Polymeric Depots Research Articles

Multiresponsive Polymer Tracers for ¹⁹F MRI Based on Poly[N-(2,2-difluoroethyl) Acrylamide

Polymers with lower critical solution temperature (LCST) are molecularly soluble in their solutions at low temperatures but, when heated above their cloud point temperature, these polymers assemble into supramolecular particles or macroscopic precipitates. These particles or precipitated polymeric depots can be used for diagnostics, targeted drug delivery, controlled drug release from a depot or a combination of diagnostics and therapy (theranostics). Herein, we describe smart polymer systems which contain N-(2,2-difluoroethyl)acrylamide monomer unit (DFEA) and form polymeric nanoparticles upon heating or precipitate after injection to polymeric implants/depots. Due to a high fluorine content and to relaxation properties of this element, these polymers are suitable as tracers for the 19F MRI method, a promising non-invasive diagnostic tool. Moreover, DFEA copolymers can contain monomers that react to additional physicochemical properties, resulting in multiresponsive polymers (pH- or redox-responsive), which can be used for smart drug delivery systems with controlled release of drugs in the target environment.

DEVELOPMENT AND VALIDATION OF UV SPECTROSCOPIC METHOD OF PALIPERIDONE PALMITATE IN BULK AND ITS APPLICATION FOR DRUG LOADING AND ENTRAPMENT EFFICIENCY ANALYSIS OF LONG-ACTING INJECTABLE MICROSPHERES

Objective: The objective of the current study was to develop simple, precise and cost-effective ultraviolet (UV) spectroscopic method for estimation of paliperidone palmitate (PP) as a bulk and in the polymeric depot dosage form.
 Methods: UV spectrophotometer with quartz sample cells and spectral manager software was used for analysis samples. 20 % Methanol in Mili-Q-Water was used as a solvent for the sample and standard preparations. Method validation was carried out as per ICH Q2 (R1) guidelines. Stress degradation studies were carried out to check the stability-indicating performance of the developed method. The validated method was applied for the estimation of the PP content of long-acting injectable microspheres of PP.
 Results: The wavelength of maximum absorption was found to be 283 nm. The proposed method was validated in the range of 5-30 µg/ml of PP. The mean recovery for 80%, 100% and 120% standard solution was found to be 99.03%, 99.21% and 99.35% respectively with less than 2% relative standard deviation (RSD). Intra-day and inter-day method precision ranged from 0.54 to 1.62% and 0.67 and 1.24% respectively. Limit of detection (LOD) and limit of quantitation (LOQ) were estimated to be 0.03 and 0.10 µg/ml respectively. The developed method was found to be robust and rugged. Stress degradation studies were carried out under acidic, alkaline, hydrolytic and oxidative and photo stress. The proposed method was capable to detect changes in assay due to stress conditions.
 Conclusion: The developed method was successfully employed for routine analysis of drug loading in long-acting injectable microspheres of PP.

Nanofibrous Polydioxanone Depots for Prolonged Intraperitoneal Paclitaxel Delivery.

Prolonged chemodrug delivery to the tumor site is a prerequisite to maintaining its localised therapeutic concentrations for effective treatment of malignant solid tumors. The current study aims to develop implantable polymeric depots through conventional electrospinning for sustained drug delivery, specifically to the peritoneum. Non-woven electrospun mats were fabricated by simple electrospinning of Polydioxanone solution loaded with the chemodrug, Paclitaxel. The implants were subjected to the analysis of morphology, mechanical properties, degradation and drug release in phosphate buffer and patient-derived peritoneal drain fluid samples. In vivo studies were conducted by surgical knotting of these implants to the peritoneal wall of healthy mice. Non-woven electrospun mats with a thickness of 0.65±0.07 mm, weighing ~ 20 mg were fabricated by electrospinning 15 w/v% polymer loaded with 10 w/w% drug. These implants possessing good mechanical integrity showed a drug entrapment efficiency of 87.82±2.54 %. In vitro drug release studies in phosphate buffer showed a sustained profile for ~4 weeks with a burst of 10 % of total drug content, whereas this amounted to >60% in patient samples. Mice implanted with these depots remained healthy during the study period. The biphasic drug release profile obtained in vivo showed a slow trend, with peritoneal lavage and tissues retaining good drug concentrations for a sustained period. The results indicate that non-woven electrospun mats developed from biodegradable Polydioxanone polymer can serve as ideal candidates for easily implantable drug depots to address the challenges of peritoneal metastasis in ovarian cancer.

