Controlled release drug delivery system

pre-master research

1. Controlled release drug delivery system

2. Introduction Every drug molecule needs a delivery system to carry the drug to the site of action upon administration to the patient. Delivery of the drugs can be achieved using various types of dosage forms including { tablets, capsules, creams, ointments, liquids, aerosols, injections, and suppositories }. Most of these conventional drug delivery systems are known to provide immediate release of the drug with little or no control over delivery rate. To achieve and maintain therapeutically effective plasma concentrations, several doses are needed daily, which may cause significant fluctuations in plasma levels.

3. Introduction Because of these fluctuations in drug plasma levels, the drug level could fall below the minimum effective concentration ( MEC ) or exceed the minimum toxic concentration ( MTC ). Such fluctuations result in unwanted side effects or lack of intended therapeutic benefit to the patient. Sustained-release and controlled-release drug delivery systems can reduce the undesired fluctuations of drug levels, thus diminishing side effects while improving the therapeutic outcome of the drug.

4. Introduction The terms sustained release and controlled release refer to two different types of drug delivery systems, although they are often used interchangeably: Sustained-release dosage forms are systems that prolong the duration of the action by slowing the release of the drug, usually at the cost of delayed onset and its pharmacological action. Controlled-release drug systems are more sophisticated than just simply delaying the release rate and are designed to deliver the drug at specific release rates within a predetermined time period.

5. Controlled release drug delivery system

6. Controlled release drug delivery system Design and development of controlled/sustained release delivery systems have been used to prolong the proprietary status of drug products. A typical example is modifying an existing drug product that requires several doses a day to a single daily dosing to maintain the dominance over generic competition.

7. Controlled release drug delivery system Advantages of controlled release drug delivery systems include: Delivery of a drug to the required site. Maintenance of drug levels within a desired range . Reduced side effects. Fewer administrations. Improved patient compliance. Disadvantages of using such delivery systems include: Possible toxicity of the materials used. Dose dumping. Requirement of surgical procedures to implant or remove the system. Higher manufacturing costs.

8. Controlled release drug delivery system For some drugs, controlled delivery is necessary, since immediate release dosage forms cannot achieve the desired pharmacological action. These include: Highly water soluble drugs that need slower release and longer duration of action. Highly lipophilic drugs that require enhancement of solubility to achieve therapeutic level. Short half-life drugs that require repeated administration. Drugs with nonspecific action that require the delivery to target sites.

9. Controlled release drug delivery system An ideal drug delivery system should deliver precise amounts of a drug at a preprogrammed rate to achieve a drug level necessary for treatment of the disease. For most drugs that show a clear relationship between concentration and response, the drug concentration will be maintained within the therapeutic range, when the drug is released by zero-order rate.

10. Controlled release drug delivery system In order to design a controlled release delivery system, many factors must be considered such as: Physicochemical properties of the drug. Route of drug administration. Pharmacological and biological effects.

11. PHYSICOCHEMICAL PROPERTIES OF DRUG

12. PHYSICOCHEMICAL PROPERTIES OF DRUG Physicochemical properties play a major role in biological effectiveness of a drug such as: Solubility. Stability. Lipophilicity. Molecular interactions. Solubility is a measure of the amount of solute that can be dissolved in the solvent.

13. PHYSICOCHEMICAL PROPERTIES OF DRUG For a drug to be absorbed, it must first dissolve in the physiological fluids of the body at a reasonably fast dissolution rate. Drug molecules with very low aqueous solubility often have lower bioavailability because of the limited amount of dissolved drug at the site of absorption. In general, drugs with lower than (10 mg/mL) in aqueous solutions are expected to exhibit low and erratic oral bioavailability.

14. PHYSICOCHEMICAL PROPERTIES OF DRUG Once the drug is administered, biological fluids that are in direct contact with a drug molecule may influence the stability of the drug. Drugs may be susceptible to both chemical and enzymatic degradation, which results in a loss of activity of the drug. Drugs with poor acidic stability, when coated with enteric coating materials, will bypass the acidic stomach and release the drug at a lower portion of the gastrointestinal (GI) tract. Drugs can also be protected from enzymatic cleavage by modifying the chemical structure to form prodrugs .

15. PHYSICOCHEMICAL PROPERTIES OF DRUG The ability of a drug to partition into a lipid phase can be evaluated by the distribution of drug between lipid and water phase at equilibrium. A distribution constant, the partition coefficient K , is commonly used to describe the equilibrium of drug concentrations in two phases. The partition coefficient of a drug reflects the permeability of the drug through the biological membrane and/or the polymer membrane. Commonly, the partition coefficient is determined by equilibrating the drug in a saturated mixture of octanol (lipid phase) and water.

