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In the realm of injectables, a discernible shift has taken place from conventional aqueous injections to a spectrum of differentiated long-acting injectable dosage forms. This evolution has gained substantial traction over the past two decades, with numerous products entering the market based on complex injectable drug delivery systems, particularly long-acting injectable formulations.
Long-acting injectables present a versatile range of formulation compositions and routes of administration. They can be categorized based on their route of administration or site of action, offering options such as systemic or locally acting injectables. Various formulations are available, including oil-based formulations, polymer-based implants or in-situ implants, polymer-based nanoparticles and microparticle drug suspensions. Additionally, innovative devices like intrauterine devices and vaginal rings have been developed to administer long-acting reversible contraceptives to improve women's health. Emerging technologies, such as microarray-based patches, hold promise for providing prolonged therapeutic effects.
In a recent research article, it is reported that approximately 29% are in the form of implants or devices, while nearly 25% are in microencapsulation or polymeric form, including in-situ hydrogels and chemical modifications such as liposomes and suspensions. Regarding the route of administration, the majority (74%) are injectable, with about 30% administered via other routes. These formulations offer extended durations of drug release, with approximately 55% lasting for weeks and 77% for months.
Now, let us delve into the disease segments where long-acting injectables are predominantly utilized. These formulations are particularly beneficial in disease areas necessitating high-frequency or daily dosing regimens. Physicians often initiate treatment with oral therapies, which may progress to conventional injectables for weekly administration. However, as disease progression occurs and patient adherence wanes, transitioning to monthly injections becomes imperative. This is where long-acting formulations play a crucial role in maintaining therapeutic efficacy while improving patient compliance.
Long-acting injectables have demonstrated therapeutic efficacy across various disease segments. Contraceptive therapies, for instance, offer an alternative to daily regimens, providing protection for weeks or months. Similarly, in AIDS treatment, long-acting injectables help enhance treatment adherence and maintain steady plasma levels. In cases of eye disorders, such as acute macular degeneration, long-acting nano suspensions offer promising solutions to prevent vision loss, especially among the geriatric population.
Psychiatric disorders pose unique challenges in treatment adherence, where patients may be reluctant to continue therapy. Long-acting injectables are a considerable choice in case of poor adherence to treatment and frequent relapses. Long-acting injectables ensure increased adherence to treatment, improved social functioning, and reduce relapse, hospitalization and treatment costs. Additionally, diseases like malaria and tuberculosis, requiring prolonged treatment durations, benefit from the transition to long-acting injectables, improving patient compliance.
The advantages of long-acting therapies are manifold. They enhance treatment adherence by reducing dosing frequency, balance onset, and maintain steady plasma levels, thereby improving therapeutic efficacy. Moreover, modified pharmacokinetic profiles contribute to improved safety, reduced dosing frequency, and reduced relapse rates, ultimately enhancing patients' quality of life in chronic diseases.
Although long-acting formulations appear promising, developing them is no simple task. Over time, science has advanced, and technology has evolved, providing the expertise necessary to create these intricate delivery systems. Multiple publications, scientific articles, and books are available, offering guidance for the development of long-acting injectables. The scientific community has devised solutions, such as in vitro-in vivo correlations (IVIVC), machine learning (ML) models to streamline the drug product development process.
Creating an IVIVC involves conducting extensive pharmacokinetic (PK) studies over months or even years to compare test formulations with comparator products, which could be conventional injections or branded generics. This prolonged development period may not always be feasible or affordable. Therefore, there is a pressing need to expedite development while maintaining accuracy. IVIVC has the potential to achieve this by establishing strong correlations between in vitro characteristics and in vivo performance of the drug delivery system. Machine learning (ML) and AI based prediction algorithm techniques are used to build the IVIVC for long-acting injectables. These techniques involve the development of algorithms to analyse data and identify statistical patterns or relationships which can be leveraged to make predictions about new data, establish links between target product profile and input formulation parameters etc.
