Wednesday, April 6, 2011

CONTROLLED RELEASE: Challenges and New Technologies of Oral Controlled Release

Significant advances have been attained in developing and commercializing oral controlled release products. Many platforms are available for delivering small molecule drugs with good aqueous solubility in prolonged or delayed release forms.
However, there are significant challenges in developing controlled release formulations for drugs with poor aqueous solubility, which require both solubilization and engineering of release profile. To deliver drugs at zero-order release rate, preferably independent of the gastrointestinal (GI) tract environment, many efforts and achievements have been made besides osmotic pump drug delivery systems.
Moreover, many of the new therapeutics under development are large molecules like peptides, proteins, oligonucleotides, and vaccines. Their physical, chemical, and biopharmaceutical attributes, distinct from small molecule drugs, demand novel controlled-release technologies to diminish barriers for oral delivery like instability in the GI tract and poor absorption. Those unmet technology needs create great opportunities for research, development, and innovation. Breakthroughs in controlled oral delivery for water-insoluble drugs and biopharmaceuticals are likely to have a significant impact on the pharmaceutical and biotechnology industries.
On the other hand, the continuous improvement of current delivery technologies is also important when it comes to decreasing cost and increasing efficiency. Those advancements include novel excipients, processes, and equipment as new tools formulation scientists can use to develop oral controlled-release formulations.

Oral Controlled Delivery for Water-Insoluble Drugs

Table 16.1
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With few exceptions, for small molecule drugs, drug products have to be dissolved in GI fluids in order to be absorbed. For a water-insoluble drug, the absorption and bioavailability could be restricted by dissolution rate and solubility in the GI tract. There are many established approaches to formulating water-insoluble drugs as oral dosage forms.
Strategies include salt formation, microenvironmental pH control, solubilization by surfactants, complexation with cyclodextrins, solid dispersion, lipid-based formulation, and nanoparticles formulation (Table 16.1). A strategy is chosen based on the molecular and physical properties of a drug. For a water-insoluble drug, substantial formulation and process development are necessary to formulate a drug product with enhanced bioavailability.
Developing a controlled-release formulation for a water-insoluble drug is very challenging. A controlled oral delivery may be needed to achieve prolonged exposure or time-based release under certain circumstances. This approach could improve efficacy, reduce side effects, or achieve a more desirable dose regimen. However, many platforms for controlled release have been established for drugs with acceptable aqueous solubility. (These platforms have been thoroughly reviewed in previous chapters.) The release rate of a soluble drug in a solid dosage form is slowed down in a certain mode to achieve controlled release. It is clear that direct plug-in of current matrix-based or coating-based delivery systems without technology fabrication will fail to achieve acceptable controlled release of a water-insoluble drug. On the other hand, in vitro dissolution methods based on a sink condition generated by surfactants may provide misleading correlation for in vivo behaviors.
A combination of solubilization and release modulation is needed to achieve controlled release for a water insoluble drug. If a drug can be solubilized by a surfactant or a complex agent, inclusion of a solubilizing agent in polymer-based matrix tablets may provide a solution. Rao and colleagues studied the matrix tablet formulation of prednisolone, a sparingly water-soluble drug, using sulfobutylether-b-cyclodextrin (SBEBCD) as a solubilizing agent. SBEBCD promotes a sustained and complete release in a hydroxypropyl methylcellulose-based tablet formulation.1 Another study also demonstrated that SBEBCD worked as a solubilizing agent and an osmotic agent for controlled porosity osmotic pump pellets of prednisolone.2 A complete and sustained release of prednisolone has been observed.
It is clear that direct plug-in of current matrix-based or coating-based delivery systems without technology fabrication will fail to achieve acceptable controlled release of a water-insoluble drug.
It has been reported that controlled release felodipine tablets have been effectively prepared using Poloxamer as a solubilizing agent and Carbopol as a controlled release matrix.3 Many drugs need more complicated formulation approaches to enhance the dissolution, such as amorphous solid dispersion, emulsion, microemulsion, self-emulsifying, and nanoparticles. Among these, amorphous solid dispersion is the most popular approach to enhancing solubility and dissolution.
There are numerous publications about the development of controlled release formulations of water-insoluble compounds using solid dispersion as a solubilization approach. For a solid dispersion, drug molecules are stabilized in a high-energy state with hydrophilic polymers such as polyethylene glycol, polyvinyl povidone, and polyvinyl alcohol. Solid dispersions could be prepared by spray drying or melting extrusion. Mehramizi reported that an osmotic pump tablet of glipizide has been developed using glipizide/polyvinylpyrrolidone dispersion as the core, where the solid dispersion enhanced the solubility and ensured the complete release.4
Figure 16.1: Proposed mechanism of drug release from DCMT
Figure 16.1: Proposed mechanism of drug release from DCMT.6
Hong and Oh studied the dissolution kinetics and physical characterization of three-layered tablets of nifedipine solid dispersion with poly(ethylene oxide) matrix capped by Carbopol.5 They discovered that the swelling and morphological change of Carbopol layers minimized the release of rapidly erodible PEO200K (MW 200,000) and changed the nifedipine release to a diffusion-controlled process. However, the physical stability of solid dispersions must be monitored for polymer-based matrix systems, membrane coatings, or osmotic systems during prolonged release. All three approaches need water to diffuse inside formulation to solubilize drugs and advance the release. Drugs may crystallize out during the prolonged exposure to water due to supersaturation inside dosage form or change of glass transition temperature because of interaction with water.
Nanoparticle formulation can be used to formulate poorly soluble drugs to enhance bioavailability. The drug dissolution rate is increased due to the increase of surface area. However, little literature exists regarding the controlled release of poorly soluble drugs with nanoparticles as carriers. It is thought that an erosion-based system may be more suitable because drug solubility is not changed. Diffusion-controlled matrix or membrane coating system is challenging to achieve the goal.

