oral controlled drug delivery system

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oral controlled drug delivery system

  1. 1. ORAL DRUGORAL DRUG DELIVERYDELIVERY SYSTEMSYSTEM Presented By- Musale Baliram Sugriv M. Pharmacy Ist year (Pharmaceutics) 1
  2. 2. Oral controlled release systemOral controlled release system Oral route has been most popular & successfully used route for controlled delivery of drugs because of following reasons- Convenience & ease of administration. Greater flexibility in dosage form design. Ease of production & low cost of such a system. 2
  3. 3. • An oral CDDS can be designed as- • CONTINUOS RELEASE SYSTEM– release drug continuously over an extended period of time. • PULSATILE RELEASE SYSTEM– are characterized by a time period of no release followed by a rapid & complete or extended drug release. 3
  4. 4.  CONTROLLED RELEASE ORAL FORMULATION A.CONTINUOUS RELEASE SYSTEMS B. PULSED RELEASE SYSTEM 1.CONTINUOUS TRANSIT SYSTEM 1.TIME SPECIFIC SYSTEM MATRIX OSMOTIC PRESSURE RESERVOIR RUPTURABLE COATING ORAL OSMOTIC SWELLABLE COATING ION-EXCHANGE RESINS DIFFUSIVE COATING PULSINCAP 2. GASTRORETENTIVE SYSTEM 2.COLON SPECIFIC SYSTEM LOW DENSITY SYSTEM TIME HIGH DENSITY SYSTEM PH MODIFIED SHAPE SYSTEM TIME/PH DEPENDENT MUCOADHESIVE SYSTEM ENZYME OSMOTIC PRESSURE 4
  5. 5. Matrix type oral CDDSMatrix type oral CDDS Are possibly the most common of monolithic devices for controlling the release of drugs for following reson- 1. Easy of fabricate compared to reservoir 2. No danger of accidental dose dumping compared to monolithic reservoir. In such device active agent present as dispersion within polymer matrix. & formed by compression of polymer/ drug matrix or by melting 5
  6. 6. Conventional matrix tablet designConventional matrix tablet design 6
  7. 7. Reservoir type oral CDDSReservoir type oral CDDS Are those where the drug crystal, particle, granule, pellet ,minitablet or tablet is present as core encapsulated with a rate controlling wall, film/membrane having a well defined thickness. Drug release occurs predominantly by diffusion. Advantage of such system –  zero order delivery is possible  Release rate modulated by polymer type, polymer membrane thickness, & membrane porosity. Disadvantage- higher cost of formulation. 7
  8. 8. Reservoir pellet design for oral drugReservoir pellet design for oral drug deliverydelivery 8
  9. 9. Oral osmotic (OROS) CDDSOral osmotic (OROS) CDDS Based on diffusion & erosion, osmotic system are more complex in design but provide better zero- order drug delivery. They work on principle of osmotic pressure to release the drug at a constant zero-order rate. 9
  10. 10. In design OROS system compries of 4 basic component 1.A rigid shape retaining semipermiable membrane(SPM) that surrounds drug/ osmogent core 2.A drug layer 3. Osmogent –that embites water & generates osmotic pressure that drives dispersed drug through delivery orifice. Commonly used osmogent are sodium chloride, dextrose, mannitol. Swellable osmopolymer include PEO, HPMC. 4.Delivery orifice which is generally laser-drilled into semipermeable membrane. 10
  11. 11. GASTRORETENTIVEGASTRORETENTIVE DRUG DELIVERYDRUG DELIVERY SYSTEMSYSTEM 11
  12. 12. 12 • INTRODUCTION • APPROPRIATE CANDIDATE DRUGS FOR GRDDS • ADVANTAGES • LIMITATIONS • APPROACHES • EVALUATION TEST CONTENTS
  13. 13. 13 INTRODUCTION • Oral drug delivery is widely used in pharmaceutical field to treat the diseases. • Some drugs are absorbed at specific site only ,these require release at that specific site. • Gastro retentive drug delivery(GRDDS) is one of the site specific drug delivery for the delivery of the drugs at stomach. • It is obtained by retaining dosage form into stomach and drug is being released at controlled manner at specific site
  14. 14. 14 APPROPRIATE CANDIDATE DRUGS FOR GRDDS • Drugs acting locally in the stomach. E.g. Antacids and drugs for H. Pylori viz., Misoprostol. • Drugs that are primarily absorbed in the stomach. E.g. Amoxicillin • Drugs that is poorly soluble at alkaline pH. E.g. Furosamide, Diazepam, Verapamil, etc. • Drugs with a narrow absorption window. E.g. Cyclosporine, , Levodopa, Methotrexate
  15. 15. Drugs which are absorbed rapidly from the GI tract. E.g. Metronidazole, tetracycline. Drugs that degrade in the colon. E.g. Ranitidine, Metformin. Drugs that disturb normal colonic microbes E.g. antibiotics against Helicobacter pylori. 15
