 3 (32.3%) and para 1 (20.2%). The mean gestational age at delivery was significantly higher among intramuscular group (36.14±2.23 versus 35.07±2.97 weeks; p=0.000). The frequency of preterm delivery was significantly lower in intramuscular group (24.9% versus 39.6%; p=0.000) as compared to oral group.Conclusions: Frequency of preterm delivery was significantly lower in patients treated with intramuscular progesterone (24.9% versus 39.6%; p=0.000) as compared to oral progesterone.

A155 REAL-WORLD USE OF CORTIMENT IN ULCERATIVE COLITIS: A POPULATION-BASED STUDY

Abstract Background Ulcerative colitis (UC) is a relapsing and remitting disease with variable severity. BudesonideMMX (Cortiment®) was approved by Health Canada for the treatment of mild to moderate UC in July 2016. It offers the advantage of extensive first pass hepatic metabolism resulting in decreased systemic corticosteroid toxicity. Most public drug plans in Canada do not cover it, limiting its use to private insurance and self-pay. Aims To characterize the UC patients who use Cortiment® and explore prescribing patterns and short-term outcomes. Methods Population-based administrative data identified patients who were covered by the Alberta Health Care Insurance Plan and dispensed Cortiment® from August 1, 2016 to December 31, 2017. Analyses identified: age, sex, rural/urban status, Material [MDI] and Social Deprivation Indices [SDI], UC-related medications 6-months before and 10-weeks following Cortiment® dispensing, and disease exacerbation indicators (new dispense of corticosteroids, hospitalization with inflammatory bowel disease (IBD) as most responsible diagnosis, or IBD-related surgery). Results We identified 427 UC patients dispensed Cortiment®. The median age was 47 years (25th %: 35; 75th %: 59) and 57.4% were females. Most individuals (91.3%, n=390) resided in an urban setting, as compared to approximately 73% of all UC cases. Distribution of patients across SDI was consistent while the MDI had a higher proportion in the more well-off categories. 77.5% had a UC-related drug therapy in the 6 months prior to Cortiment® dispensing and 71.7% had a UC-related drug dispensed in the 10-weeks following. Approximately, 30% had a disease exacerbation indicators in the 10 weeks following dispensing: 24.8% new corticosteroid, 3.7% UC-related hospitalization, and <2.3% UC-related surgery. Conclusions Despite lack of public drug coverage, Cortiment® was dispensed across socioeconomic classes. The high dispensing within urban sites suggests that rural UC patients may have less access to Cortiment®. While a quarter of Cortiment® dispensings had a new concurrent dispensing of prednisone, <5% of these patients were admitted to hospital for a flare of UC. Funding Agencies Ferring Pharmaceuticals

Oleic Acid Vesicles for Transdermal Delivery of Propranolol Hydrochloride: Development and Characterization

Background: Pharmaceutical scientists are exploring transdermal route for treatment of various systemic diseases nowadays. Transdermal nanocarrier systems show various advantages like bioavailability enhancement of drugs, avoidance of first pass hepatic metabolism, and reduction of dosing frequency of bioactive therapeutic molecules. Objective: The objective of the present research work was to encapsulate Propranolol hydrochloride into oleic acid vesicles and carry out in-vitro and in-vivo evaluation of oleic acid vesicular gel containing Propranolol hydrochloride. Method: Propranol hydrochloride loaded oleic acid vesicles were prepared by exploring thin film hydration method. Developed vesicles were evaluated for morphology, size, zeta potential and polydispersity index (PDI). Thermal behavior of drug loaded vesicles was checked using differential scanning calorimetry (DSC) and depth of skin penetration was determined using confocal laser scanning microscopy (CLSM). Oleic acid vesicles dispersed in Carbopol 934R gel were subjected to in-vivo evaluation in male Sprague Dawley rats through measurement of plasma concentration and tissue distribution of Propranolol hydrochloride. Results: Optimized formulation having oleic acid : Propranol hydrochloride in the ratio 7 : 3 showed highest entrapment (56.1 ± 0.7%), acceptable size (291.3 ± 2.2 nm), the optimum value of PDI (0.219 ± 0.043) and zeta potential (-27.13 ± 0.25 mV). The results of DSC analysis showed effective encapsulation of drug inside the vesicles and CLSM analysis revealed penetration of vesicles upto stratum spinosum layer of skin. The results of in-vivo study revealed capability of vesicular gel to prolong the release of Propranolol hydrochloride upto 24 h with a Cmax value of 83.6 ± 3.0 ng/mL which was higher compared to the marketed tablet of Propranolol hydrochloride [InderalR (40 mg), Abbott India Ltd.] (45.6 ± 3.1 ng/mL). Tissue distribution studies revealed higher percentage of Propranolol hydrochloride in various organs after 24 h of administration of vesicular gel compared to marketed tablet. Conclusion: Developed oleic acid vesicular gel could be effective to reduce dosing frequency and avoid side effects of oral Propranol hydrochloride.

