inbound-1955922464945584191-1.pdf

lOMoARcPSD|40179230 Inbound 1955922464945584191 Perspectives in Pharmacy (Our Lady of Fatima University) Scan to open on Studocu Studocu is not sponsored or endorsed by any college or university Downloaded b...

lOMoARcPSD|40179230 Inbound 1955922464945584191 Perspectives in Pharmacy (Our Lady of Fatima University) Scan to open on Studocu Studocu is not sponsored or endorsed by any college or university Downloaded by Hannah Sarmiento ([email protected])  lOMoARcPSD|40179230 Pharmaceutical Dosage Forms, Drug Delivery Systems and Medical Devices PDDS 211 (Lecture) (BS Pharmacy) | PROF. Kristine Mae Pasion | PRELIMS SEM 1 2022 TOPIC 1.1: INTRODUCTION TO DRUGS, DOSAGE FORMS, AND DRUG DELIVERY SYSTEM PHARMACOLOGICAL EFFECT Mechanism of action DRUG BEFORE THE DAWN HISTORY medicine or other substance which has a Ancient man learned from instinct physiological effect Animism A substance recognized by an official pharmacopeia or formulary. A substance used in the diagnosis, cure, PHARMACY IN ANCIENT BABYLONIA mitigation, treatment, or prevention of Practitioners of healing of this era were disease. A substance (other than food) priests, pharmacists and physicians (2600 intended to affect the structure or any B.C.) function of the body. Religious and magical DRUG ACTION/USE PHARMACY IN ANCIENT CHINA Antipyretic - lowers body temperature First Pen-Tsao (compilation of drugs) Anti-inflammatory - ibuprofen, Emperor Shen Nung (Father of mefenamic acid pharmaceutics) Analgesic - pain killer Anesthetics - reduce pain sensation Antihypertensive - reduce blood DAYS OF THE PAPYRUS EBERS pressure Most important pharmaceutical record Antineoplastic - used for cancer (1500 b.c.) Antipsychotic - brain chemistry, reduce 800 prescription and 700 drugs symptoms of hallucinations Georg Ebers Cardiac Drugs - cardiac contraction University of Leipzig Diuretics - water pills Papyrus Ebers - 60 ft. long and foot wide Antibacterial - counter blocking bacterias dating back the 16th century BC Antiviral - virus Drugs for cough and colds - neozep etc. HIPPOCRATES Hemostatics - manage bleeding; Introduction of scientific pharmacy tranexamic acid Father of medicine GIT drugs - laxatives, antacids Drugs for respiratory system - mucolytics(phlegm), antitussive (dry THEOPHRASTUS cough), expectorants Father of Botany Hypnotics and sedatives - S2 license De Historia Plantarum De causis plantarum THERAPEUTIC EFFECT any substance other than food used in prevention, treatment, cure of disease 1 Downloaded by Hannah Sarmiento ([email protected])  lOMoARcPSD|40179230 Pharmaceutical Dosage Forms, Drug Delivery Systems and Medical Devices PDDS 211 (Lecture) (BS Pharmacy) | PROF. Kristine Mae Pasion | PRELIMS SEM 1 2022 DIOSCORIDES FIRST OFFICIAL PHARMACOPEIA Father of medicinal botany De materia Medica - development of The idea of a pharmacopeia with official pharmaceutical botany and study of status, to be followed by all apothecaries, naturally occurring medicinal plants originated in Florence The Nuovo Physician and botanist Receptario, originally written in Italian, was published and became the legal standard for the city-state in 1498 CLAUDIUS GALEN Greek pharmacist-physician FIRST HOSPITAL IN COLONIAL AMERICA Galenicals - semi-solid dosage forms Galen’s cerate - ointment based He originated so many preparations of Colonial America's first hospital was vegetable drugs by mixing and melting established in Philadelphia in 1751; the Galenic Pharmacy first Hospital Pharmacy began operations there in 1752 DAMIAN AND COSMAS FIRST OFFICIAL PHARMACOPEIA Pharmacy’s Patron saints who symbolizes twinship of health professions, medicine and pharmacy Philadelphia College of Pharmacy (1821) OTHER PHARMACISTS MONASTIC PHARMACY Jonathan Roberts – first hospital Remnants of the Western knowledge of pharmacist Pharmacy and Medicine were preserved William Proctor Jr. – Father of American in the monasteries pharmacy Leon Maria Guerrero – first Filipino THE FIRST APOTHECARY SHOPS pharmacist The Arabs separated the arts of apothecary and physician, establishing in PHILIPPUS AUREOLUS THEOPHRASTUS BOMBASTUS VON HOHENHEIM Bagdad late in the eighth century the first privately owned drug stores 1221 - Florence, Italy Also called Paracelsus A Swiss physician and chemist who introduced chemical science from the traditional botanical science SEPARATION OF PHARMACY AND MEDICINE KARL WILHELM SCHEELE Pharmacy was officially separated from Greatest of the Pharmacists-Chemists medicine for the first time in 1240 AD, Discovered the following organic acids: when a decree of Emperor Frederick II of lactic, tartaric, citric, oxalic, and also the Germany regulated the practice of arsenic acid, he identified glycerin, pharmacy within the part of his kingdom 2 Downloaded by Hannah Sarmiento ([email protected])  lOMoARcPSD|40179230 Pharmaceutical Dosage Forms, Drug Delivery Systems and Medical Devices PDDS 211 (Lecture) (BS Pharmacy) | PROF. Kristine Mae Pasion | PRELIMS SEM 1 2022 invented new methods of preparing information on 84 internal and 16 external calomel and benzoic acid. drugs and preparations published in 1778 In 1817, Dr. Lyman Spalding proposed the FRIEDRICH SERTURNER creation of national pharmacopeia. He was called “the Father of USP” He recognized and proved the importance January 1, 1820 - conducted the first of a new class of organic substances: United States Pharmacopeial Convention alkaloids. assembled in Washington, D.C. isolated morphine from opium December 