Avoidance Of First-pass Metabolism Research Articles

Review on in-situ nasal gel drug delivery system

The review was carried out to discuss in detail about the in-situ gel nasal drug delivery system as these system have better systemic bioavailability through nasal route as compared to oral route of administration. In-situ gel is a novel dosage form for nasal delivery of various drugs. It is infusing into the nasal cavity as low viscous solution and after sometime it forms gel when it contact with the nasal mucosa. The main advantage of using nasal delivery is avoidance of first pass metabolism, high permeability of some drugs in nasal epithelium, quick drug absorption across this membrane, rapid onset of action, improved patient compliance and comfort, sustained and prolonged action in comparison to other drug delivery systems. The formation of gel depends on factors like temperature modulation, pH change, and presence of ions, ultra violet irradiation, polymorphism, dissolution rate, solubility, viscosity and osmolarity. The review was focused on anatomy and physiology of nose, advantages, disadvantages, mechanism of drug delivery to the nose, types of dosage form for nasal delivery, barriers in nasal drug delivery, factors influencing nasal absorption, mucoadhesive polymer used in nasal drug delivery system and evaluation of in-situ gel nasal drug delivery system.

Nanostructured Lipid Carriers: A New Paradigm in Topical Delivery for Dermal and Transdermal Applications.

Topical drug delivery offers many advantages over oral delivery, such as avoidance of first-pass metabolism, targeting of the active ingredients for a local effect, and patient compliance. However, the achievement of dermal and transdermal delivery needs to conciliate difficulties in permeation across skin barrier at different levels (skin surface, epidermis, dermis, and hypodermis). Nanostructured lipid carriers (NLCs) are recently invented second-generation lipidic carriers. The present article intends to provide an insight of composition, production, and application of these carriers in topical delivery for local and systemic effects. We also discuss key considerations for standardization and critical scale-up issues. In the last decade, the volume of work on NLCs is reflected in various research reports including patents on the development of NLCs, which gives a deeper insight of this emerging field of innovation. These carriers have significance because of their uniqueness to facilitate the interactions at interfaces with the barrier membranes. NLCs are truly a "nanosafe" carrier due to their biodegradable composition and have immense promise to overcome the challenges of dermal and transdermal delivery.

Oral transmucosal delivery of naratriptan

Naratriptan (NAR) is currently used as the hydrochloride salt (NAR.HCl) for the treatment of migraine and is available in tablet dosage forms for oral administration. Buccal drug delivery offers a number of advantages compared with conventional oral delivery including rapid absorption, avoidance of first pass metabolism and improved patient compliance. We have previously prepared and characterised the base form of NAR and shown that it has more favourable properties for buccal delivery compared with NAR.HCl. This study describes the design and evaluation of a range of formulations for oral transmucosal delivery of NAR base. Permeation studies were conducted using excised porcine buccal tissue mounted in Franz cells. Of the neat solvents examined, Transcutol® P (TC) showed the greatest enhancement effects and was the vehicle in which NAR was most soluble. The mechanisms by which TC might promote permeation were further probed using binary systems containing TC with either buffer or Miglyol 812® (MG). Mass balance studies were also conducted for these systems. The permeation of TC as well as NAR was also monitored for TC:MG formulations. Overall, TC appears to promote enhanced membrane permeation of NAR because of its rapid uptake into the buccal tissue. Synergistic enhancement of buccal permeation was observed when TC was combined with MG and this is attributed to the increased thermodynamic activity of NAR in these formulations. Significantly enhanced permeation of NAR was achieved for TC:MG and this was also associated with less TC remaining on the tissue or in the tissue at the end of the experiment. To our knowledge this is the first report where both enhancer and active have been monitored in buccal permeation studies. The findings underline the importance of understanding the fate of vehicle components for rational formulation design of buccal delivery systems.

Compounded Topical Analgesics for Chronic Pain.

Analgesic medications compounded for topical use are gaining popularity for the management of chronic pain. The advantages of topical pain medications include reduction of systemic adverse effects, improved patient acceptance, few drug interactions, ease of dose determination, avoidance of first-pass metabolism, and direct access to the target site. Compounded topical medications typically use a mixture of 3 or more single medications to achieve multiple complementary effects at lower doses of each individual medication. Herein, we review the mechanisms, adverse effects, and evidence for some of the most commonly used medications in topical compounds for pain management. Because more topical medications are used for chronic pain, dermatologists can expect an increase in irritant and allergic contact dermatitis related to these medications.

