Copy-of-Copy-of-DDS-LEC PDF Pharmaceutical Dosage Forms

LEC NOTES-Phar 2104 | Pharmaceutical Dosage Forms, Drug Delivery systems and Medical Services FIRST SEMESTER | ACADEMIC YEAR 24-25 | RELLES ARE YOU READYYY???? citizenship, aimed to cr...

LEC NOTES-Phar 2104 | Pharmaceutical Dosage Forms, Drug Delivery systems and Medical Services FIRST SEMESTER | ACADEMIC YEAR 24-25 | RELLES ARE YOU READYYY???? citizenship, aimed to create a perfect system of physiology, pathology, and treatment.He originated so many preparations of vegetable drugs by mixing or melting the individual ingredients that the field of pharmaceutical preparations was once commonly An agent intended for use in the diagnosis, referred to as “Galenic pharmacy”. mitigate, treatment, cure, or prevention of 4.)Emperor Frederik II, 1240 AD disease in humans or in other animals. -regulated the practice of pharmacy within the part of One of its most astounding qualities is the his kingdom called the Two Sicilies. diversity of their actions and effects on the body. 5.)Paracelsus (1493 - 1541 AD) The use of drugs predates recorded human -Swiss physician and chemist. history in man's efforts to relieve pain and -He influenced the transformation of pharmacy from a suffering, recover from injury, and extend life. profession based primarily on botanical science to one based on chemical science. Drugs have existed as long as humans. Their 1.) Karl Wilhelm Scheele discovery was led by human disease and the -Discovered Lactic acid, citric acid, oxalic acid, tartaric instinct to survive. acid, arsenic acid, glycerin, calomel, benzoic acid, Disease was believed to be caused by demons oxygen or evil spirits entering the body. 2.)Friedrich Serturner -in 1805 isolated morphine from opium.-Quinine, cinchonine, and brucine. 1.) Ebers papyrus 3.) Joseph Caventou & Joseph Pelletier -dominated by drug formulas, with more than 800 - solated quinine and cinchonine from cinchona and formulas or prescriptions being described and more strychnine and brucine from nux vomica. than 700 drugs mentioned. 4.)Joseph Pelletier and Pierre Robiquet 2.) Botanical - isolated quinine and cinchonine from cinchona and 3.) Mineral strychnine and brucine from nux vomica. -isolated caffeine 4.)Animal 5.)Pierre Robiquet 5.) Vehicle use -separated codeine from opium. 6.)Philadelphia College of Pharmacy, 1821 -The nation's first school of pharmacy. In 1820 1.) Hippocrates (ca. 460 - 377 BC) -a Greek physician, is credited with the introduction of 7.)United States Pharmacopeia, 1820 - was created scientific pharmacy and medicine. to aid in establishing standards for drugs in the United -Father of Medicine State. -Pharmakon - drug 2.) Dioscorides (first century AD) 1.)Pharmakon- means drug -a Greek physician and botanist, was the first to deal with botany as an applied science of pharmacy. 2.) Poiein- means to make Pharmacognosy- a term formed from two Greek words, 3.)Pharmacopeia- means to make drugs pharmakon, drug, and gnosis, knowledge. 1580:drug standards book In Bergamo, Italy 3.) Galen (ca. 130-20 AD) -a Greek pharmacist– physician who attained Roman  LEC NOTES-Phar 2104 | Pharmaceutical Dosage Forms, Drug Delivery systems and Medical Services FIRST SEMESTER | ACADEMIC YEAR 24-25 | RELLES Many city, state, and the national multinational pharmaceutical companies that develop pharmacopeias were established (as it still and market products today) Great Britain, London, Edinburgh, and Dublin 4.)Canada generally uses the USP-NF. pharmacopeias replaced by. British -does not have its own national pharmacopeia Pharmacopoeia in 1864 Lititz Pharmacopoeia, 1778. 5.)USP-NF is the only "nongovernmental" Lyman Spalding- Father of the USP pharmacopeia in the world. 1820, the United States Pharmacopeia (USP) established by physicians 1830, pharmacists became involved. The manufacturer must rigidly adhere to USP under continuous revision established initial drug and drug product The National Formulary(NF) published in 1888 standards and assay methods. by the APhA These and future standards are adopted as 1975, the USP purchased NF new monographs by the USP-NF In 2006, a spanish edition of the USP NF was introduced Today, the USP-NF Is revised annually in hardcopy and online International consortium to develop and promote uniform or harmonized international standards. ISO 9000 t0 ISO 9004 - Among the various -adopt standards for drug substances, ISO standards used in the pharmaceutical pharmaceutical ingredients, and dosage forms industry are those in the series ISO 9000 to reflecting the best in the current practices of medicine ISO 9004. and pharmacy and provide suitable tests and assay procedures for demonstrating compliance with these standards. “The first federal law in the United States designed 1.) USP - includes detailed monograph of drug to regulate drug products manufactured substances and their dosage forms domestically was the Food and Drug Act of 1906.” 2.) NF - includes detailed monograph of pharmaceutic The law required drugs marketed interstate to ingredients. comply with their claimed standards for strength, purity, and quality. 1.)Homeopathic pharmacopeia -used by pharmacists and homeopathists as well as by The FDA created to enforce the Federal Food, law enforcement agencies that must ensure the quality Drug, and Cosmetic Act of 1938. of homeopathic drugs. The purpose of FDA was to enforce standards for the pharmaceutical industry. The term homeopathy was coined by Samuel “New Drug Application" Hahnemann (1755–1843) "Safety." ★ homoios, meaning similar "Grandfathered drugs." ★ pathos, meaning disease Issue: Sulfanilamide mixed with diethylene glycol - 100 persons died. 2.)International pharmacopeia The 1938 Act prohibits the distribution and use -published by the World Health Organization (WHO) of of any new drug or drug product without the the United Nations with the cooperation of member prior filing of a New Drug Application (NDA) countries. and approval of the FDA. - It is intended as a recommendation to national pharmacopeia revision committees to modify their pharmacopeias according to international standards. Prescription status of drugs. Rx only or Caution: Federal law prohibits 3.)European pharmacopeia dispensing without prescription. -are used within their legal jurisdictions and by Refill authorization.  LEC NOTES-Phar 2104 | Pharmaceutical Dosage Forms, Drug Delivery systems and Medical Services FIRST SEMESTER | ACADEMIC YEAR 24-25 | RELLES Prescription drugs must bear the symbol “Rx Only” or the legend “Caution: Federal Law Prohibits Dispensing Without Prescription.” According to the Durham-Humphrey Amendment, prescriptions for legend drugs may not be refilled (dispensed again after the initial filling of the prescription) without the express consent of the prescriber. Issue: Thalidomide - causes phocomelia to the baby the purpose of the enactment was to ensure a greater degree of safety for approved drugs, and manufacturers were now required to prove a drug both safe and effective before it would be granted FDA approval for marketing. 1. Birth defect or mental retardation rate is 3% to Investigational new drug application (IND) 5% in general population. 