Clinical research unit 1

Drug development is the process of bringing a new pharmaceutical drug to the market once a lead compound has been identified through the process of drug discovery. It includes preclinical research on microorganisms and animals, filing for regulatory status, such as via the United States Food and Drug Administration for an investigational new drug to initiate clinical trials on humans, and may include the step of obtaining regulatory approval with a new drug application to market the drug
Drug development is considered as a series of well defined steps, culminating, if successful, in market authorization, of the drug

1. DRUG DEVELOPMENT PROCESS Dr. S P Srinivas Nayak Assistant Professor, PIPR Parul University.

2. Definition Drug development is the process of bringing a new pharmaceutical drug to the market once a lead compound has been identified through the process of drug discovery . It includes preclinical research on microorganisms and animals, filing for regulatory status, such as via the United States Food and Drug Administration for an investigational new drug to initiate clinical trials on humans, and may include the step of obtaining regulatory approval with a new drug application to market the drug Drug development is considered as a series of well defined steps, culminating, if successful, in market authorization, of the drug Dr S P Nayak - PARUL UNIVERSITY 2

3. Dr S P Nayak - PARUL UNIVERSITY 3

4. Various Steps Involved in Drug Development Process New drug discovery Preclinical testing Investigational New Drug Application (IND) Clinical Trials (phase I,II,II trails) New Drug Application (NDA) Post Marketing Surveillance / phase IV clinical trials Dr S P Nayak - PARUL UNIVERSITY 4

5. New Drug Discovery Definition : Drug discovery is the process of identifying compounds that have the potential to become useful new therapies Common ways of developing new drugs From natural products e.g. plants and animals changing the chemical structure of existing molecules 3 . Studying disease process 4. Using computers to design new drugs 5. Serendipity : observation by chance e.g. penicillin Dr S P Nayak - PARUL UNIVERSITY 5

6. New Drug Discovery (cont.) The first phase, target selection , involves choosing a disease to treat and then developing a model for that disease AND target validation The second phase, drug selection(Lead identification) , is a process that involves finding a drug or group of drugs that work within that model system and Lead optimization The third phase, product development , is a process that involves discovering a biological target such as a particular enzyme, receptor or ion channel that the scientific team believes may be linked to a pathologic process Dr S P Nayak - PARUL UNIVERSITY 6

7. in 1.dafajhska 11. 2 SCHGA a 1. Identification and validation of biological target 2. Development of assay and screening of large compound collections 3. Optimizing hit compounds to improve efficacy, safety, stability etc. Robotic high throughput screening Safety, pharmacokinetics and pharmaceutics Intellectual property Application of Genomics/ Bioinformatics Compound collection Combinatorial biosynthesis/ chemistry Inputs from the global market/business 4. Selection of final candidate(s) Molecular modelling Figure : The Drug Discovery Process Dr S P Nayak - PARUL UNIVERSITY 7

8. Current Methods Used In Drug Discovery Process This includes - Identification of novel pathways that are associated with disease, selection of target in the pathway and development of screens Screening large compounds and natural compounds (from plants, animal products or microorganisms) for the desired activity Molecular modelling using powerful software graphics and stimulation programs to generate 3D structures of target molecules and model the affinity of different molecules at these targets Dr S P Nayak - PARUL UNIVERSITY 8

9. Current Methods Used In Drug Discovery Process 4. Targeted synthesis, i,e . the creation of original molecules with biological activities that target particular stages of disease process. Researchers design and synthesize molecules that bind to particular locus on a target 5. Combinatorial chemistry consists of systematically modifying and existing compound chemically to act on a selected target. Screening of multiple compounds sometimes produce clue about how structural modification alters the action of a compound . Subsequent chemical modification of a lead compound can result in a compound with enhanced properties, such as improved absorption, enhanced safety, longer duration of action or increased efficacy Dr S P Nayak - PARUL UNIVERSITY 9

