Most Drugs Commercially Available Market Oral Dosage Form Biology Essay


Most of the drugs are commercially available in the market as oral dosage form because drug delivery via oral route is considered to be the most convenient and widely accepted by the community. An ideal oral dosage form drugs show continuous therapeutic action by maintaining the therapeutic plasma drug concentration in the system for a prolonged period of time. This constant level of the drug can be achieved by repeated administration of the drugs provided that patients follow the stringent regimen of the drug. The optimal patient compliance can be obtained when the therapeutic effect of the drug is sustained for the desired duration of time with the least frequency of administration (1). Over decades ago, the advancement of pharmaceutical sciences have given rise to development of modified release oral dosage form which was designed to control the manner of the drug release to meet those objectives above which include improved therapeutic effect and patient compliance (2).

Rationale for modified release oral dosage form

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Modified release oral dosage form was introduced because it showed therapeutics benefits and improve patient's quality of life. Controlled-release preparation generally simulate the intravenous infusion profile as it maintains a steady plasma drug level within a narrow window with the absence of sharp peaks and reduces the fluctuations in the drug and metabolite concentrations in the circulation, the tissues and the gastro-intestinal tract. This type formulation has an equivalent profile of the AUC of plasma concentration versus time curve with the total AUC of multiple dosing with conventional immediate release drugs which is illustrated in figure 1. This profile is responsible for the reduction of the possibility of developing side effects (3). Modified release dosage form allows the patient to administer only one tablet or capsule every 12 to 24 hours which will improve patient's compliance and convenience besides enable the patient to avoid night dosing. The lesser administration frequency of the drugs with modified release dosage form also decreases the costs of nursing time in the hospital which will then benefit other patients who are in need of nursing assistance. Hence, it can be concluded that modified release dosage form improve one's quality of life. Despite of all the advantages, there are still loopholes in modified release dosage form. Prolonged action preparation is not flexible as it is designed to last for a fixed period of time. Modified release oral dose is also susceptible to erroneous intake of the preparation. Some patient might unintentionally chew the tablets or capsule which will cause the drug to be released prematurely. The development of modified release oral dosage form is also influenced by the safety concern of 'dose dumping'. Dose dumping is an event at which the active ingredient of the drugs is released at high doses in a short period of time which my put the patient in the position of developing drug toxicity (4).

Figure 1: Profile of plasma drug concentration of immediate release formulation (- -) agaisnst a zero-order controlled-release formulation ( ___ ) (3)

Where MEC is the minimum effective concentration and MSC represents the maximum safe concentration

Methods of dosage form development

In order to study the variables which influence the modified release oral dosage form, it is paramount to understand the principles that are used in the development of modified release oral dose. Essentially, there are 4 types of principles that have been used to develop oral modified release dosage forms which are diffusion and/or dissolution control, ion exchange, repeat action and osmotic pressure. The method chosen for a particular formulation is dictated by the physicochemical and pharmacokinetics properties of the particular drug, the volume to be administered, and the economic, marketing and patient condition. The dosage forms are represented as either a tablet or a multiparticulate system which usually supplied in capsule form (5).

Most of the modified release oral dosage form in the market is based on the diffusion and/or dissolution control system. The drug release from its dosage form via diffusion can be described with Fick's Law as below:

Where Q = Quantity of drug, D = Diffusion constant, d = diffusion layer, A = area, C = concentration and t= Time (5)

For multiparticulate system which consists of coated particles filled into a capsule, these products maybe coated with water insoluble polymer, partially water-soluble membrane or pH dependent soluble membrane. However, in this study, the product of interest is uncoated products which are usually represented as tablets and are generally known as matrix system. A matrix system is a uniform homogenously mixture of drug, excipients and polymer that is fixed in a solid dosage form. Matrix can be classified according to the physicochemical nature of the matrix which are hydrophobic matrix, lipid matrix, hydrophilic, biodegradable and mineral matrix (5, 6). This study focuses on the hydrophilic matrix system as HPMC is chosen as the polymer for the matrix. Hydrophilic matrix system releases the drug through controlled matrix hydration which results in gel formation change in texture behaviour, followed by the erosion of the matrix, drug dissolution and finally the drug will diffuse out of the matrix into the targeted sites. These processes are dependent on the solubility and concentration of the drug and the changes in matrix characteristic as illustrated in figure 2 (7). The matrix is tabletted either by direct compression, compression granule or flaking process.

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Figure 2: Interrelationship between the gradient of water concentration against textural behaviour and concentration gradient of polymer or drug in a hydrophillic matrix system (7).