  16. 16. 16 ADVANTAGES • Enhanced bioavailability • Sustained drug delivery reduced frequency of Dosing • Targeted therapy for local ailments in the upper GIT • Reduced fluctuations of drug concentration • Improved selectivity in receptor activation • Reduced counter-activity of the body • Extended effective concentration • Minimized adverse activity at colon
  17. 17. 17 LIMITATIONS • The drug substances that are unstable in the acidic environment of the stomach are not suitable candidates to be incorporated in the systems. • These systems require a high level of fluid in the stomach for drug delivery to float and work efficiently. • Not suitable for drugs that have solubility or stability problem in GIT. • Drugs which are irritant to gastric mucosa are also not suitable. • These systems do not offer significant advantages over the conventional dosage forms for drugs, which are absorbed throughout GIT. 17
  18. 18. 18 APPROACHES FOR PROLONGING THE GASTRIC RESIDENCE TIME F S HD S A S S S 18 • High-density systems. (HDS) • Floating systems. (FS) • Swelling and expanding systems. (SS) • Mucoadhesive & Bioadhesive systems. (AS) F S HD S A S S S
  19. 19. Classification of GRDDSClassification of GRDDS 1.LOW DENSITY SYSTEM/ FLOATING DOSAGE FORM a) Effervescent system /Gas generating system b) Non-effervescent systems Sweling/expanding system Inherently low density system 2.HIGH DENSITY SYSTEM 3. MODIFIED SHAPE SYSTEM 4. MUCOADHESIVE SYSTEM 19
  20. 20. 1. LOW DENSITY SYSTEM/ FLOATING1. LOW DENSITY SYSTEM/ FLOATING DOSAGE FORMDOSAGE FORM  Prepared by incorporating a high level(20-75%w/w) gel-forming hydrocolloids. E.g.:- Hydoxyethylcellulose, hydroxypropylcellulose, HPMC & Sod. CMC into the formulation and then compressing these granules into a tablets or capsules.  It maintains the bulk density less than 1 20
  21. 21. Have a bulk density less than gastric fluid & so remain buoyant in stomach called as HYDRODYNAMICALY BALANCED SYSTEM 21
  22. 22. a. Effervescent / Gas generating system It increases size of drug delivery system as well as decrease its density & provides floating properties This system formulated as matrices / resinate. Following are types of gas generating GRDDS Conventional matrix tablets Layered matrix tablets Core coated tablet Ion-exchange resin complexs 22
  23. 23. • GAS GENERATING SYSTEM Carbonates or bicarbonates, which react with gastric acid or any other acid (e.g., citric or tartaric) present in the formulation to produce CO2 , are usually incorporated in the dosage form, thus reducing the density of the system and making it float on the media. 23
  24. 24. b. NON-EFFERVESCENT SYSTEMb. NON-EFFERVESCENT SYSTEM SWELLING / EXPANDING SYSTEMSSWELLING / EXPANDING SYSTEMS These systems use a gel forming / swellable hydrocolloid such as polysaccharides like guargum, cellulosics- HPMC, synthetic polymers- PEO, carbomer. It consist of embedding drug powder/ pellets in gel forming hydrocolloids. After oral administration dosage form swell on contact with gastric fluid The formed swollen gel-like structure acts as reservoir & allows sustained release of drug through gelatinous mass. 24
  25. 25. INHERENTLY LOW DENSITYINHERENTLY LOW DENSITY SYSTEMSSYSTEMS Two types— a. Entrapment of air (hollow microspheres/microballoons) Emulsion solvent diffusion method Modified solvent evaporation method Dehydration of swollen hydrogel Hollow chamber system b. Incorporation of low density materials. 25
  26. 26. Polymers used commonly: Polycarbonates, Cellulose acetate, Calcium alginate, Eudragit S, agar and methoxylated pectin etc HOLLOW MICROSPHERES 26
  27. 27. Emulsion- solvent diffusion methodEmulsion- solvent diffusion method A solution of polymer & drug in ethanol/ methylene chloride is poured in aq. Solution of PVA .ethanol partitions into external aq. Phase & polymer participates around methylene chloride droplets.Then subsequent evaporation of entrapped methylene chloride leads to formation of internal microcavity within microparticles 27
  28. 28. MODIFIED SOLVENTMODIFIED SOLVENT EVAPORATION METHODEVAPORATION METHOD Drug powder is dispersed into solution of cellulose acetate butyrate & eudragit RL 100 in acetone. The dispersion pressurised under CO2 gas , which dissolves & forms bubbles following the release of pressure. Generated CO2 bubbles are entrapped within dispersed drug-polymer droplets & leads to formation of internal cavities within hardened microsphers. 28
