CONTROLLED DRUG DELIVERY SYSTEMS Pradip Sontakke

ONTROLLED DRUG DELIVERY SYSTEM

1. CONTROLLED RELEASE DRUG DELIVERY SYSTEM Presented By: Mr. Pradip F. Sontakke Assistant professor Dept. of Pharmaceutics SHREE SAMBHAJI COLLEGE OF PHARMACY KHADKUT , NANDED .

2. What is NDDS ? Novel Drug delivery System (NDDS) refers to the approaches, formulations, technologies, and systems for transporting a pharmaceutical compound in the body as needed to safely achieve its desired therapeutic effects.  NDDS is a system for delivery of drug other than conventional drug delivery system. NDDS is a combination of advance technique and new dosage forms which are far better than conventional dosage forms.

3. The Aim Novel Drug Delivery System is to provide a therapeutic amount of drug to the appropriate site in the body. T o accomplish promptly and then maintain the desired drug concentration. For drugs to reach the targeted site with little or no side effects. To minimize drug degradation and loss. To increase bioavailability of the drug and the fraction of the drug absorbed in the required site.

4. Table of Content

5. Introduction of CRDDS A Controlled Release Drug Delivery System (CRDDS) is a sophisticated pharmaceutical formulation designed to release a drug in a controlled manner over an extended period. The primary goal is to maintain consistent drug levels in the bloodstream, improve therapeutic efficacy, reduce dosing frequency, and minimize side effects. Consistent Drug Levels : Maintains a steady concentration of the drug in the blood, avoiding the peaks and channel associated with conventional dosage forms. Extended Release: Releases the drug slowly and continuously over a prolonged period, reducing the need for frequent dosing. Targeted Delivery : Can be designed to release the drug at a specific site in the body, enhancing therapeutic outcomes and minimizing systemic side effects.

6. RATIONALE OF CRDDS The basic rational for CRDDS is to alter the pharmacokinetic and pharmacodynamics of pharmacologically active drug by Modifying its structure and properties. Medical Rationale – Reduced dosing frequency – no need to intake drug multiple time in a drug Minimized plasma concentration fluctuations –Reduce fluctuations by slowing the absorption rate and prevent toxicity. Better patient compliance – CRDDS are ideal for delivering the drug at the target site of the body over an extended time period . Lower adverse effects – In CRDDS , The dosing intervals are increased and fluctuations in plasma levels are reduced to minimize the risk of undesirable side effects.

7. 2 ) Biological rational – CRDDS Can also alter the properties such as absorption ,distribution elimination ,etc. Absorption –for CRDDS drugs should have good absorption and the drugs with poor absorption is not suitable for CRDDS. Distribution – For CRDDS distribution is good but during formulation considered drug disposition . Elimination – those drugs which have slow elimination rate and have large half life so they maintain therapeutic blood levels for an extended time periods. RATIONALE OF CRDDS

8. ADVANTAGES OF CRDDS Optimized Drug Concentration : Controlled release systems maintain a steady and consistent drug concentration within the therapeutic range over an extended period of time. This helps avoid fluctuations in drug levels, reducing side effects and improving patient compliance. Reduced Dosing Frequency: These systems often require less frequent dosing compared to immediate-release formulations. This simplifies the dosing regimen for patients and improves adherence to the treatment plan. Minimized Side Effects : Controlled release systems can reduce the occurrence of peak concentrations that may lead to adverse effects. By delivering the drug in a controlled manner, they can minimize side effects and improve patient comfort. Enhanced Efficacy : In some cases, drugs with a narrow therapeutic window or drugs that need to be maintained at a constant level for maximum efficacy can benefit from controlled release systems. This ensures that the drug remains effective over the entire dosing interval.