16. PHYSICOCHEMICAL PROPERTIES OF DRUG Drugs with a high partition coefficient can easily penetrate biological membranes, as they are made of lipid bilayers, but are unable to proceed further because of a higher affinity to the membrane than the aqueous surroundings. Drugs with a low partition coefficient can easily move around the aqueous areas of the body, but will not cross the biological membranes easily.

17. Route of drug administration

18. Oral rout of administration The oral route is most widely utilized route because of its ease of administration and the large surface area of the GI tract (200 m2). The presence of microvilli makes this the largest absorptive surface of the body (4500 m2).

19. Oral rout of administration The challenges of oral administration are : Short GI transit time. Extreme acidic ph. Abundant presence of digestive enzymes. First-pass metabolism in the liver. Several products were designed to prolong the retention time of a drug in the gastrointestinal tract. A hydro dynamically balanced drug-delivery system (HBS) is designed to prolong gastric residence time of the drug. This dosage form is also called floating capsules or tablets because of this characteristic.

20. parenteral rout of administration Another commonly used route for drug delivery is parenteral administration. The routes used for parenteral therapy include: Intradermal. Subcutaneous. Intravenous. Intracardiac. Intramuscular. Intraarterial. Intrasynovial.

21. parenteral rout of administration Parenteral administrations offer immediate response , in such situations as cardiac arrest or shock, and good bioavailability for drugs that undergo degradation by digestive enzymes in the GI tract. The disadvantages of parenteral administrations are difficulty of administration, requirement of sterile conditions, and cost of manufacturing.

22. Transdermal rout of administration Skin, with surface area of 2m 2 , is a commonly used route for drug delivery. Advantages of the transdermal route include: Avoidance of the first-pass effect. Potential of multiday therapy with a single application. Rapid termination of drug effects. Easy application of medication in an emergency.

23. Transdermal rout of administration The limitations are: Skin irritation and/or sensitization. Variation of intra and inter individual percutaneous absorption efficiency. The limited time that the patch can remain affixed. Higher cost.

24. Pharmacological and biological effects

25. Pharmacological and biological effects Pharmacological and biological effects are important in the design of the drug delivery systems. Biological factors, such as {age, weight, gender, ethnicity, physiological processes, and disease state} , will change the pharmacokinetics and pharmacodynamics of a drug. For example: 1- Dosing newborn infants requires caution because of their immature hepatic function and higher water content in the body. 2- Geriatric patients may suffer from reduced sensitivity of certain receptors that may lead to insensitivity to certain drugs .

26. Pharmacological and biological effects 3- It has been found that different ethnic groups respond to drugs differently. Ex: Diuretics and calcium channel blockers are recommended as first-line therapy in hypertensive Black patients, while beta blockers work better for Caucasian patients. 4- Pathological changes may influence the distribution and bioavailability of the drug by altering the physiological process. Ex: Decrease kidney and/or liver functions will affect the clearance of many drugs .

27. Types of controlled release drug delivery system

28. Types of controlled release drug delivery system PRODRUG. DIFFUSION-CONTROLLED DELIVERY SYSTEMS. DISSOLUTION/COATING-CONTROLLED DELIVERY SYSTEMS. BIODEGRADABLE/ERODIBLE DELIVERY SYSTEMS. OSMOTIC PUMP. ION EXCHANGE RESINS. HYDRO DYNAMICALLY BALANCED DELIVERY SYSTEMS. NEW MACROMOLECULAR DELIVERY APPROACHES.

29. PRODRUG

30. PRODRUG The molecule with the most potent form does not always have the desired physicochemical properties needed for drug dissolution and/or absorption. In fact, of all the pharmaceutically active ingredients, 43% are sparingly water soluble or insoluble in water. In the prodrug approach for drug delivery, active ingredients are chemically modified by connecting specialized functional groups that will be removed in the body after administration, releasing the parent molecule. These latent groups are used in a transient manner to change the properties of the parent drug to achieve a specific function, e.g., alter (permeability, solubility, or stability) .

31. PRODRUG After the prodrug has achieved its goal, the functional group is removed in the body ( enzymatic cleavage or hydrolysis ) and the parent compound is released to elicit its pharmacological action.