  29. 29. DEHYDRATION OF SWOLLEN HYDROGELDEHYDRATION OF SWOLLEN HYDROGEL System consist of hydrated drug loaded calcium alginate core, which is coated with PVA membrane .Drying of hydrogel result in formation of air compartment owing to shrinkage of hydrated core HOLLOW CHAMBER SYSTEM These system prepared by coating drug on hollow core such as poprice , empty gelatin capsules / polystyrene beads followed by coating the drugs with rate- controlling membrane 29
  30. 30. • Prepared by dropping sodium alginate solution into aqueous solution of calcium chloride, causing the precipitation of calcium alginate • Freeze dry in liquid nitrogen at -40o c for 24h. • Beads-spherical and 2.5 mm Swellable agents have pore size ranging between 10nm to 10µm. Superporous hydrogels will swell more than the swelling ratio 100,This is achieved by co-formulation of a hydrophilic particulate material, and Ac-Di- Sol (crosscarmellose). ALGINATE BEADS SUPERPOROUS HYDROGELS 30
  31. 31. LOW DENSITY MATERIALSLOW DENSITY MATERIALS Fats & low density polymers used to prepare floating drug matrices.e.g. Polypropylene foam powder ,matrix-forming polymers ,drug & an optional filler. Polypropylene foam powder based drug microparticals prepared by soaking microporous foam particals in organic solution of drug & polymer. 31
  32. 32. 2. HIGH DENSITY2. HIGH DENSITY SYSTEMSYSTEM Density of system is larger than gastric juice (>1.4 g/ml) , the device settles down to bottom of stomach , remaining located below the pylorus. Iron oxide , titanium dioxide & barium sulphate used to increase density of drug pellets. The drug is coated on heavy core & then covered by diffusion controlled membrane. The approach is not very successful. 32
  33. 33. 3. MODIFIED SHAPE SYSTEM / UNFOLDING3. MODIFIED SHAPE SYSTEM / UNFOLDING SYSTEMSYSTEM These system consist of atleast one erodible polymer , one non-eroidible polymer & drug that is dispersed within polymer matrix. Drugs incorporated in several geometric shapes such as tetrahedron, ring, disc, spiral, pellet/ sphere which can be packed into gelatine capsule & unfold after dissolution of capsule shell. 33
  34. 34. 4. BIOADHESIVE SYSTEMS / MUCOADHESIVE SYSTEM4. BIOADHESIVE SYSTEMS / MUCOADHESIVE SYSTEM Bioadhesive polymer e.g. carbomer, chitosen used to coat dosage form so that it adheres to gastric mucosa. Adv.is –in stomach is intimate contact with mucosa leading to short pathways for locally acting drugs such as antibiotics against H. pylori. 34
  35. 35. Marketed productMarketed product BRAND NAME ACTIVE INGREDIENT Cifran OD Ciprofloxacin Madoper L-DOPA,benserazide Valrelease Diazepam Topalkan Aluminium mg.antacid Almagate flat coat Aluminium mg. antacid 35
  36. 36. EVALUATIONTESTS:EVALUATIONTESTS: Evaluation of tabletsEvaluation of tablets Buoyancy lag timeBuoyancy lag time In vitro dissolution behaviourIn vitro dissolution behaviour Swelling indexSwelling index Hardness & friabilityHardness & friability Weight variationWeight variation Evaluation of microspheres & beadsEvaluation of microspheres & beads Particle size analysisParticle size analysis Surface characterizationSurface characterization In vivo evaluation (Gamma scientigraphy)In vivo evaluation (Gamma scientigraphy) 36
  37. 37. Buoyancy lag time & duration ofBuoyancy lag time & duration of buoyancybuoyancy The buoyancy lag time & duration of buoyancy determined in USP dissolution apparatus II in acid enviornment. The lag time interval between introduction of tablet into dissolution medium & its buoyancy to top of dissolution medium was taken as buoyancy lag time / floating lag time & duration of buoyancy was observed vissually. 37
  38. 38. In vitro dissolution behaviourIn vitro dissolution behaviour Release of medicament studied by USP II type dissolution apparatus (paddle type) dissolution performed at predetermined speed & temperature 37±0.5ºc in appropriate dissolution medium. 5mL sample withdrawn at predetermined interval . Absorption of withdrawn sample measured spectrophotometrically with with suitable dilution & corresponding concentration determined from calibration curve. 38
  39. 39. Swelling indexSwelling index Tablet weigh individually (W0) & placed in dissolution medium’ Temperature maintain at 37±0.5ºc At regular interval sample removed & swollen weight (Wt) of each determined at predefined time interval % swelling index =Wt-Wo /Wo x 100 Wt– weight of tablet at time t W0– initial weight of tablet. 39
