Large Molecular Weight Drugs Research Articles

Inhaled Nanoparticulate Systems: Composition, Manufacture and Aerosol Delivery.

An increasing growth in nanotechnology is evident from the growing number of products approved in the past decade. Nanotechnology can be used in the effective treatment of several pulmonary diseases by developing therapies that are delivered in a targeted manner to select lung regions based on the disease state. Acute or chronic pulmonary disorders can benefit from this type of therapy, including respiratory distress syndrome (RDS), chronic obstructive pulmonary disease (COPD), asthma, pulmonary infections (e.g. tuberculosis, Yersinia pestis infection, fungal infections, bacterial infections, and viral infections), lung cancer, cystic fibrosis (CF), pulmonary fibrosis, and pulmonary arterial hypertension. Modification of size and surface property renders nanoparticles to be targeted to specific sites, which can serve a vital role in innovative pulmonary drug delivery. The nanocarrier type chosen depends on the intended purpose of the formulation and intended physiological target. Liquid nanocarriers and solid-state nanocarriers can carry hydrophilic and hydrophobic drugs (e.g. small molecular weight drug molecules, large molecular weight drugs, peptide drugs, and macromolecular biological drugs), while surface modification with polymer can provide cellular targeting, controlled drug release, and/or evasion of phagocytosis by immune cells, depending on the polymer type. Polymeric nanocarriers have versatile architectures, such as linear, branched, and dendritic forms. In addition to the colloidal dispersion liquid state, the various types of nanoparticles can be formulated into the solid state, offering important unique advantages in formulation versatility and enhanced stability of the final product. This chapter describes the different types of nanocarriers, types of inhalation aerosol device platforms, liquid aerosols, respirable powders, and particle engineering design technologies for inhalation aerosols.

Combined use of microbubbles of various sizes and single-transducer dual-frequency ultrasound for safe and efficient inner ear drug delivery.

We have previously applied ultrasound (US) with microbubbles (MBs) to enhance inner ear drug delivery, with most experiments conducted using single-frequency, high-power density US, and multiple treatments. In the present study, the treatment efficacy was enhanced and safety concerns were addressed using a combination of low-power-density, single-transducer, dual-frequency US (I SPTA= 213 mW/cm2) and MBs of different sizes coated with insulin-like growth factor 1 (IGF-1). This study is the first to investigate the drug-coating capacity of human serum albumin (HSA) MBs of different particle sizes and their drug delivery efficiency. The concentration of HSA was adjusted to produce different MB sizes. The drug-coating efficiency was significantly higher for large-sized MBs than for smaller MBs. In vitro Franz diffusion experiments showed that the combination of dual-frequency US and large MB size delivered the most IGF-1 (24.3± 0.47 ng/cm2) to the receptor side at the second hour of treatment. In an in vivo guinea pig experiment, the efficiency of IGF-1 delivery into the inner ear was 15.9 times greater in animals treated with the combination of dual-frequency US and large MBs (D-USMB) than in control animals treated with round window soaking (RWS). The IGF-1 delivery efficiency was 10.15 times greater with the combination of single-frequency US and large size MBs (S-USMB) than with RWS. Confocal microscopy of the cochlea showed a stronger distribution of IGF-1 in the basal turn in the D-USMB and S-USMB groups than in the RWS group. In the second and third turns, the D-USMB group showed the greatest IGF-1 distribution. Hearing assessments revealed no significant differences among the D-USMB, S-USMB, and RWS groups. In conclusion, the combination of single-transducer dual-frequency US and suitably sized MBs can significantly reduce US power density while enhancing the delivery of large molecular weight drugs, such as IGF-1, to the inner ear.

Supramolecular Assemblies of Heterogeneous Mesoporous Silica Nanoparticles to Co-deliver Antimicrobial Peptides and Antibiotics for Synergistic Eradication of Pathogenic Biofilms.

