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Recent pharmaceutical research yeomatrix focused on controlled drug delivery having an advantage over conventional methods. Adequate controlled plasma drug levels, reduced side effects as well as improved ggeomatrix compliance are some of the benefits that these systems may offer.
Controlled delivery systems that can provide zero-order drug delivery have the potential for maximizing efficacy while minimizing dose frequency and toxicity. Thus, zero-order drug release is ideal in a large area of drug delivery which has therefore led to the development of various technologies with such drug release patterns.
Systems such as multilayered tablets and other geometrically altered devices have been created to perform this function. One of the principles of multilayered tablets involves creating a constant surface area for release.
Polymeric materials play an important role in the functioning of these systems. Technologies developed to date include among others: This review discusses the novel altered geometric system technologies that have been developed to provide controlled drug release, also focusing on polymers that have been employed in such developments.
Modified or controlled release oral drug delivery systems have, over the last few decades, been shown to offer advantages over conventional systems [ 1 — 6 ]. These include increased patient compliance [ 78 ], selective pharmacological action; reduced side-effect profile and reduced dosing frequency [ 9 ].
These systems may therefore have a significantly beneficial outcome in therapeutic efficacy. Controlled release offers prolonged delivery of drugs and maintenance of plasma levels within a therapeutic range [ 1011 ]. Furthermore, by pairing drug administration rate with drug elimination rate, steady-state plasma levels can be maintained [ 1213 ].
Currently most drug delivery systems exhibit first-order drug release kinetics where the plasma level of the drug is extremely high after administration and then decreases exponentially.
This poses disadvantages such as minimal therapeutic efficacy due to reduced drug levels; or drug toxicity which can occur at high concentrations [ 14 ].
This type of drug release does not allow for appropriate plasma drug level balance. Peak-to-trough fluctuations as depicted in Figure 1 may occur with first-order drug release that may cause dose dependent side effects [ 1516 ]. Plasma drug concentration versus time profile exhibiting the effect of zero-order drug release on plasma drug levels adapted from Shahiwala et al. Drug delivery systems should ideally exhibit zero-order drug release kinetics which allows for a constant quantity of drug to be released over an extended period of time, resulting in uniform and sustained drug delivery [ 217 — 21 ].
Zero-order is a desired drug release kinetic in antibiotic delivery, the treatment of hypertension, pain management, antidepressant delivery and numerous other conditions that require constant plasma drug levels [ 142223 ].
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Thus, various studies have been undertaken attempting to develop systems that are easily able to provide zero-order or near zero-order drug release [ 24 — 31 ]. The utilization of geometric principles have for many years been considered and employed in order to modify drug release behavior from non-linear to zero-order or near zero-order release geomztrix [ 32 — 38 ].
Thus far researchers have attempted to control dissolution behavior of drug delivery systems by modifying and controlling the geometry of the employed devices e.
One of the principles involved in altering the geometry of tablets is to create a constant surface area for drug release to enable the achievement of zero-order kinetics [ 4243 ]. These geometric manipulations may also be employed to develop drug delivery systems for the treatment of specialized biological conditions where zero-order drug release is geomatfix optimal, for example chronotherapy for heart conditions [ 46 ] or the scheduled treatment of asthma and inflammation [ 47 ].
Bimodal drug release may also be desirable with drugs that have variable absorption sites along the gastro-intestinal tract [ 1248 ]. In addition, the polymeric materials used to construct these technologies play an important role in the functioning of these specialized systems [ 4041 ]. Thus far, various types of polymers have been investigated for their ability to control drug release [ 50 ]. Polymers are the essential drug carriers of multilayered matrix tablets and their properties are an important factor in the behavior of these devices.
In the past, polymers that were mainly employed for such purposes were the hydropolymers [ 40 ], while currently polymers investigated range from swollen and non-swollen gsomatrix 40 gechnology, 51 ], porous and non-porous [ 52 — tdchnology ] to erodible or non-erodible polymers [ 555 ].
In general, the technilogy by which polymers perform their functions are by erosion [ 56 ], dissolution and swelling [ 57 ].
Some studies have shown that drug release from hydrophilic polymer matrices exhibit a typical time dependent profile in which the drug tschnology is controlled ensuring swelling of the polymer [ 58 — 62 ]. This review thus discusses geoatrix application of altered geometric technology and its role in controlled oral drug delivery, focusing primarily on the types of polymers that have been employed in developing geometrically modified systems, the interplay of system geometry and polymeric selection ultimately contributing to the type of drug release patterns that are attained.