Ion exchange principle is however different from other system as it is independent of pH but dependent rather on the ionic environment of the gastrointestinal tract as resinous material is used as the agent of the matrix. Ion exchange principle can be explained by the Pennkinetic system in which the drug-resin complex is coated with a polymer and formulated as modified release dosage form. This type of formulation permits the diffusion of water through coating but does not allow the drug to migrate out into the suspension base. However, the ion in the gastrointestinal tract will permeate the coating and hence release the drug from its bound state into the circulatory system. Rate of drug release in ion exchange formulation is dependent on the thickness of the coating (5).

Repeat action method is usually used for soluble drugs as the drug will need to be completely released once the coat is broached. The drug release is dependent on the pH and gut action. Osmotic pressure method basically places the semi permeable membrane around the core that contains drug. The membrane will allow the transport of water via osmosis process into the core resulting in the formation of drug solution which will be pumped through the small orifice in the coating. In this system, the size of the delivery orifice is critical as to ensure for effective drug delivery the size of the orifice must be smaller than the theoretical maximum size but large enough to minimize the hydrostatic pressure inside the system (5).

Choice of polymer in modified release oral dosage form

Hydrophilic polymer matrix system has been widely used since the early 1960s in application of the oral controlled drug delivery because it is simple to formulate, easy to manufacture, cost-effective, has broad regulatory acceptance and has the ability to load the drugs with broad range of solubility (8). hydroxypropylmethylcellulose (HPMC) and polyethylene oxide are(PEO) are usually employed for the formulation hydrophilic matrix (7). HPMC is commonly used due to its favourable properties such safe, easy to manage, inexpensive, compactable, capable of loading large amount of drug and the drug release is least affected by the process variables (9). Due to the potential showed by HPMC in the modified release development, HMPC is chosen as the polymer in this study. HPMC is a derivative of cellulose which has cellulose backbone consisting of methoxylic and hydroxypropoxylic moieties substituted onto the glucose units. Pure cellulose has crystalline structure which makes it insoluble in water but however, the incorporation of substituents along the cellulose chain will breaks down the crystal structure and hence make it water soluble such as HPMC (9).

Commercially, there are various grades of HPMC depending on the molar mass and the extent of substitution and the manipulation of these two values is essential to ensure that the favourable gel layer thickness and release rate is obtained (10). Certain range of viscosities and average degree of substitution that must be achieved when formulating this type of dosage form has been stated by the pharmacopeia in order to standardised the grades of commercial HPMC used in the pharmaceutical industry. In modified released formulation that employs HPMC as the polymer, the rapid gel formation of HPMC around the tablet is responsible for the rate of drug release and the drug is released via 2 mechanisms depending on the solubility of the drugs. For water soluble drugs, the dosage form will undergo erosion and followed by the diffusion of the drug out of the gel layer, whereas only erosion of the gel is accountable for the release of poorly soluble drugs (11, 12).

In order to understand the design of HPMC modified release oral dosage form, it is important to understand the percolation theory. Percolation theory was introduced by Leuenberger et al. in 1987 to enhance the nature of solid dosage forms and this theory is based on the formation of clusters and site or bond percolation phenomenon. The system is described as lattice where the sites of this lattice are randomly occupied and if these sites are fully occupied, the neighbouring sites will form bonds at random and this is called as bond-percolation (13, 14). In optimizing the design of HPMC, it is essential to consider the percolation threshold. Percolation threshold is a point where there is maximum probability of development of an infinite or percolating cluster of a substance which can be explained as a group of neighbour-occupied sites in a lattice that extends from one side to the rest of the sides of the lattice and ultimately percolates the whole lattice. In order to design an optimal HPMC matrix system, the formulation must be beyond percolation threshold to allow formation of the infinite cluster which will control the hydration and rate of drug release (15).

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HPMC retards the release of drug by rapid gellation of HPMC at the surface of a matrix when it comes in contact with water. The formation of gel will control the passage of drugs into the release site via diffusion and the rate of release of the drug through this system is dependent on the square root of time and it follows Equation 2,

where Wr is the amount of drug dissolved, t is the timem, W0 represents the dose of the drug, S is the effective diffusional area, V is the ffective volume of the hydrated matrix and D' is the apparent diffusion coefficient of the drug in the hydrated matrix (16).