Pathogenic biofilms protected by extracellular polymeric substances frequently compromise the efficiency of antibacterial drugs and severely threaten human health. In this study, we designed a multi-stimuli-responsive magnetic supramolecular nanoplatform to co-deliver large and low molecular weight drugs for synergistic eradication of pathogenic biofilms. This co-delivery platform was composed of mesoporous silica nanoparticles (MSNs) with large pores (MSNLP) capped by β-cyclodextrin (β-CD)-modified polyethylenimine (PEICD) and adamantane (ADA)-decorated MSNs containing a magnetic core (MagNP@MSNA) capped by cucurbit[6]uril (CB[6]). The host MSNs (H, MSNLP@PEICD) and the guest MSNs (G, MagNP@MSNA-CB[6]) spontaneously form coassemblies (H+G), based on the host-guest interactions between β-CD and ADA. Under the stimulus of pathogen cells together with heating by an alternating magnetic field (AMF), the supramolecular coassemblies released both the large molecular weight antimicrobial peptide melittin (MEL) and the low molecular weight antibiotic ofloxacin (OFL) with high efficiency. As compared to free drugs (MEL and OFL) or unattached MSNs (H or G), the drug-loading H+G coassemblies (H-MEL+G-OFL) exhibited much higher capacity for biofilm eradication, thoroughly removing biofilm biomass and killing the pathogenic cells, and displaying no obvious toxicity to mammalian cells. This strong antibiofilm capacity was severely decreased when the host and guest components were prevented from coassembling but administered simultaneously, revealing the critical role of the supramolecular assembly in biofilm removal. Moreover, an in vivo implantation model showed that the coassemblies eradicated the pathogenic biofilms from the implants, preventing host tissue damage and inflammation. Therefore, the co-delivering and multi-stimuli-responsive nanocarriers could overcome the anti-infection difficulties during treatment of infections because of protective biofilms.

Long - Term Effects of Topical Amniotic Membrane Stem Cell Metabolite Product (AMSC-MP) and Fractional CO2 Laser in Photoaging

Background: Photoaging causes wrinkles, lentigines, keratoses, dyspigmentation, telangiectasia, decreased elasticity, rough texture, and pale color. Facial wrinkles and mottled skin can negatively affect perceived attractiveness, self-esteem, personality, and level of acceptance. Stem cells are important cells in the skin, and they are the source for continuous regeneration of the epidermis. It can be extracted from many sources, including amnion. Amnion membrane stem cell (AMSC) can be cultured and secretes metabolite product, and it can rejuvenate aging skin. Laser-Assisted Drug Delivery (LADD) involves selective destruction of the layers of the epidermis and dermis to allow penetration and absorption of topical drugs as well as large molecular weight drugs such as stem cells. Purpose: To evaluate the long-term effects of topical administration of AMSC metabolite products (AMSC -MP) and fractional CO2 laser on the clinical improvement of photoaging compared to previous skin conditions. Methods: This was an observational study which was aimed to evaluate the long-term effects of clinical improvement after topical therapy of AMSC-MP and fractional CO2 laser in patients with photoaging. Results: The results of the analysis showed a decrease in wrinkles, dark spots, skin tone, and pores. Conclusion: Based on Janus-II® assessment, there was improvement degrees of wrinkles, dark spots, and pores in patients with photoaging who received fractional CO2laser fractional for 12 weeks. There were no side effects found in this study.

Use of the permitted daily exposure (PDE) concept for contaminants of intravitreal (IVT) drugs in multipurpose manufacturing facilities

A toxicological evaluation to determine the product specific permitted daily exposure (PDE) value is an accepted method to determine a safe limit for the carry-over of product residues in multipurpose manufacturing facilities. The PDE calculation for intravitreal (IVT) injection of small and large molecular weight (MW) drugs follows the guiding principles set for systemic administration. However, there are specific differences with respect to the volume administered with IVT administration, pharmacokinetic and pharmacodynamics (PK-PD) parameters and potential for toxicity. In this publication, we have proposed a method to derive PDEIVT in the presence of IVT dose. In the absence of an IVT dose we have a proposed default extrapolationof the systemic PDE for intravenous (IV) administration to the PDEIVT dose by applying a factor of 500 based on comparison of the volume of vitreous humour with the plasma volume, as well as provided examples for PK-PD and toxicity considerations.

