Changes in Pharmaceutical Formulations and Drug Delivery Systems

During the month of February, the author received a message from Pharmaceutical Technology's editor in chief announcing the celebration of the magazine's 30th anniversary. The message noted that two of the original members of the magazine's editorial advisory board, myself included, are still active. The editor suggested that the author write a retrospective essay focusing on the evolution of pharmaceutical formulations and drug-delivery systems during the past three decades. The author readily accepted, recognizing that such an article would provide a link between past, present, and future trends in this important pharmaceutical discipline. This article addresses significant developments in therapeutic approaches using simple chemical moieties (1970s–1980s), macromolecules and genetically engineered drugs (1980s–1990s), and gene therapy (1990s to date).

During the past three decades, Pharmaceutical Technology played an important role in disseminating information to pharmaceutical scientists and technologists and witnessed the "centennial celebrations" of the US Food and Drug Administration, which is responsible for setting guidances and regulating the pharmaceutical industry. Over the years, FDA has provided the necessary stimulus for significant therapeutic advances using comprehensive science-based protections that ensure the highest quality of products essential for health and survival. Thus, the agency's role has spanned from the passage of pure food and drug laws at the turn of the last century to addressing the regulatory challenges posed today by cutting-edge sciences such as genomics and proteomics, as well as new initiatives such as personalized medicine.

Key advancements in formulation and drug delivery

Ten years ago, the author joined this magazine's 20th anniversary celebration and presented an article that concluded "Pharmaceutical Technology will continue to provide stimulus for future advancements and the magazine will provide guidance to industry to effectively use resources, optimize processes, and maintain high quality standards and professional stature." In retrospect, this prediction was justified.

Active pharmaceutical ingredients

During the past three decades, active pharmaceutical ingredients advanced beyond the established, traditional drug substances such as small chemical molecules, biochemicals, fermentation products, antibiotics, hormones, vitamins, enzymes, simple peptides, biologics, vaccines, and prodrugs. Novel substances that currently are acceptable include genetically engineered products, macromolecules, proteins, newer biologics, genes, interferons (IFNs), interleukins (ILs), tumor necrosis factor (TNF), human insulin, human growth hormones, erythropoietin (EPO), blood-clotting factors (TPA), monoclonal antibodies (mAb), and hepatitis B vaccine.

Formulation approaches

During the past 30 years, pharmaceutical scientists and technologists concentrated on the design, development, validation, and manufacture of various traditional pharmaceutical formulations, including solid orals, liquids and suspensions, sterile preparations, semisolids, topicals, injectables, and aerosols, among others. Consistent with technological advancements during the past 10–15 years, numerous formulations and drug delivery concepts emerged for enhanced therapeutic applications that also improved patient compliance. Examples include formulations using recombinant protein drugs, human growth hormones, TPA, hepatitis B vaccines, macromolecular proteins, newer biologics, genes, IFN, IL, TNF, EPO, mAb, and advanced therapeutic vaccines.

Milestone. 30 years of Pharmaceutical Technology

Because these formulations were relatively new, the industry needed to address several challenges such as storage, handling, and manufacturing while assessing their stability, compatibility, and scale-up and manufacturing issues before commercial distribution.

Thus, during the past two decades, the focus has been on new compounds, new therapies, new technologies, improved formulations, manufacturing challenges, and solutions to delivery challenges in gene therapy and biologics. In addition, designing drug-delivery systems that comply with applicable regulatory standards has been a consistent priority. Examples of these new approaches are described below.

Solid orals. Sustained release, rapid-dissolving formulations, sublingual, self-emulsifying drug delivery for poorly water-soluble lipophilic drugs, and oral delivery of macromolecules are some examples.

Oral vaccines. Vaccines have been delivered by injection since the early 1800s, when Edward Jenner first immunized a boy against smallpox by using the fluid from a cowpox sore. Researchers are now looking at alternative, more user-friendly routes of delivery for vaccines. Oral vaccines for diabetes are one example.

Milestone. 30 years of Pharmaceutical Technology

Topicals. Semisolids and topicals (e.g., ointments, creams, lotions, and suppositories) have been the traditional formulations. Currently available technological advancements include transdermal patches, iontophoretic patches, transdermal and transmucosal gene delivery, liposome and topical delivery, and microporation patches for the administration of analgesics through skin.

