Controlled drug delivery system

Powerpoint presentation on controlled drug delivery system. Its introduction, terminologies, rationale, advantages, disadvantages, selection of drug, approaches for designing controlled release formulations and physicochemical and biological properties of drug

1. CONTROLLED DRUG DELIVERY SYSTEM Presented By : Ms. Srushti P Chahande Mpharm -II (Pharmaceutics) Department of Pharmaceutical Sciences, Rashtrasant Tukdoji Maharaj Nagpur University, Nagpur- 440033 1

2. CONTENTS: Introduction Definitions Rationale of Controlled DDS Advantages of Controlled DDS Disadvantages of Controlled DDS Selection of drug candidate for Controlled DDS Approaches for designing controlled release formulations Physicochemical and Biological properties of drug relevant to control release formulation. 2

3. INTRODUCTION: To achieve as well as to maintain the drug concentration within the therapeutically effective range needed for treatment, it is often necessary to take conventional drug delivery system several times a day. This results in a significant fluctuation in drug levels. Recently, several technical advancements have been made. They have resulted in the development of new techniques for drug delivery. These techniques are capable of controlling the rate of drug delivery, sustaining the duration of therapeutic activity, and/or targeting the delivery of drug to a tissue 3

4. DEFINITIONS: Sustained - release: These are dosage forms designed to  release  (liberate) a drug at a predetermined rate in order to maintain a constant drug concentration for a specific period of time with minimum side effects Any of the dosage form that maintains therapeutic blood or tissue levels of drug by continuous release of medication for a prolonged period of time, after administration of a single dose. The onset of its pharmacologic action is often delayed, and the duration of its therapeutic effect is sustained Controlled-release: Controlled release dosage form is a dosage form that release one or more drugs continuously in predetermined pattern for a fixed period of time, either systemically or locally to specified target organ.  Designed to slowly release a drug in the body in a prolonged controlled fashion. The release of drug ingredients from a controlled-release drug delivery system proceeds at a rate profile that is not only predictable kinetically, but also reproducible from one unit to another. 4

5. Figure 1: A hypothetical plasma concentration-time profile from conventional multiple dosing and single doses of sustained and controlled DDS. 5

6. RATIONALE OF CONTROLLED DRUG DELIVERY SYSTEM: 1. The basic rationale of a controlled release drug delivery system is to optimize the biopharmaceutics, pharmacokinetics, and pharmacodynamics properties of a drug in such a way that its utility is maximized through reduction in side effects and cure or control of disease condition in the shortest possible time by using smallest quantity of drug, administered by most suitable route. 2. To provide a location specific action within the GIT. 3. To avoid an undesirable local action within the GIT. 4. To provide programmed delivery pattern. 5. To increase the extend of absorption/bioavailability. 6. To extend the time of action of drug after administration. 6

7. ADVANTAGES: Total dose is low. Reduced GI side effects and other toxic effects. Reduced dosing frequency Better patient acceptance and compliance. Less fluctuation in plasma drug levels. More uniform drug effect. Better stability of drug. Reduction in total health care cost. 7

8. DISADVANTAGES: Decreased system availability Poor invitro- invivo relation Retrieval of drug is difficult in case of toxicity, poison or hyper-sensitivity reaction. The physician has less flexibility in adjusting the dosage regimen. This is fixed by dosage form design. All drugs are not suitable candidates for controlled release medication. Drugs with long biological half life (e.g. Digoxin-34 hours) are inherently long acting and thus are viewed as questionable candidates for sustained release formulations. Drugs with narrow requirements for absorption (e.g. drugs which depend on position of G1T for optimum absorption are also poor candidates). Drugs like Riboflavin and ferrous salt, which are not effectively absorbed in lower intestine are poor candidates. Drugs which are having very short half life ( Furosemide) are not suitable candidates. 8

9. SELECTION OF DRUG CANDIDATE FOR CONTROLLED DRUG DELIVERY SYSTEM: i ] Oral Route: T he drug should have following properties to be a succesful candidate It must get absorbed through the entire length of GIT. Main limitation is transit time (mean of 14 hours), which can be extended for 12-24 hours. Dose as high as 1000mg can be given through this route. ii] Intramuscular/subcutaneous route: This route is preferred because- The action is to be prolonged for 24 hours to 12 months. Small amount of drug is administered (2ml/2gm). Factors important are solubility of drug in surrounding tissue, molecular weight, partition coefficient and pKa of drug. iii] Transdermal route: This route is selected for drugs which- Show extensive first pass metabolism upon oral administration or drugs with low dose. Important factors to be considered are partition coefficient of drugs, contact area, skin condition, skin permeability of drug, skin perfusion rate, etc. 9