2. Two important factors to consider when assessing the teratogenic potential of a medication Stage of pregnancy and the amount of medication taken 3. Evaluate each patient individually for an accurate risk assessment. 4. Teratogens: Radiation -served to consolidate and codify control authority over Infections drugs of abuse into a single statute. Maternal and metabolic imbalance Drugs and environmental chemicals 1.Consolidates: Drug Abuse Control Amendments of 1965 Harrison Narcotic Act of 1914 FDA's strongest labeling requirements for Other laws high-risk medicines Most serious warning placed in the labeling of 2.DEA-Drug Enforcement Administration a prescription medication Chloramphenicol was the first The Comprehensive Drug Abuse Prevention and Advertisements or "reminder ads" are not Control Act of 1970 established five “schedules” allowed for the classification and control of drug substances that are subject to abuse. Each firm must register with the FDA and submit information. Enacted to provide the FDA with the legislative authority to compile a list of marketed drugs Exemptions: Compounded Preparations Research products National Drug Code number system -appear on all manufacturers' drug labeling. -Once a number is assigned to a drug product, it is a permanent assignment.  LEC NOTES-Phar 2104 | Pharmaceutical Dosage Forms, Drug Delivery systems and Medical Services FIRST SEMESTER | ACADEMIC YEAR 24-25 | RELLES Changes to speed FDA approval of generic food additives, human drugs and biologicals, drugs and the extension of patent life for radiologic and medical devices, animal d innovative new drugs were the major and feeds, and cosmetics. components of the Drug Price Competition and The Center for Drug Evaluation and Research Patent Restoration Act of 1984. (CDER) Hasten FDA approval The Center for Biologics Evaluation and Extend patent life Research (CBER) Abbreviated new drug application (ANDA) Streamline FDA policies and codify regulations Guidelines and regulations Sets policies, establishes standards, issues To reduce the risks of adulterated, misbranded, guidelines, and promulgates and enforces rules and repackaged, or mislabelled drugs regulations governing the affected industries and their products Reimportation-Prohibits the reimportation of drug products manufactured in the United States except by Monitors for regulatory compliance through reporting the manufacturer of the product. requirements, product sampling and testing, and establishment inspections Sales restrictions-Prohibits selling, trading, purchasing, or the offer to sell, trade, or purchase a Establishes product labeling requirements, drug sample. disseminates product use and safety information, issues product warnings, and directs product recalls Sample distribution-Samples may be distributed only to (a) practitioners licensed to prescribe such drugs Acts as the government's gatekeeper in making safe and (b) at the written request of the practitioner, to and effective new drugs, clinical laboratory tests, and pharmacies of hospitals or other health care medical devices available through a carefully institutions. conducted application and review process Wholesale distributors- Manufacturers are required to maintain a list of their authorized distributors. Class I - Reasonable probability of serious adverse These products, which include vitamins, health consequences or death minerals, amino acids, and botanicals, legally are not considered drugs if they have not been Class II submitted for review on NDAs and thus have not been evaluated for safety and efficacy by -May cause temporary or medically reversible the FDA consequences Labeling claims regulations Not legally considered drugs Class III USP-NF standards The act forbids manufacturers or distributors of - Not likely to cause adverse health these products to make any advertising or consequences labeling claims that indicate that the use of the product can prevent or cure a specific disease. A disclaimer must appear on the product: “This product is not intended to diagnose, treat, cure, or prevent any disease.” RPh- Registered Pharmacist The mission of the FDA is to protect the public PharmD- Doctor of Pharmacy health against risks associated with the DPh- Doctor of Pharmacy production, distribution, and sale of food and  LEC NOTES-Phar 2104 | Pharmaceutical Dosage Forms, Drug Delivery systems and Medical Services FIRST SEMESTER | ACADEMIC YEAR 24-25 | RELLES Board of Pharmaceutical To gain marketing approval: -To serve society as the profession responsible for the appropriate use of medications, devices, and The drug must be safe and effective for its services to achieve optimal therapeutic outcomes. proposed use All processes and controls used must meet established quality standards -Pharmaceutical care is that component of pharmacy practice that entails the direct interaction of the pharmacist with the patient for the purpose of caring for that patient's drug-related needs. 1. State laws and regulations 2. American Society of Health-System Pharmacists 3. United States Pharmacopeia General Chapters Pharmaceutical Compounding- Nonsterile Pharmaceutical Compounding-Sterile 1. Natural sources -Established the requirement for each state to 2. Synthesized in laboratories develop and mandate Drug Utilization Review (DUR) programs to improve the quality of pharmaceutical care 3.Genetic engineering provided to Medicaid patients. ○ Recombinant DNA ○ Monoclonal antibodies 4.Human gene therapy -a medical intervention based on the modification of the genetic material of living cells. A pharmacist respects the covenantal relationship between the patient and pharmacist. A pharmacist promotes the good of every Produces desired effects patient in a caring, compassionate, and Convenient administration confidential manner. Minimal dosage A pharmacist respects the autonomy and Minimal dosing frequency dignity of each patient. Optimal onset A pharmacist acts with honesty and integrity in Optimal duration of activity professional relationships. No side effects Eliminated from body efficiently, completely, and without residual effect A pharmacist maintains professional a goal drug would produce the specifically desired competence. effect, be administered by the most desired route A pharmacist respects the values and abilities (generally orally) at minimal dosage and dosing of colleagues and other health professionals. frequency, have optimal onset and duration of activity, A pharmacist serves individual, community, exhibit no side effects, and following its desired effect and societal needs. would be eliminated from the body efficiently, A pharmacist seeks justice in the distribution of completely, and without residual effect. health resource.  LEC NOTES-Phar 2104 | Pharmaceutical Dosage Forms, Drug Delivery systems and Medical Services FIRST SEMESTER | ACADEMIC YEAR 24-25 | RELLES Screening New Molecular Entity (NME) - s an active ingredient that has never before been marketed in the United Random or Untargeted Screening -Random or States in any form (26). untargeted screening involves the testing of large numbers of synthetic organic compounds or change in a previously approved drug substances of natural origin for biologic activity. product’s formulation or method of manufacture constitutes newness under the High-throughput screening- are capable of law since such changes can alter the examining 15,000 chemical compounds a week using therapeutic efficacy and/or safety of a product. 