9. 5. Improved Patient Convenience : With less frequent dosing, patients experience greater convenience and better quality of life. This is particularly advantageous for chronic conditions where long-term medication is required . 6. Steady Plasma Levels : Controlled release systems maintain a steady concentration of the drug in the bloodstream, reducing the need for frequent dose adjustments and providing a more consistent therapeutic effect. 7 . Better Treatment of Chronic Conditions : Chronic conditions often require prolonged drug therapy. Controlled release systems can provide a sustained therapeutic effect, improving the management of such conditions. 8 . Reduced Fluctuations in Drug Levels : Fluctuations in drug levels can lead to therapeutic gaps and reduced efficacy. Controlled release systems minimize these fluctuations, ensuring a more stable drug effect. 9 . Enhanced Pharmacokinetics : Controlled release systems can modify drug release kinetics to match the drug's pharmacokinetics, leading to optimized absorption, distribution, metabolism, and excretion profiles.

10. DISADVANTAGES OF CRDDS 1. Complex Manufacturing: The design and production of controlled release formulations are often more complex and require advanced technology compared to conventional dosage forms. 2. Higher Cost: The development, manufacturing, and quality control of CRDDS are typically more expensive, leading to higher costs for both manufacturers and patients. 3. Variable Release Rates: Inconsistent release rates can occur due to variations in the manufacturing process, leading to unpredictable therapeutic outcomes. 4. Patient Variability: Differences in individual patient physiology, such as variations in gastrointestinal transit time, pH, and metabolic rates, can affect the drug release and absorption.

11. 5.Risk of Dose Dumping: Any failure in the release mechanism (e.g., damage to the coating or matrix) can result in the rapid release of the entire drug dose, potentially leading to toxicity. 6. Limited Dose Adjustment: Once formulated, controlled release systems offer limited flexibility in dose adjustment, making it challenging to tailor doses for individual patient needs. 7. Specialized Equipment and Facilities: The production of CRDDS often requires specialized equipment and facilities, which may not be available in all manufacturing settings. 8. Regulatory Challenges : Obtaining regulatory approval for CRDDS can be more challenging due to the need for extensive testing to demonstrate consistent release profiles and therapeutic efficacy 9. Environmental Factors : Factors such as temperature, humidity, and storage conditions can affect the stability and release characteristics of CRDDS.

12. Selection of drug candidates for CRDDS Identify the Target Disease or Condition: Understand the specific disease or condition that you're aiming to treat. Consider the drug's pharmacological properties and its mode of action. Drug Properties: Choose drugs with suitable physicochemical properties, such as molecular weight, solubility, stability, and lipophilicity. These properties can affect how the drug is loaded into the delivery system and how it is released. Therapeutic Index: Drugs with a narrow therapeutic index, meaning there's a small difference between the effective and toxic doses, can benefit from controlled release systems that maintain steady drug levels within the therapeutic window. Half-Life: Drugs with relatively short half-lives can benefit from controlled release to maintain consistent therapeutic levels in the body, reducing the need for frequent dosing. Dose Frequency: If the drug requires frequent dosing, a controlled release system can reduce the dosing frequency and improve patient compliance.

13. 6. Drug Release Profile: Determine the desired release profile: zero-order (constant release rate), first-order (exponential release), or other specific profiles based on the therapeutic needs. 7. Biocompatibility: Ensure that both the drug and the materials used in the delivery system are biocompatible and safe for use in the body. 8. Patient Factors: Consider patient-related factors such as age, weight, metabolism, and any contraindications that might affect drug release and efficacy. Selection of drug candidates for CRDDS

14. Approaches to design CRDDS Formulation Dissolution controlled systems A) Matrix type B) Encapsulation type Diffusional systems A) Reservoir devices B)Matrix devices Bio erodible and combination of diffusion and dissolution systems Osmotically controlled system Ion-exchange systems

15. Dissolution Controlled System Controlled release preparations of drugs could be made by decreasing their rate of dissolution. The approaches to achieve this include preparation of appropriate salts or derivatives, coating the drug with a slowly dissolving material or incorporating it into a tablet with a slowly dissolving carrier. The dissolution process at a steady state is described by Noyes Whitney equation: Where dC /dt = Dissolution rate D = Diffusion coefficient of drug through pores A = Surface area of the exposed solid Cs= Saturated solubility of the drug C = Concentration of drug in the bulk solution h = Thickness of the diffusion layer  

