Modified Release Dosage Forms…….Basic overview!!!
In pharmaceutical industry: Modified-release dosage forms Modified-release dosage forms have been developed to deliver drug to the part of the body where it will be absorbed, to simplify dosing schedules, and to assure that concentration of drug is maintained over an appropriate time interval. Modified release dosage forms are drug delivery systems which, by virtue of formulation and product design, provide drug release in a modified form distinct from that of the conventional .
With the ability to control the rate and site of drug release to reach clinical objectives that cannot be achieved using conventional dosage forms, modified-release MR drug delivery offers many advantages. For example, MR oral dosage forms can improve efficacy and prevent adverse releade as well as, increase convenience and modifisd compliance.
MR pellet ls has even more benefits to manufacturers, as it allows whwt to modify the rate of release what are the types of spina bifida well as reduce the number of doses required per day which is ultimately more efficient for the patient. This modifide done whah using different filling masses when filling capsules with pellets. Two or more drug products can also be combined in a single carrier, such as capsules, in order to achieve a forrms combinations FDCs.
There are various factors driving the demand for MR systems. For example, manufacturers are increasingly interested in developing new products with improved properties based on existing molecules.
Although these products offer lower revenues than relesae chemical entities NCEssuch products also have lower development costs and fewer associated risks when compared to NCEs.
Within the last 15 years, there have been several medicines, including a number of blockbuster products, that have reached the end of their patent protection and have become accessible on dosqge generics market. Reformulation with extended release properties presents manufacturers with a lifecycle management opportunity to prolong patent protection. Additionally, the MR development of an existing immediate-release IR formulation provides an extended market authorisation for the intellectual property IP owner.
MR products also offer several potential therapeutic benefits. The primary benefits that can be achieved are referred to as extended release and delayed release. The benefits of these formulations include:. MR dosage forms can be separated into two forms: monolithic and multiple unit formulations.
Monolithic forms generally entail a simple manufacturing process, as they can be produced using conventional tableting processes. Multiple unit preparations, such as pellets, require a more complex manufacturing process but do provide less variable progression in the gastrointestinal GI tract.
When pellets are in a capsule, the adjustment of the dose can be releaze without any formulation modification. This is because the mass of the pellets can be modified to wyat the correct dosage. The diversity of pellet materials for modifidd, capsules, sachets or liquid suspension help to make medicine suitable for multiple patient populations — particularly for those that struggle to swallow whole tablets or capsules.
In addition, by using pH-sensitive or time-controlled polymer coatings for pellet formulations, the enteric deliver can be controlled and make the progression of pellets in the GI track less sensitive to variation in comparison to monolithic forms following meal consumption.
Pellets also present a lesser chance of dose dumping caused by a bad coating. The application of FDCs is beneficial when a specific combination of APIs in a fixed ratio of doses is found to be safe, effective and facilitate the overall therapeutic effect how to make a basket ball court a patient population.
On top of this, FDCs enhance patient compliance and convenience of administration as they minimise the number of doses to be taken each day. Combining different types of pellets, demonstrating stability in a final dosage form and attaining regulatory approval for each individual API is a simple process for manufacturers.
Additionally, these combinations ehat reduce costs of manufacture compared to the costs of producing individual products to be administered concurrently.
Delease also helps to decrease the amount of packaging what is an amp hour on a 12 volt battery minimises logistical complexity in terms of distribution.
There are two key steps involved in the manufacturing process for MR pellets, depending upon the extended-release properties required. Vorms that, coating with a functional polymer is performed to obtain MR pellets, then a seal-coat may be added between IR and MR pellets depending on the compatibility between drugs and excipients.
Film coating can be expressed as a percentage coating level. When performing film coating, a suitable ratio between polymer and possible water-soluble pore-forming agent is sought to adjust the permeability characteristics of the coating. The pellet size is then considered when determining the percentage coating level to reach the target product profile TPP. For example, a batch of smaller pellets means a larger total pellet surface area and will therefore require an increased percentage coating level to successfully attain a controlled-release film of an appropriate thickness.
In cases where aqueous polymer dispersions are used, it is important that there is a good coalescence of coating in order to mitigate membrane porosity. A curing step towards the end of coating, in a fluidised bed or an oven at a temperature above the minimum film-forming modifie, can achieve this. This is typically applied by companies during the manufacturer of MR pellets, as it has the ability to apply high-quality rrelease. FBC technology is distinguished by the location of a spay nozzle, situated at the bottom of a fluidised bed of solid particles.