  40. 40. Hardness & friabiltyHardness & friabilty Hardness– force applied to break tablet Resistance of tablet to chipping, abrasion, breakage under condition of storage, transformation, handling before usage depends on its hardness. Measured by using Monsanto hardness tester. Friabilty– Roche friabilator Take tablet in plastic chamber , revolving at 25 rpm & dropping tablet at height of 6 inch in each revaluation. %Friabilty = intial wt of tab.—final wt of tab./initial wt  of tabX100 40
  41. 41. Weight variationWeight variation USP provides wt. variation test by weighing 20 tablet individually , calculating average wt & comparing the individual tablet wt. To average. Tablet meet USP test if no more than 2 tablet outside the % limit. 41
  42. 42. Evaluation for microspheres & beadsEvaluation for microspheres & beads Particle size analysis Surface characterisation Particle size analysis- determined using optical microscopy Surface characterisation- determined using (SEM) scanning electron microscopy 42
  43. 43. In vivo evaluation (GammaIn vivo evaluation (Gamma scientography)scientography) This method helps to locate dosage form in GI tract by which we can predict & correlate gastric emptying time & passage of dosage form in GIT. Gamma rays are emitted by nucleotide are focused on camera , which helps to monitor the location of dosage form in GI tract. 43
  44. 44. COLON TARGETED DRUG DELIVERY SYSTEM 44
  45. 45. INTRODUCTIONINTRODUCTION The most useful drug delivery system to treat colonic disorder & colon cancer are failing due to inappropriate concentration of drug that do not get to the site of action. Colon targeted drug delivery system are suitable site for absorption of peptides & proteins. The CDDS highly desirable for local treatment of variety of bowl diseases such as ulcerative colitis, crohn’s disease,colonic cancer. 45
  46. 46. 46 Promising site for drug delivery Local disorders Systemic absorption oDrugs unstable in upper GIT oDrugs poorly absorbed from GIT oDrugs that necessitate targeting at site Colon as a site for drug delivery
  47. 47. Advantages of Colon TargetedAdvantages of Colon Targeted drug delivery systemdrug delivery system Drug directly reaches the target site. It reduces dose of drug to be administrated. It minimizes side effect It enhances drug utilization. 47
  48. 48. Anatomy & Physiology of colonAnatomy & Physiology of colon GI tract is divided into – Stomach Small intestine Large intestine The large intestine extend from ileocaecal junction to anus which is divided into 3 main parts-colon, rectum, anal canal. 48
  49. 49. Colon itself consist of – Caecum (Asending colon) Hepatic flexure (Transvers colon)-longest Splenic flexure (Descending colon) Sigmoidal colon The wall of colon composed of 4 layers Serosa Muscularis externa Sub-mucosa Mucosa 49
  50. 50. Function of colonFunction of colon Formation of suitable environment for colonic microorganism. Act as storage reservoirs of waste matter. Removal of content of colon at proper time. Absorption of potassium ion & water from lumen, concentrating fecal content & secretion & excretion of potassium & bicarbonates. 50
  51. 51. GastrointestinalTransit -- Gastric emptying of various dosage form is highly inconsistant & depends primary on whether the subject is fed or fasting & properties of dosage form. The arrival of dosage form in colon is determined by rate of gastric emptying & intestine transit time. Intestinal transit time Organ Transit time (hrs) Stomach <1 (fasting) >3 (fed) Small intestine 3-4 Large intestine 20-30 51
  52. 52. 52 Ulcerative colitis  Inflammatory bowels disease (IBD) Crohn’s disease Colonic polyps Colorectal cancer Others as amebiasis, diarrhoea etc Disorders of Colon
  53. 53. Criteria Pharma - cological class Nonpeptide drug Peptide drug Drug used for local effect in colon against disease Anti- inflammatory drugs Oxyprenolol Metoprolol Nifedine Amylin Antisense oligonucleotide Drugs poorly absorbed from upper GIT Antihypertensiv e Antianginal drugs Ibuprofen Isosorbides Theophylline Cyclosporine Desmopressine Drugs for colon cancer Antineoplastic drugs Psedoephedrine Epoetin Glucagon Drugs that degrade in stomach & small intestine Peptides & proteins 5-florouracil Doxorubicin Gonadoreline Insulin 53
  54. 54. Approach for colon targetedApproach for colon targeted drug delivery systemdrug delivery system Following approaches used for CDDS . 1. By using pH sensitive polymer. 2.Time controlled release drug delivery system for colon. 3. Microbially controlled system for colon. a) Prodrug b) Azo-polymeric prodrug. c) Polysaccharide based delivery system. 4. Osmotically controlled drug delivery system 54
