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© 2021 MJH Life Sciences™ and pharmaceutical technology. all rights reserved.

Consistency, robustness, and understanding of API and controlled release excipients are critical to successful drug dosing.

Controlling the release speed and/or release location of APIs provides drug developers with new ways to develop drugs that are more patient-friendly but equally effective. Jessica Mueller-Albers, director of strategic marketing for oral drug delivery, said that controlling the release of API eliminates fluctuations in drug plasma levels, which usually leads to fewer side effects and can also reduce daily needs Evonik’s healthcare solutions in the number of doses.

Sudhakar Garad, global head of drug analysis at the Novartis Institute of Biomedical Research, added that the ideal controlled-release product allows oral treatment to be administered once a day, and parenteral treatment no less than once a week, up to once every six weeks. Controlled-release doses are also easy to swallow or administer, are cost-effective, stable at room temperature for at least two years, and are easy to package and transport.

Mueller-Albers observed that other important characteristics include excellent blocking effect at low polymer doses, very good tableting behavior, no ethanol effect on the swelling properties of API to avoid dose dumping when patients drink alcohol, and polymer layer Thin to ensure short processing and coating time.

Given the evolving nature of APIs and the growing desire to develop more targeted drugs, achieving these goals can be challenging. Fortunately, there are multiple controlled release mechanisms available today.

Simon Chen, vice president of Bora Pharmaceuticals, said that successful controlled-release formulations can release drugs at a specific rate and target location within a specific period of time, such as the gastrointestinal (GI) tract, skin, muscle, etc.

Brad Beissner, a development scientist at Metrics Contract Services II, asserts that the most important feature when designing a controlled-release formulation is to ensure the robustness of its API release, especially for APIs with a narrow therapeutic range.

Anil Kane, Global Head of Pharma Technical and Scientific Affairs, said: “A carefully formulated controlled-release formulation is designed to release drugs in a reliable and consistent manner at a predetermined release rate and optimal absorption site.” Service, at Thermo Fisher Scientific. Crucially, the formula performs consistently across the global patient population, age group, and disease state.

Ron Vladyka, Catalent's head of scientific services for oral and professional drug delivery, said robustness in manufacturing consistency is also critical for controlled release formulations. "The decisive factor in the development of a dosage unit from a prototype to a commercially viable product is its ability to be reproduced in a commercial environment," he said.

Firouz Asgarzadeh, vice president of BioDuro Pharmaceuticals, said that drug release must also be consistent, predictable and repeatable in different populations. He pointed out that a predictable release profile makes it easier to determine the number of doses required to maintain the therapeutic level of API in the patient's plasma and stay below the toxic level. Asgarzadeh added that regardless of the variability within the patient, robust reproducibility is needed in a large number of patients to avoid the need to personalize each drug for each patient.

According to Torkel Gren, senior technical director, it is also necessary to control the release rate of API at appropriate locations in the digestive tract in a precise and reproducible manner to achieve the best bioavailability of the drug after oral administration and ensure a repeatable clinical response. Officials at Recipharm And the person in charge of strategic investment. “This usually means that process parameters and the quality of excipients must be very carefully and strictly controlled to ensure that the required release rate is consistently obtained throughout the batch and to avoid changes during and after the test,” he observed.

In general, Tejas Gunjikar, head of application development and innovation for the IFF South Asia Pharmaceutical Solutions business, concluded that controlled release formulations should provide the required and consistent controlled release; they should be scalable, stable, and easy to manage; and Should help reduce the frequency of administration and side effects, these factors can improve the patient's treatment outcome. "This formula is usually the most acceptable and has achieved commercial success," he asserted.

Controlled release formulations and processes, if not carefully designed, may lead to inconsistent drug release, resulting in therapeutic response, dose dumping and/or substandard quality. Kane said that if the controlled release mechanism does not work, dose dumping may occur, which may lead to side effects or toxicity when the drug safety window is small. In addition, if the pharmaceutical production process is not sound, it may result in substandard quality, including deviations, substandards, and batch substandards, all of which may lead to production and/or financial losses, he added.

According to Vladyka, the robustness of the drug product is established in the early stages of formulation development, and robust excipients are selected. "Generally speaking, the selection of controlled-release dosage form excipients is based on the quality target product profile and physical and chemical characteristics of the API, but is subject to the technology used to manufacture the controlled-release unit," he said.

Additional improvements or selections of key excipient properties may be required to adjust controlled or local drug release, such as further adjusting the size of core beads used in the layering process or selecting specific batches of polymers based on functional group substitution values . Philippe Gorria, Senior Director of Formulation, pointed out that in some cases, different polymers with different molecular weight distribution, degree of substitution and other characteristics must be used in combination, all of which must be carefully controlled to achieve the required API release rate. Development of Recipharm .

