Targeted drug delivery system

NDDS Topics: Targeted drug delivery system

1. Mr. Shashank Chaurasiya Asst. Professor Bansal College of pharmacy, Bhopal

2. S. No . CONTENTS 1. INTRODUCTION 2. DIFFERENCE BETWEEN : TARGETED & CONVENTIONAL DRUG DELIVERY SYSTEM 3. DRUG TARGETING STRATEGIES 4. CARRIER CONCEPTS IN DRUG DELIVERY 5. SITE-SPECIFIC DRUG DELIVERY 6. MARKETED PREPARATIONS 7. CURRENT MARKET SALES DATA OF TDDS 8. CONCLUSION 9. REFERENCES

3. Targeted drug delivery means accumulation of pharmacologically active moiety at desired target in therapeutic concentration at the same restricting its access to normal cellular lining, thus minimizing therapeutic index. The drug can be targeted to intracellular sites, virus cells, bacteria cell and parasites using different scientific strategies have proven highly effective. [1] HISTORY The concept of targeted drugs is not new, but dates back to 1906 when Ehrlich first postulated the ‘magic bullet’. The durability of this concept is a strong indication of its appeal, but the ‘magic bullet’ continues to be a challenge to implement in the clinic.

4. Sr. no. Targeted Drug Delivery System Conventional Drug Delivery System 1. Specific Location Equally distributed 2. High efficacy Lower efficacy 3. Less side effects More side effects 4. Low frequency High frequency 5. Low fluctuation in circulating drug levels High fluctuation in circulating drug levels DIFFERENCE BETWEEN : TARGETED & CONVENTIONAL DRUG DELIVERY SYSTEM

5. DRUG TARGETING STR A T E GIES Passive T a r geting Inverse T a r geting Active T a r geting Ligand- M e diated T a r geting Physical T a r geting Dual T a r geting Double T a r geting Co m bina t ion Targeting

6. 1. Passive Targeting :- Drug del i v er y sys t e m s w h i c h are targeted to systemic circulation are ch a ract e riz e d a s Pa s s i ve d e l i v e ry systems. The ability of some colloid to be taken up by the Reticulo Endothelial Systems (RES) especially in liver and spl e e n m ake them ideal su b str a te f or passive hepatic targeting of drugs. 2. Inverse Targeting :- In this type of targeting attempts are made to avoid passive uptake of colloidal carrier by RES and hence the process is referred to as inverse targeting.

7. Active Targeting :- In this approach carrier system bearing drug, reaches to specific site on the basis of modification such as coating of surface with either a bioadhesive, nonionic surfactant or specific cell or tissue antibodies (i.e. monoclonal antibodies) or by albumin protein are made on its surface rather than natural uptake by RES Ligand -mediated Targeting :- Ligand-targeted nanoparticles bind selectively to target cells, such as tumor cells.

8. 5. Physical Targeting :- The external triggers can be employed both with and without active targeting. In the case of only external triggers being used, then the targeting strategy is known as ‘physical targeting’. The commonly employed external triggers are ultrasound, magnetic field, electric field and infrared radiation. 6.Dual Targeting :- In this targeting approach carrier molecule itself have their own therapeutic activity and thus increase the therapeutic effect of drug. For example, a carrier molecule having its own antiviral activity can be loaded with antiviral drug and the net synergistic effect of drug conjugate was observed .

9. 7. Double Targeting :- The combination is made between spatial control & temperature controlled drug delivery ,when these two methodologies are combined, it is called as Double targeting.

10. 8. Combination Targeting :- The use of both external triggers and active targeting is known as ‘combined targeting’. External triggers can also be used along with passive targeting and forms a subset of combined targeting.

11. LIPOSOMES NIOSOMES SUBMICRON EMULSIONS MULTIPLE EMULSIONS NANOPARTICLES RESEALED ERYTHROCYTES MICROSPORES MAGNETICALLY MODUL A TED DRUG DELIVERY

12. 1. LIPOSOMES Liposomes were first described by Bangham in 1965. The name liposome is derived from two Greek words: 'Lipos' meaning fat and 'Soma‘ meaning body. Mechanisms of Liposomes: Liposome attaches to cellular membrane and appears to fuse with them, releasing their content into the cell. They are taken up by the cell and their phospholipids are incorporated into the cell membrane by which the drug trapped inside is released 3 . I n case of Liposomes p h a goc y te are taken ce l l, t he up , the phospholipid walls are acted upon by organelles called lysosomes and the active pharmaceutical ingredients are released.

