Drug Delivery - Exam 1

FDA's mission

Promote and protect the public health by helping safe and effective products reach the market in a timely way, and monitoring products for continued safety after they are in use

Products FDA regulates

* Food
* Drugs
* Medical devices
* Biologics
* Animal feed and drugs
* Cosmetics
* Radiation-emitting products

Entry process of new chemical entity to marketplace

1. Preclinical - drug discovery
2. Phase 1 - drug development/primary concentration of drug delivery
3. Phase 2 - clinical trials
4. Phase 3 - manufacture
5. Registration
6. Phase 4 - sales and marketing

Benefits of drug delivery to patient

* Compliance
* Efficacy and tolerability

Benefits of drug delivery to industry

* Life Cycle Management
* Differentiate products in crowded market
* Rescuing research and development drop outs
* Outsourcing
* Providing delivery systems for next gen of medicines

Efficacy and tolerability

* Drug delivery enables delivery of medication to body by optimizing clinical efficacy and tolerability by maintaining plasma concentrations within therapeutic window
* Despite using same drug, the difference in efficacy can be considerable
* Situations that ensure clinical differentiation:
* Fast melt tablets for fast dissolution and onset of clinical effects
* Enteric coated tablets to protect stomach from irritant drugs
* Insoluble drug formulations to enhance absorption and reduce inter-patient variability in plasma levels
* Multiparticulate dosage forms that reduce effect of food on absorption
* Targeted release dosage forms to selectively release drugs at specified areas of GI tract

Life Cycle Management

* To maintain product revenues, companies devise means of prolonging the life-cycle of their products upon patent expiration (maximizing ROI)
* Intense generic competition upon patent expiration of branded product
* Within 1y of patent expiration, brand erosion of up to 70% can occur due to aggressive price discounting by generic manufacturers
* Drug delivery can extend life-cycle by launching improved formulation of dosage form 2/3y years prior to patent expiry

Drug delivery benefits

* Develop more 'user friendly' dosage forms of medicines with ultimate aim of increasing dosing convenience to patient
* Ex: reduce dosage
* Enable medicines to be administered in more presentable format
* Effervescent sachets that produce pleasant tasting medicines
* Providing medicine that increases patient compliance
* $8.5 billion cost of relapse visitations

Drug delivery: topical/local vs. systemic

Topical/local: delivery of drug mainly locally without entering circulation

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Systemic: delivery to whole body

Routes of drug administration (both local and systemic)

* GI (oral)
* Parenteral
* Mucosal
* Nasal
* Buccal
* Pulmonary
* Occular
* Rectal
* Transdermal

GI administration (oral)

* Most preferred route of administration is oral
* Disadvantages prohibit oral administration of certain classes of drugs especially peptides and protein
* Hepatic first pass metabolism
* Enzymatic degradation within GI tract

Anatomical/physiological descriptions of G.I. tract

* 3 major segments: stomach, small intestine, and large intestine/colon
* Stomach: storing, mixing, and size reducing of ingested materials with aid of gastric secretions
* Small intestine plays major role in drug absorption due to larger surface area from villi
* Comprises of more than 60% of total length of G.I. tract
* Large intestine: absorption of water and electrolytes; storage and elimination of fecal material
* Systemic absorption of drugs through large intestine is very small
* Rich in bacteria

Dissolution and drug absorption

* Dissolution: drug particle assimilates into fluid at absorption site
* Drug will be dissolved in stomach (acidic conditions) or intestines (low acidic) depending on pH-dependent solubility of drug
* Stomach - 1.5-3.5 pH
* Duodenum - 2-6 pH
* Ascending colon - 5.5-7 pH
* Jejunum - 7-9 pH