16. Dissolution Controlled System It is classified as ………….. Matrix type Encapsulation type Matrix Type Matrix dissolution devices are prepared by compressing the drug with slowly dissolving carrier into tablet Controlled dissolution by Altering porosity of tablet Decreasing its wettability Dissolving at slower rate The drug release is determined by dissolution of the polymer. Drug Rate –controlling surface Drug Reservoir

17. The drug particles are coated or encapsulated by microencapsulation techniques with slowly dissolving materials like cellulose, poly ethylene glycols, polymethacrylates, waxes etc. the dissolution rate of coat depends upon the solubility and thickness of the coating.  Those with the thinnest layers will provide the initial dose. The maintenance of drug levels at late times will be achieved from those with thicker coating. Fig. 3 Encapsulation Dissolution Controlled System Encapsulation type

18. Basically the diffusion process shows the movement of drug molecules from a region of a higher concentration to one of lower concentration. The flux of the drug I (in amount/area-time), across a membrane in the direction of decreasing concentration is given by Fick's law, J = -D dc/dx Where, J = flux ,amount /area –time D = diffusion coefficient of drug in the polymer ,area /time Dc/dx = change in conc. With respect to polymer distance Diffusion systems are characterized by the release rate of a drug is dependent on its diffusion through an inert water insoluble membrane barrier. There are basically two types of diffusion devices. Diffusion Controlled System

19. Reservoir devices In the system, a water insoluble polymeric material encloses a core of drug, which controls release rate. Drug will partition into the membrane and exchange with the fluid surrounding the particle or tablet. Additional drug will enter the polymer, diffuse to the periphery and exchange with the surrounding media. The polymers commonly used in such devices are Ethyl cellulose and Poly-vinyl acetate . Fig. 1 Reservoir Diffusion type

20. The rate of drug released (dm/dt) can be calculated using the following equation , Where, A = Area, D= Diffusion coefficient, K = Partition coefficient of the drug between the drug core and the membrane, L = Diffusion pathlength and Δ C= Concentration difference across the membrane

21. Matrix devices A solid drug is homogenously dispersed in an insoluble matrix and the rate of release of drug is dependent on the rate of drug diffusion and not on the rate of solid dissolution. Advantages: Easier to produce than reservoir or encapsulated devices, can deliver high molecular weight compounds. Disadvantages: Cannot provide zero order release, removal of remaining matrix is necessary for implanted system. Fig. 2 matrix Diffusion type

22. The rate of dissolution (dm/dt) can be approximated by Where, S = Aqueous solubility of the drug. A = Surface area of the dissolving particle or tablet. D = Diffusivity of the drug and h = Thickness of the boundary layer

23. Bio erodible and combination of diffusion and dissolution systems Bio erodible (or biodegradable) systems refer to materials that can break down within the body through natural biological processes. These materials are often used in medical applications such as drug delivery systems, sutures, and implants. The breakdown products of bio erodible materials are usually harmless and can be naturally eliminated from the body . Characteristics: Biocompatibility : Must not evoke an adverse immune response. Controlled Degradation : The rate of degradation should match the intended application, ensuring therapeutic efficacy. Safety : Degradation products must be non-toxic and safely excretable. Applications: Drug delivery (e.g., PLGA nanoparticles for controlled release) Temporary implants (e.g., biodegradable stents) Tissue engineering scaffolds

24. Combination of Diffusion and Dissolution Systems Combination systems involving diffusion and dissolution are advanced drug delivery mechanisms designed to optimize the release profile of a therapeutic agent. These systems leverage both the principles of diffusion (movement of drug molecules from high to low concentration) and dissolution (process by which the drug dissolves in bodily fluids). Diffusion : Mechanism : Drug molecules migrate through a carrier material (e.g., polymer matrix) based on concentration gradients. Control : Rate of diffusion is influenced by factors like polymer density, molecular size of the drug, and temperature. Dissolution: Mechanism: Drug particles dissolve in surrounding bodily fluids, making the drug available for absorption. Control: Rate of dissolution is affected by the solubility of the drug, surface area, and the dissolution medium.