10 to 20 biologic assays (23). A combination of two or more old drugs or a -To be effective, this change in the usual proportions of drugs requires a sizable and chemically diverse collection of Proposed new use, new regimen, new route of compounds to examine, which many pharmaceutical administration, or new dosage form and chemical companies have in chemical libraries. Molecular modification of known agents - a chemical alteration of a known and previously A prototype chemical compound with desired characterized organic compound (frequently a lead activity that may not possess all the desired compound; see "A Lead Compound") for the purpose features of enhancing its usefulness as a drug. Synthesis of derivatives which will ultimately lead to successive generations of the same Mechanism-based drug design - is molecular pharmacologic type modification to design a drug that interferes specifically with the known or suspected biochemical pathway or mechanism of a disease process. When first synthesized or identified from a natural source, an organic compound is represented by an empirical formula, for example, C16H19N3 O5 S·3H2 A compound that requires metabolic O for amoxicillin, which indicates the number and biotransformation after administration to relationship of the atoms in the molecule. produce the desired pharmacologically active compound As knowledge of the relative locations of these atoms increases, the compound receives a systematic Solubility - A prodrug may be designed to possess chemical name solubility advantages over the active drug, enabling the use of specifically desired dosage forms and routes of Nonproprietary (Generic) Name- U.S. Adopted administration Names (USAN) Council - A nonproprietary name of a drug serves numerous Absorption - A drug may be made more water or lipid and varied purposes, its principal function being to soluble, as desired, to facilitate absorption via the identify the substance to which it applies by means of a intended route of administration. designation that may be used by the professional and lay public free from the restrictions associated with Biostability - If an active drug is prematurely registered trademarks. destroyed by biochemical or enzymatic processes, the design of a prodrug may protect the drug during its transport in the body. -Prospective drug substances must undergo preclinical Prolonged release - Depending on a prodrug’s rate of testing for biologic activity to assess their potential as metabolic conversion to an active drug, it may provide useful therapeutic agents. prolonged drug release and extended therapeutic activity The science concerned with drugs, their sources, appearance, chemistry, actions, and uses  LEC NOTES-Phar 2104 | Pharmaceutical Dosage Forms, Drug Delivery systems and Medical Services FIRST SEMESTER | ACADEMIC YEAR 24-25 | RELLES It can include properties, biochemical and mammalian reproduction. Included in these physiologic bioran, romation, a of extie, studies are fertility and mating behavior; early absorption, distribution, embryonic, prenatal, and postnatal development; multigenerational effects; and Pharmacodynamics - the study of the biochemical teratology. and physiologic effects of drugs and their mechanisms Genotoxicity or mutagenicity studies - of action; performed to determine whether the test compound can affect gene mutation or cause Pharmacokinetics - which deals with the absorption, chromosome or DNA damage. distribution, metabolism or biotransformation, and excretion (ADME) of drugs Clinical Pharmacology - which applies pharmacologic principles to the study of the effects and actions of drugs in humans. -each drug substance has intrinsic chemical and physical characteristics that must be considered before ADME studies the development of a pharmaceutical formulation a. the extent and rate of drug absorption from various routes of administration, including the Drug solubility one intended for human use b. the rate of distribution of the drug through the -A drug substance administered by any route must body and the site or sites and duration of the possess some aqueous solubility for systemic drug’s residence absorption and therapeutic response. Poorly soluble c. Rate, primary and secondary sites, and compounds (e.g., less than 10 mg/mL aqueous mechanism of the drug's metabolism in the solubility) may exhibit incomplete, erratic, and/or slow body absorption and thus produce a minimal response at d. the proportion of administered doses desired dosage. eliminated from the body and its rate and route of elimination. Necessary for absorption/transport Biochemical transformation into If less than about 10 mg/mL, may exhibit either readily-eliminated polar compounds incomplete or erratic absorption and produce a minimal response Can be increased by modifying the structure, form, complexation, or particle size reduction -Adverse or undesired effects of drugs Partition coefficient Toxicity Studies: -a drug molecule must first cross a biologic membrane Acute or short-term toxicity studies - of protein and lipid, which acts as a lipophilic barrier to determine the toxic effects of a test compound many drugs. when administered in a single dose and/or in multiple doses over a short period, usually a The drug must pass the biological membrane single day. of protein/lipid, which acts as a lipophilic Subacute or subchronic studies - In barrier to many drugs. designing an animal toxicology program, Preference of drug for lipid:water. relationships to projected human clinical Indicative of ability to penetrate biologic studies for safety must be considered. multiphase systems. Dissolution rate -The speed at which a drug substance dissolves in a medium is called its dissolution rate. Carcinogenicity studies - a component of chronic testing and is undertaken when the Speed/rate at which a substance dissolves compound has shown sufficient promise as a Indicates a drug's absorption potential drug to enter human clinical trials. Reproduction studies - are undertaken to reveal any effect of an active ingredient on  LEC NOTES-Phar 2104 | Pharmaceutical Dosage Forms, Drug Delivery systems and Medical Services FIRST SEMESTER | ACADEMIC YEAR 24-25 | RELLES Physical form -The crystal or amorphous forms and/or the particle size of a powdered drug can affect the dissolution rate, and thus the rate and extent of absorption, for a number of drugs. Crystalline versus amorphous Particle size - Stability -The chemical and physical stability of a drug Phase I substance alone, and when combined with formulation components, is critical to preparing a successful - Determine human pharmacology of the drug, pharmaceutical product. structure-activity relationships, side effects with increasing doses, possible early evidence of Both physical and chemical properties effectiveness Addition of formulation