15, 1820 - the first United States Pharmacopeia was published in English and Latin CAVENTOU AND PELLETIER 1888 - The first edition of National Formulary of Unofficial Preparation was In 1820 Caventou and Pelletier published. announced the methods for separation of June 30, 1906 - President Theodore quinine and isolated cinchonine from the Roosevelt signed into law the first Federal cinchona bark and strychnine and brucine Pure Food and Drug Act and changed the from nux vomica title to National Formulary, designating both USP and NF as establishing legal standards for medical and pharmaceutical DRUG STANDARDS substances. The scientific basis for drugs and drug 1975, the United States Pharmacopeial products developed. Convention, Inc. Purchased the National To ensure quality Formulary, unifying the official compendia and thereby provided the mechanism for PHARMACOPEIAS / FORMULARIES single, national compendium. July 01, 1980 - The first combined compendium, representing the USP XX Organized sets of monographs or books of these standards. and NF XV became official. In 2002 - USP 25/NF20, the pharmacopeia was published annually. OFFICIAL COMPENDIA USP/NF is released every November and made official on May of the next year. compilation of drugs and other related Since 2020, 3 times a year (revision) May, substances which are recognized as legal Aug,Dec standards of purity, quality and strength by government agencies of respective countries of their origin. PHARMACOPEIA The term pharmacopeia comes from the Greek word “pharmakon” (drug) and The official compendium contains drug “poiein” (make) monographs which assure availability of 1580, the term was first used in quality drugs and pharmaceutical connection with a local book in Italy products. 1864, the first British Pharmacopeia In US, the first American pharmacopeia was a 32-page booklet containing 3 Downloaded by Hannah Sarmiento ([email protected])  lOMoARcPSD|40179230 Pharmaceutical Dosage Forms, Drug Delivery Systems and Medical Devices PDDS 211 (Lecture) (BS Pharmacy) | PROF. Kristine Mae Pasion | PRELIMS SEM 1 2022 MONOGRAPH Requires filing of NDA (New drug Application) Official title Synonyms KEFAUVER-HARRIS AMENDMENT Chemical formula Purity rubric Initiated by the 1960 Thalidomide Packaging and storage (sedative and tranquilizer) tragedy Reference standards Marketed as (Kevadon) an OTC for Labeling sedation Identification and preparation before use Requires filing for IND prior to NDA Identification Enacted to ensure greater degree of Assay safety for approved drugs and OTHER PHARMACOPEIA effectiveness Thalidomide is the standard treatment for IP – (International Pharmacopeia) the fever and painful skin lesions ○ guidelines for drug quality required associated with erythema nodosum by certain practitioner and other leprosum (ENL), multiple myeloma and agency HPUS - Homeopathic cancer. Pharmacopeia of united states BP - British Pharmacopeia DURHAM-HUMPHREY AMENDMENT EP - European Pharmacopeia JP - Japanese Pharmacopeia Drug products were categorized into “Rx only” drugs and OTC DRUG REGULATION AND CONTROL Rx drugs may only be refilled upon consent of the prescriber June 30, 1906 - President Theodore Roosevelt signed into law the first Federal COMPREHENSIVE DRUG ABUSE Pure Food and Drug Act. And he PREVENTION AND CONTROL ACT OF 1970 designated both USP and NF as establishing legal standards for medical control on drug abuse and pharmaceutical substances. led by DEA in DOJ prohibited misbranded and adulterated food and drugs in commerce. CLASSIFIED THE CONTROLLED SUBSTANCES: FEDERAL FOOD, DRUG, AND COSMETICS Schedule I: no accepted medical use, ACT OF 1938 high potential for abuse (heroin, mescaline, peyote, LSD) Assures products are safe for human use Schedule II: accepted medical use, high deaths of more than 100 people in 15 potential for abuse – may lead to psycho states or physical abuse ( morphine, cocaine, Due to sulfanilamide incident (elixir) methamphetamine (shabu) ) Solvent – diethylene glycol, antifreeze Schedule III: medical use, less potential solution for abuse (codeine, hydrocodone) 4 Downloaded by Hannah Sarmiento ([email protected])  lOMoARcPSD|40179230 Pharmaceutical Dosage Forms, Drug Delivery Systems and Medical Devices PDDS 211 (Lecture) (BS Pharmacy) | PROF. Kristine Mae Pasion | PRELIMS SEM 1 2022 Schedule IV: accepted medical use, low adverse reaction data from investigational potential for abuse (Benzodiazepine or or marketing experience, and the risks BDZ; diazepam, midazolam, difenoxin) involved in use of the drug in pregnant Schedule V: accepted medical use, low women clearly outweigh potential benefits. potential for abuse (dihydrocodeine, - Benzodiazepines, Oral diphenoxylate) contraceptive pills or OCP, ARB (with sartan suffix) will cause renal FDA PREGNANCY CATEGORIES dysgenesis Category A: Adequate and well-controlled OTHER LAWS studies have failed to demonstrate a risk to the fetus in the first trimester of Drug Listing Act pregnancy (and there is no evidence of - Provide the FDA with the risk in later trimesters). legislative authority to compile a - Iron supplements, Folic Acid, list of marketed drugs to assist in Levothyroxine, the enforcement of federal laws Category B: Animal reproduction studies requiring that drugs be safe and have failed to demonstrate a risk to the effective and not adulterated or fetus, and there are no adequate and misbranded well-controlled studies in pregnant women. Drug Price Competition and Patent - Tranexamic acid – hemostatic Restoration Act agent - Applications for generic copies of Category C: Animal reproduction studies an originally approved new drug have shown an adverse effect on the fetus can be filed through an and there are no adequate and abbreviated new-drug application well-controlled studies in humans, but (ANDA) potential benefits may warrant use of the Prescription Drug Marketing Act 1987 drug in pregnant women despite potential - The act is intended to reduce the risks. risks of adulterated, misbranded, - Digoxin repackaged, or mislabeled drugs Category D: There is positive evidence of entering the legitimate marketplace human fetal risk based on adverse through “secondary sources.” reaction data from investigational or Dietary Supplement Health and marketing experience or studies in Education Act humans, but potential benefits may - Regulate the labeling claims made warrant use of the drug in pregnant for these products such as the women despite potential risks. vitamins, minerals, amino acids, - Antineoplastic agents (vincristine, and botanicals vinblastine, paclitaxel), Atenolol FDA Modernization Act (beta-blocker) - Expands the capacity of FDA in - Safest: methyldopa regulating pharmacy standards Category X: Studies in animals or and practices humans have demonstrated fetal abnormalities and/or there is positive evidence of human fetal risk based on DRUG PRODUCT RECALL 5 Downloaded by Hannah Sarmiento ([email protected])  lOMoARcPSD|40179230 Pharmaceutical Dosage Forms, Drug Delivery Systems and Medical Devices PDDS 211 (Lecture) (BS Pharmacy) | PROF. Kristine Mae Pasion | PRELIMS SEM 1 2022 Class I – cause serious adverse effects or Drug product may be improved death Modification on drug formulation as Class II – cause temporary or medically obtained from manufacturing scale-up and validation process may be done reversible adverse health consequences Additional clinical studies Class III – not likely to cause adverse health consequences SOURCES OF NEW DRUG Plant Sources TOPIC 1.2: NEW DRUG DEVELOPMENT ○ Reserpine PROCESS ○ Rauwolfia serpentina ○ (reserpine) tranquilizer and hypotensive ○ agent CLINICAL STUDIES ○ reserpine and periwinkle are indole alkaloids Phase I ○ Vinca rosea (Periwinkle) ○ Vinca rosea 20-100 people ○ Vinblastine and Vincristine (indole Tolerance and safety alkaloids) Toxicological studies ○ For cancer ○ Pacific Yew Tree ○ Taxus brevifolia Phase II ○ paclitaxel – treat variant cancer Animal Sources 100-500 people ○ Endocrine glands of cattle, Efficacy and therapeutic index sheep and swine - Thyroid Single Blinded – participant don’t know extract, insulin and pituitary which group they belong (positive and hormone (replacement therapy) negative) ○ Pregnant mares - Source of Double Blinded – both researcher and estrogens participants don’t know ○ Embryo – vaccines Microbiological World ○ penicillin, cephalosporin, Phase III tetracyclines, aminoglycosides, lovastatin (Aspergillus terreus) 500-5000 people Biological longest; 5 years ADR (Adverse Drug Reactions) Genetic Engineering dose, efficacy, toxicity and side effects Performed with the final dosage form Recombinant DNA – combination of two developed in phase II DNAs from different species; human Side effects are monitored insulin(?), vaccine and somatostatin (human growth hormone) Monoclonal Antibody Production – Phase IV takes place in laboratory using human tissues real use of molecule Product recall; 100’s-1000’s Determine if pediatrics and geriatrics Post marketing studies Goal Drug 6 Downloaded by Hannah Sarmiento ([email protected])  lOMoARcPSD|40179230 Pharmaceutical Dosage Forms, Drug Delivery Systems and Medical Devices PDDS 211 (Lecture) (BS Pharmacy) | PROF. Kristine Mae Pasion | PRELIMS SEM 1 2022 Produce specifically the desired effect ○ the science of the properties of the Administered by the most desired route drugs and its effects in the body Minimal dosage and dosage frequency Pharmacokinetics Have optimal onset and duration of activity ○ the handling of a drug within the Exhibit no side effects Would be eliminated completely and body, it includes the ADME without residual effect processes Pharmacodynamics Prodrug ○ the study of the interaction of drugs with cells Analytical studies metabolized A compound that requires metabolic Toxicology biotransformation after administration to ○ the study of the Adverse Effects of produce the desired pharmacologically the chemical agents on living active compound. organisms Pharmaceutics ○ the general area of study Lead Compound concerned with the formulation, manufacturing stability and active ingredient, A prototype chemical effectiveness of a pharmaceutical compound that has a fundamental desired dosage form biologic or pharmacologic activity. Preformulation METHODS OF DISCOVERY Choosing a Disease The characterization of the physical and ○ focus is on the financial return chemical properties of the active drug Choosing a Drug Target substance in relation to the desired ○ receptor, enzymes and nucleic acid dosage form. ○ Molecular modification – structure activity relationship File IND Application studies TYPES OF BIOASSAYS Patent the drug – an exclusive right to the use and profits of a novel In vivo test pharmaceutical for a limited term ○ inducing a clinical condition and special consideration is given on Orphan treated with the test drug drugs (for rare diseases) and Treatment In vitro test IND ○ drugs activity is tested on isolated tissues, cells or enzymes Submission of a New Drug In