In-Situ Nasal Gel Drug Delivery: An Overview

Intranasal Therapy has been an accepted form of treatment in the Ayurvedic system of Indian medicine. The nasal delivery is a feasible alternative to oral or parenteral administration for some drug because of the high permeability of the nasal epithelium, rapid drug absorption across this membrane and avoidance of first pass metabolism. Prolonged drug delivery can be achieved by various new dosage forms like in situ gel. In situ forming polymeric formulation are drug delivery system that is in sol form before administration in the body, but once administered, undergoes gelation in situ to form a gel. In situ nasal drug delivery system is the type of mucoadhesive drug delivery system. In situ nasal gel drug delivery system is advantageous over the conventional drug delivery system like sustained and prolonged release of drug, reduced frequency of administration. Thus this review focuses on nasal drug delivery, various aspects of nasal anatomy and physiology, nasal absorption mechanism, and In-situ nasal gel evaluation.

Optimization of Thermoreversible In Situ Nasal Gel of Timolol Maleate.

Nasal route had shown better systemic bioavailability due to its large surface area, porous endothelial membrane, high total blood flow, and avoidance of first-pass metabolism. Timolol maleate is a beta blocker used primarily in the treatment of hypertension. Drug undergoes extensive hepatic first-pass metabolism (80%). The drug has half-life of 4 hrs. Oral bioavailability of timolol maleate is 61%. The aim of the present study was to optimize controlled release in situ nasal delivery for timolol maleate. HPMC and Poloxamer 407 were selected as polymer in formulation of thermoreversible in situ nasal gel. Optimization was carried out using 32 factorial design. It was observed that formulations f1 and f4 revealed the highest % drug release, that is, 93.57% and 91.66%, respectively. Factorial design study indicated that the drug release and viscosity were most significant dependent factors. Ex vivo diffusion study through nasal mucosa indicated 67.26 ± 2.10% and 61.07 ± 2.49% drug release for f1 and f4 formulations. f1 was the optimized batch. This batch thus can act as a potential nasal delivery with enhanced bioavailability for the drug.

Recent Patents in Pulmonary Delivery of Macromolecules.

Pulmonary delivery is a non-invasive form of delivery that holds tremendous therapeutic promise for topical and systemic administration of several macromolecules. Oral administration of macromolecules has several limitations such as low bioavailability, degradation of drug before reaching circulation and insufficient absorption across intestinal membrane. Administration of macromolecules such as proteins, peptides and nucleic acids via inhalation offers great potential due to the avoidance of first pass metabolism, higher surface area and rapid clinical response. However, delivery of reproducible, uniform and safe doses of inhaled particles remains a major challenge for clinical translation. Recent advances in the fields of biotechnology and particle engineering led to progress in novel pulmonary drug delivery systems. Moreover, significant developments in carriers and delivery devices prevent denaturation of macromolecules and control their release within the lungs. This article reviews the advances in pulmonary drug delivery systems by focusing on the recent patents in delivery of macromolecules. Furthermore, recent patents in gene delivery to the lungs have also been discussed. List of patents included in this review is comprehensive in terms of pulmonary delivery of therapeutics. It includes inventions related to proteins and peptides, DNA therapeutics, siRNA and other genetic materials with therapeutic applications. The diseases targeted by these therapeutic molecules are varied including but not limited to different forms of cancer, respiratory diseases etc.

Current Nanotechnological Approaches for an Effective Delivery of Bioactive Drug Molecules to Overcome Drug Resistance Tuberculosis.

Tuberculosis (TB) is an airborne communicable disease, mainly caused by aerobic, non-motile, rodshaped, weakly gram-positive, acid-fast tubercular bacillus Mycobacterium tuberculosis (MTb). Mycobacterium has worsened the problem in humans by acquiring various types of resistances like Multi-drug resistance (MDR), Single-drug resistance (SDR), and Extensive drug resistance (XDR). Some clinical problems and challenges associated with conventional TB chemotherapy include poor patient compliance, longer duration of chemotherapy, lesser cell permeability, primary drug resistance, difficulty in maintaining higher drug concentrations at the infected site, and degradation of the drug before reaching the target site. Thus, newer micrometric or nanometric carriers drug delivery approaches are needed. Colloidal (vesicular and particulate) drug carriers offer numerous advantages over conventional therapy such as better systemic bioavailability, rapid onset of therapeutic action, avoidance of first-pass metabolism, providing sustained and controlled release, fewer dosing frequencies, desired pharmacokinetic prole and route of administration. This review article present updates and fabrication of drug delivery approaches for tuberculosis chemotherapy in order to improve patient compliance.