  55. 55. Oral administration / Colon targeted dosage form Remain intact in stomach Remain intact in small lntestine Drug release in colon High intracolonic drug conc. Dose reduction Improved efficacy APPROACHES OF CDDS Oral administration/ conventional dosage form Absorption of drug either in stomach / small intestine Low intracolonic drug conc. Large dose requried Poor efficacy Low therapeutic index Side effect 55
  56. 56. GI TRACT SEGMENT PH STOMACH 1-3 SMALL INTESTINE 5-7.5 LARGE INTESTINE 6.8-7.8 RECTUM 7.8-8 1. By using pH sensitive polymer1. By using pH sensitive polymer The polymer which are pH depended in colon targeted drug delivery are not suitable at low pH level but become progressively more soluble as pH increase. Although these pH dependent polymers can protect a drug moiety in stomach from acidic environment. 56
  57. 57. Mechanism of action of a pH dependent system for targeted drug delivery to the colon pH sensitive polymer + drug core DRUG CORE Colonic pH Release of drug in Colon 57
  58. 58. Sr. No. Polymer Threshold pH 1 Eudragit® L 100 6.0 2 Eudragit® S 100 7.0 3 Eudragit® L –30D 5.6 4 Eudragit® FS 30D 6.8 5 Eudragit® FS 30D 5.5 6 Polyvinyl acetate phthalate 5.0 7 Hydroxy propyl methyl cellulose phthalate 4.5-4.8 8 Cellulose acetate trimelliate 4.8 9 Cellulose acetate phthalate 5.0 Polymer of methacryli c acid are mostly used 58
  59. 59. 2.Time controlled release drug delivery system for2.Time controlled release drug delivery system for coloncolon Time controlled release system (TCRS) such as sustained release dosage form are also very promising drug delivery system.  However due to potentially large variation of gastric emptying time of dosage form in humans, in these approaches, colon arrival time of dosage forms can not be accurately predicted, resulting in poor colonical availability. The dosage form may also be applicable as colon dosage forms by prolonging the lag time of about 5-6 hr. 59
  60. 60. » Releases the drug after a predetermined lag time » The lag time usually starts after gastric emptying because most of the time-controlled formulations are enteric coated. » Drug release from these systems is not pH dependent 60
  61. 61. Lag Phase of 5 hrs. obeserved 61
  62. 62. Disadvantage of these system are- 1. Gastric emptying time varies markedly between subjects / in manner dependent on type & amount of food intake . 2. Gastrointestinal movement , specially peristalsis or contraction in stomach result in gastrointestinal transit of drug. 3. Accelerated transit through different regions of colon has been observed in patients with IBD , carcinoid syndrome & ulcerative colites 62
  63. 63. 3. Microbially triggered drug delivery to colon3. Microbially triggered drug delivery to colon The microflora of colon consist mainly of anaerobic bacteria e.g. bacteroides , bifidobacteria, enterococci, entrobacteria..etcThis vast microflora fulfil it’s energy needs by fermenting various types of substrates that have been left undigested in small intestine, e.g. di & tri saccharides , polysaccharides ..etc.for this fermention, microflra produces a vast number of enzyme like glucoronidase, galactosidase, arabinosidase, nitroreductase etc. Because of presence of biodegradable enzymes only in colon , use of biodegradable polymer for CDDS seems to be more specific approach. 63
  64. 64. 64 Prodrugs Drug Carrier Molecule Enzymatic stimuli in the biological environment of the GIT breaks the bond Concept of prodrug s Prodrugs Drug Carrier Molecule Concept of prodrug s Prodrugs Drug Carrier Molecule Concept of prodrug s Prodrugs Drug Carrier Molecule Concept of prodrug s
  65. 65. a. Prodrug approach for drug delivery to colona. Prodrug approach for drug delivery to colon Prodrug is a pharmacologically inactive derivative of parent drug molecule that requires spontaneous /enzymatic transformation in vivo to release active drug. For colonic delivery , prodrug is designed to undergo minimal hydrolysis in upper tracts of GIT & undergo enzymatic hydrolysis in colon there by releasing the active drug moiety from drug moiety. Metabolism of azo compound by intestinal bacteria is one of most extensively studied bacterial metabolic process. 65
  66. 66. 66 Bacteria in colon Hydrolysis of sulphasalazine (A) into 5-aminosalicylic acid (B) and sulfapyridine (C). ( A ) ( B ) ( C )