13. APPLICATION OF LIPOSOMES IN PHARMACEUTICAL INDUSTRY Sr. No. Lipo s ome Utility Examples Disease States Treated 1. Sustained- Release Systemic antineoplastic drugs, hormones, corticosteroids, drug depot in the lungs Cancer, bio therapeutics 2. RES Targeting Immuno modulators, vaccines, antimalarials, macrophage-located diseases Cancer, MAI, tropical parasites 3. Site-Avoidance Amphotericin B – reduced nephrotoxicity, doxorubicin – decreased cardiotoxicity Fungal infections, cancer 4. Drug protection Cytosine arabinoside, interleukins Cancer 5. Specific Targeting Cells bearing specific antigens Wide therapeutic applicability

14. Sr. No. Liposome Utility Examples Disease States Treated 6. Extra vasation Leaky vasculature of tumours, inflammations, infections Cancer, bacterial infections 7. Accumulation Prostaglandins Cardiovascular diseases 8. Enhanced penetration Prostaglandins Cardiovascular diseases 9. Drug depot Lungs, subcutaneous, intramuscular, ocular Wide therapeutic applicability

15. 2. NIOSOMES A Nios o m e ionic surfactant-based fo r m ed m o s tly i s a non- V es icle by nonionic surfactant and an ex c i p ient. T h e y cholester o l i n co r pora t ion as are structurally similar to liposomes in having a bilayer, however, they are more stable than liposomes .

16. APP LI C A TIO N S OF NIOSOMES Drug T a r geting Anti- ne o pla s t i c T rea t m e n t Leishmaniasis Delivery of Peptide Drugs Studying Immune Respon s e T ra n sder m al Drug Delivery Systems Carriers for H ae m oglobin O phthal m ic drug delivery

17. 3. SUBMICRON EMULSIONS Submicron emulsion can be defined as emulsions with mean droplet diameters ranging from 50 to1000 nm. Usually, the average droplet size is between 100 and 500 nm. The globules can exist as water-in-oil and oil-in-water forms, where the core of particle is either water or oil, respectively . Limitation of submicron emulsion The main limitation of submicron emulsion is use of high amount of surfactant and cosurfactant that may be harmful for human consumption.

18. ADVANTAGES OF SUBMICRON EMULSION [7] Th e r m od y namic a lly Stable Ease of m anufa c tur i ng and scale-up Improved drug solubilization & bioavailability Wide application in colloidal drug delivery systems

19. 4. MULTIPLE EMULSIONS Multiple emulsions are the emulsion systems in which the dispersed phase contains smaller droplets that have the same composition as the external phase. This is made possible by “Double Emulsification”. There are 2 types of Multiple Emulsions : MULTIPLE EMULSI O NS Oi l - i n -wate r - i n - oil (O/W/O) emulsion system W a t e r - i n - oi l - i n - water (W/O/W) emulsion system

20. BIOMEDICAL & PHARMACEUTICAL APPLICATIONS OF MULTIPLE EMULSIONS Sr. No. Applications Drugs Entrapped (Examples) 1. Enhanced Oral Bioavailability Heparin, Insulin, Griseofulvin 2. Masking Action Chlorpromazine HCL, Chloroquin 3. Enzyme Immobilization Urease, Lipase, Amylase, Pancreatic enzymes 4. Vaccine Adjuvants Influenza virus, Tetanus toxoid 5. Drug over Dosage treatment Salicylates, Barbiturates, Quinine sulphate 6. In Cancer therapy & drug targeting Methotrexate, Cysteamine, Adriamycin HCl 7. Other Applications Food & Cosmetics

21. 5. NANOPARTICLES

22. P o l y saccharides Proteins Syn t he t ic po l y m e r s Rolland et. al ., (1989) designed a site specific drug delivery system consisting of polymetacryclic nanoparticles. The main goal in designing nanoparticles as a delivery system are to control size of particle, surface characteristics and discharge of pharmacologically active agents in order to achieve the site specific action of the drug at the therapeutically optimal rate and dose regimen. P r epara t ion PARTICLE SIZE 1.Ultrafine particles -1 and 100 nm in size. 2.Fine particles -100 and 2,500 nm. 3.Coarse particles -2,500 and 10,000 nm .