components to create a successful pharmaceutical product Phase II Absorption Hydrolysis: moisture in packaging - Controlled clinical studies for effectiveness in Heat and Humidity patients with the condition Phase III -An initial product is formulated using the information -Several hundred to several thousand patients gained during the preformulation studies and with the in controlled and uncontrolled trials. consideration of the dose or doses, dosage form, and route of administration desired for the clinical studies and for the proposed marketed product. placebo (placebo control) or an active drug Dosage form, Dosage strength, Route of (positive control), a standard or comparator drug administration product. Initial formulations Clinical supplies Both a placebo and an active drug may be used as controls in the same study Study designs -Filed when adequate safety and usefulness as a new drug has been demonstrated through preclinical studies Usual dose Contents: Dosage regimen Initial/Priming/Loading dose Code of Federal Regulations Maintenance dose Form FDA-1571 Prophylactic dose Therapeutic dose Minimum Effective Concentration Minimum Toxic Concentration Protects the safety and rights of the human Median Effective Dose (ED50) subjects Median Toxic Dose (TD50) Ensures that the study allows the evaluation of the drug's safety and effectiveness Age Pharmacogenetics Body weight  LEC NOTES-Phar 2104 | Pharmaceutical Dosage Forms, Drug Delivery systems and Medical Services FIRST SEMESTER | ACADEMIC YEAR 24-25 | RELLES Body surface area May reveal additional: Sex Pathologic state Side effects Tolerance Serious and unexpected adverse effects Concomitant drug therapy Drug interactions Time and conditions of administration Dosage form and route of administration 2.)Continued clinical investigations Better understand the drug's MOA Indicate possible new therapeutic uses Permits the use of an investigational drug in Demonstrate need for new formulations patients not enrolled in a clinical study. Additional side effects, adverse effects and/or Patients have serious or immediately drug life-threatening disease. No satisfactory alternative is available. -adverse drug experience that is both serious (life threatening or fatal) and unexpected (not contained in -Orphan disease is a rare disease or condition the approved drug product labeling), regardless of the affecting fewer than 200,000 people in the United source of the information, within 15 working days of States and of which there is no reasonable expectation receipt of the information. that R&D costs will be recovered by product sales. Adverse drug experiences must be reported to Examples: the FDA within 15 working days of receipt of information. Chronic lymphocytic leukemia The FDA may require to revise product Cystic fibrosis labeling or other actions. Gaucher disease Annual Reports -A sponsor may withdraw an IND at any time, ending all clinical investigations. All stock of clinical supplies must be returned to the sponsor or otherwise destroyed. -nonclinical laboratory studies and clinical The sponsor can withdraw at any time. investigations may be omitted, except those pertaining Inactive status to the drug’s bioavailability. FDA termination for reasons of safety, efficacy, or regulatory compliance. Nonclinical laboratory studies and clinical investigations may be omitted, except for studies pertaining to drug's bioavailability. Generic drug products (based upon innovator's NDA). -Must meet specific labeling requirements in the CFR and approved for each product by the FDA -BLAs are submitted to the FDA’s CBER for the Labeling includes: manufacture of biologics such as blood products, vaccines, and toxins. Labels on immediate container Package insert For the manufacture of Biologics: Company literature Advertising Blood products Promotional materials Vaccines Toxins 1.)Continued data collection for drugs after they are marketed -The Federal Food, Drug, and Cosmetic Act, as amended, contains specific regulations pertaining to  LEC NOTES-Phar 2104 | Pharmaceutical Dosage Forms, Drug Delivery systems and Medical Services FIRST SEMESTER | ACADEMIC YEAR 24-25 | RELLES the approval for the marketing and labeling of drugs 2.)Employees- must be educated, trained and have intended for animal use (6). the experience needed 1. Specific regulations involved 3.)Consultants- should possess the required 2. The Animal Medicinal Drug Use qualifications Clarification Act of 1994 (AMDUCA) -Allows veterinarians to prescribe extralabel uses of approved animal drugs and approved Structure, space, design, and placement of human drugs for animals. equipment must enable thorough cleaning, inspection, and safe and effective use of the designated operations. All work must be logged in, inspected by a supervisor, and signed off. -harmonizing, or bringing together, the regulatory -Each piece of equipment must be of appropriate requirements with the long-range goal of establishing a design and size and suitably located to facilitate uniform set of standards for drug registration within operations for its intended use, cleaning, and these geographic areas. maintenance. International marketplace 1.)Appropriate: US FDA, EU, Japan, and geographic representatives Design To establish a uniform set of standards for drug Size registration 2.)Suitably located to facilitate: KAYA PA NE?? WATER BREAK DANAY DW UHAW KANAGID OH! Intended use Cleaning Maintenance Written procedures Established by the FDA -That describe the receipt, identification, Ensure that minimum standards are met for storage, handling, sampling, testing, and approval or drug product quality rejection of all drug product components, product First cGMP regulations were promulgated in containers, and closures must be maintained and 1963 under the Kefauver-Harris Drug followed Written procedures. Ensure correct identity, strength, quality, and 21 CFR, Part 211 contains minimum good purity. manufacturing practice requirements for Any deviation must be recorded and justified. preparation of finished pharmaceutical All product ingredients, equipment, and drums products for administration to humans or or other containers must be distinctively animals. identified. deals with the responsibilities of the quality control unit, 1.)Written procedures - Written procedures must be employees, and consultants established and followed for the holding and distribution of products. Responsibilities of the: Holding 1.)Quality control unit- authority and responsibility Distribution Quarantined for all functions affecting product quality.  LEC NOTES-Phar 2104 | Pharmaceutical Dosage Forms, Drug Delivery systems and Medical Services FIRST SEMESTER | ACADEMIC YEAR 24-25 | RELLES 2.)Stored and shipped under appropriate conditions - Products must be stored and shipped under conditions that do not affect product quality. 