Anti-PSMA/CD3 Bispecific Antibody Delivery and Antitumor Activity Using a Polymeric Depot Formulation.

Small therapeutic proteins represent a promising novel approach to treat cancer. Nevertheless, their clinical application is often adversely impacted by their short plasma half-life. Controlled long-term delivery of small biologicals has become a challenge because of their hydrophilic properties and in some cases their limited stability. Here, an in situ forming depot-injectable polymeric system was used to deliver BiJ591, a bispecific T-cell engager (BiTE) targeting both prostate-specific membrane antigen (PSMA) and the CD3 T-cell receptor in prostate cancer. BiJ591 induced T-cell activation, prostate cancer-directed cell lysis, and tumor growth inhibition. The use of diblock (DB) and triblock (TB) biodegradable polyethylene glycol-poly(lactic acid; PEG-PLA) copolymers solubilized in tripropionin, a small-chain triglyceride, allowed maintenance of BiJ591 stability and functionality in the formed depot and controlled its release. In mice, after a single subcutaneous injection, one of the polymeric candidates, TB1/DB4, provided the most sustained release of BiJ591 for up to 21 days. Moreover, the use of BiJ591-TB1/DB4 formulation in prostate cancer xenograft models showed significant therapeutic activity in both low and high PSMA-expressing tumors, whereas daily intravenous administration of BiJ591 was less efficient. Collectively, these data provide new insights into the development of controlled delivery of small therapeutic proteins in cancer. Mol Cancer Ther; 17(9); 1927-40. ©2018 AACR.

Time-dependent distribution of SN-38 from injectable polymeric depots in brain tumor model

Distribution study of drugs in tissues is essential to provide the information on the accumulation and penetration of drugs especially anticancer drugs from the local drug delivery system. Fluorescence and histophotological images of drug-treated tissues were used to examine drug distribution and accumulation in tumors. This work investigated the distribution profiles of SN-38 in U-87MG-bearing mice received SN-38-loaded depots via intratumoral injection. Distribution profile of SN-38 was followed-up by its self-fluorescent property. Depots comprised of three main components including PLEC (poly(D,L-lactide-random-ε-caprolactone)-block-poly(ethylene glycol)-block-poly(D,L-lactide-random-ε-caprolactone)) copolymer, glycofurol, and SN-38. Depots containing 1.6 ± 0.4 mg of SN-38 were injected into the tumors (200–250 mm3) and monitored up to 18 days post-injection. Tumors at each time point were sectioned and images were acquired with fluorescence microscope. Results showed that SN-38 penetrated into the tumors at the distance of 0.75 mm from the boundary of depots. Distributed SN-38 provided the necrotic area surrounding the depots. Fluorescence images were reconstructed and showed as 3D images. High level of SN-38 accumulation in tumors was found up to day 18 post-injection at 35.4 μg g−1 of tumors. This result can confirm and explain the distribution and penetration of SN-38. The information will be valuable to the design of depots administration in clinical trial.

Glucose-Responsive Insulin Delivery with Fast Response Using Charge-Switchable Polymeric Depot

The conventional method for controlling blood glucose levels (BGLs) involves the repeated subcutaneous injection of insulin, which is challenging to achieve satisfied blood glucose regulation and could often lead to hypoglycemia. Therefore, the development of self-regulated, glucose-triggered insulin delivery systems has attracted considerable attentions these years. Herein, we describe a new glucose-responsive insulin delivery formulation with ultrafast response both in vitro and in vivo, dependent on a glucose-triggered charge switch of a cationic polymer. A polymer (designated as poly(EDAA0.4-FPBA0.6)) with pendant amine and 4-carboxy-3-fluorophenylboronic acid was synthesized. Next, a stable complex with high insulin loading capacity (50%) and slow basal insulin release rate was prepared from an equal weight of insulin and polymer in PBS at 7.4. The addition of F-insulin to glucose solution led to decrease of the glucose level by 10 and 30 mg/dL for 100 and 400 mg/dL glucose solution, respectively, within 10 min. Meanwhile, the ζ-potential of poly(EDAA0.4-FPBA0.6) nanoparticles was decreased from the original +40 mV in the absence of glucose, to +22 mV in 100 mg/dL glucose solution, and further decreased to less than +8 mV in 400 mg/dL glucose solution. As a consequence, the insulin release kinetic from the complexes was highly glucose dependent. The in vivo therapeutic efficacy of F-insulin was evaluated in type 1 diabetic mouse model induced by streptozotocin. The BGLs of F-insulin treated group decreased to below 200 mg/dL within 30 min, and further maintained BGLs within the normal range (< 200 mg/dL) for more than 8 hours. Disclosure Z. Gu: None.