  67. 67. b. Azo polymeric new drugb. Azo polymeric new drug In which use of polymers as drug carriers for drug delivery to colon . Synthetic, naturally, sub-synthetic polymers used form colon targeted polymeric prodrug with azo linkage between polymer & drug moiety. The various azo polymers are evaluated for coating materials over drug core.These are susceptible to cleavage by azo reductase enzyme. Coating of protein & peptide drug capsules crosslinked with azoaromatic group Polymer to protect drug from degradation in stomach & small intestine. In colon azo bonds reduced & drug is released 67
  68. 68. c. Polysaccharide based delivery systemc. Polysaccharide based delivery system Polysaccharides offer an alternative substrate for the bacterial enzymes present in the colon. Most of them are hydrophilic in nature. Natural polysaccharides are either modified or mixed with water insoluble polymers. 68
  69. 69. 63 Polysaccharides used for Colon Drug Delivery • Chitosan • Pectin • Guar gum • Chondroitin sulphate • Dextran • Cyclodextrins • Almond gum • Locust bean gum • Inulin • Boswellia gum • Karaya gum
  70. 70. 70 Different bacterial species acting on Polysaccharides in colon Polysaccharides Bacterial species Amylose Chitosan Chondroitin sulphate Cyclodextrins Dextran Guar gum Bacteriodes Bifidobacterium Bacteriodes Bacteriodes Bacteriodes Bacteriodes Bacteriodes Ruminococccus
  71. 71. Polysaccharides Drug targeted to colon Guar gum Pectin Inulin Amylase Cyclodextrin (β) Dextran Chitosan Eudragits Rofecoxib , Tinidazole Naproxen Azathioprine 5-Amino salicylic acid Albendazole Ibuprofen Satranidozole 5-fluorouracil List of few studies on Polysaccharides 71
  72. 72. 4. Osmotically Controlled Drug Delivery Systems Delivery port Osmet pump Depend up on the osmotic pressure exerted by osmogens on drug compartment with which though drug get released slowly through the orifice. 72
  73. 73. MARKETED PRODUCTS Sr. no . Marketed name Company name Disease Drug content 1) Mesacol tablet Sun pharma, India Ulcerative colitis Mesalamine 2) SAZO Wallace , India Ulcerative colitis, crohn’s disease Sulphasalazi ne 3) BUSCOPAN German remedies Colonic motility Hyoscine butyl bromide 4) Entofoam Cipla, India Ulcerative colitis Hydrocortiso ne acetate 73
  74. 74. EVALUATION TESTEVALUATION TEST In-vitro dissolution test In-vivo test string technique Endoscopy technique Gamma scintigraphy Radiotelemetry Roentgenography 74
  75. 75. IN-VITRO DISSOLUTIONTESTIN-VITRO DISSOLUTIONTEST Dissolution of CDDS is usually complex, dissolution Describe in USP Disso. Carried out by conventional basket method. Dissolution tests for CDDS in different media simulating pH condition & times likely to be encountered at various location in GI tract. Following media were used- pH 1.2 to simulate gastric fluid. pH 6.8 to simulate jejunal region of small intestine. pH 7.2 to simulate ileum segment. Enteric coated CDDS studied in gradient disso. Study in 3 buffer systems. 2 hr at pH 1.2, then 1 hr at pH 6.8& finally at pH 7.4 75
  76. 76. IN-VIVO METHODIN-VIVO METHOD String method- A tablet is attached to piece of string & subject swallows tablet, leaving free end of string hanging from his mouth at various times. withdrawing tablet from stomach by pulling out the string & physically examining the tablet for the sign for disintegration. 76
  77. 77. Endoscopy technique- It is optical tech. in which fibre gastroscope is used to directly moniter behavior of dosage form after ingestion Gamma scintigraphy- Most useful to evaluate in-vivo behavior of dosage form in animal & humans.it requirs presence of gamma emmiting radioactive isotopes 77
  78. 78. PULSATILE DRUGPULSATILE DRUG DELIVERYDELIVERY SYSTEMSYSTEM 78
  79. 79. PULSATILE DRUG DELIVERY SYSTEM Is defined as the rapid and transient release of a certain amount of drug molecules within a short time-period immediately after a predetermined off-release period. In various diseases in which we can recomend the pulsatile drug delivery system such as duodenal ulcer, cardiovascular diseases, arthritis, asthma, diabetes, neurological disorder, cancer, hypertension and hypercholesterolemia . 79
  80. 80. 80 Pulsatile drug delivery systems (PDDS) are gaining importance as they deliver a drug at time and site specific manner resulting in improved therapeutic efficacy as well as compliance. Intelligent drug delivery system capable of adjusting drug release rates in response to a physiological need.