However, the soluble drug which is formulated in HPMC matrix system is release via erosion and diffusion process. Taking into account for these two release mechanisms, the kinetics of drug release from matrix is demonstrated by the mathematical models that have been developed by Korsmeyer et al. in 1983. This equation provides leeway for the effect of hydration, swelling and glass transition temperatures on release and ultimately illustrates that the release of drug from polymeric system follows a non-Fickian (anomalous) behaviour.

where M/M, is the fractional release of the drug, t is the release time, k is a constant incorporating structural and geometric characteristic of the release device and n is the release exponent indicative of the mechanism of release. This equation assumes that the drug is released immediately once the matrix is in contact with the fluid (12, 16).

This study uses paracetamol as the active ingredient in order to investigate the rate of release of the drugs in modified release oral dosage form. Paracetamol which has the pH value of 5.5-6.5 is the drug of choice as it is very soluble corresponding to the low value of log P, 0.49 and stable in the ordinary lab condition. Paracetamol is a non-steroidal anti-inflammatory drug (NSAID) and is the most frequently prescribed as analgesic and antipyretic agent in the relief of fever, headaches, and other minor aches and pains. Chemically, it is know as 4-hydroxy acetanilide (acetaminophen) (17) (18).

Factors affecting dissolution test of modified release oral dose

Drug dissolution testing is a fundamental part of pharmaceutical products development and manufacturing as it is often employed to guide and assessed the design of new formulation based on in vitro dissolution rates. It is also has been used extensively as a quality control tool to assess the robustness and uniformity of manufacturing batches and minimized batch-to-batch variation. Dissolution test has been used as a quality control device due to its ability in indentifying the crucial manufacturing variables variations which influence the quality of the tablets such as the effect of binder, mixing, granulation procedure, coating parameters, and excipients type (19-21). In 1970s, USP method was introduced to carry out the dissolution tests and the significance of this test is based on the fact that drugs must present in form of solution in order to be absorbed and available to the systemic circulation. The dissolution test does not only identify the variability in the manufacturing processes but can also be used as an in vivo surrogate, provided that it is under strictly defined conditions. This vivo surrogate is used to determine the efficacy of the drug in vivo and identify potential problems of drug release and absorption in human body which will then potrays the bioavailibility of a drug product in humans (20, 21) (22).

Making an allowance for the role and effectiveness of drug dissolution testing in therapeutic development, it is essential to ensure that the test is accurate and reproducible. Hence it is our utmost concern to identify the variability sources that lead to the variation of dissolution testing result. Variation in the results could affect the competency and dependency of dissolution test as the in vivo surrogate in determining the safety and efficacy of a drug product. Eventhough, the success in relating the in vitro test results to in vivo nature of the drug which corresponds to the bioavailbility of the drug remains ambiguous, the in vitro test is still required and necessary (20) (22).

Many studies have discussed and presented that there are different factors that can affect the rate of drug release from a hydrophilic matrix system such as such as physicochemical properties of the polymer and drug, concentration of the polymer and drug, drug:polymer ratio, type and quantity of excipients and variability of the USP apparatus (14, 23, 24)  In a research lab, HPMC is often kept in uncontrolled conditions and the container is often exposed to the environment due to the frequent opening of the lid of the container. Theoretically, the water residual is capable of interacting with HPMC that is present as solid when it is exposed to atmosphere and this association will then affect the physical, chemical, and pharmaceutical properties of the formulation. The modification in the pharmaceutical properties of the formulation such as the glass transition temperature, stability, powder flow, compaction, and dissolution rate will have significant impact on the rate of drug release (24). A study by Nokhodchi et al. showed that there was an increase in the particle size which resulted on the reduction in the amount of internal absorption and in increase in the amount of external adsorption when different grades of HPMC is placed in three locations of moisture (24).However, there is no further explanation on the effect of moisture on the rate of drug release from the matrix. USP apparatus has been used widely as in vivo surrogate for drug dissolution testing as it is considered to be accurate, precised and robust. However, the hydrodynamics aspect of the apparatus remains complex and inconsistent on different side of the vessel. The hydrodynamics variability will alter the apparent diffusion boundary layer thickness and hence significantly influence the dissolution rate. Hydrodynamics variability is often contributed by the variation in paddle and vessel conditions. In order to obtain precise results of in vitro rate of drug release of modified release oral dosage, it is essential to understand the hydrodynamics aspect of the USP apparatus. (25)

The objective of this study is to investigate the effect of 3 storage conditions (high humidity, uncontrolled, and unopened container) on the rate of erosion, gel formation and drug release rate. Secondly, the study will also look into the effect of damaged vessel and pedal speed on the rate of drug release; and finally, to explore the association of the erosion rate and gel formation with the rate of drug release.