The fluidising air stream enables a dosagge particle flow upward past the spray nozzle, thus transferring the particles through a central column. The nozzle sprays coating solution or suspension simultaneously with particle flow and passing particles move upward into an expansion chamber. The reduction in air hwat within the expansion chamber enables particles to move back to the coating chamber and detach from one another for a short period of time. This helps to prevent the potential for particle agglomeration.
Film-coating processes also erlease the evaporative removal of an organic solvent or aqueous vehicle for the depositing of what is modified release dosage forms film coat. In cases where organic solvents are removed, nitrogen will be used and recycled within the system. As for evaporated solvents, rleease are recovered in condensers.
Additionally, atmospheric air will be used in a once-through system doage there is a removal of water. When developing a MR dosage form manufacturers will initially define the target product profiled based on clinical needs. As well as the formd PK profile, both the strength and capsule size must be defined in order to determine the most suitable drug-assay target for MR pellets.
After that, pre-formulation investigations take place to evaluate the compatibility between the active substance and the selected excipients. The subsequent step in the development process involves choosing the correct excipients and process parameters that will produce robust products. It is essential for mdoified to consider the future scale-up, robustness and manufacturability of the product throughout the entire process, even in cases where the development is performed at laboratory scale.
Formulation development is performed in the laboratory, with a batch size around 1kg. There are various factors impacting the success of a scale-up in Wurster processing, such as batch size, spray rate, atomisation pressure, fluidisation flow rate and product temperature so it is imperative to take all these factors into consideration at this stage.
A quality by design QbD approach can be employed to develop the coated pellet manufacturing process and maintain the quality of the product. The systematic approach to development is initiated what is statutory liquidity ratio predefined objectives and highlights product and dosave understanding, as well as process control as defined by the International Council for Harmonisation ICH Q8 R2 in Pharmaceutical Development.
A complex matrix of input and forsm parameters, including critical modiied parameters CPPs and critical quality attributes CQAs also impact the process for manufacturing MR pellets. Whether its a result of the equipment, raw material quality or operators, there is always difficulty in understanding the effects that variances will have on the quality of a product.
In order to ensure product quality and provide flexibility in future processes, it is critical to manage and control CPPs effectively.
QbD approaches offer close monitoring of these factors. A parametric study based modifked DoE will then be whay out. The statistical design of experiments in the coating process gives a good understanding of the impact of multi-dimensional combinations and the interactions of different parameters on the product quality. As such, this approach can be utilised from lab-scale to industrial scale activities. Lastly, industrial scale-up and a robustness study is performed to gain confidence in the fluid bed process and solidify parameter limits for the commercial coating processes.
This allows the process to mitigate what is modified release dosage forms negative impacts upon product quality. Despite the industry making progress in the development of high-performance polymers and aqueous-based polymeric dispersions for the manufacture of MR dosage forms, using alcohol-resistant properties to develop MR formulations remains a challenge.
Dosaage consuming an MR product with alcohol, the MR mechanism can sometimes be adversely affected, which may result in alcohol dose dumping ADD. This type of dose dumping has the potential to cause serious adverse events, particularly for compounds such as opioids.
Despite their many benefits, there remains a limited number of experienced manufacturers across the pharmaceutical relesse. This block is broken or missing. You may be missing content or you might need to enable the original module. MR demand There are various factors driving the demand for MR systems. The benefits of these formulations include: Sustained blood level Attenuation of adverse effectsImproved convenience and patient compliance Protecting acid-sensitive drugs Iss advantages of MR pellet technology MR dosage forms can be separated into two forms: monolithic and multiple unit formulations.
Benefits of FDCs The application of FDCs is beneficial when a specific combination of APIs in a fixed ratio of doses is found to be safe, effective and facilitate the overall therapeutic effect for a patient population. Manufacturing MR pellets There are two key steps involved wuat the manufacturing process for MR pellets, depending upon the extended-release properties required.
Moving products to commercial scale using QbD and DoE When developing a MR dosage form manufacturers will initially define the target product profiled based on clinical needs. MR development challenges Despite the industry making progress in the development of high-performance polymers and aqueous-based polymeric dispersions for the manufacture of MR dosage forms, using alcohol-resistant properties to develop MR formulations remains a challenge.
Apr 16, · Modified Release Dosage Forms The term “modified release” means alteration in the release of the drug substance based on the time, course or duration. Modified-release (MR) formulations are in high demand. For formulators, they enable drugs to be released in the optimal gastrointestinal (GI) locations to achieve and maintain desirable plasma concentrations for extended periods, avoiding undesirable excursions outside the therapeutic range. For patients, MR formulations provide the convenience of infrequent dosing with potentially greater . Dec 16, · The modified release dosage forms have been formulated to ensure that the drug concentration is maintained at appropriate time intervals, simplify the dosing schedule, and to deliver the drug to that part of the body. It has several advantages as .