23. METHODS OF P R E P A R A T I O N Solvent Eva p o r a t ion Nano Prec i pita t ion E m ulsific a t i o n / Solvent Diffusion Salting Out Dialysis S u pe r cri t i c al Fluid Technology (SFT)

24. APPL I C A T I ONS Cancer therapy MATERIAL PURPOSE Poly (alkyl cyanoacrylate) Targeting, reducing toxicity, enhanced nanoparticles with anti cancer agents, uptake of anti tumour agents, oligo nucleotides improved invitro and invivo stability Intracellular targeting Poly (alkyl cyanoacrylate) polyester Target reticuloendothelial intercellular nanoparticles with anti parasitic or infections Prolonged systemic circulation anti viral agents Poly esters with adsorbed ethylene glycols or pluronics poly Prolonged systemic drug effect, avoid uptake by the reticuloendothelial system Vaccine adjuvant Poly (methyl methacrylate) Enhanced immune response alternate nanoparticles with vaccines (oral and acceptable adjuvant Peroral absorption IM immunization) Poly (methyl nanopart i cl e s w i th therapeutic agents p rot e c t ion m e tha cr y l a te ) En h anced bioav a ila b i l i t y proteins and from GIT enzymes

25. Ocular delivery Po l y ( m e t h y l nanoparticles with inflammatory agents, anti-bacterial agents for glaucoma m e t h a c r y l a t e) I m proved re t e n t i on of dru g / steroids , anti- reduced wash out Oligonuleotide delivery of Algin a te nano p ar t icles , po l y ( D,L – Enh a nc e d de l iv e r y lactic acid) nanoparticles oligonucleotides DNA delivery DNA - gela t in nano p ar t i c l es, DNA - Enhan c ed d e l ive r y and chitosin nanoparticles significantly higher expression levels Other applications Po l y ( a l k yl c y a noa c r y l a t e ) Cros s es blood-brain nanoparticles with peptides Poly (alkyl immunoassays, b arri e r , improved cyanoacrylate) nanoparticles, absorption and permeation for nanop a rticl e s w i th adsorbed e nz y m es, tr a nsder m al ap p l i c a t i ons, nanoparticles with radioactive or enzyme immunoassays, radio contrast, copolymerized peptide imaging agents, oral delivery of nanoparticles of activated peptides peptides

26. 6.RESEALED E R Y T HROCY T ES Erythrocytes, the most abundant cells in the human body, have potential carrier capabilities for the delivery of drugs. Erythrocytes b i o d e grad a bl e , are b i oc o m pat i ble, po s sess v e ry l ong circulation half lives and can be loaded with a v a ri e ty of c he m i c a l ly biologically active compounds a nd us i ng various chemical and physical methods. Application of erythrocytes as promising slow drug release or site- targeted delivery systems for a variety of bioactive agents from different fields of therapy has gained a remarkable degree of interest in recent years.

27. METHO D S OF DRUG LOADING Osmotic Shock T urb u lence Shock Erythrocyte Sedi m entation Rate (ESR) Use of red cell loader H y poton i c dilution Chemical perturbati o n of the membrane Entrap m ent by endoc y tosis Loading by electric cell fusion Load i ng by lipid fusion

28. APPLICATIONS OF RESEALED E R Y THROC Y TES [9] Slow drug release Enzyme de f i c i e ncy / r eplacement therapy T reat m ent of hepatic tumors Treatment of parasitic diseases Removal of RES iron overload Removal of toxic agents Delivery of antiviral agents Enzy m e therapy I m p r o v e m ent in oxygen delivery to tissues Microinjection of m acr o m olecules

29. 7.MICROSPHERES Microspheres as carriers of drug become an approach of controlled release dosage form in novel drug delivery system. Microspheres are sometimes referred to as microparticles. Microspheres can be prepared from various natural and synthetic materials. Polymer microspheres, Glass microspheres and ceramic microspheres are commercially available. [1] Common types of polymer microspheres :- 1.Polyethylene microspheres 2. Polystyrene microspheres

30. APPLICATIONS [8] In vaccine delivery In immune system Targeting using m i c ropart i cu l a t e carriers Magnetic microspores Immuno- m i c rospher e s Chemo- emboli z a t ion Imaging Micr o -sponges Surface modified m i c rospher e s

31. 8. MAGNETICALLY MODULATED DRUG DELIVERY Magnetic drug delivery is a novel approach to deliver drug using engineered ‘smart’ micro carriers which appears to overcome a number of limitations facing current methods of delivering medicines. Principle of Magnetism for micro particles Magnetic carriers are normally grouped according to size. At the lower end, we have the ferrofluid s, which are colloidal iron oxide solutions. Encapsulated magnetite particles in the range of 10–500 nm are usually called magnetic nanospheres and any Magnetic particles of just below 1–100µm are magnetic microspheres. In general, magnetic liposomes are also included when speaking about magnetic carriers