"In any case, the influence of excipients has laid a solid foundation for the optimization and development of drug product formulations and processes, enabling the development of robust products that can be reliably produced in a commercial environment," said Vladyka.

Using the most appropriate drug release mechanism or principle to design a controlled release dosage form and the selection, quality and quantity of key functional excipients is the key, Kane commented.

True Rogers, senior scientist in the IFF Pharmaceutical Solutions business, said that for successful controlled release formulations, the most preferred excipients have highly reproducible performance and can be safely used for oral controlled release. Examples of such materials are cellulose derivatives, including hydroxypropyl methyl cellulose (HPMC), ethyl cellulose, cellulose acetate phthalate, etc., and synthetic excipients such as polyethylene oxide and Polymethacrylate. According to Rogers, certain naturally derived excipients based on seaweed and natural gums are also used, but to a lesser extent.

Asgarzadeh points out that because 100% synthetic excipients have smaller batch-to-batch variation and higher levels of regulation and control, they are more commonly used to achieve robust controlled release formulations.

"In the final analysis," Gorria asserts, "Controlled-release excipients must be suitable for the manufacturing process, suitable for controlled drug release, and provided in clear, repeatable quality."

Although excipients are traditionally regarded as inactive ingredients, they do play a functional role in controlled release formulations. Therefore, Asgarzadeh emphasizes that it is essential to have an in-depth understanding of the material science and structural properties of the selected excipients in order to overcome the various challenges faced by formulators. "Wise choice of excipients will help achieve the ideal release profile of controlled-release drug products, which will ultimately affect the drug's targeted therapy effect on patients," he said.

Kane also emphasized that although the selection of excipients with appropriate functions and their corresponding content in drug formulations is critical to the performance of controlled release drugs, a deeper understanding of how excipient variability affects drug performance and recommended controls Strategy is also an important consideration.

According to Vladyka, functional excipients that have a direct impact on the performance and stability of the dosage unit include polymers, pH adjusters, and surfactants. When combined with multiple activation and controlled release technologies, these excipients are used for control and Mitigating negative factors. He added that suitable binary or ternary polymer mixtures can inhibit or delay the recrystallization of amorphous drugs. In addition, the availability of various excipient types and grades can optimize API performance in controlled release formulations and delivery systems under development.

In addition, according to Chen, different excipients can not only help change the release rate of APIs that use the same release mechanism, but also change the release rate of APIs produced using different manufacturing processes, such as coating, mixing, hot melt extrusion ( HME), spray drying, etc.

"One advantage of using multifunctional excipients or polymers from experienced suppliers is that they can be applied to a wide range of drugs and used in different formulation methods, such as diffusion-based or matrix systems, as well as different Technology, such as granulation, coating, tableting and HME,” Mueller-Albers agreed. She also pointed out that excipients with long-term tracking records have been studied in numerous in vivo tests and used in marketed products, laying a solid foundation for the success of in vitro-in vivo correlation (IVIVC).

Garad pointed out that for high-dose controlled-release formulations, some special excipients play an important role in achieving higher API loads.

However, it is important that the excipient supplier thoroughly understand their manufacturing process and provide quality by design (QbD) samples that represent the range of key material properties observed, such as polymer molecular weight, relative substitution level, particle size, etc. , Besner asserted.

Besner said that formulators can also be proactive. For example, for hydrophilic matrix tablets, which account for at least 25% of the formula weight, the rate-controlling polymer helps limit the impact of any natural raw material changes and ensures uniform release between tablets in batches. At the same time, the slow-release coating is designed to a specific mg/cm2 coating thickness according to the surface area of ​​the substrate, and the film coating process can be expanded more easily, and it provides greater guarantee for repeatable results.

The excipients used in controlled-release formulations consist of two broad categories: matrix and reservoir system. Joao Marcos Cabral de Assis, Global Technical Marketing Manager of BASF's Oral Platform Pharmaceutical Solutions, explained that the two systems and the controlled release mechanisms of matrix solubility (hydrophilic or hydrophobic) are different.

Gorria said excipients that can form films and tablet matrices are particularly suitable because they can limit drug dissolution and/or drug diffusion, and even control drug release through the osmotic pump effect. Sensitivity to pH also affects the choice of excipients for pharmaceutical preparations at specific locations in the intestinal tract. According to Beissner, controlled-release formulations are usually achieved by using high molecular weight water-soluble polymers to form hydrophilic matrix tablets or by using film coatings of mainly water-insoluble polymers.