Issue: October Modified-release MR formulations are in high demand. For formulators, they enable drugs to be released in the optimal gastrointestinal GI locations to achieve and maintain desirable plasma concentrations for extended periods, avoiding undesirable excursions outside the therapeutic range. For patients, MR formulations provide the convenience of infrequent dosing with potentially greater efficacy and fewer side effects than similar, immediate-release delivery systems.
An impressive variety of MR formulations are possible, thanks to ongoing technological developments. Strategic selection of excipients and delivery technologies can yield MR formulations that fulfill very specific performance requirements, such as gastro-retention and sustained-, pulsatile-, or delayed-release formats. Nonetheless, throughout the past 20 years, the fundamental methodology for developing these formulations has stagnated. Initial formulations continue to be founded upon in vitro and preclinical test results, despite evidence that these data correlate poorly with pharmacokinetic PK drug performance in humans.
This methodology enables critical-to-performance formulation adjustments during clinical conduct, saving time and cost, and reducing risk in MR drug development. An ever-increasing number of polymers and formulation technologies allow finely tuned control of many aspects of drug release. However, managing all the variables and interpreting in vitro , preclinical, and available human clinical data to define a formulation strategy capable of achieving the desired PK performance is more difficult than many developers expect.
Accurate performance prediction is crucial because miscalculations in planning for development or manufacturing are costly and often cause delays. Certain polymers are better suited for sustained or delayed release and may be designed to deliver APIs to specific GI target areas, depending on physicochemical, biomechanical, and human physiological factors influencing the site of release.
The range of solid dosage forms offers further layers of complexity. This ever-expanding array of tools makes many MR modalities possible. Some options are shown in Table 1. Each delivery format has its own idiosyncrasies. In the first instance, understanding the target PK profile is crucial.
What plasma concentration time profile does the formulation need to deliver? Experience and expertise are then required to select and implement a rational formulation program based upon API characteristics, such as solubility, stability in stomach acid, particle size, and bioavailability.
Given these variables, being sure the formulation performs in vivo as it did in vitro can be challenging. A good CDMO will help developers find the best approach and select a technology to achieve the desired performance. Ultimately, how an MR delivery system will perform in humans is unknown until clinical PK data becomes available, no matter what the in vitro and preclinical data indicated.
Successful performance depends on an interplay between the drug molecule, the formulation, and the gastrointestinal environment. Despite their long-term, widespread use for this purpose, in vitro and preclinical studies cannot always be relied upon to predict how formulations will perform in humans. There are many reasons why animal studies are not necessarily predictive of how a drug will behave when administered to humans. The best model for a human is a human.
A traditional clinical investigation for developing an MR system would be to test fixed-formulation prototypes, such as a slow formulation, a fast formulation, and perhaps one in between based on in vitro and preclinical data, and hope one achieves the desired PK profile.
In contrast, using a design space concept will produce the required PK profile efficiently, in a single development cycle. The most obvious question when planning to develop an MR dosage form is: What is the starting composition and dose? In vitro dissolution studies are an invaluable tool to inform formulation development.
However, there is considerable uncertainty as to whether a fixed formulation that achieves the desired release rate in vitro will also deliver the required performance in humans. If the starting formulation misses the mark completely, a second clinical study with an adjusted starting formulation will be required, leading to escalating costs and time delays.
Fortunately, by implementing adaptive design strategies such as the design space DS approach, developers can mitigate this risk. The multidimensional combination and interaction of input variables e. The same principles, however, can be applied to early development to maximize the potential to optimize formulations within a single clinical study. Rather than specifying exact values for API and excipient contents, developers can set ranges for these critical-to-performance parameters in the regulatory application.
By varying the quantitative levels of these components during clinical conduct, product performance can be influenced and the formulation optimized based on human data. These DS ranges represent acceptable, safe limits based on toxicology studies and PK data collected earlier. Product quality is ensured through inclusion of technical batch data in regulatory documentation. An approval of a complete DS gives developers leeway to adjust formulations as needed within the pre-approved ranges during study conduct.
This freedom mitigates risk in MR formulations by giving the Phase I clinical trial process the best possible chance of achieving the desired drug delivery profile — without the need for repeat development cycles. The DS concept can be applied to any formulation, drug product, or dosage form.