32. PRODRUG The prodrug approach has been used for one or more of the following reasons: To change half-life. To cross a biological barrier. To increase retention time. To target a specific site.

33. PRODRUG A- To change half-life: Half-life is defined as the time required by the biological system for removing 50 % of administered drug. Drugs with very short half-life may not be therapeutically beneficial unless this characteristic is improved. Attaching the drug to a polymer as part of a pendent will enhance its half-life. Modification of the drug to protect the site of degradation or metabolism is another method to achieve longer half-life. B- To cross a biological barrier: Drugs with unbalanced hydrophilic or hydrophobic properties will not effectively cross the biological barriers. Attachment of functional groups can change the properties of the parent drug and allow the prodrug to cross the barrier.

34. PRODRUG C- To increase retention time: When intended for a part of the body with high tissue turnover rate, such as intestinal mucosa, a drug linked to a ( muco -adhesive polymer ) can increase adhesion to the site and increase bioavailability of a drug that has low residence time. D- To target a specific site: Connecting specialized functional groups that have site-specific affinity ( peptide, antibody, etc . ) Can allow the parent drug to be delivered to the targeted area of the body to produce site specific therapeutic action.

35. DIFFUSION-CONTROLLED DELIVERY SYSTEMS

36. DIFFUSION-CONTROLLED DELIVERY SYSTEMS Diffusion process has been utilized in design of controlled release drug delivery systems for several decades. This process is a consequence of constant thermal motion of molecules, which results in net movement of molecules from a high concentration region to a low concentration region. The rate of diffusion is dependent on { temperature, size, mass, and viscosity of the environment }. Molecular motion increases as temperature is raised as a result of the higher average kinetic energy in the system. where E = kinetic energy k = Boltzmann’s constant T = temperature m = mass v = velocity

37. DIFFUSION-CONTROLLED DELIVERY SYSTEMS This equation shows that an increase in temperature is exponentially correlated to velocity (v2). Size and mass are also significant factors in the diffusion process. At a given temperature, the mass of molecule is inversely proportional to velocity. Larger molecules interact more with the surrounding environment, causing them to have slower velocity. Accordingly, large molecules diffuse much slower than light and small particles. Diffusion is fastest in the gas phase, slower in the liquid phase, and slowest in the solid phase.

38. DIFFUSION-CONTROLLED DELIVERY SYSTEMS According to the diffusion principle, controlled-release drug delivery systems can be designed as a reservoir system or a matrix system. Drugs released from both reservoir and matrix type devices follow the principle of diffusion, but they show two different release patterns as shown.

39. DIFFUSION-CONTROLLED DELIVERY SYSTEMS In a reservoir system , if the active agent is in a saturated state, the driving force is kept constant until it is no longer saturated. For matrix systems , because of the changing thickness of the depletion zone, release kinetics is a function of the square root of time. A typical reservoir system for transdermal delivery consists of a backing layer , a rate-limiting membrane , a protective liner , and a reservoir compartment . The drug is enclosed within the reservoir compartment and released through a rate-controlling polymer membrane.

40. DISSOLUTION/COATING-CONTROLLED DELIVERY SYSTEMS

41. DISSOLUTION/COATING-CONTROLLED DELIVERY SYSTEMS Controlled release of drug from delivery systems can also be designed by enclosing the drug in a polymer shell or coating . After the dissolution or erosion of the coating, drug molecules become available for absorption. Release of drug at a predetermined time is accomplished by controlling the thickness of coating . In this systems, drug molecules are enclosed in beads of varying thickness to control the time and amount of drug release. The encapsulated particles with thin coatings will dissolve and release the drug first , while a thicker coating will take longer to dissolve and will release the drug at later time .

42. DISSOLUTION/COATING-CONTROLLED DELIVERY SYSTEMS Coating-controlled delivery systems can also be designed to prevent the degradation of the drug in the acidic environment of the stomach, which can reach as low as pH (1.0). Such systems are generally referred as enteric-coated systems . In addition, enteric coating also protects the stomach from ulceration caused by drug agents. Release of the drug from coating controlled delivery systems may depend upon the polymer used. A combination of diffusion and dissolution mechanisms may be required to define the drug release from such systems.

43. BIODEGRADABLE/ERODIBLE DELIVERY SYSTEMS

44. BIODEGRADABLE/ERODIBLE DELIVERY SYSTEMS Biologically degradable systems contain polymers that degrade into smaller fragments inside the body to release the drug in a controlled manner. Zero-order release can be achieved in these systems as long as the surface area or activity of the labile linkage between the drug and the polymeric backbone are kept constant during drug release.