Controlling the burst release of doxorubicin from polymeric depots via adjusting hydrophobic/hydrophilic properties

The control of initial burst release of drugs from polymeric depots is a promising approach to achieve the dose level of therapeutic agents after administration. This study describes the method to control initial burst release of doxorubicin (Dox) from injectable polymeric depots made from PLGA 70:30, by modifying the weight ratio between protonated and deprotonated Dox that were incorporated into the depots. High initial burst release within 24 h was found at 86.6 ± 5.3% in depots incorporating with 100% protonated Dox. Burst release values were dramatically reduced to 48.5 ± 2.5, 41.8 ± 1.5, 35.1 ± 2.4, 27.3 ± 2.9, and 22.0 ± 2.1% when protonated Dox ratio was reduced to 98.75, 97.5, 95, 90, and 85%, respectively. To investigate the released Dox activity, cell viability of human hepatocellular carcinoma cells (HepG2) treated with extracted medium from 100 to 85% protonated Dox-loaded depots were 5.81 ± 1.11% and 7.44 ± 0.72%. Results show that the high burst release was reduced when deprotonated Dox was used. SEM confirmed the mechanism of Dox release from PLGA depots. The incorporation of deprotonated Dox could be a promising method in controlling drug release from polymeric depots for cancer treatment in the future.

Hierarchical Microplates as Drug Depots with Controlled Geometry, Rigidity, and Therapeutic Efficacy.

A variety of microparticles have been proposed for the sustained and localized delivery of drugs with the objective of increasing therapeutic indexes by circumventing filtering organs and biological barriers. Yet, the geometrical, mechanical, and therapeutic properties of such microparticles cannot be simultaneously and independently tailored during the fabrication process to optimize their performance. In this work, a top-down approach is employed to realize micron-sized polymeric particles, called microplates (μPLs), for the sustained release of therapeutic agents. μPLs are square hydrogel particles, with an edge length of 20 μm and a height of 5 μm, made out of poly(lactic- co-glycolic acid) (PLGA). During the synthesis process, the μPL Young's modulus can be varied from 0.6 to 5 MPa by changing the PLGA amounts from 1 to 7.5 mg, without affecting the μPL geometry while matching the properties of the surrounding tissue. Within the porous μPL matrix, different classes of therapeutic payloads can be incorporated including molecular agents, such as anti-inflammatory dexamethasone (DEX), and nanoparticles containing imaging and therapeutic molecules themselves, thus originating a truly hierarchical platform. As a proof of principle, μPLs are loaded with free DEX and 200 nm spherical polymeric nanoparticles, carrying DEX molecules (DEX-SPNs). Electron and fluorescent confocal microscopy analyses document the uniform distribution and stability of molecular and nanoagents within the μPL matrix. This multiscale, hierarchical microparticle releases DEX for at least 10 days. The inclusion of DEX-SPNs serves to minimize the initial burst release and modulate the diffusion of DEX molecules out of the μPL matrix. The biopharmacological and therapeutic properties together with the fine tuning of geometry and mechanical stiffness make μPLs a unique polymeric depot for the potential treatment of cancer, cardiovascular, and chronic, inflammatory diseases.

Development of self-forming doxorubicin-loaded polymeric depots as an injectable drug delivery system for liver cancer chemotherapy.

The objective of this work was to develop self-forming doxorubicin-loaded polymeric depots as an injectable drug delivery system for liver cancer chemotherapy and studied the release profiles of doxorubicin (Dox) from different depot formulations. Tri-block copolymers of poly(ε-caprolactone), poly(D,L-lactide) and poly(ethylene glycol) named PLECs were successfully used as a biodegradable material to encapsulate Dox as the injectable local drug delivery system. Depot formation and encapsulation efficiency of these depots were evaluated. Results show that depots could be formed and encapsulate Dox with high drug loading content. For the release study, drug loading content (10, 15 and 20% w/w) and polymer concentration (25, 30, and 35% w/v) were varied. It could be observed that the burst release occurred within 1-2 days and this burst release could be reduced by physical mixing of hydroxypropyl-beta-cyclodextrin (HP-β-CD) into the depot system. The degradation at the surface and cross-section of the depots were examined by Scanning Electron Microscope (SEM). In addition, cytotoxicity of Dox-loaded depots and blank depots were tested against human liver cancer cell lines (HepG2). Dox released from depots significantly exhibited potent cytotoxic effect against HepG2 cell line compared to that of blank depots. Results from this study reveals an important insight in the development of injectable drug delivery system for liver cancer chemotherapy. Schematic diagram of self-forming doxorubicin-loaded polymeric depots as an injectable drug delivery system and in vitro characterizations. (a) Dox-loaded PLEC depots could be formed with more than 90% of sustained-release Dox at 25% polymer concentration and 20% Dox-loading content. The burst release occurred within 1-2 days and could be reduced by physical mixing of hydroxypropyl-beta-cyclodextrin (HP-β-CD) into the depot system. (b) Dox released from depots significantly exhibited potent cytotoxic effect against human liver cancer cell lines (HepG2 cell line) compared to that of blank depots.