Dosage forms suitable for oral route

* Liquid
* Oral solution of drugs with added substances to make preparation pharmaceutically stable and aesthetically acceptable
* Rapid absorption
* Dispersed system - more rapid absorption than solids
* Emulsion: heterogeneous system consisting of 1+ immiscible liquid dispersed in another liquid in form of fine droplets.
* Suspension: heterogeneous system consisting of finely divided insoluble solid particles dispersed uniformly in liquid vehicle
* Solid - majority of preparations
* Powders
* Tablets: generally fast dissolving compressed form of powdered drug along with some inactive ingredients
* Capsules: drugs with or without inactive ingredients are enclosed in either hard or soft, soluble shell generally prepared from suitable form of gelatin

GI administration (oral) advantages/disadvantages

* Advantages:
* Simple
* Convenient
* Safest
* Disadvantages:
* Slow onset of action
* Irregular absorption
* Possible enzymatic, pH related degradation

GI administration (oral) dosage forms

* Tablets
* Capsules
* Suspensions
* Solutions
* Emulsions
* Elixirs
* Syrups

Mucosal and parenteral drug delivery

* Directly into blood stream or via absorptive mucosa
* Bypasses hepato-GI first-pass elimination

Parenteral routes of administration

* IV
* IM
* ID
* SC
* Intra-articular - joints
* Intrasynovial - joint fluids
* Intraspinal - spinal column
* Intrathecal - spinal fluid
* Intra-arterial - arteries
* Intracardiac - heart

Injections

* Injections: sterile, pyrogen-free preparations intended to be administered parenterally
* Pyrogen: fever inducing agent
* Parenteral: outside of intestine, anything other than oral

IV route

* Provide rapid action
* Optimum blood levels achieved with accuracy and immediacy
* Maximum bolus injection volume is 1 ml/kg
* In emergency situations, IV administration of drug may be life-saving
* Antecubital area veins are preferred

Subcutaneous route

* Injection of drug beneath surface of skin for

small amounts of medication

* Given in loose interstitial tissues
* Outer surface of upper arm
* Anterior surface of thigh
* Lower portion of abdomen
* Max amount of medication that can be injected subcutaneously is \~1.3 ml

Intradermal route

* Injection into corium (dermis), the more vascular layer of skin just beneath epidermis
* Various agents injected for:
* Diagnostic determinations
* Desensitization
* Immunization
* Usually about 0.1 mL is administered

Oral mucosal route

* Buccal mucosa is on cheek
* Sublingual mucosa is on ventral tongue and on floor of mouth
* Can bypass hepatic first-pass metabolism


* Advantages:
* Absence of proteolytic enzymes
* Good for drugs inactivated by liver enzyme
* Disadvantages:
* Only for potent drugs because of small surface area, \~ 100 square centimeters
* Desirable only for tasteless drug

Dosage forms suitable for oral mucosal route

* Most common dosage form is small tablet
* Dissolve rapidly and readily absorbed to systemic circulation
* Ex: nitroglycerin and certain steroid sex hormone

Rapid-dissolving tablets

* Consist of active drug and lactose moistened with alcohol-water mixture to form paste
* Placed under tongue to provide rapid onset
* Advantages:
* Used for drugs destroyed in GI tract
* Not difficult to swallow
* Convenient to carry and administer than oral liquids
* Disintegrates/dissolves within \~ 15-30 seconds

Nasal route

* Local action of drug and systemic
* Delivery of protein and peptide drugs
* Advantages:
* Ease of administration
* Rapid absorption
* Avoidance of hepatic first-pass metabolism
* Useful for potent drugs because of smaller surface area, \~ 200 square centimeters

Dosage forms suitable for nasal route

* Most commonly used dosage forms is the liquid solution
* Good for large polar molecules such as peptides, polysaccharides
* For conventional molecules, provides:
* Pulsatile or sustained plasma profiles
* Fast absorption and rapid onset of action
* Avoidance of first-pass metabolism
* Avoidance of effects of gastric stasis and vomiting in, for example, migraine patients

Dosage form

Combination of drug with nonmedical agents, referred as pharmaceutical ingredients

Why we need dosage forms?