Enhancing topical analgesic administration: review and prospect for transdermal and transbuccal drug delivery systems.

Topical administration is an appealing method for drug delivery due to its non-invasiveness, self-controlled application, avoidance of first-pass metabolism in the liver and reduction of systemic side effects compared to other conventional routes such as oral and parenteral. However, topical administration must overcome the permeable barriers that skin and mucosa represent for the drug to achieve its desired therapeutic effect. Penetration of drugs through human skin is mainly impaired by the stratum corneum- the uppermost keratinized skin layer. In contrast, the stratified squamous epithelium (a nonkeratinized tissue) represents the major physical barrier for transbuccal drug administration in humans. Different technologies have been studied to enhance the bioavailability or local effects of drugs administered through skin and buccal mucosa. Those technologies involve the use of physical or chemical enhancers and new dosage forms such as vesicles, cyclodextrins, nanoparticles and other complex systems. Combinations of these technologies may further increase drug delivery in some cases. As analgesia is one of the main therapeutic effects sought through topical administration, this paper focuses on the review of drug delivery systems to improve the topical and transdermal/transbuccal drug delivery of substances with known analgesic action. A discussion of their possibilities and limitations is also included.

Electrospun drug loaded membranes for sublingual administration of sumatriptan and naproxen

Sublingual administration of active pharmaceutical substances is in principle favourable for rapid onset of drug action, ready accessibility and avoidance of first pass metabolism. This administration could prove very useful in the treatment of migraines, thus two frequently used drugs were selected for our study. Sumatriptan succinate, naproxen, and its salt as well as combinations of these were incorporated into nanofibrous membranes via the electrospinning process. DSC measurements proved that the resulted membranes contained non-crystalline drug forms. SEM imaging approved good homogeneity of diameter and shape of the membrane nanofibres. The nanofibrous membranes always showed the rapid and mutually independent release of the tested drugs. The drugs exhibited very high differences in sublingual permeation rates in vitro, but the rates of both substances were increased several times using nanofibrous membranes as the drug carrier in comparison to drug solutions. The released drugs subsequently permeated through sublingual mucosa preferentially as non-ionized moieties. The prepared nanofibrous membranes proved very flexible and mechanically resistant. With their drug load capacity of up to 40% of membrane mass, they could be very advantageous for the formulation of sublingual drug delivery systems.

Topical Therapies in the Management of Chronic Pain

Chronic pain, whether localized or generalized, is a widespread, often debilitating condition affecting > 25% of adults in the United States. Oral agents are the cornerstone of chronic pain treatment, but their use may be limited in certain patients, particularly the elderly. Topical therapies offer advantages over systemically administered medications, including the requirement of a lower total systemic daily dose for patients to achieve pain relief, site-specific drug delivery, and avoidance of first-pass metabolism, major drug interactions, infections, and systemic side effects. Several types of topical agents have been shown to be useful in the treatment of patients with chronic pain. Both capsaicin and topical diclofenac have been shown to be effective in the treatment of patients with chronic soft-tissue pain. In patients with hand and knee osteoarthritis (OA), the American College of Rheumatology generally recommends oral treatments (acetaminophen, oral nonsteroidal anti-inflammatory drugs [NSAIDs], tramadol, and intra-articular corticosteroids) and topical NSAIDs equally, favoring topical agents only for patients who have pre-existing gastrointestinal risk or are aged > 75 years. Topical NSAIDs have been shown to provide relief superior to that of placebo and comparable to that of oral ibuprofen. Similarly, ketoprofen gel has been shown to be superior to placebo and similar to oral celecoxib in reducing pain in patients with knee OA. Different formulations of topical diclofenac (including the diclofenac hydroxyethyl pyrrolidine patch, diclofenac sodium gel, and diclofenac sodium topical solution 1.5% w/w with dimethyl sulfoxide USP) have been shown to be superior to placebo and comparable to oral diclofenac in the treatment of patients with pain due to knee OA, with a lower incidence of gastrointestinal complaints than with the oral formulation. In patients with neuropathic pain, topical forms of both capsaicin and lidocaine have been shown to be useful in the treatment of postherpetic neuralgia and diabetic peripheral neuropathic pain. Lidocaine has also demonstrated efficacy in relieving patient pain due to complex regional pain syndrome and may be useful in the treatment of patients with neuropathic pain who have cancer, although clinical trial results have not been consistent. Data suggest that topical therapies may offer a safe, well-tolerated, and effective alternative to systemic therapies in the treatment of patients with chronic, localized musculoskeletal and neuropathic pain.