25. Combination Approach Here the drug is dissolved in the polymer, but instead of an insoluble or eroding polymer, as in previous systems, swelling of the polymer occurs. This allows entrance of water, which causes dissolution of the drug and diffusion out of the swollen matrix. In these systems, the release rate is highly dependent on the polymer swelling rate, drug solubility and the amount of soluble fraction in the matrix. This system usually minimizes burst effects, since polymer swelling must occur before drug release. Fig Combination of Diffusion and Dissolution Systems

26. Osmotically controlled system An osmotically controlled system is a type of drug delivery system that utilizes osmotic pressure to deliver drugs at a controlled rate. These systems often include a semipermeable membrane, a reservoir containing the drug, and an osmotic agent. When the system is exposed to bodily fluids, the osmotic agent attracts water, creating pressure that forces the drug through an orifice or membrane at a steady rate. Osmotically controlled systems are designed to provide a constant drug release, which can improve therapeutic efficacy and reduce side effects compared to conventional drug delivery methods. These systems can be used for both oral and implantable drug delivery applications.

27. These systems generally appear in two different forms. The first one contains the drug as a solid core together with electrolyte, which is dissolved by the incoming water. The electrolyte provides the high osmotic pressure difference. In the first example, high osmotic pressure can be relieved only by pumping solution, containing drug, out of the hole. The second system contains the drug in solution in an impermeable membrane within the device. The electrolyte surrounds the bag. Both systems have single or multiple holes bored through the membrane to allow drug release. Similarly in the second example, the high osmotic pressure causes compression of the inner membrane and drug is pumped out through the hole. Fig. osmotically controlled system

28. Ion-exchange systems Ion-exchange systems generally use resins composed of water-insoluble, cross-linked polymers. These polymers contain salt-forming functional groups in repeating positions on the polymer chain. The drug is bound to the resin and released by exchanging with appropriately charged ions in contact with the ion-exchange groups Where, X and Y are ions in the GI tract. The free drug then diffuses out of the resin. The drug-resin complex is prepared by mixing the resin with drug solution either by repeated exposure of the resin to the drug in a chromatography column or by prolonged contact in solution. INVERSLY +

29. The Rate of drug diffusing out of the resin is controlled by the area of diffusion, diffusional path length and rigidity of the resin, which is a function of the amount of cross- linking agent used to prepare the resin. This approach to controlled release, however, has the limitation that the release rate is proportional to the concentration of the ions present in the area of administration. Although the ionic concentration of the GI tract remains rather constant with limits, the release rate of the drug can be affected by variability in diet, water intake and individual intestinal content. Ion-exchange systems

30. Physicochemical and Biological Properties of the drug relevant to CRDDS Formulation Physicochemical Properties Dose Size I mpact on Formulation: The dose size of a drug can significantly influence the design of a controlled release system. High dose sizes (greater than 0.5 g) can create challenges in formulating a dosage form that is easy to swallow and acceptable to patients. Considerations: For high-dose drugs, formulators might need to explore high-density formulations, use of compressible excipients, or multiparticulate systems to ensure patient compliance and ease of administration . 2. Aqueous Solubility Impact on Release Rate: Drugs with low aqueous solubility often exhibit slow dissolution rates, which can limit the rate of drug release from the delivery system. This can be advantageous for controlled release but may also require solubility enhancement techniques. Enhancement Techniques: Methods such as solid dispersions, use of solubilizing agents, and inclusion complexes (e.g., cyclodextrins) can improve solubility and ensure a consistent release profile.

31. Partition Coefficient (log P) Optimal Range: The partition coefficient, typically measured as log P, indicates the drug's lipophilicity. Drugs with a log P value between 1 and 3 are generally considered optimal for oral controlled release systems because they balance aqueous solubility and membrane permeability. Formulation Strategies: For drugs outside this range, strategies such as modifying the chemical structure, using permeability enhancers, or developing prodrugs can be employed to improve suitability for controlled release. 4. Drug Stability Stability Concerns: The drug must remain stable throughout its passage in the gastrointestinal tract, where it encounters varying pH conditions (acidic in the stomach, alkaline in the intestines). Protection Strategies: Enteric coatings, pH-sensitive polymers, and protective matrices can be used to shield the drug from degradation and ensure its stability and release at the desired site.