* Safe and convenient delivery
* Protection of drug
* Conceal bad taste or odor
* Provide liquid preparations
* Clear liquid dosage forms
* Controlled release drug delivery
* Optimal drug action through different administration sites

Drug and drug product stability

* Chemical: each active ingredient retains its chemical integrity and labeled potency, within specified limits
* Physical: original physical properties, including appearance, palatability, uniformity, dissolution and suspendability are retained
* Microbiologic: sterility or resistance to microbial growth is retained according to specified requirements
* Antimicrobal agents that are present retain effectiveness within specified limits
* Therapeutic: therapeutic effect remains unchanged
* Toxicologic: no significant increase in toxicity occurs
* Stability: extent to which a product retains same properties and characteristics that it possessed at time of its manufacture

Drug stability: mechanisms of degradation

* Hydrolysis: drug molecules interact with water molecules to yield breakdown products of different chemical constitutions
* Oxidation: substance combines with oxygen to form oxides
* Chemically, most frequently encountered destructive processes

Stability testing: kinetic study

* Half-life is time required to decrease concentration of active component in the drug form by 50%
* Kinetic study begins by measuring concentration of drug being examined at given time intervals under specific set of conditions including:
* Temperature
* pH
* Ionic strength
* Light intensity
* Drug concentration
* Measurement of drug concentration at various time intervals reveals stability or instability of drug under specified conditions with passage of time

Pharmaceutic ingredients

* Solvent: dissolve drug substance
* Flavors and sweeteners: make product more palatable
* Colorants: enhance product appeal
* Preservatives: prevent microbal growth
* Stabilizers: prevent drug decomposition
* Diluents/fillers: increase bulk of formulation
* Binders: increase adhesion of powdered drug and pharmaceutic substances
* Antiadherents or lubricants: assist smooth tableting process
* Disintegrating agents: promote tablet break-up after administration

Sterilization and preservation

* Physical methods:
* Autoclaving for 20 minutes at 15 PSI pressure and 120 °C
* Dry heat at 180 °C for 1 hour
* Bacterial filtration
* Chemical method: use preservatives

Bioavailability and bioequivalence

* Bioavailability: rate and extent to which active drug ingredient or therapeutic moiety is absorbed from drug product and becomes available at site of drug action
* Bioequivalence: comparison of bioavailability of different formulations, drug products, or batches of same drug product

Blood concentration-time curve

* Presented by concentration-time curve of administered drug in appropriate tissue system, e.g. plasma
* If drug is given orally, 3 phases can be distinguished:
* Absorption phase - leading to peak in plasma concentration
* Redistribution phase - where plasma concentration falls rapidly as drug is taken up by various tissues
* Elimination phase - slower phase of decline as drug is metabolized or excreted

Parameters for assessment and comparison of bioavailability

* Parameters are used for describing and comparison of bioavailability:
* Cmax
* Tmax
* AUC

Excretion of drugs

* Urine (kidney)
* Feces - poorly absorbed drugs that remain in GI tract
* Bile - drug’s reabsorption from GI tract is minimal
* Lungs - volatile drugs through expired breath


* Sweat
* Saliva
* Milk

New drug delivery system development is largely based on

* Promoting therapeutic effects of drug
* Minimizing its toxic effects by:
* Increasing amount and persistence of drug in vicinity of ‘target” cell
* Reducing drug exposure of “non-target” cells

Novel drug delivery systems based on physical mechanisms and biochemical mechanisms

* Physical mechanisms:
* Osmosis
* Diffusion
* Erosion
* Dissolution
* Electrotransport
* Biochemical mechanisms:
* Monoclonal antibodies
* Gene therapy and vector systems
* Polymer drug abducts
* Liposomes

Novel drug compositions

* Therapeutic efficacy of products can be enhanced and toxicity can be decreased by incorporating novel polymer technology
* Degradable bonds can be used to attach active drug to synthetic or naturally occurring polymer
* Upon delivery to target site and in presence of certain enzymes or through hydrolysis (etc. product can be cleaved releasing active drug at specific site of action)

Cancer vaccines

* Cancer treatment by vaccines includes 3 main steps:
* Immunization
* Activation of immune system
* Killing of cancer cells
* Treated cancer cells, cancer cell-dendritic cell conjugates or cancer specific peptides might be used as tumor antigens