10. New technologies that are pivotal to the drug discovery and development Medical genetics : genetic linkage studies are used to sift through the human genome to link genes with particular disease, while genetic association studies are used to look for gene sequences in unselected individuals to determine whether they are more common in one disease than another Combinatorial biosynthesis : it is a technique for modelling and building libraries of chemical compounds for consideration as drug candidates Within these libraries, information system are being designed to link chemical structures with various biological activities Dr S P Nayak - PARUL UNIVERSITY 10

11. New technologies that are pivotal to the drug discovery and development (cont.) Robotic high-throughput screening : using miniaturization and fully automated robotic technology, compounds generated from combinatorial chemistry are tested in primary activity screens, identifying lead compound for further biological testing and chemical optimization Bioinformatics : information systems developed for analysis of biological, particularly genomic data. Bioinformatics is used for gene identification and mapping, comparing sequence data in search of similarities, linking genes with their associated proteins and biological functions. Ultimately , it is used to identify and validate new targets and to model disease processes Dr S P Nayak - PARUL UNIVERSITY 11

12. Preclinical Testing Preclinical tests are performed in laboratory, using a wide array of chemical and biochemical assays, cell culture and animal models. The pharmacological activity of every new compound is carefully analyzed Preclinical testing involves : Pharmacology testing Toxicology testing Animal Pharmacokinetics testing Dr S P Nayak - PARUL UNIVERSITY 12

13. Pharmacology testing These are the studies to explore the pharmacological activity and therapeutic potential of compounds. These tests involve the use of animals, isolated cell cultures and tissues, enzymes and cloned receptor sites as well as computer models If the results of the test suggest potential beneficial activity, related compounds (each a unique structural modification of the original) are tested to see which version of the molecule produces the highest level of pharmacological activity and demonstrates the most therapeutic promise, with the smallest number of potentially harmful biological properties Dr S P Nayak - PARUL UNIVERSITY 13

14. Pharmacology testing (cont.) Animal pharmacology studies allow the effects of the lead compound on the disease process ( pharmacodynamics ) to be corelated with the concentration of compound needed to achieve these effects ( pharmacokinetics ) Animal pharmacology testing is performed in animal models of human disease. Animal model of human disease may occur : 1. Naturally i.e , squirrel monkeys develop dementia in old age that is behaviorally and histologically similar to Alzheimer's disease in humans Dr S P Nayak - PARUL UNIVERSITY 14

15. Pharmacology testing (cont.) 2. By introduction of genetic defect in germ cells of an animal strain so that its reproduction produces off springs with the disease of interest. For example, introducing a mutation that prevents the serotonin 2C receptor from functioning results in animals that exhibit anxiety 3. Using toxins that selectively destroy a particular type of cells. Eg : administrating the neurotoxin MPTP selectively destroys dopaminergic neurons in the brain, producing Parkinson's like disease state Dr S P Nayak - PARUL UNIVERSITY 15

16. Toxicological testing Toxicological studies will be carried out in both in vitro and on animal species known to have drug metabolism and disposition parameters (the fate of the drug in the body) resembling those in humans, although the pharmaceutical industry is always striving to replace animal experiments with meaningful In vitro studies (such as the Ames test) Toxicology and safety testing determine the potential risk a compound poses to man and the environment Generally, two or more species ( one rodent, one non-rodent) are tested because a drug may effect one species differently from another Dr S P Nayak - PARUL UNIVERSITY 16

17. Toxicity studies are done to calculate : Maximum tolerated dose Gross pathology to indicate target organs Satisfactory therapeutic with regard to animal efficacy studies They are conducted to : Select or reject lead candidate General indication of suitability Dose selection and guidance to clinician Toxicological testing (cont.) Dr S P Nayak - PARUL UNIVERSITY 17

18. Types of Toxicology Investigations Toxicity Studies Required for Complete Preclinical Development of the Drug Types Duration of the study Acute toxicity 2 week studies in 3-4 species to determine maximum tolerated dose Sub- acute toxicity 6 month studies in 2 species Chronic toxicity Up to 12 month studies in rats and a non rodent to determine If adverse effects occur with repeated daily dosing Oncology studies- at least 18 months in mice - 2 years in rat Dr S P Nayak - PARUL UNIVERSITY 18