Most controlled-release drugs are formulated in a hydrophilic matrix, releasing API through drug diffusion and matrix erosion. Cellulosic polymers, such as HPMC, hydroxypropyl cellulose, hydroxyethyl cellulose, and methyl cellulose, are the most commonly used polymers in sustained release formulations. Alginate, carbomer and gelatin are less common examples of these materials.

The hydrophobic matrix releases the API through drug diffusion because the matrix is ​​insoluble in water and will not be corroded. Therefore, according to Assis, API solubility is a key factor in the success of these formulations. He pointed to carnauba wax, cetyl alcohol, hydrogenated castor oil, microcrystalline wax, ethyl cellulose (EC), stearic acid and polyvinyl acetate (PVAc) as examples of lipophilic bases.

The choice of hydrophilic or hydrophobic matrix (such as pH-dependent or pH-independent polymethacrylate) mainly depends on the solubility of the drug, because the potential self-blocking effect of the drug at higher pH values ​​will affect the release kinetics Learning has an impact, according to Muller-Albers. The same is true for highly soluble drugs that may require a strong block during gastric passage.

Soluble ingredients are usually added to lipophilic matrices and insoluble film coatings as pore formers to better regulate drug release. Typical pore formers are povidone (polyvinylpyrrolidone [PVP]), polyethylene glycol-polyvinyl acetate (PEG-PVAc) graft copolymer, sugar and PEG.

The reservoir system consists of a core containing the drug, which can be multiparticulate or a single tablet coated with an insoluble film. Assis says that drug release in these systems is done entirely through diffusion and is regulated by the thickness of the membrane, permeability modifiers, and added core components that change water attractiveness. This application is mainly provided by insoluble film-forming excipients such as methacrylate, EC and PVAc.

In order to select suitable excipients, Mueller-Albers recommends that formulators consider the properties of the API, such as its solubility, charge, etc.; the type and design of the dosage; the strength and duration of the blocking effect; the preferred manufacturing process (ie, direct compression) Tablets, granulation, coating, HME, spray drying, etc.); and whether it needs to be easy to swallow, such as pediatrics and elderly patients.

Kane added that a thorough understanding of polymer functions and material properties is the key to successful design of controlled release, especially for matrix and permeability zero-order drug release. For example, Chen commented that for sustained-release formulations, pH-dependent excipients such as methacrylate polymers will provide gastric resistance; EC will be a pH-independent controlled release option, such as multiparticulate drug delivery systems ( For example, pellets in capsules); HPMC will be the main choice for monolithic controlled-release drug delivery systems; and poly(DL-co-glycolide) (PLGA)-based polymers will be preferred for microsphere depot injection formulations .

As with most preparations, Beissner adds that drug solubility is a major factor in the choice of excipients. "Low-molecular-weight polymers are generally used to generate more erosion-based drug release profiles for low-solubility drugs, and high-molecular-weight polymers and high-solubility drugs that swell more and provide a diffusion-based drug release profile," he explained. At the same time, the API release rate of the sustained-release coating was changed by changing the ratio of water-insoluble and water-soluble polymers in the formulation and the thickness of the film coating.

In addition, Gorria added that for tablets with a hydrophilic matrix, powder flowability and compatibility will be important, while for products containing coated pellets, the polymer must be sprayable and produce a strong coating on each pellet. film. It also depends on whether the release of the API will be restricted by slow dissolution, formation of a semi-permeable membrane, or passage through a gel.

According to Vladyka, other guiding factors may include predicting patient characteristics of the target population. For example, in the case of pediatric preparations, the choice of excipients may be limited due to safety issues and the availability of process equipment. "The available process equipment can determine the type of excipients that will be used in the manufacturing process," he explained.

For example, Assis pointed out that for poorly compressible APIs, PVAc can provide the plastic deformation required to increase compressibility and allow simple direct compression, thereby saving processing time and costs.

Similarly, according to Assis, EC coatings require large amounts of plasticizers to achieve the necessary film elasticity, which leads to complex formulations and processes. In addition, although some water-based EC dispersions are available, they have long curing times and require high temperatures, so most EC coating solutions require the use of organic solvents. He observed that PVAc-based coatings are attractive alternatives to water-based dispersion films, with high flexibility, pH-independent drug release, lower curing temperature and lower dose dumping risk.

Find the right starting formula

Formulation scientists face multiple challenges when formulating controlled-release pharmaceutical products. According to Gunjikar, these challenges are due to the properties of the drug, such as its solubility, dosage, handling, processability, interaction with other ingredients of the formulation, and the need to be delivered to a certain part/area of ​​the body at a certain speed. Scheduled rates; API release is incomplete; the most important thing is to be able to provide repeatable performance to consistently achieve the desired treatment results.