Blood brain barrier

* BBB keeps many substances out of brain, the walls of vessels that carry blood into brain form barrier
* Tight construction of vessels in head guards against brain entry
* Blood gases such as oxygen and small nutritional molecules are main outsiders that can make it in
* Tight junctions between brain capillary endothelial cells
* Cells lining blood vessels in brain are lot closer than anywhere else in body

Functions of blood brain barrier (BBB)

* Protects the brain from "foreign substances" in blood that may injure brain
* Protects brain from hormones and neurotransmitters in rest of body
* Maintains constant environment for brain

Phospholipid bilayer

* Electron microscopic examinations of cell membranes have led to development of lipid bilayer model
* Most common molecule in model is phospholipid, which has polar (hydrophilic) head and 2 nonpolar (hydrophobic) tails

General properties of BBB

* Large molecules do not pass through BBB easily
* Low lipid (fat) soluble molecules do not penetrate into brain
* Molecules that have high electrical charge to them are slowed

Transport through blood brain barrier

* 3 main routes of transport through BBB:
* Between cells (Paracellular route)
* Cells
* Chemicals
* Hydrophilic
* Through cells (Transcellular route)
* Gas
* Water
* Lipophilic
* Active transport
* Receptor-mediated endocytosis

Active transport

* Hydrophilic compounds cannot cross barrier in absence of specific mechanisms such as membrane transporters or endocytosis
* Transport systems include transporters for amino acids, monocarboxylic acids, organic cations, hexoses, nucleosides, and peptides

Systemic drug delivery to brain

* Making highly lipophilic drugs
* Increasing passive entry of "restricted" drugs into central nervous system
* Targeting drugs to brain by redox chemical delivery systems
* Conjugating drugs to molecules actively transported through BBB
* “Masking” drugs using special drug delivery systems (nanoparticles, liposomes, etc.)

BBB can be broken down by:

* Hypertension (high blood pressure)
* Development: BBB is not fully formed at birth
* Hyperosmolitity
* Microwaves
* Radiation
* Infection
* Trauma, ischemia, inflammation, pressure
* Injection of irritating substances into carotid artery to disrupt barrier's protective properties

Systemic drug delivery to brain: summary

Over 95% of typical drugs are too water-soluble or have molecular weight too large to cross BBB

Gliadel Wafer

Slowly release drug, over long period of time

Liver targeted drug delivery

* Liver targeting can be achieved by coupling of drugs to (neo)glycoproteins that are specifically taken up by various target cells in liver
* Drugs can also be coupled directly to HSA to obtain liver-specific delivery
* Specific uptake of lactosylated human serum albumin (HSA1) by hepatocytes, mannosylated HSA by Kupffer cells, and succinylated HSA by endothelial cells was already shown
* Liver-specific delivery of potent anti-inflammatory drug dexamethasone to Kupffer and endothelial cells when coupled to HSA has been shown

Ocular drug delivery

* Blood-retina barrier protects back of eye
* Cornea protects front of eye

Drug delivery by eye drops (local)

* Limited by inefficient penetration into front of eye
* Virtually no penetration to back of eye

Systemic medications

Limited by inefficient penetration into back of eye (blood-retina barrier)

Intraocular injection

Circulatory process quickly reduces bioavailability

Drug delivery to eye

* Less than 1% of medication applied to surface of eye will actually reach disease site
* Medications are frequently administered systemically at very high doses to overcome blood-retina barrier


* Drug injections into back of eye are occasionally used, but are quickly removed by eye's natural circulatory process, often necessitating frequent injections that can carry toxicity risks

Drug elimination from eye

* Solution instilled as eye drops into ocular cavity may disappear from precorneal area of eye by any of composite of following routes:
* Nasolacrimal drainage
* Tear turnover
* Productive corneal absorption
* Nonproductive conjunctival uptake