3.)FIFO - Ordinarily, the oldest approved stock is distributed first. The quality of all components affects the quality of the finished pharmaceutical product APIs and excipients must comply to GMP -Written procedures are required for the receipt, standards since it is critical in the FDA's identification, storage, handling, sampling, and testing preapproval inspection program for NDAs and of drug product and issuance of labeling and ANDAs. packaging materials Expiration dating- to ensure that the drug product meets applicable standards at the time of use Must be produced under cGMP standards Flexibility in the regulations is applicable during Tamper-evident packaging - On November 5, 1982, the preclinical testing and in the earlier part of the FDA published initial regulations on the clinical tests. tamper-resistant packaging in the Federal Register These regulations were promulgated after criminal tampering with over-the-counter (OTC) drug products Additional mandates specific for blood, earlier in that year resulted in illness and deaths. bacterial, and viral products are found in the regulations due to their nature. -Have one or more indicators or barriers to entry which, if breached or missing, can reasonably be expected to provide visible evidence to consumers that tampering has occurred. Approval process similar to pharmaceuticals. Similar standards in place. Thousands of medical devices are covered. Intraocular lenses, hearing aids, intrauterine Complete production, control, and distribution devices, cardiac pacemakers, clinical records: chemistry analyzers, catheters, bypass machines, dental x-ray equipment, surgical Maintained for not less than 1 year after gloves, condoms, prosthetic hip joints, traction expiration date of the batch. equipment, and powered wheelchairs. must be identified by lot number and product Result to FDA Regulatory actions quality must be determined through appropriate testing -Noncompliance determined during a premarket Salvaging or reprocessing are allowed if approval inspection of facilities as part of an NDA or specifications are met ANDA application likely would result in a delay of Complete records must be maintained approval of an otherwise approvable application. Noncompliance with cGMP regulations during a regularly scheduled FDA inspection can lead to various actions, depending on the severity of the offenses. Not part of the GMP requirements, but when used effectively they can enhance process developments, production efficiency, product quality and compliance, Good Compounding Practices Applicable to State-Licensed Pharmacies-Model Act Eight recommendations Compounding vs Manufacturing  LEC NOTES-Phar 2104 | Pharmaceutical Dosage Forms, Drug Delivery systems and Medical Services FIRST SEMESTER | ACADEMIC YEAR 24-25 | RELLES 8.)Multiple-unit: -Contain more than a single unit/dose 9.)Tamper-resistant 10.)Light-resistant: USP: that which holds the article and is or may -Protects the contents from the effects of light be in direct contact with the article by virtue of the specific properties of the material of Immediate container - that which is in direct which it is composed, including any coating applied to contact with the article at all times it. Alternatively, a clear and colorless or a translucent Must be clean and dry before it is filled, and container may be made light resistant by means of an must not physically or chemically interact with opaque covering, in which case the label of the the drug container bears a statement that the opaque covering is needed until the contents are to be used or administered. 1.)Well-closed: -Minimally acceptable container; Protects the contents from extraneous solids and from loss of the article under the ordinary or customary conditions of handling, shipment, storage, and distribution 2.)Tight: -Protects the contents from contamination by extraneous liquids, solids, or vapors, from loss of the article, and from efflorescence, deliquescence, or evaporation under the ordinary or customary conditions of handling, shipment, storage and distribution, and is capable of tight reclosure 3.)Hermetic: Plastic- most widely used -Impervious to air or any other gas under Advantages: ordinary conditions Lighter and more resistant to impact vs glass 4.)Sterile Hermetic: Versatility Consumer preference (plastic squeeze bottles) -For parenteral preparations Popularity of blister packaging and unit-dose dispensing 5.)Single-dose: Problems encountered: -Holds a quantity intended for a single dose and cannot be resealed once opened Permeability - ability of moisture vapor or gas to enter the plastic 6.)Multiple-dose: Leaching - movement of container components into the contents -Hermetic container that allows successive Sorption - binding of molecules to polymer withdrawals of portions without changing the strength materials of the contents or endangering the remaining portion's Physical changes (deformation, softening or quality or purity. hardening) due to contents or external factors. 7.)Single-unit: Types of Plastics: -Unit-dose Package; Holds a quantity intended 1.)Polyethylene to be administered as a single dose immediately after opening Widely used Good water barrier  LEC NOTES-Phar 2104 | Pharmaceutical Dosage Forms, Drug Delivery systems and Medical Services FIRST SEMESTER | ACADEMIC YEAR 24-25 | RELLES Poor oxygen barrier Not too clear Odors, flavors, gases permeate Cannot be autoclaved 2.)Polypropylene Very popular Excellent barrier to water, gases Not too clear Can be autoclaved 3.)Polyvinyl Chloride Clear, rigid To ensure the stability of a pharmaceutical Good oxygen barrier preparation for the period of its intended shelf life, Permeable to water the product must be stored in proper conditions. Yellows when exposed to heat or UV light; The labeling of each product includes the desired Unsuitable for gamma sterilization conditions of storage. Used for parenteral solutions and in blister -Increases the rate of chemical reactions packaging 1.)High temperatures: 4.)Polystyrene Sublimation (solid) Rigid Solvent loss (liquid) Crystal clear Chemical decomposition of dyes (color fading) Used for solid dosage forms Phase separation (emulsions) 5.)Polycarbonate Increased sedimentation (suspensions) Increased disintegration times (tablets) Clear, transparent Rigid 2.)Low temperatures Possible replacement for glass Crystal formation in solutions Expensive Phase separation (emulsions) 6.)Polyethylene terephthalate Increased sedimentation (suspensions) Cracking of sugar-coated tablets Excellent transparency and luster Can be sterilized with gamma radiation 3.)Humidity 4.)Gases Reduce accidental poisonings. 