Biodegradable and conductive chitosan–graphene quantum dot nanocomposite microneedles for delivery of both small and large molecular weight therapeutics

Chitosan–graphene quantum dot nanocomposites are used in microneedle arrays for transdermal delivery of small and large molecular weight drugs.

A Review-Vaginal Drug Delivery System

The vagina is an important application site for drug delivery, especially for local therapy of different diseases, such as bacterial, fungal and protozoa infections, for HIV prevention, delivery of contraceptives, spermicides or labor-inducers and for the treatment of precancerous lesions. It may also serve an alternative route for systemic drug delivery. In recent years, the vaginal route has been rediscovered as a potential route for systemic delivery of peptides and other therapeutically important macromolecules. A great deal of interest has been notice in the design and application of different dosage forms via the vaginal route. Several studies have proven that the vagina is an effective route for drug administration intended mainly for local action, but systemic effects of some drugs also can be attained. The major advantages of this route include accessibility, good blood supply, the ability to bypass first-pass liver metabolism, and permeability to large molecular weight drugs, such as peptides and proteins. This review, therefore, summarizes various vaginal drug delivery systems with an introduction to vaginal physiology and factors affecting drug absorption from the vaginal route.

Effects of antibiotic physicochemical properties on their release kinetics from biodegradable polymer microparticles.

This study investigated the effects of the physicochemical properties of antibiotics on the morphology, loading efficiency, size, release kinetics, and antibiotic efficacy of loaded poly(DL-lactic-co-glycolic acid) (PLGA) microparticles (MPs) at different loading percentages. Cefazolin, ciprofloxacin, clindamycin, colistin, doxycycline, and vancomycin were loaded at 10 and 20wt% into PLGA MPs using a water-in-oil-in water double emulsion fabrication protocol. Microparticle morphology, size, loading efficiency, release kinetics, and antibiotic efficacy were assessed. The results from this study demonstrate that the chemical nature of loaded antibiotics, especially charge and molecular weight, influence the incorporation into and release of antibiotics from PLGA MPs. Drugs with molecular weights less than 600Da displayed biphasic release while those with molecular weights greater than 1,000Da displayed triphasic release kinetics. Large molecular weight drugs also had a longer delay before release than smaller molecular weight drugs. The negatively charged antibiotic cefazolin had lower loading efficiency than positively charged antibiotics. Microparticle size appeared to be mainly controlled by fabrication parameters, and partition and solubility coefficients did not appear to have an obvious effect on loading efficiency or release. Released antibiotics maintained their efficacy against susceptible strains over the duration of release. Duration of release varied between 17 and 49 days based on the type of antibiotic loaded. The data from this study indicate that the chemical nature of antibiotics affects properties of antibiotic-loaded PLGA MPs and allows for general prediction of loading and release kinetics.

A simple method of microneedle array fabrication for transdermal drug delivery

The outermost layer of skin, stratum corneum, being lipophilic limits the passive transport of hydrophilic and large molecular weight drugs. Microfabrication technology has been adapted to fabricate micron scale needles, which are minimally invasive, yet able to deliver the drugs across this barrier layer. In this study, we fabricated microneedles from a biocompatible polymer, namely, poly (ethylene glycol) diacrylate. A simple lithographical approach was developed for microneedle array fabrication. Several factors including polymerization time, ultraviolet light intensity and distance from light source were studied for their effects on microneedle formation. The microneedle length and tip diameter can be controlled by varying these factors. The microneedles were shown to be able to penetrate cadaver pig skin. Model drug rhodamine B was encapsulated in the range of 50 µg to 450 µg per microneedle array. The fabricated microneedles containing rhodamine B increased the permeability by four times than the control. Altogether, we demonstrated that the microneedle arrays can be fabricated through a simple single-step process and needles were mechanically strong to penetrate skin, increasing the permeability of encapsulated drug through skin.