Ocular drugs. Ophthalmic solutions, suspensions, and ointments are clearly no longer sufficient to combat some current virulent diseases. To optimize topical ocular delivery systems, prolonged contact time with the cornea surface and better penetration through the cornea are necessary. In situ gel production and viscosity changes can be triggered by change in temperature, pH, and ion or electrolyte composition. In addition, retinal drug delivery, topical eye drops, sustained protein delivery to the retinal tissue, and nanotechnology for drug delivery to the anterior segment of the eye are some newer concepts.

Nasal formulations. Extensions to traditional nasal formulations such as aerosols include inhalation sprays (i.e., intrarespiratory delivery), nasal delivery of powders and liquids, nebulizers, and metered-dose inhalers. Nasal formulations are available for products such as inhaled insulin and protein and peptide delivery. These formulations have various applications, including inhaled nasal vaccines for seasonal diseases such as influenza, pandemic situations, pain management, and smoking-cessation products.

Parenterals. Traditional injectable formulations such as solutions, lyophilized formulations, biological products, and vaccines advanced into newer formulation and delivery systems such as dual-chamber prefilled syringes, dual-chamber vials, targeted monoclonal antibodies, nucleic acids and protein microspheres, microparticulates, microneedles, liposomes, buccal transdermals, nanoparticles, bioconjugates, and submicron emulsions.

Particle-size concepts. Polyaminoacid-based nanocarriers for the slow release of protein and peptides, targeted nanoparticles, micellar nanoparticles, oil-in-water nanoemulsions, and nanometer-sized droplets represent the emerging trends.

Targeted-delivery concepts. Researchers are pursuing site-specific, targeted drug delivery to treat colorectal cancer, Alzheimer's disease, Parkinson's disease, AIDS, heart disease and stroke, and alcohol and drug-addiction. In addition, pain management and the noninvasive delivery of opioid pain medications are other therapies being investigated. Researchers also are studying cochelate drug-delivery technology, which could potentially transform drugs such as amphotericin-B into patient-friendly, orally available products. It may be noted that cochelates are made of naturally occurring substances that are modified to encapsulate, protect, and deliver certain drug molecules that are either broken down by gastrointestinal enzymes and acids or cannot be absorbed through the gastrointestinal tract. Similar concepts extend to biochelates, in situ gels, and pulmonary drug delivery for the recombinant human interferon Alfa-2b.

Gene-delivery concepts. As researchers gain insight into the human genome, and doctors realize the clinical and commercial potential of treating patients based on their genetic make-up, genotyping technologies are taking center stage and paving the way to new drug discoveries and diagnostics. Hemophilia and hereditary protein C deficiency are prime examples of conditions that can be treated using the concepts of gene therapy.

Summary

Researchers are seeking to uncover better therapeutic approaches to various unmet clinical needs. They are studying diseases such as AIDS, Alzheimer's disease, Parkinson's disease, life-threatening and debilitating illnesses, and infectious diseases. Virological drug-delivery concepts by classified routes of administration such as the mouth, the gastrointestinal tract, the area under the tongue, veins, arteries, muscles, the skin, the heart, the spine, bones, joints, the eye, the nose, lungs, the rectum, the vagina, the urethra, and the colon, as well as transdermal and transmucosal delivery may lead to significantly improved therapies, help combat diseases, and improve the overall quality of life.

Pharmaceutical Technology will continue to gather information about the most important features of emerging technologies for the next generation of scientists and technologists.

Ram Murty, PhD, is president and CEO of Murty Pharmaceuticals, 518 Codell Dr., Lexington, KY 40509-1016, tel. 859.266.2446 ext. 211, fax 859.266.6976, rmurty@mpirx.com He also is a member of Pharmaceutical Technology's editorial advisory board.

Where were you 30 years ago?

"I was devising and implementing rapidly evolving good manufacturing practices regulations and procedures to meet stringent validation commitments for pharmaceutical processes (including aseptically processed sterile pharmaceuticals). My technical capabilities and responsibilities grew swiftly from research, quality control, and regulatory compliance to the management of overall operations.