45. BIODEGRADABLE/ERODIBLE DELIVERY SYSTEMS Another advantage of biodegradable systems is that: when formulated for depot injection, surgical removal can be avoided. These new delivery systems can protect and stabilize bioactive agents. enable long-term administration. have potential for delivery of macromolecules.

46. OSMOTIC PUMP

47. OSMOTIC PUMP This type of delivery device has a semipermeable membrane that allows a controlled amount of water to diffuse into the core of the device filled with a hydrophilic component. A water-sensitive component in the core can either dissolve or expand to create osmotic pressure and push the drug out of the device through a small delivery orifice, which is drilled to a diameter that correlates to a specific rate.

48. OSMOTIC PUMP In an elementary osmotic pump, the drug molecule is mixed with an osmotic agent in the core of the device. For drugs that are highly or poorly water soluble, a two compartment push-pull bilayer system has been developed, in which the drug core is separated from the push compartment. The main advantage of the osmotic pump system is that constant release rate can be achieved , since it relies simply on the passage of water into the system, and the human body is made up of 70% water.

49. OSMOTIC PUMP The release rate of the device can be modified by changing: The amount of osmotic agent. Surface area and thickness of semipermeable membrane. The size of the hole.

50. ION EXCHANGE RESINS

51. ION EXCHANGE RESINS The ion exchange resin system can be designed by binding drug to the resin. After the formation of a drug/resin complex, a drug can be released by an ion exchange reaction with the presence of counter ions. In this type of delivery system, the nature of the ionizable groups attached determines the chemical behavior of an ion exchange resin.

52. ION EXCHANGE RESINS First-generation ion-exchange drug delivery systems had difficulty controlling the drug release rate because of a lack of control of exchange ion concentration. The second-generation ion-exchange drug delivery system (Penn kinetic system) made an improvement by treating the drug-resin complex further with an impregnating agent such as polyethylene glycol 4000 to retard the swelling in water. These particles are then coated with a water-permeable polymer such as ethyl cellulose to act as a rate-controlling barrier to regulate the drug release.

53. Hydro dynamically balanced drug delivery systems

54. Hydro dynamically balanced drug delivery systems Hydro dynamically balanced drug delivery systems have great potential as controlled-release drug delivery systems. They allow increased penetration of the mucus layer and therefore may increase drug concentration at the site of action. These systems can reside in the stomach for several hours, so in this way they significantly prolong the gastric residence time of drugs resulting in improvement of the dissolution as well as bioavailability of the drugs that are poorly soluble in a high pH environment. These systems are also used for local delivery of drugs to the stomach and proximal small intestine.

55. Hydro dynamically balanced drug delivery systems Gastro retention property helps to provide better availability of new products with new therapeutic possibilities and benefits for patients. Lots of attempts have been made to develop hydro dynamically balanced delivery systems, { Swelling, floating, high-density, and muco -adhesive systems } have been developed to increase gastric retention time of the dosage forms. Various factors may affect the gastric retention time of the drug delivery systems, such as: Density of dosage form. Gender. Posture. Age. Gastric ph. Size of dosage form. Food intake and nature of food, motility of intestine

56. NEW MACROMOLECULAR DELIVERY APPROACHES

57. NEW MACROMOLECULAR DELIVERY APPROACHES “polymerized liposomes” The advances in biotechnology have introduced many proteins and other macromolecules that have potential therapeutic applications. These macromolecules bring new challenges to formulation scientists, since the digestive system is highly effective in metabolizing these molecules, making oral delivery almost impossible, while parenteral routes are painful and difficult to administer. A potential carrier for oral delivery of macromolecules is polymerized liposomes. Liposomes are lipid vesicles that target the drug to selected tissues by either passive or active mechanisms.

58. NEW MACROMOLECULAR DELIVERY APPROACHES “polymerized liposomes” Advantages of liposomes include: Increased efficacy and therapeutic index. Reduction in toxicity of the encapsulated agent. Increased stability via encapsulation. One major weakness of liposomes is the potential leakage of encapsulated drugs due to the stability of liposome. Unlike traditional liposomes, the polymerized liposomes are more rigid because of cross-linking and allow the polymerized liposomes to withstand harsh stomach acids and phospholipase. This carrier is currently being tested for oral delivery of vaccines.

