From ALZA to Zosano Pharma: Pioneering Drug Delivery Innovation for Over Three Decades

Almost all drugs face the issue of drug delivery, which not only affects the efficacy of the drug but also becomes a critical factor in determining the success or failure of drug development. From in vitro microneedle injection for delivering small-molecule chemical agents to using liposomes (LNPs) to encapsulate and deliver large-molecule drugs in vivo, methods of drug delivery are continuously innovating.

Founded in 1968, ALZA is a leader in this field:From the groundbreaking transdermal patch technology, which has enabled a new model of non-invasive, sustained drug delivery, to breakthroughs in osmotic pump technology, and the launch of liposome products.From its founding in 1968 to its acquisition by Johnson & Johnson in 2001, over the course of 33 years, ALZA utilized innovative drug delivery systems to turn numerous therapies from impossibilities into realities, time and again revitalizing existing drugs.

ALZA is derived from the four letters of its founder Alejandro Zaffaroni’s name. Before founding ALZA, Zaffaroni worked at Syntex, a small Mexican company engaged in contraceptive drug development, where he conducted research on steroid hormones. As Syntex's operations in the United States expanded rapidly, Zaffaroni sold his shares in Syntex for $3 million and began to establish his own business.

Dr. Alejandro Zaffaroni, Founder of ALZA

Although Zaffaroni had a background in synthetic biology, he had already recognized the limitations of traditional drug formulations and drug molecules themselves, as well as the immense potential of drug delivery technology. Zaffaroni's initial idea was to develop a TDDS drug carrier system capable of penetrating the skin to achieve sustained and controlled drug release.

TDDS refers to a new method of drug administration on the skin surface, allowing the drug to pass through the skin at a constant rate (or near-constant rate) into the systemic circulation to produce systemic or local therapeutic effects. Transdermal preparations have the advantages of convenient use, avoiding the first-pass effect and gastrointestinal inactivation, but they also have the disadvantages of low drug loading, complex processes, and difficulty in industrialization.

After decades of arduous research and development, ALZA has developed three major transdermal drug delivery system technology platforms: D-Trans Transdermal Drug Delivery, D-Trans Transdermal Drug Delivery Technology, and E-Trans Iontophoresis Technology. Among them, the D-Trans Transdermal Drug Delivery Technology can achieve efficacy lasting up to a week; Macroflux Microneedle Transdermal Drug Delivery Technology uses precise microneedle delivery to accurately control drug dosage while reducing skin irritation; and the E-Trans Iontophoresis Technology enables patient-controlled analgesic therapy.

Relying on these three transdermal patch technology platforms, ALZA's transdermal patch products have achieved fruitful results. In 1979, ALZA's first scopolamine transdermal patch (Transderm Scop) successfully obtained FDA approval, marking ALZA's official entry into the successful realm of transdermal patch technology. Since then, the company has had a series of successes, with almost one new transdermal patch being launched every two years.

In 1981, ALZA's nitroglycerin transdermal patch (Transderm-Nitro) received FDA approval and was widely used for the long-term treatment of coronary heart disease and the prevention of angina pectoris. In 1984, ALZA's third transdermal patch product, clonidine transdermal patch (Catapres), also successfully obtained FDA approval. In 1990, the company successfully launched fentanyl transdermal patch (Duragesic), which achieved the first application of fentanyl in the field of chronic pain, with a duration of 72 hours. Its global sales peaked at $2.2 billion, making it the only transdermal patch product with peak sales exceeding $2 billion globally. In the following two years, the company continued to innovate, launching the first smoking cessation patch, nicotine transdermal patch, and testosterone transdermal patch (Testoderm).

In the decades following ALZA's successive successes with transdermal patches, transdermal patches became a trend in the reform of drug delivery methods, with the global market once exceeding 10 billion US dollars.

With the development and upgrading of technologyALZA also developed osmotic pump technology, a controlled-release drug delivery system driven by osmotic pressure and characterized by zero-order kinetics.。

As early as 1974, ALZA had already begun research into osmotic pump technology. In 1982, it successfully designed the world's first push-pull osmotic pump, achieving zero-order drug release. Entering the 1990s, ALZA started utilizing the push-mucosal osmotic pump technology to improve methylphenidate. In 2000, the approval of Concerta brought osmotic pump technology to its pinnacle, achieving dual time-phase controlled release of methylphenidate for the first time.