5.)Light It is significantly difficult for children under 5 years of age to open or to obtain a harmful amount of its contents within a reasonable time Risk of container breakage and that is not difficult for "normal adults" to Loss of strength or potency use properly. Destructive alteration of dosage form “When no specific instructions are given, it is understood to include protection from moisture, To assist patients in taking their medications freezing, and excess heat.” on schedule Oral contraceptive pills Stability considerations Packing considerations "Drug Facts" Temperature Label format and design should be easily read Humidity and understood, especially by the elderly Time  LEC NOTES-Phar 2104 | Pharmaceutical Dosage Forms, Drug Delivery systems and Medical Services FIRST SEMESTER | ACADEMIC YEAR 24-25 | RELLES Shipping schedules Drug substances are mostly given as a part of a Liquids: many are volatile; those intended PO cannot formulation. be made into tablets without modification. Excipients - Pharmaceutical Ingredients; Nonmedicinal agents combined with the API in a formulation Particle size Particle size range Pharmaceutics - area of study concerned with the Crystal structure formulation, manufacture, stability, and effectiveness of Particle shape pharmaceutical dosage forms Physical, chemical and biologic characteristics must be considered in the design and formulation of a dosage Vapor pressure. form. Important in the operation of implantable pumps delivering medications and also in aerosol dosage forms; nasal inhalants Volatile drugs can migrate within a solid Dosage Forms provide the mechanism for the dosage form. safe and convenient delivery of accurate Personnel exposure. dosage Protection from: Destruction due to oxygen and humidity, and gastric acid (for drugs given PO) A defined melting point or range is a Conceal the unpleasant taste and odor characteristic of a pure substance. Determination of Purity and Identity Provide: Liquid preparations (dispersions or clear preparations) Dissolution rate Rate-controlled drug action Bioavailability Optimal drug action for drugs given topically Content uniformity For insertion into body orifices; Direct Taste placement into the bloodstream or tissues; Texture Optimal drug action when inhaled Color Stability Flow characteristics Sedimentation rates Physicochemical Properties of the drug Particle size significantly influences the oral substance absorption profiles of some drugs. Therapeutic considerations Age Crystalline or Amorphous Different Physicochemical properties such as -Solids, liquids, gases Melting point and Solubility. Amorphous form is always more soluble than 1.)Chemical properties the crystal form. Changes in crystal characteristics would -Structure, form, reactivity influence bioavailability and stability 2.)Physical properties -Description, particle size, crystalline structure, Some aqueous solubility for to be melting point, solubility therapeutically effective A drug must be in solution for it to enter the 3.)Biological properties systemic circulation and elicit a response -Ability to get to the site of action and elicit a To increase solubility, chemical modification response into salt or ester form  LEC NOTES-Phar 2104 | Pharmaceutical Dosage Forms, Drug Delivery systems and Medical Services FIRST SEMESTER | ACADEMIC YEAR 24-25 | RELLES Equilibrium solubility method 1.)Hygroscopic - Tend to absorb moisture from the air Small increases in solubility can be achieved 2.)Deliquescent by - Absorb moisture from the air and liquefy particle size reduction. Decreases in particle size may enhance 3.)Efflorescent dissolution rates. - Give up its water of crystallization and may become damp and pasty Adjusting the pH of the solvent can enhance solubility of the drug. Electrolytes Base form or Ester form Esters are the most important acid derivatives Dissolution may be the rate-limiting step in the used in pharmacy after salts. absorption of poorly soluble drugs, especially Important means of preparing prodrugs. those administered PO or IM. Can affect onset, intensity, and duration of response and control overall bioavailability of API is not 100% active the drug from the dosage form. Activity: "Units of activity"; "mcg/mg" Decrease in particle size, increasing the Biological potency: IU solubility in the diffusion layer, use a highly water-soluble salt of a parent substance Proteins are the most complex molecules and biotechnology products Drug must pass through the biologic Unstable and have a complicated degradation membrane (lipid barrier) to elicit a biologic profiles response. Stabilization, formulation, and delivery to the pKa, solubility, and dissolution rate data can site provide an indication of absorption. evaluation of the physical and chemical Octanol: water partition coefficient stability of the pure drug substance. Shelf life of 2 to 3 years is generally desired The presence of impurities can lead to erroneous conclusions in such evaluations. Extent of dissociation or ionization Dependent on pH of the medium Can affect absorption, distribution, and 1.)Hydrolysis elimination solvolysis process where water breaks down molecules Most important single cause of drug Most drugs are either Weak acids or Weak decomposition bases Used as Salts to increase their aqueous 2.)Oxidation solubility destroys many drug types, including Albuterol sulfate (dosed as the base) aldehydes, alcohols, phenols, sugars, Diphenhydramine HCI (dosed as the salt) alkaloids, and unsaturated fats and oils. Chemically, oxidation is loss of electrons from an atom or a molecule.  LEC NOTES-Phar 2104 | Pharmaceutical Dosage Forms, Drug Delivery systems and Medical Services FIRST SEMESTER | ACADEMIC YEAR 24-25 | RELLES 1.)Chemical stability- Each active ingredient retains its chemical integrity and labeled potency within the specified limits. temperature, humidity, and where appropriate, oxidation, light and microbial exposure. 2.)Physical stability- Sterility or resistance to microbial growth is retained according to the specified Active pharmaceutical ingredients requirements. Antimicrobial agents retain effectiveness Pharmaceutical ingredients added to prepare a within specified limits dosage form. 3.)Microbiological stability- 4.)Therapeutic stability- The therapeutic effect Drug remains unchanged. Route of administration Suitable physical dosage form 5.)Toxicologic stability- No significant increase in Use of chemical derivatives of the drug toxicity occurs. Control of certain physicochemical and/or biochemical processes that alter the rate and extent of response -Change of drug concentration with respect to time. Coloring agents Sweetening agents - lets the pharmacist estimate shelf life for a product Flavoring agents that has been stored or is going to be stored under a Surfactants different set of conditions. Solubilizing agents Antioxidants Shelf life estimation Preservatives Q10 = ef(Ea/R)[(1/T + 10) - (1/7)] Thickening agents Suspending agents Binding agents Done at each stage of product development. Solvents Product containers and closures must be Lubricants considered. Perfumes Temperature and humidity studies. Fats and oils Light studies. Changes in physical appearance, color, odor, taste, texture. Monographs on more than 300 excipients used Chemical changes of drug degradation. in dosage form preparation The pharmacist is the last professional to Additional excipients listed in the Food check for quality and stability prior to Chemicals Codes and National Formulary. dispensing. Compliance issues -To establish the shelf life and storage conditions. Odor, color, and taste Important for all age groups, especially -increase the rate of chemical degradation or physical pediatrics and geriatrics change of a drug substance or drug product by using “Electronic tongue” is used to aid in providing exaggerated storage conditions as part of long-term, a global “taste fingerprint” during formulation intermediate, and accelerated studies. development The purpose of