New drug delivery system

New drug delivery system

1. New Drug Delivery System D r . Ashishkumar Baheti Md Pharmacology

2. Introduction A therapeutic system is defined as a drug containing preparation or a device that releases one or more drugs continuously in a predetermined pattern for a fixed period of time either systemically or to a specified target organ.

3. Classical drug delivery Problems associated with this approach Reduced potencies because of partial degradation. Toxic levels of administration. Increase costs associated with excess dosing. Compliance issue due to administration pain. Show significant fluctuations in drug levels.

4. Why newer drug delivery system ? Deploy to a target site to limit side effects. Shepard drugs through specific areas of the body without degradation. Maintain a therapeutic drug level for prolonged periods of time. Predictable controlled release rates. Reduce dosing frequency and increase patient compliance.

5. Classification 1) Nonbiological DDS a) Oral DDS b) Transdermal DDS c) Ophthalmic DDS d) Intranasal Drug Delivery system e) Respiratory DDS

6. Cont. 2) Biological DDS a) Liposomal DDS b) Transfersome c) Monoclonal Antibodies d) Microspheres

7. OROS (Oral Osmotic System) Osmotic core containing drug surrounded by a semipermeable membrane with a delivery orifice Safe and effective delivery of theophylline (treatment of asthma) Other example: Metoprolol Nifedipine

8. ADVANTAGES Continuous and constant rate of drug delivery. Drug with shorter T1/2 can be used. GIT mucosa not damaged. Gastric enzyme degradation can be overcome. Good compliance.

9. Disadvantages Subject to dose dumping if membrane breaks [e.g. someone chews it] Slightly more expensive to formulate than coating tablets Possible hole plugging

10. GITS Slowly releases drug into the intestinal tract over a 24 hour period. Based on Push Pull Method. Example : Nifedipine , Doxazosin

11. Intragastric floating tablets Contains drug homogenously dispersed in hydrocolloid Action: Hydrocolloid absorbs fluid –colloid gel formed –drug released by diffusion Eg: Valium tab  Drug 

12. pH sensitive DDS Targeted drug delivery at selected pH range in GIT Prepared by coating drug with pH sensitive polymer like Ethyl cellulose Eg: Nisoldipine

13. Transdermal DDS A transdermal drug delivery device, is a device which provides an alternative route for administering medication, allowing for pharmaceuticals to be delivered across the skin barrier In 1979 first transdermal scopolamine patch for motion sickness was approved by USFDA .

14. Basic Components of Transdermal Systems The components of transdermal devices include: 1. Polymer matrix or matrices. 2.  The drug to be delivered 3.  Permeation enhancers 4. Other excipients

15. Advantages First pass metabolism avoided. Maintains constant blood drug levels. Improves bioavailability. reduced frequency of drug administration. Reduced side effects. Easy to discontinue the drug. Increased patient compliance. Noninvasive.

16. Mechanism of action Transdermal permeation of a drug involves the following steps: 1. Penetration of stratum corneum.      2.Permeation of drug through viable epidermis      3. Uptake of the drug by the capillary network in the dermal papillary layer.

17. Routes Transappendageal Transepidermal Intracellular Intercellular

18. Factors affecting transdermal DDS 1) Biological factors Thickness and integrity of stratum corneum Site of application Skin hydration Blood flow in that region

19. Contd. 2) Physicochemical Size of drug molecule Membrane permeability pH of the drug Drug metabolism by skin flora Lipid solubility Drug depot

20. Polymer Matrix The Polymer controls the release of the drug from the device. polymers for transdermal devices are: a) Natural Polymers: e.g. Cellulose derivatives, Zein, Gelatin, Shellac, Waxes, Proteins, Gums and their derivatives, Natural rubber, Starch etc. b) Synthetic Elastomers: e.g. Polybutadieine, Hydrin rubber, Polysiloxane, Silicone rubber, Nitrile, Acrylonitrile, Butyl rubber, Styrenebutadieine rubber, Neoprene etc. c) Synthetic Polymers: e.g. Polyvinyl alcohol, Polyvinyl chloride, Polyethylene, Polypropylene, Polyacrylate, Polyamide, Polyurea, Polyvinylpyrrolidone, Polymethylmethacrylate, Epoxy etc.