Silico Application ○ using computer softwares PRECLINICAL STUDIES Submitted to the FDA for review and Chemical and physical characterization approval ○ protein binding, solubility, partition Products is effective by all parameters coefficient, chirality of molecule Pharmacology 7 Downloaded by Hannah Sarmiento ([email protected])  lOMoARcPSD|40179230 Pharmaceutical Dosage Forms, Drug Delivery Systems and Medical Devices PDDS 211 (Lecture) (BS Pharmacy) | PROF. Kristine Mae Pasion | PRELIMS SEM 1 2022 Scale-up Activities Therapeutic Index Scaleup – increase in the batch size from The relationship between the desired and the clinical batch, submission batch, or to undesired effects of a drug the full-scale production batch size, using TD50/ ED50 the finished, marketed product FACTORS AFFECTING THE DOSE RELATED TERMS Age SNDA – Supplemental New Drug ○ pediatric or geriatric Application Pharmacogenetics ANDA – Abbreviated New Drug ○ genetic polymorphism ; Isoniazid Application (acetylization) BLA – Biologics License Applications Body Weight ADA - adenosine deaminase(?) ○ usual doses for drugs are Medical Devices considered generally suitable for 70-kg (150 lb) individuals. DOSAGE REGIMEN ○ drug dosage may require adjustment from the usual adult Dosage Regimen dose for abnormally lean or heavy ○ schedule of dosage patients. Usual dose Body Surface Area ○ the amount that may be expected ○ determine using nomogram to produce, in adults, the medicinal Sex effect for which it is intended ○ faster absorption in male Usual dosage range Pathologic State ○ amounts of drug that may be ○ myocardial infarction prescribed within the work of usual ○ low albumin (protein for binding medical practice acidic drugs) Pediatric dose ○ The effects of certain drugs may ○ dose administered to children be modified by the pathologic Initial dose condition of the patient. ○ also the priming or loading dose, is Tolerance the amount required to attain the ○ The ability to endure the influence desired concentration of the drug of a drug, particularly during in the blood or tissues continued use. Prophylactic dose Concomitant Drug therapy ○ the amount administered to a ○ polypharmacy patient before exposure or ○ effects of a drug may be modified contraction of the illness by the prior or concurrent Therapeutic dose administration of another drug. ○ the amount which is administered Time and conditions of administration to a patient after the exposure or ○ The time at which a drug is contraction of an illness administered may influence the dosage. 8 Downloaded by Hannah Sarmiento ([email protected])  lOMoARcPSD|40179230 Pharmaceutical Dosage Forms, Drug Delivery Systems and Medical Devices PDDS 211 (Lecture) (BS Pharmacy) | PROF. Kristine Mae Pasion | PRELIMS SEM 1 2022 ○ Absorption proceeds more rapidly involved with drug and medical device if the stomach and the upper manufacture portions of the intestinal tract are shows how the product was made and empty of food. tested which enables traceability and, in ○ A dose of a drug that is effective the event of future problems, recall from when taken before a meal may be the market less effective if administered during or after eating. CGMP AND VALIDATION Dosage Form and Route of Administration GMP requires that all manufacturing and ○ The effective dose of a drug may testing equipment has been qualified as vary with the dosage form and the suitable for use, and that all operational route of administration. methodologies and procedures (such as manufacturing, cleaning, and analytical testing) utilized in the drug manufacturing CURRENT GOOD MANUFACTURING process have been validated (according to PRACTICE predetermined specifications), to demonstrate that they can perform their A.O 220 - a term that is recognized purported function(s). worldwide for the control and management of manufacturing and quality control GMPs are enforced: testing of foods and pharmaceutical products. in the United States by the FDA "c" in CGMP stands for "current," requiring in the United Kingdom by the Medicines companies to use technologies and and Healthcare products Regulatory systems that are up-to-date in order to Agency (MHRA) comply with the regulations In Australia by the Therapeutical Goods provide for systems that assure proper Administration (TGA) design, monitoring, and control of In India by the Ministry of Health manufacturing processes and facilities Philippines by FDA This formal system of controls at a pharmaceutical company, if adequately CGMP put into practice, helps to prevent instances of contamination, mix-ups, CGMP Quality deviations, failures, and errors CGMP is everyone’s responsibility Quality Control function is to audit or CGMP AND DOCUMENTATION inspect periodically the procedures, equipment, facilities; to detect This assures that drug products meet their NON-COMPLIANCE and to CORRECT quality standards. the said deviation An extremely important part of GMP is Non-compliance may result to quality documentation of every aspect of the variation contamination, mix-ups and process, activities, and operations errors product recall Recalls result to the ff disadvantages: 9 Downloaded by Hannah Sarmiento ([email protected])  lOMoARcPSD|40179230 Pharmaceutical Dosage Forms, Drug Delivery Systems and Medical Devices PDDS 211 (Lecture) (BS Pharmacy) | PROF. Kristine Mae Pasion | PRELIMS SEM 1 2022 ○ Lost of money performed adequately ○ Bad publicity Quality Control ○ Low sales ○ The regulatory process through ○ Negative effect on