Novel delivery approach for ketotifen fumarate: dissofilms formulation using 32 experimental design: in vitro/in vivo evaluation

Orally dissolving films (dissofilms) have gained increasing popularity and attention due to their ease of administration and avoidance of first pass metabolism. Ketotifen fumarate (KF) bioavailability is reported to be only ∼50% due to hepatic first-pass metabolism. Aiming to surmount this drawback and improve patients’ compliance, a 32 full factorial design was applied to formulate KF Orodispersible films, and to investigate the effects and interactions of the concentrations of the novel film former; Lycoat NG73® and the film modifier; maltodextrin (MDX) on the characteristics of the films prepared using solvent casting technique. The dissofilms were thoroughly evaluated regarding their weight uniformity, content uniformity, moisture uptake, in vivo mouth dissolving time (MDT) and their thermal behavior via differential scanning calorimetry. Statistical analysis revealed the significant influence of Lycoat NG73® concentration on percent elongation, percent KF dissolved after 5 min, and in vivo MDT, while MDX concentration had significant effect only on percent elongation. Further, storage of the optimal selected formula (15% Lycoat NG73 and 0% MDX) at 40 °C/75% relative humidity for 12 weeks caused no significant change in appearance, KF content or drug dissolution profile. Pharmacokinetic study revealed that the orally dissolving films showed significantly higher absorption extent than the reference marketed product, while no significant difference was observed for Cmax.

Competing properties of mucoadhesive films designed for localized delivery of imiquimod

Oral mucosal delivery has gained prominence in the last two decades because the rich vasculature of the tissue enables rapid delivery and avoidance of first pass metabolism. Although commercial mucoadhesives are used for systemic delivery, systems are not currently available for treatment of local conditions. In the present work, mucoadhesive films are being developed for locally controlled release of an immune response modifier for preventing precancerous lesions from progressing to oral squamous cell carcinoma. Previous research showed that films composed of polyvinylpyrrolidone (PVP) and carboxymethylcellulose (CMC) released imiquimod in a sustained manner for 3 hr. In continuing development of the system, additional key properties were investigated with changes in composition. While adhesive properties in pull-off (0.42±0.03 to 1.1±0.1 N/cm2) and shear adhesion (1.7±0.25 to 5.6±1.4 N/cm2) increased with increasing PVP content of films, tensile properties, such as modulus (6.9±1.5 to 1.8±0.2 MPa) and ultimate strength (4.2±0.7 to 2.1±0.02 MPa), decreased as PVP content increased. Release profiles of the films showed that an increased PVP content resulted in burst release and faster erosion compared to sustained release and slower erosion with more CMC. Studies of transport kinetics showed that the films doubled the amount of imiquimod localized within epithelium compared to drug in solution, increasing their potential for local treatment of oral dysplasia. The mucoadhesive drug delivery system based on CMC and PVP offers a wide range of these properties without addition of new constituents.

Nasal drug delivery.