19. Types Duration of the study Reproductive Up to 9 month studies in 2 species to determine effects of drug on fertility and reproduction and expose any teratogenic effects Mutagenic 18-24 month in vitro and in vivo studies Types of Toxicology Investigations cont. Toxicity Studies Required for Complete Preclinical Development of the Drug Dr S P Nayak - PARUL UNIVERSITY 19

20. If the results of these toxicity studies indicate that the range between biological activity and toxicity is acceptable, the company will apply to the relevant regulatory body for permission to continue development (example: if the regulatory body is the FDA, an Investigational New Drug (IND) application can be filed at this stage) Acceptable Toxicity Extensive toxicity studies ensure that drugs causing serious toxicity do not reach the market- unless of course, the agent concerned has a potentially life saving role in treating a disease and where no other more suitable drugs are available Toxicological testing (cont.) Dr S P Nayak - PARUL UNIVERSITY 20

21. At present, HIV infection represents such a serious threat to life it is considered acceptable to use drugs to treat it which are rather toxic to human body Animal Pharmacokinetics testing Pharmacokinetic studies are used to measure how much of a drug is absorbed into the blood (drug absorption), how it is broken down chemically in the body, the toxicity of the drug, its breakdown products (metabolites), and how quickly the drug and its metabolites are excreted from the body (excretion) If the compound is successful and continues its progression through the development process, the studies will be repeated in humans Toxicological testing (cont.) Dr S P Nayak - PARUL UNIVERSITY 21

22. Investigational New Drug Application (IND) After completing preclinical testing, the company files an IND with FDA or DCGI in India to begin to test the drug in human INDA (Investigational New Drug Application) is the means through which sponsor (manufacturer or potential marketer) obtain a legal status to call its new investigational molecule as new drug Dr S P Nayak - PARUL UNIVERSITY 22

23. Investigational New Drug Application (IND) (cont.) The IND is not an application for marketing approval A sponsor will probably want to ship the investigational drug to clinical investigators in many states, it must seek an exemption from the legal requirement The IND is the means through which the sponsor technically obtains this exemption from the FDA However, its main purpose is to detail the data that provide documentation to proceed with certain human trails with the drug The IND becomes effective if FDA does not disapprove it within 30 days Dr S P Nayak - PARUL UNIVERSITY 23

24. Investigational New Drug (cont.) Drug developers, or sponsors, must submit an Investigational New Drug (IND) application to FDA before beginning clinical research In the IND application, developers must include: Animal study data and toxicity (side effects that cause great harm) data Manufacturing information Clinical protocols (study plans) for studies to be conducted Data from any prior human research Information about the investigator Dr S P Nayak - PARUL UNIVERSITY 24

25. Investigational New Drug (cont.) Asking for FDA Assistance Drug developers are free to ask for help from FDA at any point in the drug development process, including: Pre-IND application, to review FDA guidance documents and get answers to questions that may help enhance their research After Phase 2, to obtain guidance on the design of large Phase 3 studies Any time during the process, to obtain an assessment of the IND application Dr S P Nayak - PARUL UNIVERSITY 25

26. Investigational New Drug (cont.) Even though FDA offers extensive technical assistance, drug developers are not required to take FDA’s suggestions As long as clinical trials are thoughtfully designed, reflect what developers know about a product, safeguard participants, and otherwise meet Federal standards, FDA allows wide latitude in clinical trial design Dr S P Nayak - PARUL UNIVERSITY 26

27. Investigational New Drug (cont.) FDA IND Review Team The review team consists of a group of specialists in different scientific fields. Each member has different responsibilities Project Manager:  Coordinates the team’s activities throughout the review process, and is the primary contact for the sponsor Medical Officer:  Reviews all clinical study information and data before, during, and after the trial is complete Dr S P Nayak - PARUL UNIVERSITY 27

28. Investigational New Drug (cont.) Statistician:  Interprets clinical trial designs and data, and works closely with the medical officer to evaluate protocols and safety and efficacy data Pharmacologist:  Reviews preclinical studies Pharmakineticist :  Focuses on the drug’s absorption, distribution, metabolism, and excretion processes. Interprets blood-level data at different time intervals from clinical trials, as a way to assess drug dosages and administration schedules Dr S P Nayak - PARUL UNIVERSITY 28