Injectable SN-38-loaded Polymeric Depots for Cancer Chemotherapy of Glioblastoma Multiforme.

SN-38, a potent chemotherapeutic drug, has not been used clinically because of its severe side effects and poor solubility. In this work, we aimed to evaluate the effect of dose and multiple injections of SN-38-loaded polymeric depots on antitumor efficacy and toxicity in vivo. Preparation and characterization of SN-38-loaded depots were performed and evaluated in vitro using human glioblastoma cell line, U-87MG. Antitumor efficacy with different depot administrations including dose, position of depot injection and number of injections were evaluated in tumor model in nude mice. Depots encapsulated SN-38 with high encapsulation efficiency (~98.3%). High amount of SN-38 (3.0 ± 0.1mg) was prolonged and controlled release over time and showed anticancer activity against U-87MG cell line in vitro. For one course administration, depots exhibited better antitumor efficacy and reduced toxicity compared to free SN-38. Elevated doses and multiple injections of SN-38-loaded depots and free SN-38 provided greater tumor growth inhibition and animal survival. All animals received SN-38-loaded depots were well tolerated and survived while most of those received free SN-38 died at day 30. Free SN-38 showed severe toxic effect compared to minimal toxicity from SN-38-loaded depots which was due to lower SN-38 level in systemic circulation. Fluorescence imaging and histopathology confirmed that SN-38 released from depots was detected throughout tumors 35days post administration. SN-38-loaded depots were proved as a promising new treatment for highly invasive glioblastoma multiforme with low acute toxicity due to controlled release of SN-38.

Paclitaxel-loaded polymeric depots as injectable drug delivery system for cancer chemotherapy of hepatocellular carcinoma

In this work, paclitaxel-encapsulated polymeric depots were prepared and characterized as drug delivery system for cancer chemotherapy against hepatocellular carcinoma. Effects of different parameters, including drug-loading content, polymer concentration and depot weight on depot formation, percentage of sustained-release taxol and drug release profile were evaluated. Paclitaxel-loaded depots were successfully formed at the polymer concentration above 25% w/v. For all formulations, paclitaxel could be encapsulated with very high percentage of sustained-release taxol (>90%). The release rate of paclitaxel from depots could be controlled by the amount of drug-loading content, polymer concentration and depot weight. Cytotoxicity against liver cancer cell line, HepG2, was evaluated by medium extraction method. Paclitaxel releasing from depots showed cytotoxic effect against HepG2 at different incubation times, whereas blank depots exhibited no cytotoxicity.

On-demand drug delivery from local depots

Stimuli-responsive polymeric depots capable of on-demand release of therapeutics promise a substantial improvement in the treatment of many local diseases. These systems have the advantage of controlling local dosing so that payload is released at a time and with a dose chosen by a physician or patient, and the dose can be varied as disease progresses or healing occurs. Macroscale drug depot can be induced to release therapeutics through the action of physical stimuli such as ultrasound, electric and magnetic fields and light as well as through the addition of pharmacological stimuli such as nucleic acids and small molecules. In this review, we highlight recent advances in the development of polymeric systems engineered for releasing therapeutic molecules through physical and pharmacological stimulation.