Mueller-Albers agrees that the main challenge in formulating controlled-release small-molecule drug products is that the characteristics of the API will affect the release kinetics. Therefore, it is not easy to find the correct starting formulation.

In the formulation design of controlled-release drug products, Kane added that evaluating excipients is critical to the variability of drug product properties. Therefore, the most influential material properties of functional excipients (such as polymers) are determined to Important. Chain length, viscosity, swelling behavior, etc.). "This understanding of excipient variability can then be combined with knowledge of the characteristics of each API and the process parameters used to manufacture the drug, and appropriate control strategies can be developed to ensure the continuous supply of safe and effective drugs," He asserted.

"The experience of formulators is essential to solve the challenges of controlled-release small molecule drug products. For formulators with limited experience in controlled-release dosage forms, it is important to be able to provide the right excipients, technologies and solutions in a short time. Process supplier cooperation is essential. When formulators work under extreme time pressure, it is also important to have a platform solution that can be applied to multiple candidates," Mueller-Albers said.

Gunjikar agrees that in the product development and scale-up process, close collaboration between formulators and ingredient suppliers can determine ingredients and characteristics that are critical not only to quality but also to performance. "Defining the quality and performance design space will lead to more powerful pharmaceutical products," he said. Industry-leading excipient suppliers are underutilized resources in the formulation development process. Their knowledge and experience in excipient application can be used to solve problems that arise, Ron Vladyka, Director of Scientific Services for Oral and Professional Delivery at Catalent, added.

Mueller-Albers said that the most important thing is to start the initial formulation development of controlled-release dosage forms with knowledgeable partners (such as excipient suppliers). "Establishing this partnership as early as possible can accelerate development because the correct formulation and process parameters can be found faster. We have found that early communication between excipient manufacturers and formulators helps overcome challenges, for example through During the process, the curing solution cures the water-based controlled-release coating and adjusts the formula to avoid the dumping of the alcohol dose," she explained.

One of the biggest challenges of controlled release formulations is to achieve IVIVC. "The relationship between the in vitro properties of the dosage form and its in vivo response is particularly important for controlled-release oral formulations," Mueller-Albers asserted. Through the successful development and application of IVIVC, the in vivo drug performance can be predicted from its in vitro behavior. "Establishing meaningful IVIVC can provide alternatives to bioequivalence studies, improve product quality, and reduce regulatory burdens," she added.

However, it may be difficult to establish this correlation, because each patient's absorption changes under fed and fasted states, as well as differences in intestinal transit, intestinal metabolism, etc., between patients, Assis added.

Obtaining zero-level release can also be seen as a challenge for formulators. "Push-pull systems are an alternative to this type of release, but the technology required for their manufacturing is so complex that most companies avoid these systems," Assis points out. However, he recently pointed out that using a combination of a functional hydrophobic matrix polymer (such as PVAc) and a gastric juice resistant polymer (such as methacrylic acid and ethyl acrylate copolymer) mixed in an appropriate ratio, the polymer acts as a pH-dependent component. Pore ​​agent can ensure linear release.

Gorria said that one of the challenges that continues to cause problems for formulators is the difficulty in achieving targeted API release in the lower intestine.

Various forms of stability can also bring difficulties. For example, Thorsten Cech, an expert in pharmaceutical technology applications and manager of BASF's European Pharmaceutical Applications Laboratory, pointed out that changes in the dissolution characteristics are often observed when medicines are stored. Although curing can minimize these risks, this characteristic is still a potentially critical material attribute that requires thorough investigation during product development.

Beissner said that ensuring the robustness of API release is also challenging due to the inherent variability of polymers used in controlled release applications. "It is important that the controlled-release formulation can withstand this batch-to-batch variation of raw materials," he said.

In order to ensure stable and reproducible release and minimize inter-patient and intra-patient variability during the expected extended period of controlled release, Asgarzadeh observed that the polymer excipients used in these formulations need to be in the entire gastrointestinal tract Keep intact and effectively promote the diffusion of API from the core over time. The drug product passes through the excipient film to predictably release the drug independently of the patient's diet and provide therapeutic levels of API release without any physical transformation.

From Garad's point of view, dose is the biggest challenge. "In controlled-release formulations, the dosage should be lower than that of conventional pharmaceutical products, so that whether it is administered orally or parenterally, a palatable-sized preparation can be produced," he observed. Gorria explained that once multiple doses are combined and controlled-release excipients are added, the final dosage form (such as a tablet or capsule) can be very large. For children and elderly patients who have difficulty swallowing, large pills and capsules may be difficult to swallow, leading to reduced patient compliance and thus reducing the effectiveness of treatment.

