Intranasal delivery

With the advances in biotech and rDNA, the drug delivery of new molecules have become a challenging task for pharma companies, say Vivek Ranjan Sinha, Jayant Rajaram Bhinge and Aman Trehan in the concluding part of the article

Aerosol systems such as metered dose inhaler, dry powder inhalers and liquid jet or ultrasonic nebulizers are used for delivery of bronchodilators and corticosteroids for asthma or COPD (chronic obstructive pulmonary disease). But recently there has been a substantial interest in using the alveolar surface as a portal to the systemic circulation for macromolecules such as proteins and peptides.

Intranasal delivery provides safety, efficacy and greater bioavailibility. Various nasal sprays, nasal solutions, nasal inhalers, aerosol preparation are in market such as calcitonin (Miacalcin nasal spray, Novartis), butorphanol (Stadol NS nasal spray, Bristol Myers Squibb Co USA), dihydroergotamine (Migranal nasal spray, Novartis Inc), cromolyn sodium (Nasalcrom nasal solution, Fisons Pharmaceuticals), budesonide (rhinocort nasal inhaler, Astra), etc. Various other innovative technologies are coming up to deliver proteins, peptides and other drugs.

DirectHaler nasal

DirectHaler Nasal is an innovative, new and worldwide-patented dry powder nasal delivery device. The device applies advanced principles to activate the anatomy of the patient for increased nasal delivery efficiency and patient acceptability. DirectHaler Nasal is intuitively easy-to-use, which will minimise the instruction task — and ease any checking of the patient delivery technique.

The pre-metered and pre-filled powder dose in the DirectHaler Nasal, is always visible and ready for delivery because the device is primeless and transparent. The transparency allows the patient to have visual contact with the dose — ensuring confirmed “dose ready” before delivery and “dose taken” after delivery. The compact device dimensions ensure portability and discretion in using the device.

The DirectHaler Nasal is designed with attention to the key issues in dry powder nasal delivery, and for achieving improved delivery and patient compliance. DirectHaler™ Nasal provides a novel opportunity for overcoming the recognised problems of currently marketed nasal delivery devices.

AIR technology

AIR from Alkermes is a proprietary drug delivery technology composed of dry powders ideally suited for delivery to the lungs. These microparticles are produced using many common excipients (sugars, amino acids, lipids) and have a geometric size in the range of 5-30um, with an aerodynamic size of 1-5 um. The unique characteristics of these particles allow them to be used for both systemic and local delivery of small molecule, peptide, protein and other macromolecular drugs.

In addition, the release characteristics of the particles can be dramatically influenced using simple formulation changes, resulting in either rapid onset or possible sustained-release. It is a dry powder delivery of small molecules such as proteins and peptide drug particles to the deep in to alveolar system. Delivery device is breathing activated, requiring no external power source. It provides improved patient compliance and bioavailibility.

Pulmonary delivery

In past days pulmonary route is being utilized for treatment of respiratory disease but now days, it is used as portal to systemic delivery of macromolecules. Pulmonary delivery is painless and noninvasive delivery system, as it is preferred by most of the patients.

PulmoSpheres

PulmoSpheres are a new drug delivery technology platform that is a culmination of Alliance Pharmaceutical Corp.’s expertise with fluorochemicals, surfactants, emulsions, and spray-dried powders. PulmoSpheres are produced by mixing a drug and a surfactant to form an emulsion which is spray-dried into microscopic spheres that can be suspended in a fluorochemical propellant or carrier for delivery of medications into the lungs or nasal passages.

PulmoSpheres represent a novel breakthrough in particle engineering. The hollow/porous design, excellent stability of these homodispersions in HFA (“ozone friendly” propellant) suspensions, aerodynamic properties, and other attributes are expected to allow for use of PulmoSperes to deliver a variety of drug substances via metered-dose inhalers, dry powder inhalers, nebulizers, and other devices.

PulmoSpheres create a “smoky”, homogeneous plume when administered via dry powder inhalers. This may indicate that less drug loss due to precipitation out of the plume compared to other drug formulations. PulmoSpheres have been formulated with a variety of medicaments, including asthma drugs, non-steroidal and steroidal anti-inflammatory drugs, antibiotics, proteins and peptides, and other drug substances.