Based on osmotic pump technology, ALZA has developed oral osmotic pumps, implantable osmotic pumps, ocular and vaginal insert osmotic pumps. The representative product of the implantable osmotic pump is Viadur, the first leuprolide implant drug delivery system. The technical platform of this product is the Duros implantable osmotic pump—a matchstick-sized pump made of titanium alloy that protects and secures the internal drug. It is non-biodegradable, implanted subcutaneously, and provides continuous drug delivery for up to one year.

In addition to implantable agents, ALZA also developed liposome technology and was one of the earliest companies to use PEG-modified liposomes. PEG-modified liposomes refer to a new type of liposome formed by covalently bonding PEG to the surface of liposomes.

This modification method endows liposomes with four significant advantages and characteristics: First, it enhances stability, prolongs the circulation time of liposomes in the body, and reduces the risk of rapid clearance by the immune system; Second, it extends circulation time, thanks to the shielding effect of PEG, significantly increasing the residence time of liposomes in the bloodstream; Third, it improves targeting by cleverly attaching targeting molecules such as antibodies or ligands to the ends of PEG molecules, enabling liposomes to achieve precise recognition and binding to specific target cells; Fourth, it reduces the toxic side effects of drugs, as more of the drug is delivered to the target site to exert its effect, while accumulation in non-target areas is greatly minimized.

In 1995, ALZA's liposome product Doxil (doxorubicin) was approved, and later, PEG-modified Caelyx also received approval. According to clinical data, after PEG modification, the drug's distribution characteristics in the body change, with the drug tending to distribute more in skin tissues; thus, Caelyx can be used for the treatment of Kaposi's sarcoma. The greatest advantage of liposomes is the reduction of cardiovascular toxicity of doxorubicin. Doxil/Caelyx has become one of the highest-selling products in the liposome field, with peak annual sales nearing $600 million.

In 2001, Johnson & Johnson acquired ALZA Corporation for a staggering $10.5 billion, gaining access to the company’s numerous innovative achievements in the field of drug delivery systems and paving the way for future technological breakthroughs. In 2006, Johnson & Johnson spun off ALZA's transdermal patch delivery system business into an independent operation, and in 2007, the spin-off was renamed Zosano Pharma.

After becoming an independent entity, Zosano Pharma inherited the core technology of the original ALZA and focused on the research and development of transdermal microneedle delivery systems. This field was still in its infancy at the time, with few competitors involved.

Microneedle delivery systems have rapidly become a new favorite for enhancing drug delivery efficiency and patient compliance due to their minimally invasive, painless, and highly safe advantages. Research shows that microneedles, as a new carrier for in vitro drug delivery, have broad application prospects. Their potential was authoritatively recognized in 2020, being selected by Scientific American magazine as "one of the ten new technologies with the potential to change the world."

Zosano Pharma's core product—M207 (also known as Qtrypta)—is a revolutionary transdermal microneedle patch. The patch integrates a reusable applicator with a microneedle array, enabling rapid drug absorption into the bloodstream through a simple transdermal delivery process. Its microneedle array consists of nearly 2,000 titanium microneedles coated with medication, each needle being only about three times the width of a human hair. The design is ingenious, resembling a band-aid, making it easy to use and store.

During use, the microneedle patch can easily penetrate the stratum corneum of the skin, utilizing interstitial fluid in the skin to promote drug reconstitution and rapid entry into the bloodstream. This process eliminates the need for traditional subcutaneous injection needles, significantly reducing patient discomfort and enhancing treatment comfort. More importantly, the microneedle delivery system greatly improves drug absorption efficiency. According to pharmacokinetic analysis, the absorption rate of zolmitriptan via the Qtrypta patch is nearly three times faster than that of oral zolmitriptan.

Currently, Zosano Pharma is committed to accelerating the absorption of migraine medications and improving treatment outcomes through the Qtrypta patch. Clinical studies have shown that the patch achieves painless or low-pain administration in most patients, further enhancing its market competitiveness. As transdermal microneedle technology continues to mature and gain popularity, Zosano Pharma is expected to become a leader in this field, spearheading a new wave of transformation in drug delivery technology.