10. CONTROL RELEASE DOSAGE FORM RELEASE FORMULATION DESIGNS Dissolution controlled release Encapsulation Dissolution control Seed or granule coated Micro encapsulation Matrix Dissolution control 2. Diffusion controlled release Reservoir type devices Matrix type devices 3. Diffusion and Dissolution controlled systems 4. Ion exchange resins 5. pH-Independent controlled release systems 6. Osmotically controlled release 7. Hydrodynamically balance system 10

11. [I] DISSOLUTION CONTROLLED RELEASE SYSTEM Sustain release oral products employing dissolution as the rate limiting step are the principle involves in this system To achieve this type of approach, the drug particles can be coated with material of varying thickness or by dispersing them in a polymeric matrix. Figure 2: Schematic of Dissolution controlled release systems 11

12. Figure 3: The common forms of dissolution controls formulation 12

13. Dissolution controlled drug release system can be divided in to following categories: Encapsulation Dissolution control (2) Seed or Granule coated (3) Microencapsulation (4) Matrix Dissolution control Encapsulation Dissolution control: This method involves the coating of particles or granules of drug with slow dissolving materials (2) Seed or Granule coated: There are several ways to prepare a drug coated product A common method is to coat the seeds with the drug followed by a coat of slow dissolving materials such as carbohydrate sugar and cellulose, polyethylene glycol, polymeric material, and wax. (3) M icroencapsulation C oacervation / phase separation techniques Interfacial polymerization Precipitation Hot melt Salting out solvent evaporation Electrostatic method. 13

14.   (4) Matrix dissolution control: It is also called as monoliths. The drug is dispersed in media such as bees wax, carnauba wax, caster oil etc which control drug dissolution by controlling the penetration of dissolution fluid in to matrix. This can be controlled by altering the porosity of the tablet matrix, the presence of hydrophobic additives, and the wettability of the tablet and particle surface. Figure 4: Dissolution Controlled Release Systems 14

15. [II] DIFFUSION CONTROLLED RELEASE SYSTEM There are two type of the diffusion controlled release system : Reservoir type devices Matrix type devices Reservoir type devices: The drug release mechanism across the membrane involves its partitioning into the membrane and release into the surrounding fluid by diffusion. Figure 5: Reservoir type devices 15

16. The flux of drug, J, across a membrane in the direction of decreasing concentration is given by Fick’s first law: J= -D dc/dx Where, D= Diffusion coefficient in area/time dc/dx= Change of concentration with distance In term of the amount of drug release, the release rate is given by: dM /dt = ADK Δ C / l Where, A = Area D = Diffusion coefficient K = The partition coefficient of the drug between the membrane and drug core l = Diffusion path length ΔC = Concentration difference across the membrane 16

17. ( 2) Matrix type devices: In this system, a solid drug is dispersed in an insoluble matrix. The rate of drug release is dependent on “the rate of drug diffusion” but not “the rate of solid dissolution”. The drug release from this system is given by following equation: Q = [ Dε / T ( 2A - εCs ) Cs t ]1/2 Where, Q = weight in grams of drug released per unit surface area D = diffusion coefficient of drug in the release medium ε = porosity of matrix T = tortuosity of the matrix Cs = solubility of drug in the release medium A = concentration of drug in the tablet 17

18. [III] DIFFUSION AND DISSOLUTION CONTROLLED SYSTEM: T he main feature of this system is that the drug core is enclosed with a p artially soluble membrane.  Figure 6: Diffusion and Dissolution Controlled System 18

19.   The release profile of the drug from this type of the product can be described by following equation : Release rate = AD ( C1 – C2 ) / l Where, A = Surface area D = Diffusion coefficient of the drug through pores l = Diffusion pathways C1 = Co ncentration of drug in cores C2 = Concentration of drug in dissolution medium The fraction of soluble polymer in the coat will be the dominant factor controlling drug release. Such a system has been demonstrated to provide a zero order release of KCl from a tablet and doing the minimize gastrointestinal irritation effect of this compound. 19