Spinhaler

Spinhaler (Rhone-Poulenc Rhorer) is a unit dose device with drug in hard gelatin capsule. Capsule, placed in a loose-fitting rotor, is pierced by two metal needles on either side of the capsule. When rotor rotates, turbovibratory air pattern is created by the inhaled air resulting in the powder to disperse through the perforations into the air.

Rotahaler

Rotahaler (Glaxo Smithkline) is a simple two-piece device in which gelatin capsule is placed into an orifice at the rear of the device and on rotating two sections; a fin on the inner barrel pulls the two halves of the capsule apart. During inhalation, the freed half of the capsule spins, dispersing its contents, which are inhaled through the mouthpiece. The resistance to air flow is lower than that of the Spinhaler and therefore a lower inspiratory velocity is required.

Diskhaler

Diskhaler (Glaxo Smithkline) is multidose device with drug in foil blisters. In this system, drug is mixed with a coarse lactose carrier and filled into an aluminium foil blister disc, which is loaded, by the patient, into the device on a support wheel. Four to eight doses of drug are contained on each disc and the blisters are pierced with a needle as a result of mechanical leverage on the lid. When patient inhales through the mouthpiece, airflow through the blister causes the powder to disperse.

Accuhaler

In Accuhaler (Glaxo Smithkline) system drug/carrier mix is preloaded into the device in foil-covered blistered pockets containing 60 doses. As each dose is advanced, foil lid is peeled off the drug- containing pockets, with the blisters and lids being wound up separately within the device, which is discarded at the end of operation.

Turbohaler

Turbohaler (Astra Zeneca) contains a large number of doses (up to 200) of undiluted, loosely aggregated micronized drug, which is stored in a reservoir from which it flows on to a rotating disc in the dosing unit. Excess drug is removed by scrapers and fine holes in the disc are filled. On turning the disc, one metered dose is injected to inhalation channel, and this is inhaled by the patient, with the turbulent air flow created within the device breaking up any drug aggregates.

AERx

AERx (Aradigm Corporation) is pulmonary drug delivery technology based on principle of aerosol. Drug in solution form is converted in to aerosol with patient breath and directly reaches to the systemic circulation. The system aerosolizes liquid formulation that is prepacked in unit dose packets for inhalation. Each unit dose packet consists of a small blister package that stores a liquid drug formulation and an aerosolization nozzle with a membrane incorporating an array of micro-machined holes.

The AERx device creates a restorable aerosol by releasing a mechanical actuator that is activated automatically when patient’s inhalation is optimal for drug delivery. The aerosolization of the liquid drug via the disposable nozzle takes about 1 sec and produces a low velocity, fine particle aerosol necessary for optimized deposition within the lungs.

Oral transmucosal delivery

Transmucosal delivery is steadily gaining importance. It provides excellent accessibility and high patient acceptance and compliance. High perfusion rate allows rapid absorption of drug through oral mucosa. Various technologies have been developed to extend the release through mucosal delivery which are briefly described below:

MCA technology (Atrix laboratories) With a unique blend of cellulose polymers dissolved in alcohol, MCA formulations dry quickly and form tenacious, moistue-resistant films that can deliver drugs and/or promote healing. Drug delivery with the MCA technology occurs in three stages; firstly, product is applied to skin or mucosal surface; secondly, product forms tenacious moisture-resistant film and lastly, the adhered film provides sustained release of drug from hours to days.

Orajel - Ultra Mouth Sore Medicine is product based on this technology which delivers benzocaine and menthol for the relief of mouth ulcers and canker sores. The MCA technology allows the product to form a film over the sore, which provides long-lasting protection with one application.

BEMA BEMA (Atrix Laboratories, the unique polymer-based system is designed to deliver drugs across oral mucosal tissues. The BEMA film is a small, semi-soft disc that adheres to the mucosa, such as the side of the mouth, and delivers the drug as the film bioerodes.