stability testing is to provide evidence on how the quality of a drug substance or drug product varies with time under the influence of a variety of environmental factors, such as  LEC NOTES-Phar 2104 | Pharmaceutical Dosage Forms, Drug Delivery systems and Medical Services FIRST SEMESTER | ACADEMIC YEAR 24-25 | RELLES Saccharin Sorbitol Sucrose The flavoring of pharmaceuticals applies primarily to liquids intended for oral administration -are used in pharmaceutical preparations for esthetics..Complex area. Important for compliance. A distinction should be made between agents Color, taste, and odor should generally match that have inherent color and those that are employed as colorants Lighter shades preferred 1. Dyes: FD&C, D&C, external D&C Sour taste H+ 2. Lakes: Calcium and aluminum salts 3. Liquids: 0.0005% to 0.001% Saltiness Anions and cations 4. Powders: 0.1% 5. Caramel Bitter High MW salts 6. Ferric oxide: Red/yellow Sweet Polyhydroxyl compounds, polyhalogenated Sterilization and preservation compounds,and alpha Preservative selection amino acids General preservative considerations Mode of action Sharp,biting Unsaturation Preservative utilization Camphoraceous odor Tertiary "C" atom -to the stabilization of pharmaceutical preparations against chemical and physical degradation due to changed environmental conditions within a formulation, certain liquid and semisolid preparations must be preserved against microbial contamination. Dosage form 1.)Pleasant odor Ketones Route of administration Compatibility with excipients 2.)Methylparaben Floral, gauze pad Container and closure compatibility 3.)Propyl/buty| paraben Numbing mouthfeel From book prevents the growth of the type of microorganisms considered the most likely Immediate flavor identity contaminants of the preparation. Rapid full flavor development s soluble enough in water to achieve adequate Acceptable mouthfeel concentrations in the aqueous phase of a Short aftertaste system with two or more phases. No undesirable sensations The proportion of preservative remaining undissociated at the pH of the preparation makes it capable of penetrating the microorganism and destroying its integrity. -Natural versus synthetic The required concentration of the preservative does not affect the safety or comfort of the patient when the pharmaceutical preparation is Dextrose administered by the usual or intended route; Mannitol  LEC NOTES-Phar 2104 | Pharmaceutical Dosage Forms, Drug Delivery systems and Medical Services FIRST SEMESTER | ACADEMIC YEAR 24-25 | RELLES that is, it is nonirritating, non sensitizing, and nontoxic. has adequate stability and will not be reduced in concentration by chemical decomposition or volatilization during the desired shelf life of the 1.)Passive diffusion - passage through a membrane preparation. driven by the concentration gradient completely compatible with all other formulative ingredients and does not interfere 2.)Specialized transport mechanisms - involves with them nor do they interfere with the membrane components capable of forming a complex effectiveness of the preservative agent with the drug, which will then move across the e does not adversely affect the preparation’s membrane, release the drug, and would return to its container or closure. original surface. - Active transport - Facilitated diffusion Range of activity Concentration required pH requirements 1.)Active transport Compatibility - A process using a "carrier" with the additional feature of the drug being moved across the membrane Modification of cell membrane permeability against a concentration gradient; from lower Lysis and cytoplasmic leakage concentration to higher concentration Irreversible coagulation of cytoplasmic 2.)Facilitated diffusion constituents Inhibition of cellular metabolism -A specialized transport using the "carrier," but Oxidation of cellular constituents the drug is not moved against a concentration gradient. Hydrolysis It must first be dissolved in the fluid at the Benzoic acid/sodium benzoate absorption site. Alcohol Dissolution - process by which drug particles Phenylmercuric nitrate/acetate dissolve Phenol Surface Area Cresol Crystal or Amorphous Chlorobutanol Salt Form Benzalkonium chloride Other Factors Methylparaben/propylparaben Others -Particle size has an effect on dissolution rate and solubility. As shown in the Noyes-Whitney equation, -When a drug particle is broken up, the total surface Principles of drug absorption area is increased. Dissolution and drug absorption Bioavailability and bioequivalence dC Routes of drug administration Fate of drug after absorption dT Pharmacokinetic principles = KS(Cs - Ct) where -Area of study dealing with the relationship between physical, chemical, and biological sciences applied to dC/dT is the rate of dissolution (concentration drugs, dosage forms, and drug action. with respect to time). K is the dissolution rate constant. S is the surface area of the particles.  LEC NOTES-Phar 2104 | Pharmaceutical Dosage Forms, Drug Delivery systems and Medical Services FIRST SEMESTER | ACADEMIC YEAR 24-25 | RELLES C. is the concentration of the drug in the - Area under the serum concentration-time immediate Ere imity of the dissolving particle, curve that is, the solubility of - represents the total amount of drug absorbed G is the concentration of the drug in the bulk into the circulation after a single dose fluid. Bioequivalence of drug products Blood, Serum, or Plasma Concentration Time curve 1.)Crystalline Lowest energy state Ordered 2.)Amorphous Metastable state Gradually revert back to crystalline state over time Stable and unstable polymorphs Serum concentration-time curve showing peak height concentration, time of peak 1.)Solubility- Salts are generally more soluble. concentration, snd AUC. 2.)Dissolution- Salts generally dissolve faster. A Generic Drug Must: 3.)Sodium and potassium salts of weak organic Contain the same active ingredient(s) acids Be identical in strength, dosage form, and route of administration 4.)Hydrochloride salts of weak organic bases Have the same indications and precautions for use and other labeling instructions Be bioequivalent Meet the same batch-to-batch requirements for State of hydration identity, strength, purity, and quality. Complex formation Adsorption of drug 1.)Pharmaceutical equivalents --Describes the rate and extent to which an active drug - Drug products that contain identical amounts ingredient or therapeutic moiety is absorbed from a of the identical active drug ingredient. drug product and becomes available at the site of action 2.)Pharmaceutical alternatives - Drug products that contain the identical therapeutic moiety or its precursor but not necessarily -comparison of bioavailabilities. in the same amount or dosage form or as the same salt or ester. 3.)Bioequivalent drug products Drug products whose rate and extents of absorption do not show a significant difference - Pharmaceutical equivalents or when administered at the same molar dose pharmaceutical alternatives whose rate and extent of under similar conditions are bioequivalent. absorption do not show a significant difference. Blood, serum, or plasma concentration-time curve 4.)Therapeutic equivalents Parameters for assessment and comparison of bioavailability -used to indicate pharmaceutical equivalents - Peak height (Cmax) that provide essentially the same therapeutic effect - Time of peak (Tmax) when administered to the same individuals in the same dosage regimens.  