Cancer treatment in the lymphatic system: A prospective targeting employing nanostructured systems.

Cancer related to lymphangiogenesis has gained a great deal of attention in recent decades ever since specific markers of this intriguing system were discovered. Unlike the blood system, the lymphatic system has unique features that can advance cancer in future metastasis, or, conversely, can provide an opportunity to prevent or treat this disease that affects people worldwide. The aim of this review is to show the recent research of cancer treatment associated with the lymphatic system, considered one of the main gateways for disseminating metastatic cells to distant organs. Nanostructured systems based on theranostics and immunotherapies can offer several options for this complex disease. Precision targeting and accumulation of nanomaterials into the tumor sites and their elimination, or targeting the specific immune defense cells to promote optimal regression of cancer cells are highlighted in this paper. Moreover, therapies based on nanostructured systems through lymphatic systems may reduce the side effects and toxicity, avoid first pass hepatic metabolism, and improve patient recovery. We emphasize the general understanding of the association between the immune and lymphatic systems, their interaction with tumor cells, the mechanisms involved and the recent developments in several nanotechnology treatments related to this disease.

Microneedle-Mediated Transdermal Delivery of Tizanidine Hydrochloride.

Tizanidine hydrochloride is a skeletal muscle relaxant used for the treatment of spasm, a sudden involuntary muscle contraction leading to pain. The presently available oral dosage form has limitations such as high first pass metabolism resulting in low oral bioavailability. The short half-life necessitates its frequent administration to maintain the required plasma concentration. Transdermal delivery of drug avoids its first pass hepatic metabolism and gives controlled release, making it possible for reduction in dosing frequency. Drug delivery through transdermal route is severely limited by the presence of a tough stratum corneum barrier. A penetration enhancement approach is often necessary to achieve desired plasma concentrations. Microneedles are very short and sharp needles which do not cause pain. Thus, in the present investigation, preparation and evaluation of a transdermal delivery system for tizanidine hydrochloride based on microneedles are described.

Lung delivery of nanoliposomal salbutamol sulfate dry powder inhalation for facilitated asthma therapy

The motive behind present work was to discover a solution for overcoming the problems allied with a deprived oral bioavailability of salbutamol sulfate (SS) due to its first pass hepatic metabolism, shorter half-life, and systemic toxicity at high doses. Pulmonary delivery provides an alternative route of administration to avoid hepatic metabolism of SS, moreover facilitated diffusion and prolonged retention can be achieved by incorporation into liposomes. Liposomes were prepared by thin film hydration technique using 32 full factorial design and formulation was optimized based on the vesicle size and percent drug entrapment (PDE) of liposomes. Optimized liposomal formulation exhibited an average size of about 167.2 ± 0.170 nm, with 80.68 ± 0.74% drug entrapment, and 9.74 ± 1.10 mV zeta potential. The liposomal dispersion was then spray dried and further characterized for in-vitro aerosol performance using Andersen Cascade Impactor. Optimized liposomal formulation revealed prolonged in-vitro drug release of more than 90% up to 14 h following Higuchi’s controlled release model. Thus, the proposed new-fangled liposomal formulation would be a propitious alternative to conventional therapy for efficient and methodical treatment of asthma and alike respiratory ailments.

