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Coated pellets as oral drug delivery systems
Introduction
Nowadays, the discovery of new Active Pharmaceutical Ingredients (API) is more and more difficult due to the complexity and the lack of financing. So, the pharmaceutical companies develop new pharmaceutical technologies for existing molecules to improve the bioavailability and the delivery system. That is why, controlled release dosage forms have gained much attention and on the pharmaceutical market their number has increased these last years due to their temporal and spatial control of drug release. Indeed, compared to the conventional dosage forms, they offer many therapeutic benefits:
The increase of therapeutic effect
Improvement of treatment efficiency
Minimization of side effects
The reduction of administration
The increase patient convenience and compliance
Controlled release systems aim to control the kinetic of the API released from the dosage form in time. Moreover, they are capable of achieving different therapeutic effects and they can include mainly delayed release (e.g. enteric coated tablet) and sustained release (coated pellets) compared to an immediate release (figure 1) (Hong and Kinam, 2010).
To obtain a controlled release rate over time, drug delivery systems based on polymers are usually used and their functionalities are determined by the polymer properties. They can be separated in two groups: (i) matrix systems where the API is dispersed within the polymeric matrix (figure 2 a); (ii) reservoir systems where the drug is surrounded by a polymeric film controlling the drug release. The drug can be included into the core or surrounded on the inert core (figure 2 b).
• Matrix systems
A drug is dissolved or dispersed in a polymeric network to obtain a matrix system with a controlled drug release. These devices provide several advantages such as the easy-manufacture, the low cost and the capacity for incorporating a high amount of API. Various types of matrix systems can be achieved and thus the drug release mechanisms will be different. The drug release will occur due to diffusion from homogeneous matrix, or diffusion through the pores and/or by swelling and/or erosion from heterogeneous matrix.
• Reservoir systems
In this case, the API is layered around an inert core or incorporated into a water-soluble excipient matrix, the whole surrounded by a coating layer. According to the polymer properties, the drug release mechanisms and so release profiles will be different. Reservoir systems can be divided as having either:
– A non-constant activity source where the API concentration in the reservoir is below its solubility, so all the drug is dissolved and drug molecules that are released through the membrane are not replaced and so the concentration will decrease with time (first order in vitro drug release profiles).
– A constant activity source where an excess of API is present and drug molecules released are quickly replaced by dissolution of the remaining non-dissolved drug. Therefore, the drug release remains constant as long as enough excess of drug is available (zero order in vitro drug release profiles).
Once in contact with aqueous gastro-intestinal fluids, water penetrates into these systems and dissolves the drug. In the case of constant activity sources, only a part of the API is dissolved due to its low solubility. In the other case, all drugs are rapidly dissolved. Then, the drug molecules diffuse through the polymeric film by concentration gradient. Different mass transport processes occur: water diffusion, drug dissolution, its diffusion, the swelling of the polymer chains, their dissolution and/or degradation. Frequently, drug diffusion is the slowest step and therefore rate controlling, so the drug release can be characterized by mathematical models. This simplification is not always acceptable depending of the system. Certainly, an attention must be paid to potential crack formation that might occur during dissolution test. The penetration of water into the device leads to an internal hydrostatic pressure acting against the membrane. If this latter is too fragile to resist, some cracks can occur and the drug will be released by diffusion both, through the intact film and through the cracks. In addition, this created pressure might also generate a convective drug transport through the pores. The crack formation is more common when the API is highly water-soluble and the mechanical stability of the film is poor (Siepmann et al., 2012) (Lee and Li, 2010).
In this project, the studies are based on a reservoir system, the coated pellets. As defined by Ghebre-Sellassie, pellets are solid and spherical particles with a size distribution between 500 and 1500 µm reserved for oral applications (Ghebre-Sellassie I., 1989). They have generally a smooth surface, a high density and an excellent flowability (Palugan et al., 2015). The latter are coated to act as a reservoir system where the drug release is controlled on specific site according to the therapeutic activity desired. Coated pellets can be administrated in the form of hard gelatin capsules or compacted in tablets (Dashevsky et al., 2004b) while retaining their advantages of multiple-unit dosage forms (figure 3). Indeed, one of the advantageous of pellets is due to the subdivision of the total amount in several units. Its allows a distribution of the delivered dose on an extended surface area, thus decreasing the risk of dose dumping and some irritations of the mucosa (Palugan et al., 2015).