Topical ocular delivery

* Traditional dosage forms for delivery of drugs in eye have been and remain solutions and ointments
* Large proportion of topically applied drug is immediately diluted in tear film and excess fluid spills over lid margin and remainder is rapidly drained into nasolacrimal duct
* Typical corneal contact time of about 1 - 2 minutes in humans, for all instilled solution, and ocular bioavailability that is commonly less than 10%

To optimize ocular drug delivery systems, following characteristics are required:

* Good corneal penetration
* Prolonged contact time with corneal epithelium
* Simplicity of instillation for patient
* Non-irritative and comfortable form (system should not provoke lacrymation and reflex blinking)
* Appropriate rheological properties

Ocular drug delivery: overview

* Eye is logical choice for site-specific drug therapy
* Eye drops:
* Limited by inefficient penetration into front of eye
* Virtually no penetration to back of eye
* Systemic medications:
* Limited by inefficient penetration into back of eye
* Required high doses
* Drug injections:
* Circulatory process quickly reduces bioavailability
* Inserts and diffusion-controlled systems
* Non-compliance, especially in elderly people
* Biodegradable drug delivery systems (BDD)
* BDD systems are placed in eye at time of elective surgery
* BDDTM systems dissolve as they release active drug
* Ophthalmic gels/hydrogels
* Iontophoresis

Skeletal drug delivery

* Systemic drug delivery
* High dose of drugs – high systemic toxicity
* Bone targeted drug delivery
* Skeletal drug delivery system (SDDS)
* Osteotropic drug delivery system (ODDS)
* Local drug delivery - sustained drug release

Cardiovascular system: overview

* Blood vessels of cardiovascular system are divided into 2 main pathways:
* Blood vessels in pulmonary circuit carry blood from heart to lungs and back to heart
* Systemic circuit consists of pathways between heart and all other areas of body
* Newly oxygenated in lungs blood travels along pulmonary circuit to heart, where it is pumped to other parts of body via systemic circuit
* Once blood reaches other tissues, oxygen it contains is released and exchanged for carbon dioxide
* Deoxygenated blood is returned via systemic circuit to heart where it is pumped back to lungs by pulmonary circuit to drop off carbon dioxide and pick up oxygen, completing cycle

Gas exchange and partial pressure

Arterial partial pressure is \~100, below 90 is bad

Blood

* Average adult has approximately 5 liters (about 10 pints) of blood
* Blood is made up of both liquid and solid components:
* Liquid portion is called plasma and consists of

blood cells and platelets in suspension
* \~92% water
* Also contains complex mixture of proteins, vitamins, and hormones
* Solid portion consists of red blood cells, white blood cells, and platelets

Red blood cells

* Red blood cells make up over 99% of blood cells
* Red color from protein hemoglobin
* Oxyhemoglobin: hemoglobin combines with oxygen to form bright red compound
* Deoxyhemoglobin: oxygen is released and compound darkens

Red blood cell count (RBCC)

* Represents number of RBC in cubic millimeter of blood
* RBCC for a healthy adult is \~ 4.2 to 6.2 million cells per cubic millimeter

White blood cells (platelets)

* Protect body from disease by either phagocytizing (eating) bacteria or producing substances that destroy infectious particles
* White cell count (WCC) represents number of white blood cells in cubic millimeter of blood
* WCC for healthy adult is \~5 to 10 thousand cells per cubic millimeter of blood
* Platelets help repair blood vessels by adhering to damaged walls and help to trigger blood coagulation (or clotting), which prevents bleeding and blood escaping from blood vessel
* Less than half size of red blood cells

Drug delivery and cardiovascular system

Reaches systemic circulation ultimately inducing side effects in cardiovascular system and other organs

Targeted drug delivery

* Targeted drug delivery to heart, blood components and blood vessels
* Decrease in toxicity to other organs, tissues and systems
* Targeted drug delivery to other organs
* Decrease in systemic toxicity
* Decrease in cardiovascular toxicity