LEC NOTES-Phar 2104 | Pharmaceutical Dosage Forms, Drug Delivery systems and Medical Services FIRST SEMESTER | ACADEMIC YEAR 24-25 | RELLES Intramuscular injections - are performed deep into the skeletal muscles, generally the gluteal or lumbar muscles. The -Drugs are most frequently taken by oral selected site is where the danger of hitting a administration. nerve or blood vessel is minimal. 1.)Dosage forms applicable Intravenous injections Tablets, capsules - intravenous administration of drugs, an Suspensions, solutions, emulsions aqueous solution is injected directly into the Others vein at a rate 2.)Absorption Absorption of drugs after oral administration commensurate with efficiency, safety, comfort may occur at the various body sites between to the patient, and the desired duration of drug the mouth and rectum response. he higher up a drug is absorbed along the alimentary tract, the more rapid will be its Intradermal injections action, a desirable feature in most instances. -Intradermal injections are administered into the corium of the skin, usually in volumes of about 0.1 mL. Common sites for the injection Suppositories are the arm and the back. The injections are frequently performed as diagnostic measures, -are solid bodies of various weights and as in tuberculin and allergy testing shapes intended for introduction into a body orifice (usually rectal, vaginal, or urethral) where they soften, melt, or dissolve; release their medication; and exert their drug effects -Drugs are frequently applied topically to the eye, ear, and mucous membranes of the nose, usually as Enemas ointments, suspensions, and solutions. 1.)Ocular -parenteral is derived from the Greek words para, Solutions, suspensions meaning beside, and enteron, meaning intestine, which together indicate something done outside of the 2.)Otic intestine and not by way of the alimentary tract. Solutions, suspensions, powders Dosage forms applicable 3.)Nasal - Solutions, suspensions, emulsions, pellets Solutions, suspensions, sprays, drops. -most injectable preparations are either a sterile suspension or solution of a drug substance in water or in a suitable vegetable oil Oral inhalation Vaginal -Drugs in solution act more rapidly than drugs Urethral in suspension, with an aqueous vehicle providing faster action in each instance than an oleaginous vehicle. -After absorption into the general circulation from any Subcutaneous injections route of administration, a drug may become bound to blood proteins and delayed in its passage into the -subcutaneous (hypodermic) administration of surrounding tissues. drugs entails injection through the skin into the loose subcutaneous tissue. Drug metabolism, or biotransformation Excretion of drugs  LEC NOTES-Phar 2104 | Pharmaceutical Dosage Forms, Drug Delivery systems and Medical Services FIRST SEMESTER | ACADEMIC YEAR 24-25 | RELLES Kinetic approach - This approach is based on the assumption that the therapeutic and toxic effects of a drug are related to the amount of drug in the body or to the plasma (or serum) Metabolism or biotransformation involves concentration of drug at the receptor site. chemical changes to drugs within the body. Frequency of administration Results in one or more compounds that are Activity/Toxicity, Pharmacokinetics, Clinical more water soluble, more ionized, less capable Factors,Others of binding to proteins of the plasma and tissues, less capable of being stored in fat tissue, and less able to penetrate cell membranes Consequently, more easily excreted Also called detoxification or inactivation Composition -Properly prepared, powders have a uniform, small particle size that has an elegant -The excretion of drugs and their metabolites appearance. In general, powders are more stable than terminates their activity and presence in the body. are liquid dosage forms and are rapidly soluble, enabling the drug to be absorbed quickly. Kidney (urine) Feces Application - Powders have qualities that make them Lungs an attractive dosage form for certain situations. Unlike Sweat a standardized capsule or tablet,powders enable a Saliva primary care provider to easily alter the quantity of Milk medication for each dose. Reabsorption of some drugs The particles of pharmaceutical powders and granules Half-life may range from being extremely coarse, about 10 mm (1 cm) in diameter, to extremely fine, approaching -The half-life (t½) of a drug describes the time colloidal dimensions of 1 μm or less required for a drug’s blood or plasma concentration to decrease by half. This fall in drug concentration is a reflection of metabolic processes and/or excretion. Concept of clearance (CIB = Cln + Cl + Clb) Dosage regimen considerations -Particle size determinations are complicated by the fact that particles are not uniform in shape Dissolution Suspendability of suspensions Uniformity of mixtures in liquids Penetrability of particles for inhalation Empirical approach - which entails Non grittiness for ointments, creams, gels administration of a drug in a certain quantity, noting the therapeutic response and modifying the amount and interval of dosage accordingly  LEC NOTES-Phar 2104 | Pharmaceutical Dosage Forms, Drug Delivery systems and Medical Services FIRST SEMESTER | ACADEMIC YEAR 24-25 | RELLES If uniform, it will aid in mixing and distribution. 1.)Ball mills Finer particles may migrate to the bottom. Larger particles may migrate to the top. - Closed Differences may change the color intensity of a powder. - Continuous Especially important in dermatologicals. The process of reducing the particle size of a solid substance to a finer state of subdivision. 2.)Roller mills Stone mills were the original implement for 3.)Cutter mills grinding. Mortars and pestles are the symbol of 4.)Hammer mills pharmacy. 5.)Colloid mills Reduce particle size until uniform with other Facilitate crude drug extraction ingredients. Increase the dissolution rates of drugs Start with the substance present in the Aid in the formulation process smallest amount and add ingredient with next Enhance absorption larger quantity (if practical) using geometric dilution technique. Also "tracer" method. Continue adding substances until all are added Manual and uniformly mixed. Mechanical -A process that tends to result in a randomization of Trituration (to rub to pieces) dissimilar particles within a system Pill tile and spatulaMortar and pestle 1. Small-scale blending equipment Porcelain Wedgewood - Compounding Glass 2. Large-scale blending equipment - Manufacturing 1.)Levigation to make smooth Triturating while moistened with a liquid in which the powder is insoluble Pill tile and spatula Mortar and pestle 2.)Pulverization by intervention Bottle/container Plastic baggie Comminution by utilizing a solvent that can be Easily cleanable easily removed. Dust tight Provide complete discharge/recovery Convective mixing