21. Drug Physicochemical properties The drug should have a molecular weight less than approximately 1000 daltons. 2. The drug should have affinity for both – lipophilic and hydrophilic phases. 3. The drug should have low melting point.

22. Permeation Enhancers classified as:   a) Solvents water alcohols – methanol and ethanol; alkyl methyl sulfoxides   b) Surfactants Anionic Surfactants: e.g. Dioctyl sulphosuccinate, Nonionic Surfactants: e.g. Pluronic F127, Pluronic F68, etc. Bile Salts: e.g. Sodium ms taurocholate, Sodium deoxycholate, Biary system: . Propylene glycol-oleic acid and 1, 4-butane diol-linoleic acid.

23. TYPES OF TRANSDERMAL PATCHES Single-layer Drug-in-Adhesive  This system is characterized by inclusion of drug directly within the skin-contacting adhesive. . The rate of release of drug from this type of system is dependent on the diffusion across the skin.

24. Multi-layer Drug-in-Adhesive      This is similar to Single-layer Drug-in-Adhesive in that drug is incorporated directly into the adhesive but has addition of a membrane between two layers or addition of multiple drug-in-adhesive layers under a single backing film.

25. Drug Reservoir-in-Adhesive The system design has inclusion of a liquid compartment containing a drug solution/suspension separated from release liner by semi-permeable membrane and adhesive.

26. Drug Matrix-in-Adhesive The system has inclusion of semi-solid matrix containing drug solution/ suspension which is in direct contact with the release liner.

27. Transdermal Drug Delivery (TDD)

28. Examples of transdermal patch Scopolamine for motion sickness. Nicotine for tobacco cessation. Estrogen for menopausal symptoms. Nitroglycerin for angina. Lidocaine to relieve peripheral pain for shingles( Herpes Zoster). Fentanyl for cancer pain control.

29. OCUSERT Pilocarpine, a parasympathomimetic agent for glaucoma Acts on target organs in the iris, ciliary body and trabecular meshwork Ethylene-vinyl acetate copolymer Carrier for pilocarpine : alginic acid in the core of Ocusert White annular border :EVA membrane with titanium dioxide (pigment) (easy for patient to visualize)

30. Fig. 6. Schematic diagram of the Ocusert.

31. Contd. Advantages Drug application convenient (Once a week) Stabilization of Diurnal variation in IOT. Guard against dangerously high IOT due to irregularly instilled drops. Disadvantages Foreign body sensation Difficulty in retention of the device Increased cost Detailed instruction.

32. Lacrisert Patients with dry eyes (keratitis sicca) A substitute for artificial tears Placed in the conjunctival sac and softens within 1 h and completely dissolves within 14 to 18 h Stabilizes and thickens the precorneal tear film and prolongs the tear film break-up time

33. Intranasal Drug Delivery Nasal delivery Ayurvedic system of East India Psychotropic drugs and hallucinogens in South America Proteins and peptides delivery Advantages of nasal delivery Lower doses More rapid attainment of therapeutic blood levels Quicker onset of pharmacological activity Fewer side effects

34. Examples of Intranasal Drug Delivery Systems Intranasal sustained-release formulation Nasal absorption with Clofilium tosylate, enkephalin analogs Tobispray Dry, metered-dose nasal aerosol Vasoconstrictor (tramazoline), steroid (dexamethasone isonicotinate), antibiotic (neomycin sulfate)

35. RESPIRATORY DDS ADVANTAGES AVOIDS FIRST PASS METABOLISM RAPID ONSET OF ACTION CONTROLLED RATE OF ADMINISTRATION POSSIBLE

36. Aerosol drug delivery system The ideal size for a therapeutic aerosol should not be more than 5 µm to penetrate into the tracheo-bronchial tree and smaller airways if peripheral deposition is required. It includes: 1)Metered dose inhaler 2) Dry powder inhaler 3) Jet nebulizer