59. NEW MACROMOLECULAR DELIVERY APPROACHES “pulmonary rout” Pulmonary route is also being utilized as route for delivery of macromolecules. The lung’s large absorptive surface area of around 100 m2 makes this route a promising alternative route for protein administration. Drug particle size is a key parameter to pulmonary drug delivery. To reduce the particle size, a special drying process called glass stabilization technology was developed. By using this technology, dried powder particles can be designed at an optimum size of 1 to 5 μm for deep lung delivery.

60. NEW MACROMOLECULAR DELIVERY APPROACHES “pulmonary rout” Advantages of powder formulation include: Higher stability of peptide and protein for longer shelf life. Lower risk of microbial growth. Higher drug loading compared to liquid formulation. Liquid formulations for accurate and reproducible pulmonary delivery are now made possible by technology which converts large or small molecules into fine-particle aerosols and deposits them deep into the lungs. The device has a drug chamber that holds the liquid formulation and upon activation, the pressure will drive the liquid through fine pores creating the micro size mist for pulmonary delivery.

61. NEW MACROMOLECULAR DELIVERY APPROACHES “Transdermal needleless injection “ Transdermal needleless injection devices are another candidate for protein delivery. The device propels the drug with a supersonic stream of helium gas. When the helium ampule is activated, the gas stream breaks the membranes that hold the drug. The drug particles are picked up by a stream of gas and propelled fast enough to penetrate the stratum corneum ( the rate-limiting barrier of the skin ). This delivery device is ideal for painless delivery of vaccine through the skin to higher drug loading. Limitations to this device are the upper threshold of approximately(3 mg) and temporary permeability change of skin at the site of administration.

62. NEW MACROMOLECULAR DELIVERY APPROACHES “Transdermal needleless injection “

63. NEW MACROMOLECULAR DELIVERY APPROACHES “Transdermal needleless injection “

64. NEW MACROMOLECULAR DELIVERY APPROACHES “Transdermal needleless injection “ An alternative way to penetrate the skin barrier has been developed utilizing thin titanium screens with precision micro projections to physically create pathways through the skin and allow for transportation of macromolecules. Another example of macromolecular delivery is an implantable osmotic pump designed to deliver protein drugs in a precise manner for up to 1 year . This implantable device uses osmotic pressure to push the drug formulation out of the device through the delivery orifice.

65. NEW MACROMOLECULAR DELIVERY APPROACHES “Smart skin patch “ Drug-delivery systems that can dispense a continuous flow of therapeutics, without having to rely on the patient to physically take the drug. These systems don't monitor a patient's vitals, this means they can't be responsive. So when a patient needs to take a stronger dose or when they actually feel pretty good, they still receive the same continuous flow of whatever drug they're on. The scientists have come up with Nature Nanotechnology , dermal patch that not only dispenses drugs continuously, but also has the ability to determine when it's time to stop.

66. NEW MACROMOLECULAR DELIVERY APPROACHES “Smart skin patch “ HEAT-ACTIVATED SILICA NANOPARTICLES. The patch consists of a 2-inch-long rectangle made of stretchable nanomaterials. The materials contain heat-activated silica nanoparticles that monitor muscle activity and release therapeutic agents based on a patient's body temperature.

67. NEW MACROMOLECULAR DELIVERY APPROACHES “Smart skin patch “ This sort of system is ideal for people who suffer from Parkinson's disease, for instance, because the tremors that accompany the movement disorder aren't constant. When a patient starts to tremble, the patch can pick up on the motion and release a small amount of the drug it contains. The silica nanoparticles are heat-activated so "stretchable heaters" also embedded into the patch that allow them to control the rate of drug delivery if needed.

68. NEW MACROMOLECULAR DELIVERY APPROACHES “Smart skin patch “

69. WIRELESSLY CONTROLLED DRUG DELIVERY MICROSHIP

70. ActivaPatch IntelliDose 2.5 Drug Delivery System Ctivapatch IntelliDose 2.5 Iontophoretic Drug Delivery System is an intelligent, accurate iontophoresis delivery with Smart Power LED to provide visual feedback to clinicians and patients. It is a disposable, single use, non-invasive drug delivery system that utilizes an intelligent microprocessor to deliver 40 or 80mA min dosage of a negatively-charged ionic solution. The self-contained and fully integrated Smart Power system functions without a charging station or dose controller. It can be removed and reapplied to complete treatment if necessary or used for two treatment sites.

71. ActivaPatch IntelliDose 2.5 Drug Delivery System

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