Drug Delivery Technologies Q&A
Leave it to a student to ask a really hard question! The difficulty of the question lies in fact that it is actually multiple questions. If we break this down, the following “sub” questions arise:
1. Are peptides adequately absorbed from the nasal cavity?
We already have a history to indicate a level of success and a promising future for nasal delivery of peptides. Examples of commercial products include calcitonin and desmopressin nasal sprays. In addition, continued research demonstrates the potential of intranasal insulin and other peptide drugs. A wide range of formulation approaches continue to show promise to further increase nasal bioavailability, including: permeation enhancers (lipids, pegylated peptides, liposomes), nanoparticulate techniques, and mucoadhesive microspheres). A study released by Drug and Market Development Publishing points out that that peptides represent a small but increasing number of drugs. In addition, the report (Peptides 2006: New Applications in Discovery, Manufacturing, and Therapeutics) points out that peptide drugs are being developed for an increasing wide range of indications that include allergy/asthma, arthritis, diabetes, cardiovascular , CNS diseases, inflammation, and others.
2. Are peptides effectively absorbed across the blood-brain barrier (BBB)?
With respect to Alzheimer’s disease, the blood-brain barrier presents a major challenge to treatment. As a result of its unique physiology, the BBB hinders the delivery of many potentially efficacious drugs to the brain. A number of techniques are being investigated for capability to improve transport across the BBB. Examples of techniques include: vasoactive substances such as bradykinin, carrier mediated transporters such as amino acids or glucose, liposomal formulations, and nanotechnology. Some therapeutic approaches in which nanotechnology is being applied for the therapeutic investigation of Alzheimer’s disease include neuroprotections against oxidative stress, anti-amyloid therapeutics, and neuroregeneration.
3. Do peptides demonstrate pharmacologic activity for the treatment of Alzheimer’s disease?
Peptide drugs are an area of focus for new drugs targeted for Alzheimer’s disease. From the drug-delivery perspective, modified peptide drugs may overcome some deficient pharmacological properties of native peptides. These modified peptides feature changes to natural amino acid sequence, backbone replacements, cyclic structures, or other modifications such as pegylation. Adessi et.al.,(2003) showed that a chemically modified 5-amino acid β-sheet breaker peptide (iAβ5p) demonstrated increased stability in vitro, a 10-fold higher in vivo half-life and good brain uptake compared with the parent iAβ5p in an animal model. Allon Therapeutics has completed a Phase IIa study of an intranasal neuroprotective peptide to enhance memory and cognitive function in patients with mild cognitive impairment, a precursor to Alzheimer’s disease.
In summary, the question reveals a good example where multidisciplinary research efforts work synergistically to yield medical advances. For example, major advances may be found where a novel peptide drug is delivered to the brain in a nanocarrier from a formulation optimized for nasal delivery.
The easy answer is, “as early as possible,” but the real answer requires some discussion. The FDA Guidance for Industry, Container Closure Systems for Packaging Drugs and Biologicals recommends that each new drug application (NDA) or abbreviated new drug application (ANDA) contain enough enformation to demonstrate that a proposed package and its components are suitable for the intended use. In summary, the container-closure should adequately protect the dosage form, be composed of materials safe for use with the dosage form and route of administration, and function properly if it has a performance feature. Some questions that arise from the guidance include:
• Does the container-closure system protect the dosage form from environmental challenges (e.g., moisture, light, oxygen, shipping)?
• Is the dosage form identified in the Guidance as a higher (e.g., ophthalmic solution, transdermal, or nasal) or highest (e.g., inhalation or injectable) risk for packaging concerns?
• Does the container-closure system play a functional role in delivery of the drug product such as with inhalations and transdermals?
The more “yes” answers to questions such as these point to the need for earlier consideration/selection of the container-closure system during development. Current regulatory initiatives (e.g., quality by design, risk assessment) provides further urgency to an early initiation of container-closure consideration. Ultimate product quality is enhanced when the container-closure system is an integral part of early development studies. A better defined and robust design space for manufacturing will typically follow that may provide acceleration of the regulatory review process.