37. Pharmaceutical Aerosols: Cromolyn Sodium Aerosol Use: Anti-asthmatic ;Anti-allergic Amyl nitrite inhalant : Use: Vasodilator Propylhexadrine inhalant : Use: Nasal Decongestants Metaproterenol sulfate inhalation aerosol : Use: Bronchodilator Tuaminoheptane inhalant : Use: Vasoconstrictor

38. Inhaled Insulin approved in January 2006 by FDA. approved for those over 18 years of age with diabetes short-acting powder form of insulin that is inhaled before each meal Side effect -coughing, shortness of breath, sore throat and dry mouth

39. What is a liposome? A liposome is a spherical vesicle with a membrane composed of a phospholipid and cholesterol bilayer . hydrophilic Hydrophobic

40. Modes of Liposome/Cell Interaction Adsorption Endocytosis Fusion Lipid transfer

41. Why Use Liposomes in Drug Delivery? Drug Targeting can be achieved. Pharmacokinetics - efficacy and toxicity. Decrease harmful side effects. Increases duration of action and decrease frequency of administration. Protects drug

42. Classes of Liposomes Conventional Long circulating Immuno Cationic

43. Problems with conventional liposomes Tendency of liposome to localize in the RES may cause RES impairment Short circulation time Rapid uptake by liver and spleen prevents specific targeting

44. Immuno liposomes Antibodies or ligands are attached to the liposome surface to increase the binding to specific epitopes/ receptors on target cells Stealth liposomes: Formulated to escape RES and increase the circulation time. Polymers, polyethylene glycols,synthetic phospholipids are used to coat liposomes

45. Uses of stealth liposomes Targeting anticancer drugs to cancer sites. Depot applications for prolonged therapy periods. For diseases of vascular origin e.g.- haematological malignancies.

46. Liposomes Help Improve Rapid metabolism Therapeutic index Unfavorable pharmacokinetics Low solubility Irritation Lack of stability

47. Doxil Chemotherapy drug doxorubicin Anemia, damage to veins and tissue at injection, decrease platelet and WBC count, toxic to Treats Kaposi’s sarcoma lesions or cancer tumors Modifications of liposome “stealth” keeps doxorubin in blood for 50 hours instead of 20 minutes concentrates at KS lesions and tumors

48. Amphotericin B Side effects: nephrotoxicity, chills, and fever Systemic fungal infections in immune compromised patients AmB - kills ergosterol-containing fungal cells, also kills cholesterol-containing human cells

49. No decrease in effectiveness of drug against fungi Liposomal Formulation of AmB Decrease in toxicity Exact Mechanism of liposomes not understood Diffusion Lipid transfer AmB Lipid

50. Problems with Liposomal Preparations of Drugs cost Lack long term stability (short shelf life) Physical and chemical instability Freeze dry and pH adjustment Low “Pay Load” - poor encapsulation Possibility of new side effects Doxil “hand and foot syndrome” Efficacy CFTR

51. CFTR Gene Therapy Delivers cDNA of Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) to epithelial tissue of respiratory system Fuse to cell membrane and incorporate cDNA into cell Clinical trials - no significant change in symptoms Now trying adeno associated virus Cationic liposome

52. Uses Anticancer Drugs- Anti bacterial- Antiviral- DNA material- Enzymes- Radionuclide- Fungicides- Vaccines - Duanorubicin Triclosan, Clindamycin AZT cDNA – CFTR Hexosaminidase A In-111, Tc-99m Amphotericin B Hepatitis B antigen, Rabies virus glycoprotein

53. Studies with insulin show that liposomes may be an effective way to package proteins and peptides for use Clinical Trials for several liposomal formulations More studies on the manipulation of liposomes Future

54. Transfersomes Deformable and ultraflexible artificial lipid vesicle. It delivers drugs or genetic material into a cell. Its bounding membrane is more flexible than that of a liposome. penetrates the skin when applied nonocclusively. Affinity to bind and retain water.

55. Monoclonal Antibodies Antibodies that are identical because they are produced by one type of immune cell, all clone of a single parent cell. These monoclonal antibodies specifically bind to particular substance. They can then serve to detect or purify that substance.

