Sustained release/ Extended release/ Modified release/ Controlled release drug formulation is a most critical formulation for a pharmacist. That's why before going to formulate such product few factors should be considered -
Hydrophilic Polymer Matrix
A hydrophilic matrix, controlled-release system is a dynamic one involving- polymer wetting, polymer hydration, gel formation, swelling, and polymer dissolution. At the same time, other soluble excipients or drugs will also- wet, dissolve, and diffuse out of the matrix while insoluble materials will be held in place until the surrounding polymer/excipient/drug complex erodes or dissolves away.
- Soluble drug is released primarily by diffusion through the gel layer.
- Insoluble drug is released primarily through tablet erosion.
The mechanisms by which drug release is controlled in matrix tablets are dependent on many variables:
Polymer Level:
There must be sufficient polymer content in a matrix system to form a uniform barrier. This barrier protects the drug from immediately releasing into the dissolution medium. If the polymer level is too low, a complete gel layer may not form. In most studies, increased polymer level in the formulation results in decreased drug-release rates.
Based on studies examining the effect of substitution on release rate from hydrophilic matrix tablets, K-chemistry results in the slowest release compared to other polymers of similar molecular weight.
Gelation and Polymer/Polymer Coalescing:
A fast rate of hydration followed by quick gelation and polymer/polymer coalescing is necessary for a rate-controlling polymer to form a protective gelatinous layer around the matrix. This prevents the tablet from immediately disintegrating, resulting in premature drug release. Fast polymer hydration and gel layer formation are particularly critical when formulating with water-soluble drugs and water-soluble excipients.
Molecular Weight and Viscosity:
It is generally accepted that drug dissolution from tablets is slower for higher molecular weight HPMC polymers. However, there have been several instances in the literature that report no difference in release for different molecular weights. But the higher molecular weight polymer did increase the lag (hold-up) time before establishment of quasi-steady state.
In separate experiments on molecular weight of the polymer, they saw the usual trend in drug release rates: K100 LV >> K4M > K15M » K100M
Viscosity/Concentration Relationships and Blending:
The effects of polymer concentration and viscosity on drug-release rates are interrelated. For example, suppose a formulation had been developed using 25% METHOCEL K4M Premium HPMC, which gave a desired release profile. A similar release profile can be achieved in one of two ways.
First, METHOCEL K4M could be replaced with a lower viscosity polymer, for example, METHOCEL K100 Premium LV, used at some higher concentration. Second, a blend of METHOCEL K100 Premium LV and K4M Premium could be prepared to produce the same drug-release rate as the system with 25% METHOCEL K4M Premium.
Effect of Polymer Particle Size:
The particle size of HPMC polymer can greatly influence polymer performance in the hydrophilic matrix. Fractions of HPMC polymers with smaller particle size have more surface area relative to equivalent weights of fractions with larger particle size. The greater surface area provides for better polymer-water contact, thus increasing the overall rate at which complete polymer hydration and gelation occurs. This leads to the more effective formation of the protective gel barrier so critical to the performance of hydrophilic matrix tablets.
Level and Particle Size of Drug:
In most studies, increased drug concentration leads to increased drug-release rates. In a few cases, increased drug concentration leads to decreased drug-release rates. One possible explanation for the latter behavior is the effect of drug-HPMC interactions. In general there was little effect of drug particle size on drug release.
Drug Solubility:
Higher solubility of the drug generally leads to faster release. To make exact comparisons, very detailed data are needed regarding dissolution rates, drug solubility, diffusion coefficients, pH dependence of solubility, and drug-polymer interactions. Higher solubility drugs release at faster rates in most examples because their diffusional driving force would be highest.
A study suggested that- the behavior of hydrophilic matrices falls into three regimes determined by the solubility of the drug, the amount of drug present in the tablet, and the resulting porosity (interspace volume) of the matrix.
Effects of Fillers/Diluents:
The effect of fillers on drug release is dependent on the drug substance, the polymer level, and the level of the filler itself in the hydrophilic matrix tablet. The “average” release of drug from the matrices containing the insoluble fillers was somewhat longer than when the soluble fillers were used.
Effects of Binders (Direct Compression):
One useful excipient for direct compression is microcrystalline cellulose (MCC). It is now available in a wide variety of grades, differing in parameters such as mean particle size, particle size distribution, density, and moisture.
MCC may function in some formulations as a binder and/or disintegrant, depending on the level. MCC exhibits disintegrating properties at levels as low as 10%. In a formulation, the highest level (12.5%) of MCC was most likely acting as a strong tablet binder to decrease tablet porosity, and thus slow drug release.