Genetic engineering

* Prosthetic grafts are commonly implanted today to treat vascular occlusions
* First protein used is tissue plasminogen activator enzyme, which is chemical that dissolves clots
* If a vessel can produce this protein in large amounts, it can continuously wash out any clots that cause blockages in vessel and may help grafts live longer
* It will hopefully prevent clotting in circulation downstream to where graft connects to circulation

Gene transfer

* First approach involves gene transfer directly into vessel from patient
* Goal: have autologous vein graft produce thrombolytic enzyme in all its cell layers (transmurally)
* Second approach involves gene transfer into cells, which are then seeded onto artificial graft
* Construct prosthetic conduit that has salutary benefit of thromboresistance on its surface, while maintaining benefit of inert composition in its body
* Goal is to produce technique that will improve long-term outcome of vascular bypass procedures

Prosthetic bypass

Commonly implanted today to treat vascular occlusions

Pulmonary administration

* Pulmonary route has been used to administer drug to the lung for the treatment of asthma and other local action
* Onset of action is very fast and comparable to IV route
* Lungs are attractive site for systemic delivery of protein and peptide drugs
* Offer larger surface area (\~70 m2)
* Major challenge for this route is lack of reproducibility in deposition site of administered dose
* Rate of absorption of drug is expected to vary at different position owing to variable thickness of epithelial lining cells at different position of bronchial tree

**Alveolus**

* Type I Pneumocyte - flattened for gas exchange
* Covers 95% of alveolar surface (but only accounts for about 40% of pneumocyte population)
* Type II Pneumocyte – cuboidal cell that produces surfactant
* Constitutes about 60% of pneumocytes (but only 5% of surface area)
* Macrophages - white blood cells that ingest foreign material which remove potential pathogens

Lung surfactant

* Surface-active agent, which covers surface of alveoli contacted with air
* Decreases surface tension at air-alveoli interface almost to zero and therefore accomplish 2 main tasks:
* Prevents collapse of alveoli
* Decrease pressure inside alveoli
* Allows us to breath and prevents pulmonary edema.
* Complex mixture of proteins and lipids, but major component is phosphatidylcholine

Mucosa and submucosa: epithelium

* Pseudostratified ciliated columnar cells and mucous (goblet) cells are 2 major components of epithelium
* Both derive from basal cells
* Cilated cells predominate in number
* Beat at 1,000 to 1,500 cycles per minute resulting in cephalad movement of mucus blanket at 0.5-1 mm/min in small airways and 5-20 mm/min in trachea and main bronchi
* All material which accumulates in lungs is removed in about 24 hours

Challenges of drug delivery for treatment of lung diseases

* Enzymatic degradation in GI tract and liver
* Short half-life and degradation of drugs in blood stream
* Low accumulation and retention of drugs in lungs
* Low efficacy of treatment
* Possible adverse side effects to other organs and tissues
* Majority of free drugs, native nucleic acids and peptides cannot be delivered into lungs by inhalation necessitating special dosage form or delivery system that can be inhaled

Advantages of local inhalation drug delivery directly to the lungs:

* **Enhanced accumulation and retention of drugs in lungs**
* **Prevention (or at least limitation) penetration of drugs into bloodstream and accumulation in other healthy organs**


* **High efficacy of treatment**

Lung drug delivery

* Lungs absorb large molecules naturally, and drugs pass into bloodstream easily from deep lung
* Once absorbed in deep lung, they pass readily into bloodstream without need for enhancers used by other noninvasive routes

AeroDose Inhalers (Aerogen)

* Drugs can be stored in liquid or dry powder form and can be aerosolized in solution or suspension
* Optimization and customization of aerosol particle size
* Flexibility of dosing
* Breath-activation
* Dosage guidance

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* Consists of proprietary aerosol generator, electronic circuitry, batteries, inhalation sensor and drug container

Challenges of aerosol formulations

* Key challenge is getting drug to reach deep lung (for systemic delivery)
* Metered dose inhalers (MDIs), breath-activated dry powder inhalers (DPIs), liquid jet, and ultrasonic nebulizers have proved useful in management of asthma, but such devices are not designed to deliver drugs into deep lung