56. The types of mAb designed Murine source mAbs: rodent mAbs with excellent affinities and specificities. may lead to allergic or immune complex hypersensitivities. Chimeric mAbs: chimers combine the human constant regions with the intact rodent variable regions. Also cause human antichimeric antibody response (30% murine resource) Humanized mAbs: contained only the CDRs of the rodent variable region grafted onto human variable region framework

57. Evolution of Therapeutic Antibodies

58. Types of monoclonal antibodies Naked monoclonal antibodies -- those with no drug or radioactive material attached to them Most widely used at present. Conjugated monoclonal antibodies -- those joined to chemotherapy drugs, radioactive particles or toxins

59. Rituximab Chimeric monoclonal antibody that targets the CD20 B-cell antigen. This antigen is expressed on 90% of B-cell neoplasms This antibody thus leads to the elimination of all B-cells from the body (including cancerous ones), allowing new, healthy B-cells to be produced from lymphoid stem cells.

60. Trastuzumab Humanized monoclonal antibody Acts on HER2/neu (erbB2) receptor , which is overexpressed in breast cancer. Such cells, when treated with Herceptin, undergo arrest in the G1 phase of the cell cycle and experience a reduction in proliferation. This can reduce the rate of relapse of breast cancer by 50% during the first year.

61. Other monoclonal antibodies Monoclonal antibodies Antigen Target Type Alemtuzumab CD52 Humanized Daclizumab CD25 α subunit Humanized Gemtuzumab CD33 Humanized Cetuximab EGFR (ErbB - 1) chimeric Bevacizumab VEGR Humanized

62. Obstacles to the use of monoclonal antibodies in cancer treatment Antigen distribution of malignant cells is highly heterogeneous, so some cells may express tumor antigens, while others do not. Tumor blood flow is not always optimal High interstitial pressure within the tumor can prevent the passive monoclonal antibody from binding.

63. Monoclonal antibodies- cytotoxic conjugate Gemtuzumab ozogamicin (Mylotarg): Humanized monoclonal antibody against CD33. Covalently linked to caicheamicin, a potent antitumour antibiotic. Following binding to CD33, Gemtuzumab ozogamicin undergoes endocytosis with cleavage of caicheamicin within the lysosome which then enter the nucleus.

64. Radioimmune conjugates They provide monoclonal antibody targeted delivery of radioactive particles to tumour cells I -131 is commonly used isotope. The gamma particles emitted by I -131 can be used for both imaging and therapy Immunotoxin Denileukin deftitox – made from the genetic recombination of IL – 2 and the catalytically active fragment of diphtheria toxin. Approved for the treatment of recurrent T- cell lymphoma.

65. Microspheres They are roughly cellular but not living, molecules similar to a cell They are mainly used for cancer therapy and targeted drug delivery

66. Contd. Essentially solid porous particles (1 - 100 micrometer diameters). Can be made from a broad range of polymeric materials, including proteins, polysaccharides, polyesters and lipids. Can both target their drug cargo by physical trapping in blood vessels (chemoembolisation) and sustain the action of a therapeutic agent through controlled release. Doxorubicin, mitomycin C, cisplatin and 5-fluorouracil

67. Drug-Eluting Stents (DESs) Bare metal stent coated with a drug-polymer matrix Local and controlled delivery of drugs to stop restenosis So far, only TWO FDA approved DESs in USA 1) CYPHER Sirolimus-eluting Coronary Stent 2) TAXUS Paclitaxel-Eluting Coronary Stent

68. How Sirolimus Works ? Lipophilic Rapidly crosses smooth muscle cell membranes Solubility in blood very low Binds to intracellular receptor proteins FKBP12, FRAP,mTOR Reduces T – Cell proliferation and macrophage function

69. Paclitaxel Used as a anti-proliferative drug in Cancer treatment Highly lipophilic and diffuses extremely well into arterial tissues Smooth muscle cells are more sensitive to paclitaxel than endothelial cells Paclitaxel is dosed to block smooth muscle cell proliferation and migration

70. Viral vectors Viruses have evolved a way of encapsulating and delivering genes to human cells in a pathogenic manner. Scientist are attempting to take advantage of natures delivery system. Viruses would be genetically altered to carry the desired normal gene and turn off the natural occurring disease within the virus.

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