Granulation:
Direct compression is not always feasible for hydrophilic matrix formulations containing METHOCEL products. In these cases, wet and dry granulation technologies can provide better product flow on tablet presses, overall improved tablet physical characteristics, uniform drug content within the dosage form, and fewer industrial hygiene constraints.
Lubricants:
Lubricants are added to reduce sticking to the punch faces and to allow easy ejection of the tablet during tablet formation. The obvious concern here is that over lubrication could lead to coating of this hydrophobic material on the surfaces of the tablet and thereby retard release.
Modifying Internal pH:
For drugs with pH dependent solubility, an obvious strategy to alter the dissolution profile is to modify the microenvironment near the drug to increase solubility. Release rate was modulated by the addition of acidic and basic modifiers such as citric acid, p-toluenesulfonic acid, glycine, and tris-hydroxymethyl aminomethane (THAM).
Modifying Drug Solubility:
The use of cyclodextrins to encapsulate and enhance the solubility of insoluble drugs is an active area of pharmaceutical research. Cyclodextrins may be used in conjunction with HPMC. For example, Conte and co-workers have shown that diazepam encapsulated in hydroxypropyl ß-cyclodextrin is released at a fairly constant rate from matrices.
Modifying Drug Release with Other Polymers:
Other natural or semisynthetic polymers may be used in some circumstances to modify the drug-release profile. The two most commonly used polymers are sodium carboxymethylcellulose and sodium alginate. Sodium alginate is protonated at low pH and contributes to gel structure, but is in a more soluble and erodible form at higher pH. Mixtures of HPMC and sodium alginate have been used with drugs that have a pH-dependent solubility in order to obtain a more pH-independent release.
Combinations of HPMC and sodium carboxymethylcellulose (NaCMC) have been extensively studied for many years. With certain water-soluble drugs, a blend of appropriate grades of HPMC and NaCMC may minimize the release of drug during the initial phase of the release profile. This tends to “flatten” the shape of the release profile, i.e., produce a more “zero order”release. The explanation for this effect is not clear; many researchers have cited a synergistic interaction between HPMC and NaCMC.
Drug/HPMC/Excipient Interactions:
The interaction of HPMC with other molecules present in the formulation or in the medium is complex. A number of recent studies have shown this for even the simplest case, the interaction of HPMC and water. In these partially hydrated regions, the “concentration” of the drug, other excipients, water, and species from the medium may be relatively high, creating a condition favorable to interaction with HPMC. Interactions between drugs and HPMC that negatively impact polymer hydration are relatively rare.
Effects of Tablet Dimensions:
It is widely accepted that the release from HPMC matrix tablets occurs by one of two means, either diffusion of dissolved drug or release due to matrix erosion. Higuchi proposed that the amount of drug release of a soluble drug uniformly dispersed in a homogenous matrix is proportional to the unit area of exposed matrix surface.
Rekhi et al. examined the effect of surface area on the release of metoprolol tartrate from matrix tablets containing METHOCEL K100 Premium LV. A standard concave tablet and a caplet shape tablet were used to examine the effect of surface area on metoprolol tartrate release. The surface areas for the standard concave and caplet shape tablets were 3.7 and 4.8 cm2, respectively, and the release for the caplet shape tablet was faster due to its larger surface area. They normalized the release profile for the caplet shape with respect to the caplet tablet surface area and obtained a calculated release profile similar to the concave shape.
They also proposed another means of using tablet surface area to manipulate release profiles for different tablet dimensions by controlling the dose/surface area ratio. The release profile for a tablet containing 100 mg of metoprolol tartrate and having a surface area of 0.568 sq. in. (366.5 sq. mm) was similar to those of a tablet containing 50 mg and surface area of 0.284 sq. in. (183.2 sq. mm).
Advances in modified release drug delivery systems:
A) Bilayer tablets: Consists of two layers- first layer releases the drug via immediate release and second layer provides controlled release. This can also be used to formulate dosage form containing two incompatible APIs.
B) Multiparticulate systems: The APIs are coated with different concentrations of polymer for individual particle of API achieving different release pattern and improving the patient compliance.
C) Nanotechnology: This technology is on the boom. Liposomes, nanoparticles, SMEDS(Self Micro Emulsifying Delivery Systems) , SEDS(Self Emulsifying Delivery Systems) are emerging drug delivery systems for achieving modified release pattern.
D) Inserts/Bot system: Variety of machines containing API or use of nanobots containing API can be place at the target site and then machine will allow pulsatile drug delivery systems.
E) Hydrogels: These are 3D crosslinked networks of water soluble proteins. The degree of crosslinking inside the hydrogel will control the release pattern for the drug.