New Designs for Desired Release Profiles

Many formulation designs have been pursued to achieve controlled release and minimize the impact of the GI environment. Osmotic pump drug delivery systems pioneered by Alza have many proven successes in those two areas, as covered in previous chapters. The disintegration-controlled matrix tablet (DCMT) and erodible molded multilayer tablet by Egalet take an erosion approach and show some promise. On the other hand, bioadhesive polymers offer advantages in improving gastroretentive delivery and enhancing localized therapy in the GI tract. Moreover, significant progress has been made in the use of computer modeling to design controlled-release formulations.
Disintegration-Controlled Matrix Tablet: The DCMT is an erosion-based controlled-release platform. It was developed for the sustained release of solid dispersions by Tanaka and colleagues.6-7 DCMTs contain hydrogenated soybean oil as the wax matrix, with solid dispersion granules uniformly distributed in the wax. The solid dispersion granules are formulated with low-substituted hydroxypropylcellulose as a disintegrant.
Figure 16.2: Plasma concentration profiles of nilvadipine after oral administration of DCMTs to beagle dogs under fasting condition.
Figure 16.2: Plasma concentration profiles of nilvadipine after oral administration of DCMTs to beagle dogs under fasting condition.
Drug release is controlled by the process of tablet erosion. The wax only allows the penetration of water to the surface layer of the tablet, water triggers the swelling of the disintegrant on the surface, and, subsequently, tablet erosion results in the separation of solid dispersion granules from the tablet. A constant rate of tablet disintegration/erosion can be achieved by repeating the processes of water penetration and swelling/separating of solid dispersion granules (Figure 16.1).
DCMT has been successfully applied to the sustained-release formulation of nilvadipine, a poorly soluble drug with an aqueous solubility of 1 mg/mL.6 The release profile of nilvadipine from DCMT has been modified by balancing the amount of wax and disintegrant. The wax matrix prevented water penetration into the tablet and ensured the amorphous state of solid dispersion during the dissolution process. Sustained-release profiles of nilvadipine from DCMT were nearly identical in several dissolution media with varying pH and agitation speed. An in vivo study in dogs revealed that DCMTs successfully sustained the absorption of nilvadipine without reducing the bioavailability compared with IR coprecipitate tablets (Figure 16.2).7 The results suggest that DCMT is able to achieve the complete dissolution and absorption of a poorly water-soluble drug by maintaining the physical stability of solid dispersion in the GI tract.
Erodible Molded Multilayer Tablet (Egalet): Similar to DCMTs, Egalet’s erodible molded tablet is an erosion-based platform. It has the advantage of delivering zero-order or delayed release with minimal impact from gastrointestinal conditions. Egalet’s is a more sophisticated engineered delivery system, however, with erosion occurring in one dimension, while DCMT erosion takes place in all three dimensions. It is obvious that Egalet could achieve a better zero-order release. Drug is dispersed in the matrix, and the release is controlled by the rate of erosion in the tablet’s two ends. The surface area for erosion is constant.
Figure 16.3: Egalet delivery for a zero-order release.
Figure 16.3: Egalet delivery for a zero-order release.
Egalet erodible molded multilayered tablets are prepared by injection molding (IM).8 As shown in Figure 16.3, a tablet produced using Egalet technology has a coat and a matrix. Drug release is controlled through the gradual erosion of the matrix part. The mode and rate of release are designed and engineered by altering the matrix, the coat, and the geometry to achieve either a zero-order release or a delayed release. For a zero-order release, a drug is dispersed through the matrix. The coat is biodegradable but has poor water permeability to prevent its penetration. The matrix tends to erode when in contact with available water.
The erosion of the matrix is caused by GI fluids and promoted by gut movements in the GI tract. The drug release is mediated almost wholly by erosion, because the dosage form is designed to slow down the water diffusion into the matrix. The method is definitely more desirable for drugs that have chemical and physical stability issues after contacting with water. For example, if the drug is solubilized as a solid dispersion and the solid dispersion tends to crystallize after interacting with water, the erosion-based delivery will ensure the drug’s stability. It is clear that the Egalet-based delivery system is suitable for the controlled delivery of water-insoluble compounds. The unique delivery system will also prevent hydrolysis and reduce luminal enzymatic activity.
The Egalet delivery system is easily fabricated for delayed release. Delayed release is gaining popularity for the enhancement of local effect or chronotherapy.