32. M e chanism The release of macromolecules from EVAc systems without magnetic beads, suggests that molecules with molecular weight greater than 300 cannot permeate the polymer. The direct incorporation of macromolecules in the polymer-macromolecule using cast procedure caused a tortuous and complex series of pores formation within the matrix. The release rates are determined by factors affecting permeation of water into the polymer and drug out of these pores . Applications of MMDD Contraceptive Drug Delivery I n f u sion Pumps I m plants

33. SITE SPECIFIC DRUG DELIVERY Brain Bone marrow P u l m o n ary Colon t a r geted Transdermal V agina Ocular drug delivery Oncology Gastro- Retentive Drug Delivery

34. 1.BRAIN T ARGETED DRUG DELIVE R Y

35. Rate-limiting role of the BBB in brain drug development : BBB have efficient ability to restrict and separate the human brain from circulatory network & also limits the transport of water and lipidsoluble substances from blood circulation into CNS.

36. Osmotic & Chemical opening of BBB By passing the BBB Direct invasive methods Various pharmacological agents to unblock the BBB Strategies utilized to manipulate BBB to target brain

37. Brain Targeting T ec h n o l o g i e s T ransnasal Route Liposomes Nanopart i c l es Intra t hecal Delivery Intra Cerebro- ventricular Delivery Sustained and con t rol l ed release of drugs

38. 2.PULMONA R Y TARGETING OF DRUGS [11]

39. PR O D U CTI O N OF DRUG PARTICLES Mi c ron iza t ion Spray freeze drying Supercritical Fluid Crystall i zat i on Double Emulsion/ Solvent Evapora t ion Spray drying

40. ME C H A N I SM I m pacti o n Interception Diffusion Sedimentation

41. DRUG DELIVERY DEVICES Metered Dose Inhalers Dry Powder Inhalers Nebulizers

42. 3.TRANSDERMAL DRUG DELIVERY

43. The transdermal drug delivery system is a therapeutic system designed to transfer drugs through intact skin for systemic treatment & it offers controlled drug release pattern by a simple application to the skin surface, eliminating the gastrointestinal absorption associated with oral administration and providing for more efficient drug utilization. COMPONENTS OF TRANSDERMAL DEVICES

44. T E CH N OLOGI E S Membrane Per m ea t ion Controlled Adhesive Type Matrix Type Micro- re ser v oir P o r o plast i c or Moleculon Type

45. APPLICATIONS Angina Pectoris eg . nitrogly c erine Smoking Cessation eg . nicotine P o s t - m enstr u al syndrome eg.climaderm Hypogonadism eg . T es t ost e r o ne

46. 4. DRUG TARGETING TO BONE MARROW

47. Development of effective targeted bone marrow drug delivery systems is an important goal for development of diagnostic, protective, and therapeutic agents for hematopoietic disorders and infectious diseases in which colonizing pathogens are difficult to eradicate. D I S E A S ES CURED Aplastic Anae m ia Hodgkin ’ s disease L e uka e m ia Multiple M y e l o m a Thalassemia Peripheral stem cell tr a nsplan t s

48. C A R R IE R S [13] Liposomes Na n o p art i c l es of dendritic molecule M i cr o sphe r es Branched p o l y pe p t i de Porous silicon pa r t i c l es Polymer Co m plex

49. 5.COLON/ORAL T ARGETED DRUG DELIVERY [16]

50. To achieve successful colonic delivery, a drug needs to be protected from absorption and /or the environment of the upper gastrointestinal tract (GIT) and then be abruptly released into the proximal colon, which is considered the optimum site for colon- targeted delivery of drugs.

51. C A R R IERS NANOPARTICLES MICRO S P HERES H Y DR O GELS LIP OS O M ES BIOADHES I VES MICRO - EMULSI O N

52. D I S E A S ES CURED I N F L AMM A T O R Y BOWEL DISEASE CRO H N’S DISEASE IRRITABLE BOWEL S Y N D R O M E (IBS) A N GI N A A S THMA A R THRITI S

53. APPROCHES pH dependent delivery Pressure de p en d ent delivery Bacteria de p en d ent delivery Time de p en d ent delivery P u ls a t i le System