A double antigen bridging immunogenicity ELISA for the detection of antibodies to polyethylene glycol polymers

Introduction Polyethylene glycol (PEG) polymers attached to biotherapeutic molecules enhance in vivo delivery and stability of these large molecular weight drugs. However, these polymers may by themselves be immunogenic and elicit antibodies that can reduce the efficacy of the drug and contribute to potential patient morbidity. A double antigen bridging ELISA immunogenicity assay for the detection of anti-drug antibodies (ADAs) specific to PEG polymers of various sizes has been developed. Methods Hapten-labeled conjugate of 40 kDa PEG polymer was synthesized and used in a double antigen bridging ELISA. The hapten-labeled PEG is incubated with the patient sample, then this mixture is added to a 96-well microplate precoated with 40 kDa PEG, allowing PEG-specific ADA to form a bridge complex with the PEG conjugate and the PEG coated on the microplate. After incubation, the reaction mixture is removed and replaced by horseradish peroxidase (HRP)-labeled anti-hapten antibody. After sufficient incubation, the plate is washed and substrate reagent is added. Enzyme color development, directly proportional to ADA, is stopped after 20 min with 2N sulfuric acid and the absorbance in each well is measured at 450/630 nm. Dose response, drug tolerance, matrix effects, reproducibility, specificity/free drug depletion experiments and screening cut-point determination of 350 naïve normal human sera were performed. Results Using an anti-PEG mouse monoclonal IgM as a positive control, a reproducible dose response curve was demonstrated for the PEG Immunogenicity ELISA. Pre-existing PEG-specific antibodies which were proven to be highly specific to the PEG polymer structure were found in 15 human serum samples in a total population of 350 naïve donors. The assay exhibited no significant matrix effects and was shown to be highly reproducible. Discussion A double antigen bridging immunogenicity assay for the detection of antibodies to PEG in the typical polymer size ranges used in biotherapeutics has been successfully developed in ELISA format. The antibodies detected in positive samples displayed a diverse spectrum of specificities for different PEG polymer lengths and linking functional groups. The discovery of 15 confirmed positive samples among 350 naïve patient samples calls into focus the need for testing PEG-specific immunogenicity of PEGylated biotherapeutics.

Methods for Determining Agent Concentration Profiles in Agarose Gel During Convection-Enhanced Delivery

Convection-enhanced delivery (CED) is a promising technique to deliver large molecular weight drugs to the human brain for treatment of Parkinson's, Alzheimer's, or brain tumors. Researchers have used agarose gels to study mechanisms of agent transport in soft tissues like brain due to its similar mechanical and transport properties. However, inexpensive quantitative techniques to precisely measure achieved agent distribution in agarose gel phantoms during CED are missing. Such precise measurements of concentration distribution are needed to optimize drug delivery. An optical experimental method to accurately quantify agent concentration in agarose is presented. A novel geometry correction algorithm is used to determine real concentrations from observable light intensities captured by a digital camera. We demonstrate the technique in dye infusion experiments that provide cylindrical and spherical distributions when infusing with porous membrane and conventional single-port catheters, respectively. This optical method incorporates important parameters, such as optimum camera exposure, captured camera intensity calibration, and use of collimated light source for maximum precision. We compare experimental results with numerical solutions to the convection diffusion equation. The solutions of convection-diffusion equations in the cylindrical and spherical domains were found to match the experimental data obtained by geometry correction algorithm.