There is no need to remove the film because it dissolves with the moisture form the mucosa. The versatile BEMA system can incorporate a wide variety of drugs, including proteins and peptides, which can be loaded into mucoadhesive layer for delivery into the mucosal tissue while minimizing drug release into surrounding tissues or cavities.

To suit the medical needs at hand, BEMA technology can be formulated for local or systemic delivery, avoids first-pass metabolism, can be customized by modifying the residence time, bioerosion kinetics, taste, and shape and disc thickness, has the potential to increase bioavailability. BEMA technology has several potential systemic applications which include: chronic and breakthrough cancer pain management, anti-emetics, anti-psychotics and mucosal vaccines.

Specialised drug delivery technologies

Several other routes are proposed for the drug delivery such as delivery through nails, vagina, and rectum. Also several technologies have been developed for specific type of drugs.

Tocosol

Tocosol Paclitaxel (Sonus Pharmaceuticals) is an injectable, ready-to-use formulation of paclitaxel. The product does not require reconstitution, dilution or preparation prior to use. In clinical trials to date, Tocosol Paclitaxel is demonstrating encouraging anti-tumor activity in cancer patients who have failed prior chemotherapeutic regimens. The product is well tolerated when administered in a short 15-minute infusion compared to the prolonged three-hour infusion required with the available paclitaxel products. The company has completed patient enrollment in the Phase 2a clinical program for Tocosol Paclitaxel, and is currently initiating the next round of clinical studies to provide data that will be the basis for registration with US and international regulatory authorities.

Vagisite

KV Pharmaceuticals’ VagiSite system is a semisolid configuration of the site release technology intended for administration within the vaginal vault. This unique application of site release is intended to provide one-dose-to-cure dosage forms. Site release butoconazole nitrate 2% vaginal cream has received FDA approval. In addition, several other antifungals and other drug agents that typically are administered within the vaginal vault (antiprotozoals, spermicides, antibacterials/antibiotics, and buffering agents) have been prototyped.

Atrigel

The Atrigel (Atrix Laboratories Inc) drug delivery system consists of biodegradable polymers, similar to those used in biodegradable sutures, dissolved in biocompatible carriers. Pharmaceuticals may be blended into this liquid delivery system at the time of manufacturing or, depending upon the product, may be added later by the physician at the time of use. When the liquid product is injected subcutaneously or intramuscularly through a small gauge needle or placed into accessible tissue sites through a cannula, displacement of the carrier with water in the tissue fluids causes the polymer to precipitate to form a solid film or implant.

The drug encapsulated within the implant is then released in a controlled manner as the polymer matrix biodegrades with time. Depending upon the patients medical needs, the Atrigel system can deliver small molecules, peptides, or proteins over a period ranging from days to months. Advantages of Atrigel system include: broad applicability, site specific drug delivery, systemic drug delivery, customized continuous release and degradation rates, biodegradability, ease of application, safety.

Eligard, Atridox, Doxirobe, Atrisorb, Free Flow are some products based on this technology.

Future prospects

Now a days most of the drugs are delivered to patients by various routes such as oral, transmucosal, transdermal, parenteral, ocular, rectal, vaginal etc. but biotechnology and recombinant DNA technology has played a key role in the development of proteins and peptide based drugs. With in next 10-20 years protein and peptides based drugs will capture 60% of pharma market. Delivery of biomolecules is a challenge for the drug delivery scientist because of their high molecular wt, size, immunogenicity and proteinaceous nature and hence their delivery requires intelligent delivery technologies.

Conclusion

Since from last couple of years novel drug delivery technologies have been acting as the backbone of pharma business. These technologies deliver the drug safely, effectively and with better convenience. But with the advances in biotechnology and recombinant DNA technology the forthcoming molecules are challenging molecules, so their successful delivery is a challenging task for pharmaceutical scientists and companies. These cutting edge technologies are required to deliver the genetically engineered molecules, proteins and peptides. So pharmaceutical companies and scientists have to be ready to take up the tough task ahead.

The writers are with University Institute of Pharmaceutical Sciences, Punjab University, Chandigarh. E-mail: vr_sinha@yahoo.com