Mutilayered systems bilayered, triple-layered, quadruple-layered, etc. These systems have been shown to be advantageous over typical tablet systems as depicted in Table 1. Namdeo expressed that multilayered tablets have demonstrated promise, possessing various benefits, namely the ability to prevent interactions between drugs and excipients; techbology by providing an array of release profiles in one delivery system twchnology either the same or different drugs, treatment for conditions that require a regimen of more than one drug, immediate drug release using egomatrix disintegrating monolithic matrix in order to achieve an initial peak in plasma drug level, delayed drug release using an eroding monolithic matrix which may technologyy another active drug to a different part of the gastrointestinal tract, providing controlled drug release instituting a swellable monolithic matrix and better control and regulation of release profiles geomattrix retarding initial burst release and achieving zero-order kinetics [ 64 ].
It would be beneficial if research focused on further modification of these systems for improved and comprehensive drug release capabilities that enable a larger scope of application in drug delivery. Advantages of multi-layered tablets over conventional tablets Adapted from Namdeo [ 64 ]. Controlled-release multilayered tablets typically involve a drug core layer that is surrounded by barrier layers that may be techmology up of hydrophilic swellable polymers such as hydroxypropylmethylcellulose HPMC and poly ethylene oxide PEO or hydrophobic polymers such as ethylcellulose EC [ 4 ].
The barrier layers minimize and therefore delay the interaction of the gastrointestinal environment with the active core, by decreasing the surface area available for drug release or by controlling the rate at which the solvent penetrates the layers ggeomatrix 40 ]. This allows the initial burst release to be minimized and therefore the drug release can be controlled at a near constant level while the barrier layers undergo erosion or swelling [ 5 ].
The swollen barrier layers undergo erosion as time goes on, thus increasing the surface area which ultimately allows gsomatrix drug to be released. Following the same principle, it is possible to obtain a constant release profile as well as other types of dissolution patterns such as pulsatile or delayed delivery as well as extended drug delivery depending on the characteristics of the polymers employed.
In either case the system should ideally geomatri completely i. The different types of multilayered tablet designs with varying drug release behaviors are shown in Figure 2 [ 65 geoatrix. There are multilayered tablets that can provide zero-order sustained release where the tablet consists of either a hydrophilic or hydrophobic core layer with barrier layers that are press coated to the surfaces of the core layer.
This leaves the sides of the core layer exposed. It has been shown that generally constant drug release can be achieved when both barrier layers are hydrophilic and technnology core layer is hydrophobic [ 425 ]. However, other factors also need to geomafrix controlled in order to achieve zero-order drug release.
Various polymeric formulations of multilayered tablets and possible drug release behavior adapted from Chidambaram et al. The technology includes triple-layered and bilayered tablets. The triple-layered tablet which is exemplified in Figure 3 consists of an active core which is a hydrophilic matrix layer and two polymeric barrier layers on either side that are hydrophobic trchnology semi permeable [ 6667 ].
The bilayered tablet consists of the drug layer and one barrier layer [ 68 ]. The barrier layer modifies the swelling rate of the active core and reduces the surface area available for diffusion of drug [ 69 — 70 geomatrrix.
The technology essentially leads a pursatile drug release where the drug is released in pulses that are separated by defined time intervals. They provide a once-daily pulsed profile that offers the patient efficacy throughout the day negating the need for taking the dose during working hours unlike the twice-daily dosing of the conventional immediate release tablet [ 71 ].
The earlier described studies have provided practical technical ideas in the development of multilayered tablets depending on gematrix clinical applications of these systems. The studies have also provided insight on what strategies need to be considered twchnology further application. Table 2 provides the summary of the polymers influencing the behavior and release characteristics of multilayered tablets.
Summary of the type of polymers influencing the behavior and release characteristics of multilayered tablets. It is observed that there are great variations of multilayered tablet technology proving flexibility which affords possibilities for positive research development. With the intuitive selection of polymers and the appropriate employment of geometric principles, multilayered tablets may emerge as the future benchmark for the treatment of chronic diseases.
However the difficulties that may occur with the scale up of more intricate layered drug delivery systems may be considered to be unfavorable to the pharmaceutical industry. The necessity of specialized equipment may add to the difficulties in commercialization of these systems. Generally, a multilayered system should initially swell, then gel and ultimately slowly geomartix [ 472 ].