Polymeric nanoparticles and microparticles for the delivery of peptides, biologics, and soluble therapeutics

Biologically derived therapeutics, or biologics, are the most rapidly growing segment of the pharmaceutical marketplace. However, there are still unmet needs in improving the delivery of biologics. Injectable polymeric nanoparticles and microparticles capable of releasing proteins and peptides over time periods as long as weeks or months have been a major focus in the effort to decrease the frequency of administration. These particle systems fit broadly into two categories: those composed of hydrophilic and those composed of hydrophobic polymeric scaffolds. Here we review the factors that contribute to the slow and controlled release from each class of particle, as well as the effects of synthesis parameters and product design on the loading, encapsulation efficiency, biologic integrity, and release profile. Generally, hydrophilic scaffolds are ideal for large proteins while hydrophobic scaffolds are more appropriate for smaller biologics without secondary structure. Here we also introduce a Flash NanoPrecipitation method that has been adopted for encapsulating biologics in nanoparticles (40–200nm) at high loadings (50–75wt.%) and high encapsulation efficiencies. The hydrophilic gel interior and hydrophobic shell provide an opportunity to combine the best of both classes of injectable polymeric depots.

Antitumor efficacy and intratumoral distribution of SN-38 from polymeric depots in brain tumor model.

We investigate antitumor efficacy and 2D and 3D intratumoral distribution of 7-ethyl-10-hydroxycamptothecin (SN-38) from polymeric depots inside U-87MG xenograft tumor model in nude mice. Results showed that polymeric depots could be used to administer and controlled release of a large amount of SN-38 directly to the brain tumor model. SN-38 released from depots suppressed tumor growth, where the extent of suppression greatly depended on doses and the number of depot injections. Tumor suppression of SN-38 from depots was three-fold higher in animals which received double injections of depots at high dose (9.7 mg of SN-38) compared to single injection (2.2 mg). H&E staining of tumor sections showed that the area of tumor cell death/survival of the former group was two-fold higher than those of the latter group. Fluorescence imaging based on self-fluorescent property of SN-38 was used to evaluate the intratumoral distribution of this drug compared to histological results. The linear correlation between fluorescence intensity and the amount of SN-38 allowed quantitative determination of SN-38 in tumor tissues. Results clearly showed direct correlation between the amount of SN-38 in tumor sections and cancer cell death. Moreover, 3D reconstruction representing the distribution of SN-38 in tumors was obtained. Results from this study suggest the rationale for intratumoral drug administration and release of drugs inside tumor, which is necessary to design drug delivery systems with efficient antitumor activity.

HPLC analysis and extraction method of SN-38 in brain tumor model after injected by polymeric drug delivery system.

SN-38 is a highly potent anticancer drug but its poor solubility in aqueous solvent and adverse side effects limit clinical applications. To overcome these limitations, SN-38-loaded-injectable drug delivery depots have been intratumorally administered in xenograft tumor model in nude mice. The extraction and high performance liquid chromatography (HPLC) were performed in order to determine the amount of SN-38 inside tumors. SN-38 was extracted from tumors using DMSO. HPLC analysis was validated and resulted in linearity over the concentration range from 0.03 to 150 µg/mL (r(2) ≥ 0.998). Lower limit of detection (LLOD) and lower limit of quantitation (LLOQ) were 0.308 µg/mL and 1.02 µg/mL, respectively. The extraction efficiency (% recovery) of SN-38 in porcine tissues was similar to that of tumors which provided more than 90% recovery in all concentrations. Moreover, the variability of precision and accuracy within and between-day were less than 15%. Therefore, this extraction and HPLC protocol was applied to determine the amount of SN-38 in tumors. Results show higher remaining amount of SN-38 in tumor from SN-38-loaded polymeric depots than that of SN-38 solution. These results reveal that SN-38-loaded polymeric depots can prevent the leakage of free-drug out of tumors and can sustain higher level of SN-38 inside tumor. Thus, the therapeutic efficacy can be elevated by SN-38-loaded polymeric depots.

Preparation and in vitro characterization of SN-38-loaded, self-forming polymeric depots as an injectable drug delivery system

This work describes the preparation and characterization of anticancer-loaded injectable polymeric depots that consisted of D,L-lactide (LA), ε-caprolactone (CL), and poly(ethylene glycol) (PEG) or [poly(ε-caprolactone)-random-poly(D,L-lactide)]-block-poly(ethylene glycol)-block-[poly(ε-caprolactone)-random-poly(D,L-lactide)] (PLEC) copolymers for malignant gliomas treatment. PLECs were polymerized with different percentages of LA to deliver 7-ethyl-10-hydroxycamptothecin (SN-38), a highly potent anticancer drug. SN-38-loaded depots could form directly in phosphate buffer saline with more than 98% encapsulation efficiency. The release rate of SN-38 from depots was found to depend on the amount of LA in PLECs, loading content of SN-38 in the depots, and depot weight. Encapsulation of SN-38 inside depots could enhance the stability of SN-38 where all of SN-38 released after 60 days was in an active form. Depots without SN-38 were evaluated as noncytotoxic against U-87MG, whereas SN-38-loaded depots showed cytotoxic effect as a function of concentration.