The nasal cavity has for more than three decades been widely explored as a potential alternative route to oral or parenteral administration for systemically active drugs. The nasal route has shown remarkable advantages that include a rapid and high systemic availability, avoidance of first pass metabolism by the liver, and the possibility of targeting drugs directly from the nasal cavity to the brain [1, 2]. Considerable knowhow and data have been accumulated over the years from investigational work carried out by various excellent research groups in academia and industry. New nasal delivery carriers and emerging technologies have been used for product design and efficient clinical translation to nasal medicines. The nasal route for systemic administration is attractive in many therapeutic areas where a rapid onset of action is required, e.g., pain, erectile dysfunction, frigidity, migraine, seizures, insomnia, panic attacks, Parkinson rigidity, hot flushes, emesis, Alzheimer or MS attacks, and cardiovascular events. An increasing number of small molecules are being marketed as nasal products such as Zomig® (zolmitriptan), Imitrex® (sumatriptan), and Stadol NS (butorphanol tartrate) for migraine treatment, Aerodiol® (estradiol hemihydrate) for menopausal syndrome treatment, PecFent® and Instanyl® (fentanyl) for severe pain treatment, and Nicorette® (nicotine) for smoking cessation [3]. With this growing number of applications, the US market of intranasal drug products is expected to reach US$5.2 billion by 2017 [4]. It is noteworthy that most of the marketed products are based on molecules sufficiently lipophilic to enable therapeutic levels of the drug to reach the systemic circulation, thus requiring no nasal absorption enhancers. Despite the obvious advantages of intranasal drug delivery, the nasal cavity presents a number of limitations for drug absorption, including low intrinsic permeability for some drugs, such as hydrophilic molecules, peptides, proteins, and nucleotides, rapid mucociliary clearance, and enzymatic degradation [1, 2]. In order to achieve efficient and safe intranasal drug products, a number of strategies for overcoming nasal delivery barriers can be applied. In the design of a nasal product, three main cooperative entities should be taken in consideration: the drug, the delivery carrier, and the administration device. The factors to be considered in the design and development of an efficient nasal product, related to these three components, are schematically presented as a three-lobe fleur-de-lys in Fig. 1. Several important morphological and physiological constraints on nasal drug delivery including limited volume of administration requiring high drug potency or mucosal enzymatic drug degradation should be kept in mind when formulating new nasal products. Also, the key properties required from drug candidates for development of successful intranasal products would be potency, lipophilicity, and water solubility. The nasal delivery of hydrophilic or high molecular weight drugs would be in need of a nasal absorption promoter in order for the drug to be transported across the nasal membrane in sufficient quantity for therapeutic use. Innovative strategy approaches to design efficient nasal delivery systems for specific drugs are currently in various stages of research and development. These include new nasal enhanced delivery technologies, design of carriers that impede drug degradation by mucosal enzymes, modulation E. Touitou (*) Institute for Drug Research, School of Pharmacy, The Hebrew University of Jerusalem, Jerusalem 91120, Israel e-mail: touitou@cc.huji.ac.il

Design and Evaluation of Tizanidine Buccal Mucoadhesive Patches

Mucoadhesive buccal dosage forms are becoming more popular and patient acceptable dosage forms. By this route advantages are many as the dose can be reduced, avoidance of first pass metabolism and liver toxicity, etc. The Tizanidine has first pass metabolism because of this the patient has to take more dose and two to three times in a day. To overcome this problem mucoadhesive patches of tizanidine are prepared and evaluated. Tizanidine is a non-selective, α-two adrenergic agonist receptor and used as muscle relaxant. The oral bioavailability of Tizanidine is 40%, because of first pass metabolism. The polymers used are polyvinyl alcohol and polyvinyl pyrolidine. FTIR and UV spectroscopic methods reveal that there is no interaction between tizanidine and polymers. The patches evaluated for various parameters and results are satisfied. In vitro release studies in phosphate buffer (pH, 6.6) exhibited drug release in the range of 71.68 to 97.27% in 90 min. The release of tizanidine from the patches followed first order, Higuchi’s model and mechanism diffusion rate limited. In vivo buccal absorption studies in rabbits showed 68.85% of drug releases from polyvinyl alcohol patch while it 67.52 to 88.31% within 90 min in human volunteers. Good correlation among in- vitro release and in- vivo studies observed.

Single and Multiple Dose Pharmacokinetic Evaluation of a Transdermal Delivery System of Imipramine Hydrochloride

The transdermal route provides an attractive alternative to the presently used peroral therapy with tricyclic antidepressants due to the avoidance of first-pass metabolism and the associated side effects. In this investigation an earlier developed transdermal delivery system (TDS) of imipramine hydrochloride (CAS 113-52-0; IMH) was evaluated with respect to dose proportionality at three different dose levels. Linearity was observed with the lower doses. For the prediction of in vivo plasma levels, various pharmacokinetic parameters such as alpha, beta, volume of distribution, and AUC0-infinity. were determined by single dose intravenous administration (2 mg/kg). The lowest dose was selected for the multiple dose study taking into consideration the issues of stability, safety, therapeutic range and linearity of pharmacokinetics. At all dose levels the experimental plasma values were significantly lower than predicted levels (p < 0.05) but 30-50 fold higher than the therapeutic range with no significant difference at different dose levels. The plasma levels obtained by repeated application were comparable to that obtained in the single dose study. In addition, IMH exhibited dose proportional pharmacokinetics at the higher doses (above 50 mg/day). The developed TDS was able to maintain steady-state plasma levels for the entire duration of the multiple dose study.