As illustrated in Figure 16.3, the release rate of Egalet prolonged release is dependent on the erosion rate and drug concentration. It is clear that a zero-order release can be easily achieved with a uniform drug concentration in the matrix and a constant erosion rate. The erosion rate could be tailored by altering the composition of the matrix. For example, addition of polyethylene glycol could speed up the erosion.9 The in vivo erosion rate may be affected by GI mobility, however. Due to the erosion-controlled delivery, the burst release effect should be minimized in the Egalet system.
On the other hand, the Egalet delivery system is easily fabricated for delayed release. Delayed release is gaining popularity for the enhancement of local effect or chronotherapy. The release of drug is delayed for a certain period of time in the GI tract and released in a bolus dose or a designated modified release. One area of delayed release where this is applicable is in achieving colonic delivery for some therapeutic agents. On the other hand, the delayed release may provide the advantages of a time release. The release of the drug can be timed to match the natural rhythms of a disease, such as the morning stiffness and pain experienced by arthritis patients on waking.
A delayed release can be accomplished through three compartment tablets, including a coat, a drug release matrix, and a lag component. The lag component provides a predetermined delay for the drug release. After the lag component is eroded, the release drug is initiated in a designed mode as depicted in Figure 16.4. Egalet delivery technology is developed based on standard plastic injection molding to ensure accuracy, reproducibility, and low production cost. It is being actively evaluated for the development of numerous controlled-release formulations by various companies.
Bioadhesive Oral Delivery: Bioadhesive delivery could be applied to oral controlled release. Bioadhesive polymers tend to adhere to the mucin/epithelial surface and find applications in buccal, ocular, nasal, and vaginal drug delivery. These polymers could also help increase the residential time of solid dosage forms in the GI tract to improve gastroretentive delivery. On the other hand, bioadhesive polymers enable oral dosage forms to stay close to the epithelial layer and allow the quick flux of drugs after dissolution. Oral absorption or localized therapy could be improved if the disease is in the GI tract.
Bioadhesion is an interesting phenomenon that involves the attachment of a synthetic or biological polymer to a biological tissue.10 Adhesion can occur either with the epithelial cell layer or with the mucus layer. Adhesion to the mucus layer—namely, mucoadhesion—is more applicable to oral delivery. The GI tract is covered by a layer of mucus. Polymers containing hydrogen bonding groups tend to bind to the mucus layer. The mechanism of mucoadhesion is not fully understood, but it is thought that attraction forces such as hydrogen bonding, van der Waals, and charges bring polymers into close contact with the mucus. This contact further promotes the penetration of polymers and formulation of entanglements with the mucin. Many natural polymers and pharmaceutical ingredients show bioadhesive properties. Those polymers are carbomers, chitosan, starch, polymethacrylic acid, hydroxypropylcellulose, hydroxypropyl methylcellulose, and sodium carboxy-methylcellulose. Bioadhesive polymers could be formulated with drugs in monolithic or multiparticulate forms to achieve controlled release.
Figure 16.4: Egalet delivery for a delayed release
Bioadhesive delivery could benefit the controlled release of drugs with narrow absorption windows. Many drugs have a narrow absorption window from the proximal part of the GI tract due to transporter-mediated absorption. Increasing residence time in the upper GI tract could extend and enhance the absorption. It has been reported that mucoadhesive microspheres of acyclovir made from ethylcellulose and Carbopol achieved a better bioavailability than a suspension formulation.11 The mucoadhesive micro-spheres had an AUC0–t of 6055.7 ng h/mL and a mean residence time (MRT) of 7.2 hours, whereas the suspension had an AUC0–t of 2335.6 ng h/mL and an MRT of 3.7 hours. Combination of bioadhesive polymers with another mechanism might improve the degree of success of gastroretention, a challenging goal to achieve. Chavanpatil and colleagues have discussed the development of a novel sustained-release, swellable, and gastroretentive drug delivery system with additional bioadhesive properties for ofloxacin.12
Varshosaz and colleagues reported the design and in vitro test of a bioadhesive and floating drug delivery system of ciprofloxacin.13 Bioadhesive delivery is advantageous in providing sustained release for localized therapy. Deshpande and colleagues published a study about the design and evaluation of oral bioadhesive-controlled release formulations of miglitol, intended for the prolonged inhibition of intestinal a-glucosidases and the enhancement of plasma glucagon like peptide-1 levels.14 Pectin-based microspheres for the colon-specific delivery of vancomycin have been developed by Bigucci and colleagues.15 The microspheres made of pectin and chitosan show desirable mucoadhesive properties.