29. Investigational New Drug (cont.) Chemist:  Evaluates a drug’s chemical compounds. Analyzes how a drug was made and its stability, quality control, continuity, the presence of impurities Microbiologist:  Reviews the data submitted, if the product is an antimicrobial product, to assess response across different classes of microbes Dr S P Nayak - PARUL UNIVERSITY 29

30. Investigational New Drug (cont.) The FDA review team has 30 days to review the original IND submission. The process protects volunteers who participate in clinical trials from unreasonable and significant risk in clinical trials FDA responds to IND applications in one of two ways: Approval to begin clinical trials and clinical hold to delay or stop the investigation. FDA can place a clinical hold for specific reasons, including: Participants are exposed to unreasonable or significant risk Investigators are not qualified Materials for the volunteer participants are misleading The IND application does not include enough information about the trial’s risks Dr S P Nayak - PARUL UNIVERSITY 30

31.  If FDA is satisfied that the trial meets Federal standards, the applicant is allowed to proceed with the proposed study The developer is responsible for informing the review team about new protocols, as well as serious side effects seen during the trial. After the trial ends, researchers must submit study reports This process continues until the developer decides to end clinical trials or files a marketing application. Before filing a marketing application, a developer must have adequate data from two large, controlled clinical trials Dr S P Nayak - PARUL UNIVERSITY 31 Investigational New Drug (cont.)

32. Clinical trials/ Clinical Development of Drug The clinical development plan The safety and toxicity data generated from preclinical studies enables the drug company to safely initiate clinical trials Clinical trials on patients in different countries are approved and monitored by different regulatory agencies like: In India, Drug Controller General of India (DCGI) office under Central Drug Standard Control Organization (CDSCO) Dr S P Nayak - PARUL UNIVERSITY 32

33. Clinical trials/ Clinical Development of Drug (cont.) 2. In UK, Medicines and Healthcare products Regulatory Agency (MHRA) , advised by the Committee on Safety of Medicines (CSM) 3. In USA , Food and Drug Administration (FDA) Dr S P Nayak - PARUL UNIVERSITY 33

34. Phases of clinical trials Clinical research is done in four phases (I,II,III and IV), each designed to address different questions The knowledge gained from one phase is assessed before progressing to the next phase However, research in a particular phase may continue after the drug has progressed to further stages of development Dr S P Nayak - PARUL UNIVERSITY 34

35. Phases of clinical trials (cont.) Based on the data gathered from the preclinical trials/ animal testing, the sponsor has some estimation of: The drug’s therapeutic effect and dose levels Toxicity profile and dose levels This information is used in the design of phase I clinical trials Dr S P Nayak - PARUL UNIVERSITY 35

36. Phase 1 The first question in drug research is to find out the safety of drug in humans. Phase I studies, sometimes called as “first in man”, starts to answer this question by testing the investigational product in healthy volunteers If the drug has the potential for toxic adverse events, it may be given only to subjects with the targeted condition to reduce risks to healthy subjects (example: anticancer drugs are never tested in healthy volunteers) Dr S P Nayak - PARUL UNIVERSITY 36

37. Phase 1 (cont.) The main purpose of the initial phase I studies is to establish a safe dosage range During the phase I studies, sufficient information about the drug’s pharmacokinetics (ADME) and pharmacological effects should be obtained to permit the design of well-controlled, scientifically valid, phase II studies Phase 1 studies also evaluate drug metabolism, structure activity relationships, and the mechanism of action in humans Dr S P Nayak - PARUL UNIVERSITY 37

38. Phase 1 (cont.) These are generally conducted on 20-80 healthy human volunteers and typically lasts for 3-6 months Initially, a single small dose is administered to each volunteer in a hospital – type setting ( perhaps a purpose- built unit within/outside the drug company’s premises) so that the effects of the drug can be closely monitored In phase I studies, regulatory bodies (FDA) can impose a clinical hold ( i,e , prohibit the study from proceeding or stop a trial that has started) for reasons of safety, or because of a sponsor’s failure to accurately disclose the risk of study to investigators Dr S P Nayak - PARUL UNIVERSITY 38