Active pharmaceutical ingredients
During this research project, different active substances have been used as model drugs to investigate the release characteristics and to compare the influence of the API properties on the drug release profiles. So, the physicochemical properties of the drugs have an impact on the kinetics and mechanisms of the drug release.
• Propranolol hydrochloride
Propranolol hydrochloride (figure 4) is a non-selective beta adrenergic blocking agent used for the treatment of hypertension, angina pectoris, arrhythmias and many cardiovascular diseases.
Figure 4: Structural formula of propranolol hydrochloride (Pubchem, 2016a).
Propranolol hydrochloride belongs to the class 1, drugs with high solubility and high permeability in agreement with the biopharmaceutical classification system (BCS) (Eddington et al., 1998). The chemical and physical properties are mentioned in the table 1 (Pubchem, 2016a) (Vogelpoel et al., 2004) (Huang et al., 2004).
In addition, propranolol hydrochloride is a weakly basic drug with a solubility modified by the pH of the release medium. Therefore, propranolol hydrochloride is chosen as a model drug for our reservoir system and it is an appropriate candidate for formulating controlled release dosage forms due to its short half-life (Bolourchian and Dadashzadeh, 2008).
• Theophylline
Theophylline (figure 5) is a xanthine derivative mainly used as a bronchodilator for the treatment of asthma, bronchitis and emphysema.
Theophylline has a high solubility and high permeability (BCS – class 1) (Amidon et al., 1995). Some chemical and physical properties are summarized in table 2 (Pubchem, 2016b) (Dashevsky et al., 2010).
Furthermore, theophylline has a constant solubility in a wide range of pH values. An attention must be paid with this molecule as it has a narrow therapeutic range. Theophylline is selected as a model drug for the preparation of coated pellets to be compared to propranolol HCl as the water solubilities of the two molecules differ significantly.
Table of contents :
RÉSUMÉ DÉTAILLÉ
CHAPTER I: INTRODUCTION
I. Coated pellets as oral drug delivery systems
I.1. Introduction
I.2. Excipients for controlled release pellets
I.2.1. Active pharmaceutical ingredients
I.2.2. Polymers
I.2.3. Additives
I.3. Formulation of coated pellets
I.3.1. Preparation of starter core
I.3.2. Polymer coating
I.3.3. Equipment and process parameters for coated pellets manufacturing
II. The underlying drug release mechanisms with coated pellets
II.1. Diffusion
II.2. Osmotic effects
II.3. Parameters influencing the drug release
III. Characterization methods of solid dosage forms
III.1. Analytical method
III.2. Imaging methods
IV. Objectives of this work
CHAPTER II: MATERIALS AND METHODS
I. Materials
II. Methods
II.1. Pellets coated with Kollicoat SR 30 D
II.1.1. Free polymeric films
II.1.2. Coated pellets
II.2. Diprophylline loaded pellets and tablets coated with a polymer blend Aquacoat ECD 30 and Eudragit NM 30 D.
II.2.1. Free polymeric films
II.2.2. Coated pellets
II.2.3. Coated tablets
CHAPTER III: RESULTS AND DISCUSSION
Part I: Systems with ruptured film coatings
I. Propanolol HCl layered microcrystalline cores
II. Propranolol-HCl layered sugar cores
III. Comparison MCC cores versus sugar cores
III.1. Unexpected tendencies observed with propranolol HCl layered sugar cores coated with Kollicoat SR 30 D
III.2. Unexpected tendencies when increasing the drug loadings from propranolol HCl layered MCC cores coated with Kollicoat SR
IV. Impact of the type of API on drug release from pellets coated with Kollicoat SR
V. Elucidation of the underlying drug release mechanisms from pellets coated with Kollicoat SR
Part II: Diffusion controlled system
I. Formulation and design of coated pellets
II. The study of the drug release mechanisms
III. Formulation and design of coated tablets
GENERAL CONCLUSION AND PERSPECTIVES
SUMMARY
PUBLICATIONS & PRESENTATIONS RESULTING FROM THIS WORK