“FORMULATION AND EVALUATION OF BUCCAL FILMS OF SAXAGLIPTIN”

Objective: Saxagliptin is an orally anti-diabetic drug. It has an oral bioavailability of 50% due to first pass hepatic metabolism. To achieve sustained action of drug, reduce dosing frequency, bypass the hepatic first pass effect and improve bioavailability, buccal films formulation was planned.
 Methods: Compatibility of the drug with the excipients was studied with the help of FTIR. 23 factorial design was planned using concentration of Sodium alginate, concentration of Chitosan and PEG 400. Solvent casting method was used for the fabrication of films. Weight, thickness, surface pH, mucoadhesive strength, in vitro residence time, % swelling and % drug release were evaluated for the prepared film formulations.
 Results: All the films were found have surface pH close to neutral pH and were found to have content uniformity. Mucoadhesive strength was found to increase with increase in concentration of Chitosan. Drug release is more controlled by the high swelling film formers than sodium alginate. Among the film formers, though swelling is more, % drug release is also more from sodium alginate and Chitosan films because of its ionic nature and more solubility.
 Conclusion: Because of high mucoadhesive strength and more % drug release, combination of Sodium alginate with Chitosan film formulations was selected.
 Key Words: Saxagliptin, Buccal films

Chitosan-based transdermal drug delivery systems to overcome skin barrier functions

Transdermal drug delivery system has been developed or being developed to vanquish the downsides associated with conventional strategies as it avoids first pass hepatic metabolism, improved patient compliances, easy termination of therapy, possibility of self-administration etc. The main challenge in designing transdermal patch is to overcome the low permeability of skin. Several strategies have been developed to overcome the barrier properties and to enhance the transportation of drug molecules across the skin. In the last decades numerous transdermal patches fabricated from polysaccharides have been reported. There has been a growing interest in using chitosan in transdermal formulations thanks to their biocompatibility, non-toxicity, film forming ability, non- skin irritancy etc. This article highlights the application of chitosan in the development of transdermal drug delivery systems such as microneedles, films etc.
 Keywords: Transdermal drug delivery, first pass hepatic metabolism, low permeability, microneedles

Fluticasone Furoate: A Once Daily Preparation in Patients with Persistent Asthma

Asthma affects approximately 240 million people worldwide. It is characterised by an allergic pattern of smooth muscle constriction and airway inflammation, and if chronic, the inflammation can lead to structural changes and fixed airflow obstruction. Bronchodilators relieve the bronchoconstriction, while inhaled corticosteroids reduce the airway inflammation. This paper reviews fluticasone furoate (FF), a novel inhaled corticosteroid with 24-hour duration of action. It is a synthetic fluorinated corticosteroid with agonist activity at the glucocorticoid receptor (GRE). It is reported to have a fast association and slow dissociation from the GRE compared to other ICSs. FF has been found to have a greater lung retention time than all other ICS preparations which may contribute to the extended duration of anti-inflammatory action. FF has extensive first pass hepatic metabolism resulting in a low gastrointestinal bioavailability which is consistent with the findings for other ICS preparations. FF, however, will pass from the lung into the systemic circulation and therefore an adverse profile similar to all ICS is likely, but long term data are needed. FF has demonstrated treatment efficacy for asthma between 100μg and 200μg alone, but in combination with the long-acting beta agonist, vilanterol (FF/VIL 200μg/50μg OD) there were further improvements in lung function relative to monotherapy. There is an increased risk of pneumonia identified in patients with airways disease in associated with ICS preparations and surveillance will be required to determine if this also applies to FF. Once daily therapy, such as FF, may improve compliance and could hopefully be translated into further improvements in asthma-related outcomes.

Systematic approach for the formulation and optimization of atorvastatin loaded solid lipid NANOAPARTICLES using response surface methodology.