20. [IV] ION EXCHANGE RESIN: This method involves the drug release characteristics depends on the ionic environment of the resin containing drug and should be less effective to the environmental condition such as enzyme content end pH. Resin[N(CH3)]+X¯ + Z – Resin [N(CH3)]+Z + X - ( Drug-charged resin) The release rate can be controlled by coating the drug resin complex using the one of the microencapsulating process. Figure 7: Ion exchange resin 20

21. Improvement of this ion exchange type drug delivery system is occurs by the development of the pennkinetic system. In these system, the drug containing resin granules treated with the polymer such as PEG- 400 and further coated with the water soluble polymer such as ethyl cellulose act as a rate limiting barrier to control the drug release. Figure 8: Drug containing resin granules 21

22. [V] pH – INDEPENDENT C ONTROLLED R ELEASE S YSTEM: This system involves the granules are designed for the oral controlled release of acidic and basic drugs at the rate that is independent of the ph in the GI tract. They are prepared by mixing a basic or acidic drugs with one or more buffering agents, granulating with excipients and finally coating with a GI fluid permeable film forming polymer. When the GI fluid permeates through the membrane , the buffering agents adjust the suitable constant ph , there by constant rate of the drugs release occurs. 22

23. [VI] OSMOTICALLY CONTROLLED RELEASE SYSTEM In this type of drug delivery system, the osmotic pressure is the driving force that generates constant drug release.  Figure 9: Osmotically controlled release system 23

24. To regulate the flow of GI fluid for penetration through the semi permeable membrane, a layer of bioerodible polymer can be applied to the external surface of the semi permeable membrane. Several other modification of osmotic pressure controlled drug delivery have been develop. One system consists of two compartments separated by the movable partition   Another modified system is one in which delivery orifice is absents. In these system, the GI fluid is penetrate, hydraulic pressure is built up inside until the wall ruptures and the contents are release to the environments. Osmotic controlled release system requires osmotic pressure to be effective and is independent of its environments. 24

25. [VII] HYDRODYNAMICALLY BALANCE SYSTEM This system is design to prolong GI residence time of drug in area of the GIT to minimized drug reaching its absorption site in the solution state. This type of the tablet or capsules having the less density compared to the GI fluid density. This type of tablet is prepared by granulating a mixture of drug, excipients, and hydrocolloids such as hydroxyethylcellulose , hydroxypropyle cellulose, and hydroxypropylmethylcellulose . Classification of Hydrodynamically B alance S ystem: (a) Effervescent Floating Dosage Form (b) Non effervescent Floating dosage Form 25

26. Effervescent Floating Dosage Form: These are matrix type of system prepared with swellable polymer such as methylcellulose, chitosan, and various effervescent compounds like sodium bicarbonate, tartaric acid, and citric acid. These type of tablet comes in contact with the acidic gastric contents, Co2 is liberated and gets entrapped in swollen hydrocolloids, providing buoyancy to the dosage form. Figure 10: Mechanism of action in effervescent floating dosage form 26

27. (b) Non effervescent Floating dosage Form: This system is prepared from gel forming or swellable cellulose type of hydrocolloids, polysaccharides, and matrix forming polymer like acrylates. After the oral administration, this dosage forms sweiis in contact with gastric fluid and attain a bulk density of G.I. The air entrapped within the swollen matrix imparts buoyancy to dosage form. The formed swollen gel – like structure acts as a reservoir and allows sustained release of drug through the gelatinous mass. 27

28. PHYSICOCHEMICAL AND BIOLOGICAL PROPERTIES OF DRUG: [I] PHYSICOCHEMICAL PROPERTIES: Aqueous solubility. Partition coefficient Drug stability Protein binding Molecular size and diffusivity . 28

29. AQUEOUS SOLUBILITY It is an important consideration in its biological performance as a SDRF. Aqueous solubility of a drug exerts its control on the absorption process in two ways: ( i ) By influence on the dissolution rate of a compound which establish the drug concentration in solution and the driving force for tissue permeation. (ii) By its effect on the ability of the drug to penetrate tissues which is determined in part by its solubility in the tissue. Dissolution rate is related to aqueous solubility which is given by NOYES-WHITNEY’S EQUATION dc/dt=KDA.Cs Where, dc/dt=dissolution rate KD=dissolution rate constant A= total surface area of drug particle Cs=aqueous saturation solubility of drug 29