A study done by Efentakis and co-workers investigated the effect of polymeric substances on drug release.
The study focused on a core tablet that contained venlafaxine HCl and Methocel KM as the drug carrier. Bilayered and triple-layered tablets were prepared using the core tablet. The bilayered tablet consisted of a core tablet where one surface was covered with either Cellulose Acetate Phthalate CAP or Methocel E50LV, while both surfaces of the core tablet were covered with both of the polymers to form the triple-layered tablets [ 40 ]. Hydrophilic polymers were employed as drug core matrices due to their swelling ability [ 73 — 76 ].
The release profiles obtained demonstrated that drug release was slower from the multilayered tablets than from the core tablet alone [ 40 ]. When the core tablet came into contact with the dissolution medium, it swelled and expanded. This caused an increase in the diffusion path length for the drug and the drug release rate was therefore reduced. Upon employing HPMC as a barrier layer, the layer swelled concurrently with the core tablet, merging the core surfaces thereby enveloping part of the core, which resulted in the limiting of drug transport through the barriers [ 40 ].
CAP did not swell due to its impermeability and therefore drug dissolution and the drug release rate was retarded. Generally, HPMC devices presented with slower drug release when compared to CAP devices, the reason being that they form a more efficient and solid barrier.
Overall, the study showed that the characteristics of the polymers employed had a significant influence on the release profiles of the tablets although the choice of polymers employed in the study was conservative. Further research that focuses on the use of novel specialized polymers that are competent in providing zero-order drug release is necessary. A study performed by Chidambaram and co-workers assessed the behavior of layered diffusional matrices for zero-order sustained drug release.
Three different types of matrices were formulated. In the first type, the two barrier layers were hydrophilic, in the second type, one of the barriers was hydrophobic while the other was hydrophilic and in the third type, the two barrier layers were both hydrophobic [ 65 ]. Results showed that more desirable linear release profiles were obtained with the first and second type of matrices as depicted in Figure 2a,dwhile the barrier layers in the third system needed to be manipulated in order to achieve zero-order release kinetics [ 2565 ].
The proposed mechanism for the zero-order drug release from the first type of matrix was that as the hydrophilic barriers swelled and eroded, the rate of diffusion of drug tecbnology the hydrophobic middle layer decreased [ 65 technolkgy, 77 ]. According to the study, the release rate from the lateral surface was influenced by polymer viscosity and concentration. These factors ultimately influence diffusion path length as well as the diffusion co-efficient. The use of polymers that possess mechanical or chemical characteristics to intrinsically alter the geometry, via modification of the diffusion path length, of matrices for controlled release may be an interesting perspective to study for future drug delivery research.
A study undertaken by Efentakis and co-workers illustrated that the structure of a system plays an important role in its drug release geomatrid.
Oral Drug Delivery Systems Comprising Altered Geometric Configurations for Controlled Drug Delivery
They found that covering a larger area of the core tablet by a barrier layer results in the retardation of drug release to a greater extent, as it forms a more efficient barrier thereby decreasing the drug release rate [ 40 ]. Another study by Efentakis and Peponaki re-iterated the significance of structure and geometry of triple-layered tablets with isosorbide mononitrate as a model drug.
The weight and thickness of the barrier layers also had a pivotal role in drug release behavior [ 70 ]. Chidambaram and co-workers established that drug release from the surfaces of the core was dependent on the thickness of the hydrophilic barrier layers [ 65 ]. An investigation by Streubel and co-workers looked at bimodal drug release from multilayered matrix tablets.
It was discovered that by increasing the weight of the barrier layers from 50 mg to mg it resulted in a more effective retardation of drug release, thus it was concluded that by manipulating the weight and thickness of the outer layers as shown in Table 2 a desirable drug release profile of individual drugs may be achieved, thus complementing their pharmacokinetic behavior [ 69 ].
The concept of barrier layers have proven to be beneficial in multilayered tablet designs; however converting the barrier layers into additional controlled release drug matrices may hold further potential for future application [ 64 ]. Zerbe and co-workers have shown that there are also complex multilayered tablet systems with layers of various shapes that are able to provide zero-order drug release.
The triple layered tablet is composed of a drug core that has a specific shape. The core is enclosed between two rapidly erodible outer layers. The middle layer has a biconcave shape that the two outer layers tightly bond to after compression.