Rigorous Mathematical Modeling Techniques for Optimal Delivery of Macromolecules to the Brain

Several treatment modalities for neurodegenerative diseases or tumors of the central nervous system involve invasive delivery of large molecular weight drugs to the brain. Despite the ample record of experimental studies, accurate drug targeting for the human brain remains a challenge. This paper proposes a systematic design method of administering drugs to specific locations in the human brain based on first principles transport in porous media. The proposed mathematical framework predicts achievable treatment volumes in target regions as a function of brain anatomy and infusion catheter position. A systematic procedure to determine the optimal infusion and catheter design parameters that maximize the penetration depth and volumes of distribution will be discussed. The computer simulations are validated with agarose gel phantom experiments and rat data. The rigorous computational approach will allow physicians and scientists to better plan the administration of therapeutic drugs to the central nervous system.

Prediction of convection-enhanced drug delivery to the human brain

The treatment for many neurodegenerative diseases of the central nervous system (CNS) involves the delivery of large molecular weight drugs to the brain. The blood brain barrier, however, prevents many therapeutic molecules from entering the CNS. Despite much effort in studying drug dispersion with animal models, accurate drug targeting in humans remains a challenge. This article proposes an engineering approach for the systematic design of targeted drug delivery into the human brain. The proposed method predicts achievable volumes of distribution for therapeutic agents based on first principles transport and chemical kinetics models as well as accurate reconstruction of the brain geometry from patient-specific diffusion tensor magnetic resonance imaging. The predictive capabilities of the methodology will be demonstrated for invasive intraparenchymal drug administration. A systematic procedure to determine the optimal infusion and catheter design parameters to maximize penetration depth and volumes of distribution in the target area will be discussed. The computational results are validated with agarose gel phantom experiments. The methodology integrates interdisciplinary expertise from medical imaging and engineering. This approach will allow physicians and scientists to design and optimize drug administration in a systematic fashion.

Intravaginal gels as drug delivery systems.

Recently, there has been a great deal of interest in the design and application of different dosage forms via the vaginal route. Several studies have proven that the vagina is an effective route for drug administration intended mainly for local action, but systemic effects of some drugs also can be attained. The major advantages of this route include accessibility, good blood supply, the ability to bypass first-pass liver metabolism, and permeability to large molecular weight drugs, such as peptides and proteins. Among the delivery systems proposed for this route is the use of intravaginal gels, which have been found to be potential vaginal drug delivery systems. The bioadhesives used in the formulation of gels play a key role in the release of the drug through the attachment to the vaginal mucosa, where the drug diffuses from the gel to the mucus.

Physical Enhancement of Transdermal Drug Application: Is Delivery Technology Keeping up with Pharmaceutical Development?

Advances in molecular biology have given us a wide range of protein and peptide-based drugs that are unsuitable for oral delivery because of their high degree of first-pass metabolism. Though parenteral delivery is the obvious answer, for the successful development of commercial chronic and self-administration usage formulations it is not the ideal choice. Transdermal delivery is emerging as the biggest application target for these agents, however, the skin is extremely efficient at keeping out such large molecular weight compounds and therapeutic levels are never going to be realistically achieved by passive absorption. Physical enhancement mechanisms including: iontophoresis, electroporation, ultrasound, photomechanical waves, microneedles and jet-propelled particles are emerging as solutions to this topical delivery dilemma. Adding proteins and peptides to the list of other large molecular weight drugs with insufficient passive transdermal fluxes to be therapeutically useful, we have a collection of pharmacological agents waiting for efficient delivery methods to be introduced. This article reviews the current state of physical transdermal delivery technology, assesses the pros and cons of each technique and summarises the evidence-base of their drug delivery capabilities.

Is nose-to-brain transport of drugs in man a reality?