employees which industry measures actual Objectives quality performance, compares it ○ Safe with standards, and acts on the ○ Pure difference ○ Effective Component ○ Any ingredient used in the manufacture of a drug product, CGMP as a Law including those that may not be present in the finished product Administrative Order No. 220, s. 1974 Drug product SCOPE ○ A finished form that contains an ○ Organization and Personnel active drug and inactive ○ Buildings and Facilities ingredients. The term may also ○ Equipment include a form that does not ○ Components contain an active ingredient such ○ Production and Process Control as a placebo. ○ Packaging and Labeling Control Batch ○ Holding and Distribution ○ A specific quantity of a drug of ○ Laboratory Controls uniform specified quality produced ○ Records and Reports according to a single ○ Returned and Salvaged products manufacturing order during the same cycle of manufacture TERMINOLOGIES Strength ○ The concentration of the drug Active pharmaceutical ingredient (API) substance per unit dose or volume ○ Any component that is intended to Lot furnish pharmacologic activity - A batch or any portion of a batch Inactive ingredient having uniform specified quality ○ Any component other than the and a distinctive identifying lot active ingredients in a drug product number Quality Audit Lot number ○ A documented activity performed ○ Any distinctive combination of in accordance with established letters, numbers, or symbols from procedures on a planned and which the complete history of the periodic basis to verify compliance manufacture, processing, with the procedures to ensure packaging, holding, and quality distribution of a batch or lot of a Quality Assurance drug product may be determined ○ Provision to all concerned the ○ control or batch number evidence needed to establish Validation confidence that the activities ○ Documented evidence that a relating to quality are being system (e.g., equipment, software, 10 Downloaded by Hannah Sarmiento ([email protected])  lOMoARcPSD|40179230 Pharmaceutical Dosage Forms, Drug Delivery Systems and Medical Devices PDDS 211 (Lecture) (BS Pharmacy) | PROF. Kristine Mae Pasion | PRELIMS SEM 1 2022 controls) does what it purports to ○ Personnel in charge do ○ Date of validation Master Record ○ Record containing the formulation, specifications, manufacturing COMPONENTS procedures, quality assurance Shall be withheld from such use until they requirements, and labeling of a have been identified, sampled, and tested finished product for conformance with the specifications raw materials, packaging materials PERSONNEL Qualified PRODUCTION AND PROCESS CONTROL ○ healthy with an awareness of the includes all reasonable precautions that importance of good hygiene will ensure that the products have the safety, identity, strength, quality, purity BUILDINGS AND FACILITIES they claim to possess. follows a written procedure Designed for easy cleaning, in–process inspection maintenance and freedom from congestion and traffic Adequate space for operations PACKAGING AND LABELING CONTROL Adequate lighting, ventilation Assures that only those products that Adequate facilities have met the standards established in the Adequate supply of water master formula records shall be distributed Suitable housing and space for Assures that correct labels and labeling Animal care are used Safe and sanitary waste disposal Assures that correct lot no. and control of the batch are used EQUIPMENTS Assures that labels used meet the legal requirements for content Involve in the manufacture, processing, Assure that each label contains the packaging, storing, testing, or control of expiration date products and its components Assures that OTC preparations are Designed to be non-reactive, additive or contained in tamper-evident package absorptive. It should facilitate disassembly, adjustment, cleaning and maintenance LABORATORY CONTROL Affixed with standard operating procedures Include the scientifically sound, With own logbook and ID tags appropriate specifications, standards and containing: test procedures ○ Date used Include master formula record, reserve ○ Name of product where it was samples used Records of all the tests and results. ○ Date cleaned 11 Downloaded by Hannah Sarmiento ([email protected])  lOMoARcPSD|40179230 Pharmaceutical Dosage Forms, Drug Delivery Systems and Medical Devices PDDS 211 (Lecture) (BS Pharmacy) | PROF. Kristine Mae Pasion | PRELIMS SEM 1 2022 DOSAGE FORM TOPIC 2: DRUG DOSAGE FORM DESIGN Characterization of drug molecule DOSAGE FORM Involves the application of biopharmaceutical principles to the physicochemical parameters of a drug Finished formulation of a drug preparation with the goal of designing an optimum designed to contain a specific amount of a drug delivery system medication for ease and accuracy of Conducted depending on the type of dosage administration dosage form and the type of drug Levothyroxine – hypothyroidism (25 mcg) molecule Digoxin – 125 mcg (need for therapeutic effect) PREFORMULATION STUDIES Physical Description Liquid - Solid THE NEED FOR DOSAGE FORMS ○ Problems are often encountered for protection of drug substance from the for drugs in liquid state destructive influences of atmospheric ○ Volatile, unstable – amyl nitrite oxygen or moisture (if drug is (treats angina), propylhexedrine Photosensitive, TiO2 is added. a (NASAL, congestion (inhalation) opacifying agent) ○ May be needed for a SDF – Vit. A, for the protection of the drug from the E (soft gel capsules) destructive influence of gastric acid after ○ While some are used oral administration advantageously (oils) to conceal the salty, bitter, obnoxious taste ○ Solids are more stable - The form or odor of a drug substance often used for NDs to provide liquid dosage forms of Microscopic examination substances soluble in the desired vehicle ○ Particle size, size range and to provide liquid preparations of structure substances that are either insoluble or ○ Photomicrographs unstable in the vehicle (by adding Heat of vaporization suspending agent) ○ The amount of heat absorbed to provide extended drug action through when 1 g of a liquid vaporizes controlled-release design (antineoplastics = carmustine for to provide optimal drug action from topical brain tumor and lymphoma) administration sites ○ Implantable pump, inhalants and to provide for the insertion of a drug into aerosol one of the body orifice (suppositories) ○ Safety reasons to provide for the placement of drugs Melting point – identity and PURITY directly into the bloodstream (IV, SC) Phase rule diagram – to provide for optimal drug action through ○ mixtures at a temperature inhalation therapy (aerosols, inhalants) composition diagram ○ Minimum melting point – Eutexia – a substance lowers the melting 12 Downloaded by Hannah Sarmiento ([email protected])  lOMoARcPSD|40179230 Pharmaceutical Dosage Forms, Drug Delivery Systems and Medical Devices PDDS 211 (Lecture) (BS Pharmacy) | PROF. Kristine Mae Pasion | PRELIMS SEM 1 2022 point of other substances formulation development (menthol) Dissociation constant Particle size – ○ consider the lipophilic nature of ○ factor for many physical and biological membranes or medium chemical properties ○ Dependent of pH ○ dissolution rate, bioavailability, ○ Potentiometric titration is used to content uniformity, taste, texture, identify Dissociation constant color, and stability Hydrates and solvates Polymorphism – ○ hygroscopic (don’t liquefy), ○ property of occurring in several deliquescent (liquefy), efflorescent different forms. (water of crystallization) handling ○ Theobroma cacao – suppository and packaging base Organic salts ○ alpha (low melting point; 25 ○ for weak acids and bases degrees) and beta (stable form 35 ○ salts to enhance solubility degrees) Organic esters Solubility ○ for solubility, stability, resistance to ○ Particle size degradation, design to prodrug ○ pH ○ combination of Alcohol and acid ○ Dissolution rate ○ Complex organic Molecules - ○ the time it takes for the drug to biologically active proteins dissolve in the fluids at the potent, unstable absorption site ○ the constant-surface method and particulate dissolution ○ Capsule is faster to dissolve DRUG STABILITY than tablets Stability - capability of a particular ○ formulation in a specific container or Membrane permeability closure system to remain with in its ○ Lipid barrier physical, chemical, microbiological, ○ Passive diffusion for lipid soluble therapeutic and toxicological drugs specifications ○ Non lipid soluble drugs are altered ○ Everted intestinal sac technique ○ Data useful for bioavailability of the drug SHELF-LIFE ○ The rate and extent to which an Refers to the duration of time during which active drug ingredient or is a drug preparation will remain physically, absorbed from a drug product and chemically, therapeutically, toxicology and becomes available at the site of microbiology stable (possessing NLT 90% action of the labeled potency) Partition coefficient ○ measures the lipophilic character of a molecule ○ Octanol (oil-water PC), used in 13 Downloaded by Hannah Sarmiento ([email protected])  lOMoARcPSD|40179230 Pharmaceutical Dosage Forms, Drug Delivery Systems and Medical Devices PDDS 211 (Lecture) (BS Pharmacy) | PROF. Kristine Mae Pasion | PRELIMS SEM 1 2022 EXPIRATION DATE ENHANCING THE STABILITY OF DRUG PRODUCTS Limits the time during which the product There are several approaches to the stabilization may be dispensed by the pharmacist or of pharmaceutical preparation containing drugs used by the patient subject to deterioration by hydrolysis. the reduction and the elimination of water from the pharmaceutical system, This may TYPES OF STABILITY be accomplished by applying a waterproof protective coating over tablets or by Chemical – each api will retain its enclosing and maintaining the drug in chemical integrity; label potency tightly closed containers. Physical – appearance of drugs In liquid preparations, water can frequently Microbiologic – extra resistance in be replaced or reduced in the formulation microbial growth through the use of substitute liquids such Therapeutic – labeled claims (?) as glycerin, propylene glycol, and alcohol. Toxicologic – adverse effect we can In certain injectable products, anhydrous consider if ever the drug became unstable vegetable oils may be used as the drug’s solvent to reduce the chance of hydrolytic decomposition (Corn, Cottonseed, RATE REACTIONS Peanut, Sesame Oil) For certain unstable antibiotic drugs, the The description of drug concentration with drug may be supplied to the pharmacist in respect to time a dry form for reconstitution For most hydrolyzable drugs the pH of RATE REACTIONS optimum stability is on the acid side, Zero-order –loss of drug is concentration somewhere between pH5 and 6. independent, constant with time. use of buffering agent (conjugate base, First-order –loss of the drug is proportional weak acid), the stability of otherwise to the concentration remaining