32. 5 . pKa and Ionization Effect on Absorption: The extent of ionization of the drug at different pH levels affects its solubility and permeability. Drugs are usually absorbed better in their unionized form. Formulation Adjustments: Adjusting the pH of the formulation, using buffering agents, or selecting appropriate salt forms can help optimize the drug's ionization and improve absorption. 6. Molecular Size and Diffusivity Diffusion Considerations: Smaller molecules generally have higher diffusivity and are absorbed more readily through biological membranes compared to larger molecules. Formulation Plan: For larger molecules, techniques such as reducing particle size, using absorption enhancers, or designing targeted delivery systems (e.g., liposomes, nanoparticles) can be employed to enhance absorption.

33. Polymorphism Impact on Properties: Different polymorphic forms of a drug can have varying solubility, stability, and dissolution rates, which can affect the drug's release profile and bioavailability. Control Measures: Identifying and controlling the polymorphic form used in the formulation is essential. Solid-state characterization techniques (e.g., X-ray diffraction, DSC) are used to ensure consistency.

34. Biological Properties 1. Absorption Window Relevance to CRDDS: The absorption window refers to specific regions in the gastrointestinal tract where the drug is efficiently absorbed. Drugs with a narrow absorption window may benefit from targeted release formulations. Targeted Delivery: Gastroretentive systems, mucoadhesive formulations, and pulsatile release systems can be used to release the drug at specific sites within the GI tract to maximize absorption. 2. Permeability Importance: High permeability across the gut wall is necessary for efficient drug absorption and bioavailability. The Biopharmaceutics Classification System (BCS) categorizes drugs based on their solubility and permeability. Enhancement Techniques: Permeability enhancers, formulation of prodrugs, and the use of absorption-promoting excipients can be employed to improve the permeability of poorly permeable drugs.

35. 3. Metabolism First-Pass Metabolism: Drugs that undergo extensive first-pass metabolism in the liver are less suitable for oral controlled release formulations as significant portions of the dose may be metabolized before reaching systemic circulation. Formulation Strategies: Alternatives such as transdermal patches, buccal/sublingual delivery, or prodrugs that bypass first-pass metabolism can be considered. 4. Plasma Half-life Ideal Candidates: Drugs with a short plasma half-life (typically less than 4 hours) are ideal candidates for controlled release formulations, as these systems can prolong the duration of action and reduce dosing frequency. Extended Release: Controlled release systems can maintain therapeutic drug levels for extended periods, improving patient compliance and minimizing fluctuations in plasma concentrations.

36. Therapeutic Index Safety Margin: Drugs with a narrow therapeutic index require precise control over the release rate to avoid subtherapeutic levels or toxic effects. Controlled Release: Formulations need to ensure a steady release to maintain drug levels within the therapeutic range. Techniques such as zero-order release systems or feedback-controlled release systems can be used. 6. Protein Binding Pharmacokinetics: Highly protein-bound drugs may have altered pharmacokinetics and can exhibit prolonged half-lives due to the slow release from protein binding sites. Formulation Implications: These drugs may require special formulation strategies to account for protein binding effects and ensure consistent release and bioavailability.

37. Elimination Half-life Long Half-life Drugs: Drugs with longer elimination half-lives (greater than 8 hours) are less suitable for controlled release formulations as they inherently provide sustained release. Suitability: For such drugs, immediate-release formulations may suffice, and controlled release formulations may not offer significant therapeutic advantages.

38. THANK YOU SHRI SAMBHAJI COLLEG OF PHARMACY SHAMAL EDUCATIONAL CAMPUS, DEGAON ROAD, KHADKUT, NANDED 8788884756 [email protected]