Skin tolerability of transdermal patches

Introduction: Transdermal patch systems are an effective method of administering active ingredients through the skin, with considerable advantages over other drug delivery routes, for example, maintenance of constant plasma drug levels and avoidance of first-pass metabolism. However, repeated epicutaneous application may be associated with local skin reactions.Areas covered: This review addresses current issues regarding the effective/safe use of transdermal patch systems, and provides a critical analysis of the addition of ‘skin-caring’ ingredients to patch systems. Effective use of transdermal systems includes choosing an appropriate body area for application, maintaining regular skin care regimens before application and not replacing a patch in the same area (rotation) within 7 days. Another strategy, developed in an attempt to improve the tolerability of transdermal systems, is the addition of assumed ‘skin-caring’ ingredients (e.g., Aloe Vera) to patch systems. However, at present there is neither proof nor clinical evidence of any benefit. On the contrary, plant-derived ingredients might be associated with allergenic potential.Expert opinion: Transdermal systems are generally well tolerated; physicians must adequately inform patients of the most effective ways to use these formulations for maximum therapeutic benefit, while minimising local adverse events. Skin-caring agents, including Aloe Vera, cannot be recommended until well-controlled clinical trials with standardised extracts are available.

Formulations for Pulmonary Administration of Anticancer Agents to Treat Lung Malignancies

Chemotherapy plays a significant role both as primary and as supportive care for lung cancer treatment. The majority of currently available anticancer agents are administrated intravenously, causing side effects due to the systemic drug distribution. Alternatively, the bioavailability of orally administrated anticancer agents is usually compromised by the first-pass metabolism. Pulmonary administration may be a potential route for anticancer drug delivery to treat lung tumors, due to its site specific delivery, avoidance of first-pass metabolism, possibility of fewer side effects, and improved comfort for cancer patients using a needle-free delivery device. However, to attain an effective inhalational delivery, there is a requirement to design a formulation with appropriate aerodynamic properties with well-suited excipients. This review article explores work to date related to the formulations developed for pulmonary delivery of small molecule antineoplastic agents to treat primary and metastatic lung carcinomas. Ultimately, it highlights the importance of formulation design to define the role of inhalational chemotherapy.

Novel Vaginal Drug Delivery Systems: A Review

The vagina, in addition to being a genital organ with functions related to conception, serves as a potential route for drug administration. Mainly used for local action in the cervico-vaginal region, it has the potential of delivering drugs for systemic effects and uterine targeting. Within recent years the level of interest in both local and systemic vaginal drug delivery systems has increased considerably. The vagina offers numerous advantages as a site for drug delivery, such as convenient access, prolonged retention of formulations, a great permeation area, high vascularization, relatively low enzymatic activity, and the avoidance of first-pass metabolism. Currently available vaginal dosage forms have several limitations, such as leakage and messiness necessitating the need to develop novel drug delivery systems. The purpose of writing this review was to compile the recent literature on novel vaginal drug delivery systems. Keywords: Novel vaginal delivery systems, polymers, drugs used in vaginal delivery

Nanomedicine in pulmonary delivery

The lung is an attractive target for drug delivery due to noninvasive administration via inhalation aerosols, avoidance of first-pass metabolism, direct delivery to the site of action for the treatment of respiratory diseases, and the availability of a huge surface area for local drug action and systemic absorption of drug. Colloidal carriers (ie, nanocarrier systems) in pulmonary drug delivery offer many advantages such as the potential to achieve relatively uniform distribution of drug dose among the alveoli, achievement of improved solubility of the drug from its own aqueous solubility, a sustained drug release which consequently reduces dosing frequency, improves patient compliance, decreases incidence of side effects, and the potential of drug internalization by cells. This review focuses on the current status and explores the potential of colloidal carriers (ie, nanocarrier systems) in pulmonary drug delivery with special attention to their pharmaceutical aspects. Manufacturing processes, in vitro/in vivo evaluation methods, and regulatory/toxicity issues of nanomedicines in pulmonary delivery are also discussed.