with unstable compounds can be increased. respect to time; dependent in The oxidative process is diverted, and the concentration stability of the drug is preserved by agents Hydrolysis – interact with water called antioxidants (reducing agent), molecules; a solvolysis process which react with one or more compounds Oxidation in the drug to prevent progress of the ○ Oxygen chain reaction. ○ Oxidizing agents sodium sulfite (Na2SO3), sodium bisulfite ○ Trace elements (NaHSO3), hypophosphorous acid ○ Light (H3PO2), and ascorbic acid. ○ Polymerization, decarboxylation Because the stability of oxidizable drugs deamination may be adversely affected by oxygen, ○ concentration with respect to time certain pharmaceuticals may require an oxygen-free atmosphere during their preparation and storage. Oxygen-sensitive drugs may be prepared in the dry state and they, as well as liquid 14 Downloaded by Hannah Sarmiento ([email protected])  lOMoARcPSD|40179230 Pharmaceutical Dosage Forms, Drug Delivery Systems and Medical Devices PDDS 211 (Lecture) (BS Pharmacy) | PROF. Kristine Mae Pasion | PRELIMS SEM 1 2022 preparations, may be packaged in sealed containers with the air replaced by an inert Short Term/Accelerated Stability gas such as nitrogen Studies - This involves the use of TYPES OF STABILITY STUDIES exaggerated conditions of Long Term or Actual temperature, light, moisture, pH, ○ Conducted under the usual / humidity,etc., to test the stability of normal conditions of the drug formulations. environment, transport and storage - The purpose is to determine kinetic expected during product parameters, if possible and/or to distribution predict the tentative expiration dating period. ○ 25 +/- 2°C, 60 +/- 5% RH, 12 mos. ○ It makes use of different “climatic zones” also called Global A suggestion that has been made by Assessment of Stability of the US FDA that shows wide exposure by INTERNATIONAL acceptance of this method is as CONFERENCE ON follows: HARMONIZATION (ICH) 1. Three months acceptable data at 37-40°C/75% R.H. can be CLIMATIC ZONE extrapolated to a two-year expiry date. 2. If two-year controlled room temperature (R.T.) samples are CLIMATIC DEFINITIO LONG available up to two more years ZONE N TERM could be added to the expiry date CONDITIO (i.e., four years total) by storing the NS two-year R.T. Samples at 37°C/75% R.H. for three months. I TEMPERATE 21 °C / 45% RH II SUBTROPIC 25 °C / FDA 2014 bulletin: One year Controlled AL AND 60% RH MEDITERRA RT samples and stored for three months NEAN using accelerated stab testing = 1 year + 2 years III HOT AND 30 °C / DRY 35% RH IVA HOT AND 30 °C / HUMID 65% RH IVB HOT AND 30 °C / VERY HUMID 75% RH (PHILIPPINE S) 15 Downloaded by Hannah Sarmiento ([email protected])  lOMoARcPSD|40179230 Pharmaceutical Dosage Forms, Drug Delivery Systems and Medical Devices PDDS 211 (Lecture) (BS Pharmacy) | PROF. Kristine Mae Pasion | PRELIMS SEM 1 2022 APPEARANCE SIGNIFICANCE: Compression Aids - Lubricant To enable researchers to predict the shelf - Anti adherence life of a product - Glidants To determine the most stable formulation for a particular therapeutic actives PHARMACEUTICAL INGREDIENTS To serve as basis for assigning storage Acidifying agent conditions - Provide acidic medium for product To serve as basis for selecting containers stability To determine expiration date - HNO3, HCl, CH3COOH Alkalinizing agent PHARMACEUTICAL INGREDIENTS - Provide alkaline medium for product stability - Ammonia solution, sodium borate, A pharmaceutical ingredient is anything sodium carbonate, trolamine that goes into the formulation in the Adsorbent preparation of the final dosage form - Hold the molecules into its surface Active and Inactive or excipients for moisture sensitive products Inactive substance used as a carrier for - Cellulose, activated charcoal the active ingredients of a medication. In addition excipients can be used to aid the Aerosol propellant process by which a product is - Develops the pressure in the manufactured container and expels the product - CO2 (Nitrogen), INERT SUBSTANCES DCDFM(Dichlorodifluoromethane), DCTFE (Dichlorotrifluoroethane), added to achieve the final dosage form to carbon dioxide improve the taste, improve the Antioxidant appearance, and promote stability of the - Inhibits the process of oxidation for preparation. possible cause of product deterioration FOUR WIDELY USED PHARMACOPEIAS - Butylated hydroxytoluene (BHT), USP/NF sodium bisulfite, ascorbic acid International Antifungal agent British - Prevents growth of fungi European - Paraben, benzoic acid, sodium benzoate ESSENTIAL EXCIPIENT IN TABLETS Antimicrobial preservative Diluent / Filler - Prevents growth of microorganism Binder - Benzalkonium chloride, benzyl Disintegrants alcohol (usually for bacteriostatic water for injection; not for infants, can cause gasping syndrome), chlorobutanol, thimerosal, phenol 16 Downloaded by Hannah Sarmiento ([email protected])  lOMoARcPSD|40179230 Pharmaceutical Dosage Forms, Drug Delivery Systems and Medical Devices PDDS 211 (Lecture) (BS Pharmacy) | PROF. Kristine Mae Pasion | PRELIMS SEM 1 2022 Buffering agent phthalate - Resist changes in pH Solvent - Citrates, Acetates, Phosphates - An agent used to dissolve another Chelating agent substance - known as sequestering - Water (prone to microbial growth), - Used as stabilizers for heavy alcohol, glycerin, mineral oil, metals capable of promoting Peanut oil, Sesame oil, Cottonseed instability oil, Castor oil - Edetate disodium (EDTA) Stiffening