The blood-brain barrier that segregates the brain interstitial fluid from the circulating blood provides an efficient barrier for the diffusion of most, especially polar, drugs from the blood to receptors in the central nervous system (CNS). Hence limitations are evident in the treatment of CNS diseases, such as Parkinson's and Alzheimer's diseases, especially exploiting neuropeptides and similar polar and large molecular weight drugs. In recent years interest has been expressed in the use of the nasal route for delivery of drugs to the brain, exploiting the olfactory pathway. A wealth of studies has reported proof of nose-to-brain delivery of a range of different drugs in animal models, such as the rat. Studies in man have mostly compared the pharmacological effects (e.g. brain functions) of nasally applied drugs with parenterally applied drugs and have shown a distinct indication of direct nose-to-brain transport. Recent studies in volunteers involving cerebrospinal fluid sampling, blood sampling and pharmacokinetic analysis after nasal, and in some instances parenteral administration of different drugs, have in my opinion confirmed the likely existence of a direct pathway from nose to brain.

The use of molecular orbital indices to predict the surface properties of pharmaceutical powders

The electron density, frontier electron density and superdelocalisability indices have been calculated for the total molecular structures, and the parts of the molecules which are anticipated to be involved in hydrogen bonding interactions. The models used comprised of an homologous series (alkyl P-hydroxybenzoates), materials related by a common ring structure, but with differing substituents (imidazoles), and three related comparatively large molecular weight drugs (HMG-CoA reductase inhibitors). Surface energies were determined from contact angle data with water, using Neumann's equation of state. No relationship was seen between data for total molecular orbital indices for the molecules and measured contact angles or derived surface energies. However, when the hydrogen bonding atoms of the molecules were selected, a good linear correlation was observed for all three types of molecule between superdelocalisability and both contact angle and surface energy. This is expected as the hydrogen bonding regions are probably especially important in interactions with water. Two (of 16) molecules were outliers from the general relationship. These were one of the HMG-CoA reductase inhibitors and methyl p-hydroxybenzoate. It is possible that the high molecular weight of the first of these molecules was the cause of an error in calculation of the molecular orbital indices (due to optimisation to a secondary minimum). For the methyl P-hydroxybenzoate, there are considerable data in the literature to indicate that this material has idiosyncratic properties. Its curious behaviour is examined with consideration to possible crystal packing energy differences over other members in the series. The data presented here give encouragement that the surface properties of a wide range of different materials may be predicted from molecular structure, however, there are inevitable outliers which will mean that predictions will have to be confirmed with practical observations, until modelling approaches have been developed further and adequately validated.

Transdermal drug carriers: Basic properties, optimization and transfer efficiency in the case of epicutaneously applied peptides

In order to get across the intact mammalian skin, drug carriers must pass through a series of very fine pores with a diameter of typically less than 50 nm, under the influence of a suitable transdermal gradient. Well-known agent carriers, such as liposomes, fail to do this owing to their large (minimum) size. Special, composite carrying bodies called Transfersomes TM, achieve this goal by virtue of their very high and self-optimizing deformability. (The efficiency of passage for 500-nm Transfersomes through pores of 100 nm diameter is as high as that of pure water, 1500 times smaller than the former.) When applied onto the intact skin surface non-occlusively, Transfersomes penetrate the skin permeability barrier spontaneously. Subsequently, they are distributed, probably via the lymphatic system, throughout the whole body. Drug exchange between the Transfersomes and the biological surroundings may occur at this or any later stage. This permits regio-selective drug delivery by means of Transfersomes. (Topically applied corticosteroids, for example, can be confined to the viable skin with an efficiency of 99.999%.) Meticulous optimization ensures the Transfersome-mediated flux of lipids to exceed 0.1 mg cm −2 h −1, in the murine test system. Inulin, which has a low propensity for the association with Transfersomes, is carried across the skin less efficiently (10–20%). In spite of this, comparable serum values are measured 7 h after the epicutaneous or subcutaneous application of this compound in the form of Transfersomes. Combinations of peptides and Transfersomes provide a very successful means, however, for the non-invasive therapeutic use of such large molecular weight drugs on the skin. Transfersome-associated insulin is carried across the skin with an efficacy of ≥ 50% (and often ≥ 80%), for example; human trials with a number of preparations and formulations have proven this. The results measured with insulin are claimed to be representative of all substances with high encapsulation efficacy into and/or association capability with Transfersomes.