For this reason, Gallard pointed out that molecules with narrow therapeutic windows are generally not ideal candidates for controlled release. Molecules with very low clearance rates are generally not good candidates because they accumulate and cause side effects.

Chen said that APIs with very high or very low solubility pose additional challenges because it is difficult to control their release profile with excipients. For APIs with poor solubility, Vladyka pointed out that it is necessary to combine enabling technologies to increase the apparent solubility of APIs in controlled release forms. "In some cases," he said, "the two technologies may not have compatible manufacturing processes, and their choice may limit the preparation of controlled-release dosage forms."

Specifically, Vladyka pointed out the high-energy state technologies used to increase the solubility of drugs. He pointed out that these technologies may not be suitable for aqueous or organic solvent controlled release processes because their use may lead to drug recrystallization and reduced solubility. In the drug library The use of higher energy state APIs for diffusion-based drug release may lead to API recrystallization, which changes the release profile.

Despite these concerns, Cech points out that the formation of amorphous solid dispersions (ASD), especially through hot melt extrusion (HME), is an attractive solution for poorly soluble APIs. "HME has been shown to increase solubility and bioavailability and regulate release by simultaneously introducing controlled release functions," he explained. The controlled release behavior can be achieved not only by carefully selecting the polymer used to form the ASD, but also by optimizing the porosity of the tablet produced from the compacted extrudate.

Although it is possible to design a molecule suitable for a controlled release formulation, this is usually not feasible. Garad said the current approach is to take existing molecules and incorporate them into the controlled release dosage form platform technology. "The key is to combine the correct physical and chemical properties with the correct molecular pharmacokinetic properties, the correct controlled release technology, and the ideal polymer," he said.

Cech added that proactive identification of key material properties and their impact on drug release is critical. It is also necessary to study the interaction of these properties with process variables (temperature, compression pressure, etc.) and material incompatibility.

"According to the solubility of the API and other physical and chemical properties of the drug, formulators can use different methods to ensure the possibility of success and achieve the expected drug release. Such as hydrophilic or hydrophobic matrix, film formers and pore formers, Considerations such as the feasibility of the manufacturing process and product stability can be part of the QbD plan for system drug product development," Cech observes.

Vladyka also emphasized the importance of using knowledge and understanding of the drug product under development to guide method selection and at which stage of the process to start. Asgarzadeh added that a successful strategy requires a combination of deep formulation knowledge and empirical testing.

Cech pointed out that using alternative methods to study the processing process, such as determining porosity, fluidity, compaction, and tabletability, and conducting stability tests on unoptimized formulations at an early stage to select the most stable formulation may be to ensure the final Good strategy for product quality and safety. Controlled release drugs.

Pharmacokinetic models and solubility studies in various media can be used to gather information, including in simulated gastric juice (to determine logP, dose, and solution stability). The range of formulation and process development can range from a wide range of multi-dose methods to a single technology, highly concentrated development plan.

Gren agrees to study several formulation principles and excipient combinations to determine the most suitable method to meet the needs of a given project, and said that the compatibility of all ingredients in the future formulation must be determined to avoid degradation (polymer/polymerization). Substance and/or polymer/drug substance).

Vladyka said that it is also important to use high-quality excipients from industry-leading suppliers who have good quality attributes throughout the development life cycle. Since excipients play a direct role in the controlled release properties themselves, Asgarzadeh added that they should be selected based on previous experience and proven properties to meet the needs of the API itself. "The ability to test excipients in an effective animal model helps determine which excipients work best in vitro and in vivo, thereby providing a relative prediction of the release profile in humans, increasing the possibility of determining clinically successful formulations. Sex," he said.

"Since all APIs are different, there is no one-size-fits-all solution," Glenn concluded. “Therefore, once a suitable prototype is determined, the experimental design method can be used to establish a formulation and process parameter space that provides robust drug release characteristics. Then, formulators can be confident that they understand the formulation in various practical situations (several physiological media) Performance, which allows them to improve the finished product to ensure consistent performance regardless of the actual situation," he said.

Dr. Cynthia A. Challener is the contributing editor of "Pharmaceutical Technology".

Pharmaceutical technology volume. 45, No. 9 September 2021 Pages: 16-22

When citing this article, please cite C. Challener, "On-Time Delivery: The Challenge of Controlled Release Formulations", Pharmaceutical Technology, 45 (9) 2021.