There is a tremendous range of development program strategies due to the variety of dosage forms, formulations, clinical study requirements, and therapeutic objectives. Therefore, it is not possible to dictate the exact point to start considering and initiate development of the commercial container-closure. A dry-powder inhalation product may look much more like the registration product in formulation and container-closure during Phase I when compared with a solid oral dosage form which may be neat API in a hard gelatin capsule during Phase I. However, it is reasonable to say that any dosage form should be seeing the initiation of container-closure selection during Phase II and that dosage forms where the container-closure plays a functional role during Phase I.
DNA vaccines offer many potential benefits when compared to earlier generation technologies. For example, a DNA vaccine does not have the safety issues presented by a live attenuated virus to an immunocompromised individual. In addition, DNA vaccines benefit from more economical manufacturing processes and can typically be stored without refrigeration. This feature makes a DNA vaccine easier and less expensive to handle and store; a major benefit for developing countries with limited resources.
However, there are significant challenges faced in the development of DNA vaccines. In particular, efficacy for a DNA vaccine is dependent on the ability to achieve intracellular delivery of the DNA plasmid payload. When injected by conventional syringe either subcutaneously or intramuscular, tissue cell membranes are a significant barrier to uptake of the DNA material. The implementation of drug-delivery technologies to DNA vaccine development is showing significant benefits to efficacy. Electroporation is a technique shown to increase intracellular delivery by the transient increase in cell membrane permeability by producing a controlled electric field during injection of the vaccine. Upon termination of electroporation, cell membrane integrity and function is rapidly returned to normal. Electroporation has potential for DNA delivery to skeletal muscle, skin, lung, and other tissues. Another prominent technique is the “gene gun,” which uses compressed helium to drive plasmid DNA that has been adsorbed onto gold or tungsten microparticles into target cells. Both techniques have demonstrated significant increases in immune response. Other drug-delivery technologies being investigated include nasal, inhalation, and oral routes of administration. Formulation approaches to increase immune response include cationic liposomal and biodegradable microsphere technologies.
Development of DNA vaccines continues to show promise. A veterinary DNA vaccine for horses has been approved and there are currently more than 15 human diseases being investigating using the technology.
The term “microemulsion” often used to describe a variety of micellar structures from simple droplets to complex cubic compositions. In this discussion, the classic definition is assumed: a thermodynamically stable colloidal dispersion of water and oil stablized by a surfactant, and often, a co-surfactant. In comparison with coarse emulsions, microemulsions form spontaneously, are clear or transparent, have smaller droplet size (<150nm), and have lower interfacial energy.
Interest in microemulsion formulations spans the cosmetic and pharmaceutical industry because of potential for lower skin irritation, drug permeation enhancement, cosmetic properties, and drug solubilization. With increased interest in microemulsions, formulation improvements are being reported at an increasing rate. For example, microemulsions have historically included a low-to-medium-chain-length alcohol as a co-surfactant. When applied to skin, these formulations often caused irritation and dehydration. In recent years, more cases of alcohol-free microemulsions have been reported with much lower irritation potential.
The thermodynamic stability of microemulsions can contribute to improved formulation stability relative to conventional coarse emulsions by their lower potential for phase separation, creaming, flocculation, or increased droplet size (“Ostwald ripening”). This advantage can yield increased formulation robustness when challenged by prolonged temperature excursions. The favorable thermodynamic stability of microemulsions also can lead to simplified pharmaceutical product development, scale-up, technolology transfer, and manufacture. This is due partially to the lower energy input requirement to achieve the microemulsion. Simpler, low-energy mixing equipment may be adequate to prepare microemulsion formulations. In contrast, coarse emulsions often require the addition of heat, preparation of multiple side phases, and the use of rotor-stator homogenizers or high pressure microfluidization process equipment. In some cases, the low viscosity of microemulsions presents a challenge when formulating topical products because of the need to retain the drug at the application site. In these cases, it may be necessary to add viscosity modifying excipients to form a microemulsion gel formulation.
The mechanism by which microemulsions may enhance drug permeation in skin is not clear. Increased permeation may be due to several mechanisms, including: higher drug solubility in the vehicle providing a greater reservoir of drug in the vehicle; permeation enhancement properties due to one of the formulation components; and improved wetting of the skin surface due to lower interfacial tension.
In summary, microemulsion technology has advanced significantly and is a viable formulation option for topical and transdermal drug delivery products for drugs with appropriate physicochemical characteristics and therapeutic endpoints.