39. Phase 1 (cont.) Phase I trials address: How rapidly the drug is absorbed ? Where is the drug distributed in the body? Which organs or organ systems are involved in metabolism of the drug? How quickly is the drug eliminated from the body? Only about 70% of experimental drugs passes Phase I clinical trials Dr S P Nayak - PARUL UNIVERSITY 39

40. Phase 2 Phase I clinical trials gives valuable information about any adverse reactions and fate of the drug in the healthy human body, these parameters may be different in patients suffering from the disease which the drug under test is designed to treat For example: some antibiotics like benzylpenicillin only penetrate into the CSF if the meninges are inflamed whereas penetration is poor in healthy individuals Phase II clinical trials are conducted on patients. The main question asked by Phase II studies is: “ what is the most effective dosage range and is the drug safe within that range?” Dr S P Nayak - PARUL UNIVERSITY 40

41. Phase 2 (cont.) Phase II studies enroll small number of subjects, typically 100 to 300 and the trial may last from 6 months to 2 years The primary aims of Phase II clinical trials are to establish clinical efficacy, determine the incidence of ADRs, define the optimum therapeutic dosage and provide detailed pharmacokinetic and pharmacological data to substantiate the adequate trial of the drug Dr S P Nayak - PARUL UNIVERSITY 41

42. Phase 2 (cont.) Trials on patients may be conducted in an open (non-blind) manner, where the patients know whether they are receiving the drug or whether they are receiving a placebo (an inactive material serving as a negative control) and also as blind trials In single blind trials, only the patients do not know whether they are receiving the drug or the placebo In double blind trials, both the patient and the clinical investigators do not know which agent the patient is receiving Dr S P Nayak - PARUL UNIVERSITY 42

43. Phase 2 (cont.) Phase II trial address: What is the minimum effective dose? What is the maximum tolerated effective dose? Is the drug effective in mild, moderate, and severe cases of the disease or condition? Is the drug effective for all expected indications? Only about 35% of experimental drugs passes Phase II clinical trials Dr S P Nayak - PARUL UNIVERSITY 43

44. Phase 3 Phase III studies are expanded controlled and uncontrolled trials They are performed after preliminary evidence suggesting effectiveness of drug has been obtained in Phase II, and are intended to gather the additional information about effectiveness and safety that is needed to evaluate the overall benefit- risk relationship of the drug Phase III clinical trials may involve several hundreds to several thousand patients and lasts for 1-5 years Dr S P Nayak - PARUL UNIVERSITY 44

45. Phase 3 (cont.) The main aim of this phase is to verify the drug’s effectiveness and any ADRs in a large group of patients over a longer period of exposure, to establish the safety and efficacy of the drug Very often Phase III trials involve different patient sub- groups, such as children, the elderly, and perhaps those with impairments in kidney and liver function Once the Phase III has been completed satisfactorily, the drug company is in a position to apply the marketing application to the regulatory authorities to market the drug Dr S P Nayak - PARUL UNIVERSITY 45

46. Phase 3 (cont.) Phase III trials address: Overall risk-benefit relationship Adverse reactions in large group of patients over a longer period of exposure The ideal dosage regimen Is the drug allowed to be marketed? Only about 25% of experimental drugs passes Phase III clinical trials Dr S P Nayak - PARUL UNIVERSITY 46

47. New Drug Application (NDA) Following the completion of all three phases of clinical trials, the company analyzes all of the data and files an New Drug Application (NDA) with FDA, if the data successfully demonstrate safety and effectiveness The NDA must contain all of the scientific information that the company has gathered NDAs typically run 100,000 pages or more. By law, FDA is allowed six months to review an NDA Dr S P Nayak - PARUL UNIVERSITY 47

48. New Drug Application (NDA) (cont.) In almost all cases, the period between the first submission of an NDA and final FDA approval exceeds that limit; the average NDA review time for new molecular entities approved in 1992 was 29.9 months Submitting an Application Submission of a Marketing Authorization Application ( i.e NDA to FDA) to a Regulatory Authority requires extensive documentation since it covers every aspect of the product development from its initial chemical characterization to its claimed efficacy Dr S P Nayak - PARUL UNIVERSITY 48