  81. 81. 81 Necessity of PDDSNecessity of PDDS 1.Chronopharmacotherapy of disease which shows circadian rhythms in their pathophysiology- -asthmatic attack during early morning - heart attack in middle of night - morning stiffness in arthritis 2. Avoiding first pass metabolism ex. Protein & peptide 3. For which tolerance is rapidly exists ex. Salbutamol sulphate 4. For targeting specific site in intestine ex. Colon (sulphasalazine) 5. For programmed administration of hormone & drug 6.For drug having short half-life ex. ß-blocker
  82. 82. 82 Disease Chronological behavior Drugs used Peptic ulcer Acid secretion is high in the afternoon and at night. H2blockers Attention deficit syndrome Increase in DOPA level in afternoon Methylphenidate Cardiovascular diseases BP is at its lowest during the sleep cycle and rises steeply during the early morning Nitroglycerin, calcium channel, blocker, ACE inhibitors Asthma Precipitation of attacks during night or at early morning. Β2 agonist, Antihistamines Arthritis Level of pain increases at night NSAIDs, Glucocorticoids Diabetes mellitus Increase in the blood sugar level after meal Sulfonylurea, Insulin Hypercholesterolemia Cholesterol synthesis is generally higher during night than day time. HMG CoA reductase, Inhibitors Diseases that require pulsatile drug delivery
  83. 83. 83 Pulsatile DDS classified as- 1. Osmotic pressure release system a.capsule/ tablet composed of large nu.of pellets b. PORT (programmable oral release technology) 2. Reservoir system with rupturable coatings a.Time controlled explosion system (TCES) b. Pulsatile release tablet/compression/press-coated tablet 3. Reservoir system with swellable/soluble/erodible coating a. Press-coated/ multilayered tablet b. Hydrophilic sandwich capsule c.Time clock system d. Chronotropic system 4. Capsular system with polymeric plugs (Pulsincap)
  84. 84. 84 OSMOTIC PRESSURE RELEASE SYSTEMOSMOTIC PRESSURE RELEASE SYSTEM a.Capsule/ tablet composed of a large number of pellet- Each pellet has a core that contains therapeutic drug & water soluble osmotic agent. A water-permeable but insoluble polymer film encloses each core. On exposure to water , it’s penetration into pellets, osmotic agents dissolves ,which causes pellets to swell & drug release.
  85. 85. 85 Capsule based systems: Single-unit systems are mostly developed in capsule form. The lag time is controlled by a plug, which gets pushed away by swelling or erosion, and the drug is released as a “Pulse” from the insoluble capsule body.
  86. 86. 86 -The plug material consist of insoluble but permeable & swellable polymers. ex. Polymethacrylate. -Erodible polymer- HPMC, PVA, PEO. -Congealed melted polymer- saturated polyglycolated glycerides, glyceryl mono-oleate -Enzymaticaly controlled erodible polymer-pectin, agar
  87. 87. 87 b. PORT (Programmable oral releaseb. PORT (Programmable oral release technology)technology) System composed of gelatin capsule coated with SPM (ex. Cellulosic acetate) that contain immediate release drug ,an insoluble plug (ex. Lipids) & osmotic agent with second release of drug for timed release.  Upon contact with aqueous media, immediate release drug is delivered, water enter into capsule through SPM , which increase osmotic pressure & result in ejection of plug after lag time , following which second dose is delivered.
  88. 88. 88
  89. 89. 89 2. Reservoir pulsatile with rupturable coatings2. Reservoir pulsatile with rupturable coatings These system consist of 3 layers- 1.Drug containing core . 2.Pressure generating layer- effervescent excipients ( mixture of citric acid/ tartaric acid & sodium bicarbonate), swelling agents or osmagents . 3. Semipermeable polymer coating. Upon contact with GI fluids, water penetrates through polymer coating & generate pressure due to effervescence, hydration of swelling polymer or osmosis, then ruptures polymer coating leading to rapid drug release.
  90. 90. 90 Examples of rupturable systemsExamples of rupturable systems a.Time controlled explosion system (TCES) B. Pulsatile release tablet (PRT)/ compression/press-coated tablet.
  91. 91. 91 a.Time controlled explosion system (TCES) It has 4 layered spherical pellet structure, consist of inert core surrounded by a layered of drug , a swelling agent & water insoluble polymer membrane made up of ethylcellulose. It is characterised by rapid drug release with programmed lag time . When water penetrates through polymer membrane ,swelling agent expands, leading to destruction of membrane with subsequent drug release.