As the questioner points out, there are benefits to dosing drugs with consideration of the normal and cyclical rhythms of human physiology. Examples where disease conditions show cyclical patterns that correlate with circadian rhythms include:
Epilepsy: Seizures may occur only at particular times of the day or night
Allergies: Symptoms of sneezing and stuffy nose are typically worse in the morning waking hours
Asthma: Symptoms are more likely to occur in the hours prior to awakening
Rheumatoid arthritis: Pain is often most intense upon awakening.
Osteoarthritis: Symptoms typically worsen in the afternoon and evening.
Angina: Symptoms are most common during the first several after awakening.
Heart attack: Occur most commonly occurs in the early waking hours
Stroke: Most commonly occur in the early waking hours
Diabetes: Insulin levels and the counterregulatory hormones that work against the actions of insulin are in turn, influenced by the circadian rhythm.
Chronotropic drug therapy has been in the physician’s bag of treatments for decades. “Alternate day therapy” has been an option for administration of corticosteroids (e.g., prednisone) for treatment of asthma, rheumatoid arthritis, or other indicated diseases. In this practice, the dose is administered in the early morning every other day. The benefit is to minimize supression of adrenal function and the associated adverse events found in long-term therapy of corticosteroids.
Currently, there are a number of commercially available oral drug-delivery platforms targeted for chronotropic therapy. Applications include delayed-release oral technologies that are administered in the evening and delay the release of antihypertensive drugs until the early morning hours when there are normal increases in heart rate and blood pressure. In addition to oral platforms, parenteral chronotropic systems are experiencing increased utilization. The most widespread application is that of the insulin pump, which is used to administer insulin for the treatment of diabetes mellitus. With the insulin pump, patients can customize insulin delivery to meet their particular requirements. Newer applications of chronotherapy are being reported. For example, time-scheduled regimens for cytotoxic drug delivery by intravenous infusion based on a pharmacokinetic–pharmacodynamic model have been reported.
Historically, the study of circadian rhythms and related treatments in medical schools has been limited. With increased knowledge of the physiological basis, therapeutic benefits of chronotherapy, and advances in drug-delivery technologies, we can expect to see increased application of drug-delivery technologies to chronotherapy.
Yes. Inquiries to our organization which involve preclinical programs where dosing levels have reached and, perhaps, exceeded limits for reasonable administration have increased. A reasonable explanation may be the increased percentage of new drugs with challenging biopharmaceutical properties. In a recent scientific forum, it was estimated that only 10% of new drugs meet the criteria for high solubility, with the majority of new drugs displaying low solubility, low permeability, or both. In addition, strained budgets and accelerated project timing pressures seem to encourage more risky development strategies. This situation can reach a crisis point where a formulation solution is sought as a quick fix. Unfortunately, it is common that critical biopharmaceutical data (e.g., permeability, solubility, Log P/D) are not available to serve as a guide for the formulation effort. The early acquisition of data that identifies bioavailability limitations (e.g., solubility, permeability) can be critical to the development of optimized formulations with potential benefits for lower API demand and cost, increased bioavailability, and more rapid drug product development.
We can look at the progress made in the oral delivery of insulin and predict similar successes for oral delivery of insulin analogues. Numerous technologies have been applied to oral insulin delivery to overcome the two primary obstacles: degradation and low membrane permeability. Examples of these technologies include enteric coatings, micro- and nano- particulates, mucoadhesives, liposomes, permeation enhancers, and others. In many drug-delivery systems, multiples of these approaches are combined in a single platform. The fruits of these efforts are meeting the marketplace as shown by Oral-lyn, a spray buccal delivery system from Generex Biotechnology. Oral-lyn is available for sale in Ecuador, was approved in India in 2007, and is in Phase III clinical study in the United States, Canada, Russia, and several other countries. In late 2009, Novo Nordisk initiated a Phase I clinical trial of its oral insulin analog, NN1952, using the GIPET (Gastrointestinal Permeation Enhancement Technology) platform from Merrion Pharmaceuticals. The GIPET technology platform is a patented system that utilizes enteric coating and GRAS permeation enhancers to increase intestinal absorption of NN1952. We can expect the application of drug-delivery technology to the oral delivery of insulin analogues to accelerate.