Preparation of self-solidifying polymeric depots from PLEC-PEG-PLEC triblock copolymers as an injectable drug delivery system

Copolymers of (D,L-lactide-random-e-caprolactone)-block-poy(ethylene glycol)-block-(D,L-lactide-random-e-caprolactone) or PLEC were explored as materials for injectable drug delivery system. A series of six PLECs were successfully synthesized with varied D,L-lactide (LA) content (0, 10 and 20%) and molecular weight (20 and 50 kDa). All polymers were able to form depots with more than 90% encapsulation efficiency of trypan blue leading to the loading density as high as 27% w/w. The variation of trypan blue loading, LA content and molecular weight were found to have profound effects on trypan blue release profiles. Even though, GPC and SEM confirmed the higher degradation of PLEC chains, trypan blue release rate and burst release was greater as the content of hydrophilic moiety, i.e. LA, was decreased. This was primarily due to the smooth and dense surface and cross-section of PLEC depots. The results from this study suggest a possible application of these depots as injectable, self-solidifying drug delivery systems.

Use of In Vitro-In Vivo Correlation (IVIVC) to Facilitate the Development of Polymer-Based Controlled Release Injectable Formulations

In Vitro-In Vivo Correlation (IVIVC) is being increasingly used to predict bioperformance of dosage forms without conducting animal and/or human studies which are not only time-consuming and expensive but also might be considered ethically undesirable. The main aim of IVIVC methods is to develop in vitro drug release methods which are simple, robust, reproducible, inexpensive, in compliance with compendial and regulatory requirements and finally can be used in lieu of in vivo studies to direct formulation selection. This review provides a summary of currently marketed polymeric depot products and the patents related to these drug delivery systems in addition to currently available in vitro release methods used to study drug release from injectable controlled release drug delivery systems, currently available IVIVC methods and some examples of successful IVIVC for small molecules, peptides and proteins formulated in controlled release formulations administered subcutaneously or intramuscularly.

Modifying the Proliferative State of Target Cells to Control DNA Expression and Identifying Cell Types Transfected In Vivo

Although the majority of current gene transfer techniques have focused on increasing the ability of the DNA to enter the cell, it is possible that changing the proliferative and migratory state of cells will influence the cells ability to take up and express plasmid DNA. This study was designed to test the hypothesis that growth factors (basic fibroblast growth factor (bFGF) and hepatocyte growth factor/scatter factor (HGF/SF)) used to alter the proliferative and migratory state of cells can alter plasmid DNA uptake and expression. In vitro studies indicate that enhancing cell proliferation with growth factor exposure enhances plasmid DNA uptake and expression. Furthermore, dual localized delivery of bFGF and plasmid DNA in vivo increases the expression, 3-6 times over control, as compared to plasmid delivery alone. Dual delivery of a factor promoting cell proliferation and a plasmid led to a further increase in the expression of the plasmid encoding bone morphogenetic protein-2 in a rat cranial defect by specific cell populations. The results of these studies suggest that increasing the proliferative state of target cell populations can enhance non-viral gene transfer.

Novel Delivery Technologies for Protein and Peptide Therapeutics

The protein and peptide therapeutics have become an important class of drugs due to advancement in molecular biology and recombinant technology. There are more than 100 biopharmaceutical products approved and generating revenue of more than 56 billion US dollars. A safe, effective and patient friendly delivery of these agents is the key to commercial success. Currently, most of therapeutic proteins are administered by the parenteral route which has many drawbacks. Various delivery strategies and specialized companies have evolved over the past few years to improve delivery of proteins and peptides. Polymeric depot and PEGylation technologies have overcome some of the issues associated with parenteral delivery. A considerable research has been focused on non-invasive routes such as pulmonary, per oral and transdermal for delivery of proteins and peptides, in order to increase patient compliance yet their delivery via non-invasive routes remains challenge due to their poor absorption and enzymatic instability. Pulmonary route has shown some success evidenced by recent FDA approval of inhalable insulin. Development of an oral dosage form for protein therapeutics is still the most desirable one but with greater challenge. This review presents the issues of delivery of proteins and peptides, current and potential formulation technologies to improve delivery and current market trends.