  1. Rao VM, Haslam JL, Stella VJ. Controlled and complete release of a model poorly water-soluble drug, prednisolone, from hydroxypropyl methylcellulose matrix tablets using (SBE)(7m)-beta-cyclodextrin as a solubilizing agent. J Pharm Sci. 2001;90(7):807-816.
  2. Sotthivirat S, Haslam JL, Stella VJ. Controlled porosity-osmotic pump pellets of a poorly water-soluble drug using sulfobutylether-beta-cyclodextrin, (SBE) 7M-beta-CD, as a solubilizing and osmotic agent. J Pharm Sci. 2007;96(9):2364-2374.
  3. Lee KR, Kim EJ, Seo SW, et al. Effect of poloxamer on the dissolution of felodipine and preparation of controlled release matrix tablets containing felodipine. Arch Pharm Res. 2008;31(8):1023-1028.
  4. Mehramizi A, Alijani B, Pourfarzib M, et al. Solid carriers for improved solubility of glipizide in osmotically controlled oral drug delivery system. Drug Dev Ind Pharm. 2007;33(8):812-823.
  5. Hong SI, Oh SY. Dissolution kinetics and physical characterization of three-layered tablet with poly(ethylene oxide) core matrix capped by Carbopol. Int J Pharm. 2008;356(1-2):121-129.
  6. Tanaka N, Imaia K, Okimoto K, et al. Development of novel sustained-release system, disintegration-controlled matrix tablet (DCMT) with solid dispersion granules of nilvadipine. J Control Release. 2005;108 (2-3):386-395.
  7. Tanaka N, Imai K, Okimoto K, et al. Development of novel sustained-release system, disintegration-controlled matrix tablet (DCMT) with solid dispersion granules of nilvadipine (II): in vivo

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