49. New Drug Application (NDA) (cont.) The main section of a typical new drug application to the regulatory authorities are: 1. Dossier summary Administrative data; summary of the product characteristics; expert reports on chemical; pharmaceutical and clinical documentation 2. Chemical, Pharmaceutical and Biological Documentation Composition; method of preparation; control of starting materials; control tests on intermediate products; control tests on the finished product; stability Dr S P Nayak - PARUL UNIVERSITY 49

50. New Drug Application (NDA) (cont.) 3. Pharmaco-Toxicological Documentation Single and repeated dose toxicity; reproductive studies; mutagenic potential; oncogenic/carcinogenic potential; pharmacodynamics; pharmacokinetics; local tolerance Clinical Documentation Clinical pharmacology; clinical experience 5. Special Particulars Dosage form; samples; manufacturers authorization; marketing authorization Dr S P Nayak - PARUL UNIVERSITY 50

51. New Dug Application (NDA) (cont.) Successful Application Assuming that the Regulatory Authority grants a product license, the product can be marketed in the relevant countries Product Registration To be marketed, medicines needs to receive approval from the appropriate Regulatory Authorities Dr S P Nayak - PARUL UNIVERSITY 51

52. New Drug Application (NDA) (cont.) For example: In India, DCGI is the final authority for approval of a new drug for marketing FDA is the final authority for approval of a new drug for marketing in United States Only 1 in every 3 drugs which reach the market recoups its development costs Product manufacture Considerations about the large-scale manufacture of the drug molecules and the dosage forms takes place at an early stage in the development process Dr S P Nayak - PARUL UNIVERSITY 52

53. New Drug Application (NDA) (cont.) The full- scale production of the drug involves a large number of people of different scientific disciplines (such as chemists, process engineers, plant designers etc ) The life of a patent for a new drug is 20 years If it takes 10-14 years to develop the product and clinically test it before permission is granted by the regulatory authorities to market it, the drug company will wish to manufacture it as soon as it can to claim as much of the patent life as possible Once the patent has expired, other manufacturers can produce the product (called a Generic version) and sell it at lower cost Dr S P Nayak - PARUL UNIVERSITY 53

54. Post Marketing Surveillance / phase IV clinical trials Sometimes adverse drug reactions only come into light after the drug has been in the market for a while and has been used by very large number of patients. Phase IV Clinical Trials identifies such problems Withdrawal of drug from the market is not an uncommon occurrence, one notorious case in the 1960’s involved the drug Thalidomide Phase IV Clinical Trials are done after a drug has been shown to work and has been granted a license Dr S P Nayak - PARUL UNIVERSITY 54

55. Post Marketing Surveillance / phase IV clinical trials (cont.) Phase IV clinical trials address : More about the side effects and safety of the drug? What the long term risks and benefits of the drug are? How well the drug works when it’s used more widely than in clinical trials? Dr S P Nayak - PARUL UNIVERSITY 55

56. Dosage forms Pre- formulation : Before a drug can be formulated into a medicine (a dosage form) which can be administered to a patient, something must be known about its physio-chemical properties and behavior (e.g. its solubility, its crystal structure) These will dictate, to a certain extent, the dosage form(s) in which the medicine will be marketed and the dosage form(s) which can be used during drug development investigations Such data are gathered in pre-formulation studies and these play an important part in anticipating formulation problems later on Dr S P Nayak - PARUL UNIVERSITY 56

57. Dosage forms (cont.) For example: aspirin can be satisfactorily formulated as a tablet but is too unstable in aqueous solution to be formulated as a liquid dosage form Although soluble or dispersible aspirin tablets are designed to be added to water, this is only satisfactory if the resulting solution or suspension is taken immediately As a second example, benzylpenicillin is inactivated by gastric acid so is available as an injection, rather than as a preparation which can be taken orally It is manufactured as the sodium or potassium salt to make it dissolve readily in water prior to injection Its packed in vials as a powder because it is susceptible to hydrolysis if stored as a solution Dr S P Nayak - PARUL UNIVERSITY 57