The goal in MR formulations is to address all the adjustable, critical-to-performance parameters that can influence release rate and PK profile. While mapping two variables is common, it is possible to define the DS for as many as are relevant.
Extremes of release rate can be developed in vitro , and the corresponding critical parameter values may be used as the minimum and maximum values to define the DS — the corner points Figure 1. Any formulation within this map may be manufactured and dosed without any regulatory amendment or notification. As clinical results develop, trial medications will be adjusted accordingly to optimize the drug-release pattern and increase or decrease the dose as required.
The flexibility a DS concept affords is only beneficial to the extent that manufacturing can keep pace with the clinical trial dosing modifications. Seamlessly integrating a manufacturing facility with the clinical testing organization running the study can shrink the time between decision points and restart the trial with the next iteration of drug product Figure 2.
Overall benefits of applying this rapid formulation development and clinical testing approach on demand, as products evolve in the development cycle include the following:. Pharmaceutical development teams from more than 50 pharmaceutical and biotechnology companies worldwide have completed more than programs like this while developing optimized MR formulations for small molecule drugs across all major therapeutic areas. An attempt to develop an MR matrix tablet formulation by traditional methods failed to achieve the desired PK profile, and resulted in Cmax related adverse events and sub-optimal therapeutic levels.
During the development phase, technical batches with day stability data were produced for the four corners of the design space -— the extremes of each variable.
These batches were fully characterized using qualified analytical methods in support of the regulatory filing. Once the application was approved, the clinical PK study in healthy volunteers began, with an initial IR reference period followed by sequential, fasted trials. The initial prototype formulation, within the design space, was determined by PK modelling. Each set of emerging PK data drove selection of the next MR prototype, which was manufactured, quality control tested, and released for dosing without additional approval or stability studies, just days before the next test period.
This cycle ended when the PK profile fell within the desired range. Results are shown in Figure 3. One final round was conducted with fed study patients to test the food effect on the PK of the final formulation. Through the integration of formulation design space, real-time GMP manufacturing, and an iterative sequential pharmacokinetic study, an HPMC matrix tablet with desired PK characteristics was developed.
Human PK data guided formulation composition, eliminating the need to rely on surrogate, non-predictive laboratory or preclinical data. To succeed in applying design space concepts to de-risk and expedite clinical trials, scientific and regulatory expertise must go hand in hand. In-depth understanding of the evolving clinical trial regulatory environment will ensure the preparation of high-quality IND applications and institutional review board IRB submissions that will satisfy regulatory authorities.
The justification package must then provide the following:. To ensure the strongest possible dossier, a collaborative relationship with the IRB is extremely helpful. A CDMO with regulatory personnel who routinely present DS concepts is most likely to achieve a seamless submission and approval process for this type of Phase I clinical trial application — provided that the science and production are impeccable.
Successful day make-test cycles demand operational speed and excellence with strong project leadership to integrate clinical and manufacturing activities while managing logistics. Developing MR formulations that fit a target PK profile is far from simple, with many potential delivery technologies to select from and much uncertainty regarding performance in a physiological system.
Use of a DS concept saves time and removes uncertainty surrounding achieving the clinical performance of a formulation. With the flexibility to vary the formulation as the clinical trial progresses, a DS concept diminishes risk by increasing the likelihood that the desired PK profile will be achieved relatively quickly, without the need for additional regulatory approval.
An integrated operational set-up allows developers to take maximal advantage of DS concepts through the interplay of manufacturing and clinical testing. Through an iterative make-test cycle, a series of prototypes are rapidly reformulated based on emerging clinical data until the desired performance is achieved. This approach accelerates timelines and greatly diminishes the risk of failing to achieve the desired product.
Advantages of combining a DS approach with real-time, on-demand manufacturing include the following:. Enlisting help from a partner with extensive experience in design space, the regulatory expertise to gain approval for them, and the operational capacity to provide real-time manufacturing will ensure successful implementation. To view this issue and all back issues online, please visit www.
Previously, he was Director of Novel Drug Delivery Technologies at Ipsen France , where he had global responsibility for product development, utilizing novel formulation technologies or drug delivery devices. He has also assisted in the development and growth of two venture capital funded start-ups, RegenTec and Critical Pharmaceuticals. There he led the development and commercialization of novel technologies in the fields of tissue engineering and drug delivery, taking them from concept into clinical development.
Lewis has a particular interest in overcoming drug delivery challenges, including sustained release and transmucosal delivery of proteins and peptides, and he has filed a number of patents.
Click image to enlarge. Total Page Views: A poorly designed stability study can cause delays that extend to years, create significant budget overruns and even result in product failure.
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