Critical attributes, stemming from materials, manufacturing process, delivery systems, and routes of administration, play pivotal roles in IVIVC. By correlating these attributes and conducting limited PK studies, key parameters that influence drug performance can be identified. For instance, in the case of suspensions, particle size, particle size distribution and morphology significantly impact drug release profiles. Developing in silico models based on these correlations allows a deeper understanding of how to optimize formulation parameters to achieve desired effects.
In today's landscape, building in silico models has become mandatory for developing long-acting injectables due to the prolonged duration of PK studies. These models leverage mechanistic understanding, machine learning, or AI tools to simulate drug distribution and predict performance. Moreover, innovations in bioequivalence and in vitro release testing (IVRT) profiling further enhance development processes.
By harnessing in silico modelling and robust IVIVC, successful development of long-acting injectables is attainable. This data-driven approach facilitates decision-making, particularly when altering or managing PK profiles to meet therapeutic objectives. Ultimately, these advancements streamline and facilitates development processes, ensuring efficient and effective delivery of long-acting therapies to improve patient outcomes.
Now, while long-acting injectables prove highly advantageous, their complexity demands specialized knowledge and expertise. Emerging biotech or startup companies venturing into this field may lack the requisite infrastructure and talent. This is where Contract Research Organizations (CROs) or Contract Development and Manufacturing Organizations (CDMOs) step in. According to the 2023 Inside Partner Report, the CRO/CDMO industry's contribution to injectable dosage forms in North America alone amounts to approximately $1.13 billion, with an annual growth rate of 5 to 9%. More than 50% of this revenue stems from complex or long-acting injectables, reflecting a growing trend of companies seeking comprehensive support from CROs/CDMOs, spanning from drug product development to commercial manufacturing.
Particularly, companies prefer CROs/CDMOs offering end-to-end capabilities, facilitating seamless transitions from development to commercialization. Notably, CDMOs focusing on fill-finish operations or capable of handling long-acting complex injectables witness significant investment and growth. Furthermore, CRO/CDMO involvement extends beyond brand-name drug companies, as multiple entities now handle generic long-acting injectables, contributing to growth in both animal and human health sectors through strategic partnerships.
The advantages of partnering with CDMOs in developing complex drug delivery systems and ensuring commercial supply are manifold. Consider an emerging company or a product-based firm seeking to enter the realm of long-acting injectables. Establishing in-house capabilities for such ventures would entail substantial time and capital investments. In contrast, CRO/CDMOs like Syngene, equipped with integrated verticals and extensive experience, offer a distinct advantage. These entities provide comprehensive services, from ideation to commercial supply, leveraging their expertise and infrastructure for efficient and customized product development.
Long Acting Injectables Experience at Syngene: A Triad of Case Studies
In a concerted effort at Syngene, an integration program was launched to develop a novel drug polymer conjugate. This case demonstrated a successful collaboration among various departments, propelling a promising lead drug product into clinical trials. Initially focusing on synthesizing the polymer component, our team encountered challenges in controlling residual solvents. To address this, an integrated approach involving our Advanced Analytical Lab was deployed, resulting in the successful reduction of solvent levels via ultrafiltration. As a result, the project advanced into clinical phases, showcasing the efficacy and safety of the novel conjugate.
In another case, our team embarked on formulating a nanoemulsion for a generic product, presenting unique complexities in achieving desired characteristics. By meticulously controlling aqueous and non-aqueous phases, employing stabilizers, and defining critical process parameters we overcame challenges to ensure uniform droplet size and stability. Our adherence to stringent quality standards, including droplet size measurements as per USP Chapter 719, resulted in the development of a compliant nanoemulsion suitable for commercialization.
In another exciting case study, we developed of liposomes using spray drying, offering a rapid and efficient alternative to traditional methods. Despite challenges in particle size distribution and lipid stability, our multidisciplinary team collaborated to optimize spray drying parameters and refine the formulation process. Through meticulous optimization and process refinement, we successfully generated unilamellar liposomes, showcasing a scalable and efficient manufacturing process.
These case studies underscore the importance of interdisciplinary collaboration and innovative approaches in overcoming formulation challenges. Leveraging the expertise of various verticals within our organization, we navigated complexities and delivered high-quality pharmaceutical solution to meet evolving industry needs.