58. Drug characterization Spectroscopy To produce a simple method for analysis of the drug Solubility For identifying the best salt to develop and for producing liquid dosage forms Melting point Which reflects, for example, crystalline solubility Assay development Necessary for drug stability studies and perhaps employing thin layer or high pressure liquid chromatography Dr S P Nayak - PARUL UNIVERSITY 58

59. Stability In solution and in the solid state Microscopy To determine crystal morphology and particle size Powder flow and compression properties Necessary data for capsule and tablet formation Excipient compatibility To ensure that dosage forms perform correctly Drug characterization (cont.) Dr S P Nayak - PARUL UNIVERSITY 59

60. Types of Drug dosage forms Tablets and capsules Convenient and commonest dosage forms but likely to be no good if the drug cannot be absorbed in the alimentary tract of if the patient ( for e.g. child) cannot swallow them Injections and infusions Rapid action but impractical for treating chronic (long term) illnesses Pessaries and suppositories Can deliver the drug to local area where required but have limited general use Solutions, suspensions and elixirs Useful for children and elders but bulky and less useful if the drug is unpalatable or unstable in the presence of water Dr S P Nayak - PARUL UNIVERSITY 60

61. Ointments, creams and paints Use in restricted to topical application Aerosols and dry powder inhalations Good for drugs required in the large but can be difficult to administer the dose correctly Transdermal patches Convenient if the dose needs to be released over a long period ( for example: hormone replacement therapy) but can cause irritation Types of Drug dosage forms (cont.) Dr S P Nayak - PARUL UNIVERSITY 61

62. Examples for dosage forms Therapeutic considerations play an important role in deciding the dosage form to formulate Some examples include A tablet is not suitable dosage form if the drug cannot be absorbed in the alimentary tract – unless, of course, it is required to treat an ailment in the tract itself ( such as gut infection) Instead of a tablet, an injection might be suitable alternative Dr S P Nayak - PARUL UNIVERSITY 62

63. Examples for dosage forms cont. Even if the drug can be absorbed in the alimentary tract (example: intestine), a simple tablet will still be unsatisfactory if the drug is destroyed by the stomach acid In such a case the tablet might be enteric coated to prevent drug destruction while the tablet is passing through the stomach By the time the tablet reaches the intestine the coating has dissolved liberating the drug for absorption through the intestinal wall Dr S P Nayak - PARUL UNIVERSITY 63

64. Drugs which need to act immediately (example: bronchodilator drugs for treating asthmatic attacks where the airways suddenly become so constricted that the patient has difficulty in breathing) are best delivered by inhalation directly to the lungs where they can rapidly dilate the airways, rather than being swallowed in the form of tablet with the consequent delay in action while the drug is absorbed and delivered to the lungs Dr S P Nayak - PARUL UNIVERSITY 64 Examples for dosage forms cont.

65. Biopharmaceutics The study of pharmaceutical factors which affect the fate of the drug after administration is called biopharmaceutics and these factors will need to be evaluated in the development of the new drug To be effective, a drug must reach in desired concentration to the part of the body where it is required to act and, ideally, must be maintained at concentration for the appropriate period of time Dr S P Nayak - PARUL UNIVERSITY 65

66. Biopharmaceutics cont. This goal is influenced by the key interactions which take place between the drug and the body after the drug has been administered These are : Absorption Distribution Metabolism Elimination Dr S P Nayak - PARUL UNIVERSITY 66

67. Product stability After the dosage forms of the medicine have been chooses, stability studies must be undertaken because manufacturers needs to know how long their product remains therapeutically active in the packaging material they intend to use Any pharmaceutical product can be subject to chemical or microbiological deterioration and the regulatory authorities will need to be shown the manufacturer’s experimental evidence for their claimed shelf-life of the product If, for example, the medicine is principally going to be used in the tropics, it should be able to withstand climatic conditions there for the duration of its claimed active life. Dr S P Nayak - PARUL UNIVERSITY 67

68. THANK YOU ALL THE BEST..! Dr S P Nayak - PARUL UNIVERSITY 68