Atorvastatin is a lipid lowering agent with poor oral bioavailability (12%) because of poor solubility and extensive first pass hepatic metabolism. In order to overcome these issues, atorvastatin loaded solid lipid nanoparticles (ATOR-SLNs) were prepared by using glyceryl tripalmitate as lipid carrier, poloxamer 407 as surfactant and soya lecithin as emulsifier. The purpose of this work was to optimize the formulation with the application of response surface methodology to improve the physicochemical properties. The central composite rotatable design consisting of three factored factorial design with three levels was used for the optimization of the formulations. The optimized formulation was composed of drug/lipid ratio of 1:3.64, surfactant concentration of 1.5% with 5 min time for sonication. Fourier transforms infrared (FTIR) spectroscopy and differential scanning calorimetry (DSC) studies confirmed the compatibility of drug and lipid in the formulation. The optimized ATOR- SLNs showed almost spherical shape with a mean particle size of 338.5 nm, zeta potential of -24.7mV, DL of 17.7% and EE of 81.06% respectively. The in vitro drug release study showed a burst release at the initial stage followed by the prolongation of drug release from lipid matrix. Stability study revealed that ATOR-SLNs were more stable at 4±2˚C when compared with storage at 25±2˚C/60±5% RH during the six months storage period. These results indicated that the developed ATOR-SLNs is a promising approach for increment of bioavailability by improving the physicochemical properties.

PREPARATION, CHARACTERIZATION AND EVALUATION OF NEBIVOLOL LOADED CHITOSAN NANOPARTICLES

Nebivolol (NEB) is an antihypertensive drug with poor oral bioavailability (12%) in humans due to extensive first pass hepatic metabolism. Present work is an attempt to improve oral bioavailability of nebivolol by incorporating it with biodegradable polymer chitosan and preparing its nanoparticles. The results indicated stable nanoperticles with the value of ZP to be +36.4 mV ± 2 mV, the small particle size of 79.23 ± 45 nm and high entrapment efficiency of 72.56%. The in vitro release study revealed sustained release of drug for 72 h with 71.24% cumulative drug release. The promising results from the study revealed the applicability of chitosan in the formulation of NEB loaded CNPs.

Controlled buccal patches of Zaleplon using melt granulation technique: An approach to overcome early morning awakening

This study deals with the incorporation of melt granules in buccoadhesive patches prepared using polymers of opposing solubilities. Zaleplon (ZLP) is a Non-Benzodiazepine Hypnotic (NBZH) that suffers from extensive first pass hepatic metabolism and very short elimination half-life. The aim of this study was to develop a reliable dosage form that was capable of extending the release of ZLP to avoid early morning awakening so to improve sleep quality and also increase its bioavailability. ZLP was incorporated into Precirol-based melt granules and then further formulated into buccal patches prepared using HPMC, PVA and Ethyl cellulose. A Box-Behnken Design was adopted to statistically optimize the formulation variables, HPMC solution/PVA solution weight ratio, Precirol/ZLP ratio and percentage Ethyl cellulose. Fifteen formulae were prepared and evaluated regarding drug content uniformity, thickness uniformity, moisture loss, water sorption, mucoadhesion strength, surface pH, DSC and in-vitro release. The best achieved formula (composed of 5:1 Precirol:ZLP, 3:1 HPMC:PVA and 7.5% Ethyl cellulose) was able to control the release, where 87.24% of ZLP was released after 12 h and the patch showed acceptable mucoadhesion properties. The results revealed the ability of the developed ZLP buccal patches to be a candidate for overcoming early morning awakening.

Effect of administration method, animal weight and age on the intranasal delivery of drugs to the brain

BackgroundThe intranasal route of administration has proven to be an effective method for bypassing the blood brain barrier and avoiding first pass hepatic metabolism when targeting drugs to the brain. Most small molecules gain rapid access to CNS parenchyma when administered intranasally. However, bioavailability is affected by various factors ranging from the molecular weight of the drug to the mode of intranasal delivery. Comparison with existing methodsWe examined the effects of animal posture, intranasal application method and animal weight and age on the delivery of radiolabeled pralidoxime (3H-2-PAM) to the brain of rats. ResultsWe found that using upright vs. supine posture did not significantly affect 3H-2-PAM concentrations in different brain regions. Older animals with higher weights required increased doses to achieve the same drug concentration throughout the brain when compared to young animals with lower body weights. The use of an intranasal aerosol propelled delivery device mainly increased bioavailability in the olfactory bulbs, but did not reliably increase delivery of the drug to various other brain regions, and in some regions of the brain delivered less of the drug than simple pipette administration. ConclusionIn view of the emerging interest in the use of intranasal delivery of drugs to combat cognitive decline in old age, we tested effectiveness in very old rats and found the method to be as effective in the older rats.