  92. 92. 92 Time controlled explosion systemTime controlled explosion system
  93. 93. 93 B. Pulsatile release tablet (PRT)/ compression / press-coated tablet It has core tablet containing a large amount of disintigrant together with active ingredient which is press-coated with outer shell of ethylcellulose that controls water penetration. When PRT administrated orally, water penetrates through outer shell depending on thickness & composition of coating, disintegrant swells & collapses the outer shell due to high swelling pressure to release the contents as a pulse.
  94. 94. 94 Press-coated pulsatile drug delivery systems: 1.Press-coated pulsatile drug delivery systems can be used to protect hygroscopic, light-sensitive, oxygen labile or acid-labile drugs. 2. relatively simple and cheap. 3.These systems can involve direct compression of both the core and the coat. 4. Materials Such as hydrophobic, hydrophilic can be used in press-coated pulsatile drug delivery system. 5. involve compression which is easy on laboratory scale. 6. Press-coated pulsatile drug delivery formulations can be used to separate incompatible drugs from each other or to achieve sustained release.
  95. 95. 95 3. Reservoir system with3. Reservoir system with swellable/soluble/erodible coatingswellable/soluble/erodible coating In this system barrier swells, erodes / dissolves after a specific lag period & drug is subsequently released rapidly. Lag time depends on thickness of coating layer. Examples – a. Press-coated / multilayered tablets b. Hydrophilic sandwich (HS) capsule c. Time clock system d. Chronotropic system
  96. 96. 96 a. Press-coated / multilayered tablets Press-coated system based on swelling, disintegration or erosion mechanism for pulsatile drug delivery. A release pattern with two pulses obtained from a three layered tablet conatining two drug containing layers separated by a drug free gellable polymeric barrier layer. - initial rapid release drug layer - drug-free gellable polymeric barrier layer - second pulse generating drug layer - impermeable ethylcellulose layer
  97. 97. 97 Multilayered tabletMultilayered tablet
  98. 98. 98 b. Hydrophilic sandwich (HS) capsule Based on a capsule- within a capsule, in which the inter-capsular space is filled with a layer of hydrophilic polymer (HPMC) . This effectively creates a hydrophilic sandwich between the two gelatin capsules. When outer capsules dissolves, sandwich of HPMC forms a gel barrier layer & cause drug release.
  99. 99. 99 c.Time clock system Is made up of a solid dosage form, coated with a hydrophobic surfactant layer to which a hydrosoluble polymer is added to improve adhesion to the core. The outer layer redisperses in aqueous environment in a time proportional to the thickness of film.
  100. 100. 100 d. Chronotropic system Consist of drug containing core coated with high viscosity HPMC which is responsible for a lag phase in onset of release. The lag time is controlled by the thickness and the viscosity grades of HPMC. The system is suitable for both tablets and capsules
  101. 101. 101 4. Capsular pulsatile system with polymeric4. Capsular pulsatile system with polymeric plugsplugs Example of this system is pulsincap—consist of capsule with water soluble cap, an insoluble body filled with drug & sealed with a hydrogel plug . The length of plug decides lag time. On administration, soluble cap dissolves thereby allowing the hydrogel plug to swell & expand After a predetermined lag time, it is swollen to an extent that it is ejected from capsule body thereby releasing the drug.
  102. 102. 102 PULSINCAPPULSINCAP
  103. 103. 103 The plug material consist of insoluble but permeable & swellable polymers. ex. Polymethacrylate. Erodible polymer- HPMC, PVA, PEO. Congealed melted polymer- saturated polyglycolated glycerides, glyceryl mono-oleate Enzymaticaly controlled erodible polymer- pectin, agar
  104. 104. 104 Marketed technology of PDDSMarketed technology of PDDS Technology Mechanism Brand name & dosage form API Disease pulsincapTM Rupturable system Pulsincap TM Dofetilide Hypertension OROS Osmotic mechanism Covera- HS, XL tablet Verapamil HCL Hypertension
  105. 105. ADVANTAGES OF PULSATILE DRUG DELIVERY SYSTEM: 1. Extended daytime or nighttime activity 2. Reduced side effects 3. Reduced dosage frequency 4. Reduction in dose size 5. Improved patient compliance 6. Drug adapts to suit circadian rhythms of body functions or diseases. 7. Drug targeting to specific site 8. Protection of mucosa from irritating drugs. 9. Drug loss is prevented by extensive first pass metabolism . 10. Patient comfort and compliance: Oral drug delivery is the most common and convenient for patients, and a reduction in dosing frequency enhances compliance. 105
  106. 106. 106 EVALUATION OF PDDSEVALUATION OF PDDS Weight variation Thickness Hardness Friability Wetting time Drug content In-vitro dissolution method
  107. 107. 107 RS

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