agent Colorant - Agents that increase the thickness - Impart color for improved aesthetic or hardness of the preparation appeal - Cetyl alcohol, paraffin, white wax, - Dyes and Lakes yellow wax - Red ferric oxide (found in calamine Suppository base lotion; pink color), caramel, FD&C - A vehicle for drug substances and D&C formulated into suppositories Clarifying agent - Cocoa butter (rectal supp), - Used as filtering aid for the witepsol, wecobee, PEG mixtures adsorbent properties (vaginal supp) - Bentonite, talc Surfactant Emulsifying agent - Agents which reduces interfacial - Promote and maintains dispersion tension of finely divided particles of a liquid - wetting agent - Acacia, spans and tweens, TEA - Benzalkonium chloride, (triethanolamine), SLS(sodium polysorbate 80, SLS lauryl sulfate), Cetyl pyridinium Suspending agent chloride - Increases viscosity and reduces Flavorant rate of sedimentation - Imparts pleasant flavor - solid Humectant - CMC, MC, bentonite, acacia - Prevents drying out of the Sweetening agent preparation - Imparts sweetness - Glycerin, sorbitol (toothpaste or - Mannitol, saccharin, sorbitol, gums), propylene glycol sucrose, Aspartame and glycerin Levigating agent - An intervening agent used to reduce the particle size TABLET EXCIPIENTS - Mineral oil, glycerin, lanolin, Essential components – those that hydrophilic petrolatum impart satisfactory characteristics to the Ointment bases formulation (diluent, binders, disintegrants) - Semisolid vehicle for drug Compression aids – those that impart substances satisfactory compression characteristics - white ointment, yellow ointment, (glidants (tablets and capsules; flow rose water ointment, plasticizers properties), lubricants (lower friction), and - Film-coated; cellulose acetate antiadherents (prevent of adhesion)) 17 Downloaded by Hannah Sarmiento ([email protected])  lOMoARcPSD|40179230 Pharmaceutical Dosage Forms, Drug Delivery Systems and Medical Devices PDDS 211 (Lecture) (BS Pharmacy) | PROF. Kristine Mae Pasion | PRELIMS SEM 1 2022 Supplementary components – those artificial, 0.75% for natural that give additional desirable physical characteristics to the finished tablets BLENDING METHODOLOGY (colors, flavors, sweetening agents, Blending (Fruit flavors with sour, salty adsorbents) with bitter, sweet and sour) Overshadowing (methyl salicylate) Physical (precipitating, emulsifying) FLAVORANTS Chemical (complex-formation) Physiological (menthol) Used more often on liquid dosage form than solid dosage form Observe congruity SWEETENING AGENTS Correlated structures ○ Low molecular weight salts are A sugar substitute, or artificial sweetener, salty and high molecular weight is a food additive which attempts to salts are bitter duplicate the effect of sugar in taste, but ○ Increase in –OH increase the usually with less food energy sweetness ○ Aldehydes, esters and alcohols SWEETENING AGENTS pleasant Saccharin ○ Bitter taste N-containing ○ 300× sweetness (by weight), E954, compounds FDA Taste of the drug itself ○ Approved 1958 Age of patient ○ bitter aftertaste Types of the Flavors Aspartame ○ 80–200× sweetness (by weight), ELECTRONIC TONGUE NutraSweet, E951, Acesulfame potassium aid in providing a global taste fingerprint ○ 130 × sweetness (by weight), determine bitterness level Nutrinova, E950 FOUR TASTES TO BE MASKED Salty - Cinnamon, orange, raspberry Sucralose syrup, maple, butterscotch ○ 600× sweetness (by weight), Tate Bitter - Cocoa syrup, wild cherry, licorice, & Lyle, E955 mint chocolate Cyclamate Acrid or sour - Fruits or citrus-flavors, ○ 30× sweetness (by weight), Abbott, vanilla E952, Natural or artificial and Water or oil- ○ FDA Banned 1969 soluble ○ caused bladder cancer - Water-sol – 0.2% for artificial; ○ cyclohexamine 1-2% for natural - Oil-sol – 0.1% on FP for artificial; 0.2% for natural (soybean, olive and sesame oil) - Powdered – 0.1% in FP for 18 Downloaded by Hannah Sarmiento ([email protected])  lOMoARcPSD|40179230 Pharmaceutical Dosage Forms, Drug Delivery Systems and Medical Devices PDDS 211 (Lecture) (BS Pharmacy) | PROF. Kristine Mae Pasion | PRELIMS SEM 1 2022 Dyes are oil and water-soluble ADDITIONAL INFO ○ Tablets, suspensions, solutions ○ Lakes are insoluble to water alumina or organic solvents In 1958 – Delaney Clause Food additive ○ Tablets, suspension Cyclamate – safety unresolved, further ○ pH, oxidation, excessive heat studies are conducted carcinogenicity, affect dyes genetic damage, testicular atrophy Aspartame - metabolized into phenylalanine, aspartic acid, methanol PRESERVATIVES PKU mental retardation, pregnant women with PKU Used to prevent growth of microorganisms Saccharin – found to cause bladder Sterilization tumors but by a non-DNA reactive Aqueous preparations v. alcoholic or mechanism hydroalcoholic preparations Labeling The preservatives are effective in Acesulfame K – non nutritive preventing the growth of the type of sweetener,structurally similar to saccharin microorganisms considered the most Stevia – from Stevia rebaudiana bertoni, 250-300x sweetness of sucrose likely contaminants of the preparation The preservative is soluble enough in water COLORANTS The proportion of preservative remaining Natural undissociated at the pH of the preparation ○ Minerals, Plants, animals makes it capable of penetrating the ○ Ex. Red ferric oxide, anatto microorganisms and destroying its colorants, cochineal (insect; integrity Dactylopius coccus; red dye stuff) The required concentration of the ○ Sulfur, riboflavin are yello