54. 6.OCULAR DRUG DELIVERY

55. MECHANISM [ ocuserts]

56. DI S EASES CURED Co n ju n c t ivi t is B l ep h ari t is Keratitis Ca t aract I r i t is Glaucoma

57. 7.VAGINAL DRUG DELIVERY

58. Vaginal drug delivery system offers an avenue for the release of different antifungal, antibacterial and contraceptive drugs. Conventional vaginal dosage forms have several benefits like :- 1.Avoid the first pass metabolism Easy to formulate Self administration is possible 4 . Eco n o m i c al. DOSAGE FORMULATIONS Controlled/ Sustained release vaginal tablets Vaginal Nanopart i c l es Vaginal Microsphe res V ag i nal Rings

59. APPLICATIONS Contraceptive Pro g estero n e Deficiency En d o m etriosis Vaginal yeast infections Infertility Post Men o pause atrophy

60. 8.ONCOLOGY DRUG DELIVERY SYSTEM

61. Targeted drug delivery in oncology provides a localized and prolonged drug delivery to the affected organ or tissues.The treatment of cancer depends upto the stage to which the cancer has progressed.

62. CAR R IERS BIOPOLYMERS E M U L S I ONS LIPOSOMAL HYDR O G EL S MICROPARTICLES PO L Y ET HY LE NE GLYCOL CONJUGATION

63. DIS E AS E S CURED KAPOSI'S S A R C OMA O V ARIAN CANCER MULTIPLE MYEL O MA LUNG C A NC E R BREAST C AN CER

64. 9.GASTROR E TEN T IVE DRUG DELIVERY

65. Gastroretentive drug delivery is an approach to prolong gastric residence time, thereby targeting site-specific drug release in the upper gastrointestinal tract (GIT) for local or systemic effects . FACTORS CONTROLL I NG GASTRIC RETENTION Density of dosage forms Density of dosage forms Food intake and its nature Effect of gender, posture and age

66. A P P ROA C HE S High density (sinking) system or non- floating system F loating drug d e live r y systems Non- e f f e rv e s c e nt Systems H y dro d y n a mi ca l l y balanced systems Microballoons / Hollow microspheres Al g inate beads Effervescent (gas generating) systems Bioadhesive or Mucoadhesive drug delivery systems Super porous h y dro g e l systems M a g n e tic Systems

67. COM M ON L Y USED DOSAGE FORMS Float i ng tablets Floating Capsules Floating Mi c rospheres Floating Granules Floating Powders Float i ng Films

68. FORMULATION OF FLOATING HOLLOW MICROSPHERE OR MICROBALLOON

69. Sr. no. Name of preparation : M a nu f act u r er Type / Mode of delivery Uses Image 1. Depocyt : Pacira Pharmaceuticals Liposome Injection / Oral delivery Intrathecal treatment of l y m pho m a t ous meningitis. 2. Estrasorb : Graceway Pharmaceuticals Topical emulsion / Topical delivery Treatment of moderate to severe vasomotor symptoms due to menopause 3. Onivyde : Merrimack Pharmaceuticals Liposome injection / Intr a venous delivery In combination with fluorouracil and leucovorin, for the treatment of metastatic adenocarcinoma of the pancreas

70. 4. Marqibo : Talon therapeutics Liposomal injection / in t ravenous infusion Acute l y m phoblastic leukemia 5. Mepact : IDM Pharma Liposomal injection / in t ravenous infusion Treatment of high-grade resectable non- metastatic osteosarcoma 6. DaunoXome : Gilead Sciences Liposomal injection / in t ravenous infusion First line cytotoxic therapy for advanced HIV-associated Kaposi's sarcoma 7. Doxil : Ben Venue Laboratories Liposomal injection / in t ravenous infusion Ovarian cancer AI D S -re l a t ed Kaposi’s Sarcoma Multiple Myeloma

71. Type Segment Analysis : 1.Nano Tubes 2.Nano Wires 3.Nano Shells 4.Quantum Dots 5.Nano Pros Applications Segment Analysis : 1.First Order Targeting (Organ Compartmentalization) 2.Second Order Targeting (Cellular Targeting) 3.Third Order Targeting (Intracellular Targeting)

72. The current focus in pharmaceuticals is shifting to a ‘smart drug’ paradigm, in which increased efficacy and decreased toxicity are the motivating factors. Rationally designed drug delivery system enables us to precisely control drug release rates for prolonged duration and sometimes help targeting the drugs such as anti cancer agents to specific body sites. Only in recent years, the idea of development of such systems became practical. In a short time, targeted drug delivery systems have had an impact on nearly every branch of medicine.

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