30. 2. PARTITION COEFFICIENT Between the time that a drug is administered and the time it is eliminated from the body. It diffuse through a variety of biological membranes that act primarily as lipid like barriers. The major criteria in evolution of the ability of a drug to penetrate these lipid membranes is it apparent oil-water partition co-efficient , defined as: K=Co/ Cw Where, Co=equilibrium concentration of all forms of the drug. Cw =equilibrium concentration of all forms of in an aqueous phase. 30

31. 3. DRUG STABILITY In oral dosage forms, loss of drug through acid hydrolysis or metabolism in GIT. A drug in solid state undergoes degradation at much slower rate than drug in suspension/solution. Drugs with low aqueous solubility have low dissolution rate and usually suffer oral bioavailability problems. Aqueous solubility of weak acids and base is governed by pka value and pH of the medium 31

32. 4. PROTEIN BINDING Distribution of drug in to extra space is governed by dissociation of drug from protein. Drug-protein complex acts as reservoir in the vascular space for sustained drug release to extra vascular tissue for drug exhibiting high degree protein binding. Some drugs shows higher degree protein binding E x- Diazepam shows greater than 95% protein binding Figure 11: Protein binding and kinetics of protein binding 32

33. 5. MOLECULAR SIZE AND DIFFUSIVITY Ability of drug to diffuse through membrane is called as diffusivity, is a function of molecular size. In most of polymers, its possible to logD empirically to some function of molecular size as LogD =- Sv log V+Kv =- Sm log M+Km Where, V=molecular volume M=molecular weight Sv,Sm,Kv,Km are constants value of D is related to size and shapes of drugs 33

34. [II] BIOLOGICAL PROPERTIES: Absorption Distribution Metabolism Elimination and Biological half-life Side Effects and Safety Considerations 34

35. (1) ABSORPTION Rate, extent, and uniformity of absorption are the important factors when considering sustained release. Since the rate limiting step in drug delivery from a sustained release is its release from dosage form , rather than absorption, a rapid release is essential if the system is successful 35

36.  (2) DISTRIBUTION The distribution of drug in to vascular and extravascular spaces in the body is an important factor in its overall elimination kinetics. This influences the formulations of that drug in to a sustain release, primarily by restricting the magnitude of release rate and dose size. Volume of distribution obeys only one compartment model V = dose/Co W here, Co –plasma drug concentration Apparent volume of distribution is merely a propotionately constant that relates the drug concentration in blood or plasma to the total amount of drug in the body. 36

37. For two compartment models Vss = (1+ k12/k21)V1 Where, k12-rate constant for distribution of drug from central to peripheral compartment k21-peripheral to central Vss -drug concentration in blood or plasma at steady state to the total amount of drug If the amount of drug in central compartment p, is the known amount of drug in peripheral compartment T. Hence total amount of drug in body can be calculated by; T/p= k12 (k21-β) Where, β=slow disposition rate constant T/p=estimates the relative distribution of drug B/w compartments Vss =estimate extent of distribution in body 37

38.  3) METABOLISM Metabolism is the conversion of a drug to another chemical form and this is considered in the design of sustained release system for the drugs. Factors associated with metabolism 1. A bility of the drug to induce or inhibit enzyme synthesis. 2. Fluctuating drug blood level and first pass metabolism E x- nitroglycerine Figure 12: General pathway of Drug Metabolism 38

39. 4) ELIMINATION AND BIOLOGICAL HALF-LIFE The rate of elimination of drug is described quantitatively by its biological half life t1/2= 0.693 v/ cls Where, V=volume of distribution cls =systemic clearence cls = I.V administered dose AUC w here, AUC=area under curve, sq.cm Significance of Half life Drug having shorter half life requires frequent dosing, making it desirable to develop SDRS. This will be opposite for drugs with higher half lives. Drug with half life less than 2 hrs and those with more than 8hrs should not be used. E x of drugs with half life less than 2hrs: Ampicillin, furosemide, penicillin Ex of d rugs with half life more than 8hrs: Diazepam, digitoxin, digoxin 39

40. 5) SIDE EFFECTS AND SAFETY CONSIDERATIONS Minimizing side effect for a particular drug done by controlling its plasma concentration and using less total drug over time course of therapy. To measure margin of safety of drug its therapeutic index is considered. TI= TD50/ED50 Where, TD50-Median toxic dose ED50-Median effective dose 40

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