Defense mechanisms of lung

* Physical (airway)
* Upper airway filtering systems
* Reflexes: sneezing and coughing
* Mucociliary escalator
* Cellular (alveolar)
* Phagocytic: alveolar macrophage and neutrophil
* Immunologic: IgA, IgG
* In upper airways
* Filtering mechanisms in nasal cavity trap eliminate larger particles (>10μm)
* 2 reflexes: sneezing and coughing
* In conducting airways
* Mucociliary escalator: there is some IgA in this layer, produced by plasma cells in submucosa
* In alveoli
* Alveolar macrophages with some interplay with and by neutrophils
* Immunologic mechanisms: interplay between alveolar macrophages and T and B lymphocytes; IgA, IgG

**Particle size determinant**

* **>10 μm: either filtered in nose or impacted in nasal and oral pharynx and then cleared by coughing or sneezing**
* 5-10 μm: trapped in mucus blanket in conducting airways and moved cephalad by ciliary action (cilia move only in cephalad direction)
* At level of larynx they are either swallowed or expectorated
*

Dry powder technology

* Any pulmonary approach to quickly deliver drugs systemically must target
* Given that alveoli reside at base of lungs
* To reach deep lung, drug must be delivered in small-sized particles – from 1-5 microns – with slow, deep inhalation
* Large - become lodged in the upper airway
* Small - exhaled

Advantages of dry powder technology

* Most peptide and protein drugs are more stable in solid rather than liquid state
* More drug can be contained in powders than in liquid forms
* Aqueous aerosols, only 1-2% of aerosol particle is drug (rest is water)
* Powder articles can contain up to 50% to 95% of pure drug
* Risk of microbial growth, which can cause serious lung infections, is greater in liquids than solid

Powder technologies (Inhale Therapeutic Systems, Inc.)

* Just because molecule is in powdered state does not mean it or powder will be stable
* Cornerstone of Inhale’s PulmoSol dry powder formulation is technology known as glass stabilization used in drying process to stabilize pharmaceutical formulations
* PulmoSphere powder particle technology expands Inhale’s particle engineering capabilities for inhaleable peptides and proteins by adding lipid based emulsion process which may offer certain benefits for select molecules
* Produces particles that are both hollow and porous and in optimal range of 1-5 microns ideal for pulmonary delivery
* Created by proprietary spray-drying procedure where novelty lies in preparation of feedstock for spray-drying

Monomer → polymer

* Small molecule that combines with other molecules of same or different types to form polymer
* Repeatng unit (monomer residue) and “n” number that shows how many monomers are partcipatng in reaction
* Ex: H-(O-CH2-CH2-)n-OH

General applications of polymers

* Develop devices for controlling drug delivery
* Replace failing natural organs
* In oral delivery, coatings, binders, taste maskers, protective agents, drug carriers, and release controlling agents
* Transdermal patches as backings, adhesives, or drug carriers in matrix or membrane products
* Controlled/extended release

Polymer properties

* All polymers posses glass transition temperature (Tg)
* Expression of molecular motion
* Important factor for solid dosage forms
* Some polymers have melting temperature (Tm)

2 types of polymerization

1. Addition: monomer contains double bond and polymerization starts by addition of free radical on monomer
2. Condensation: monomer possesses func:onal groups such as hydroxyl, carboxyl, or amines, they can interact via condensa:on

Polymer topology

* Describes whether polymer is linear, branched or cross-linked
* If linear polymer is cross-linked, its solubility will be sacrificed at the expense of swellability
* Cross-linked polymer can swell in solvent to extent that is inversely related to amount of cross-linker

Hydrogels

* Polymer chains are in coiled conformation at rest, and assume extended conformation once they are loaded
* In dissolution of polymer, load originates from interaction of polymer and solvent as well as concentration gradient of ions inside polymer structure and solution

Chemical vs. physical gels

* Chemical gels
* Covalently cross-linked
* Will not dissolve in water or other organic solvent
* Physical gels
* Hydrogen bonding, hydrophobic interaction, and complexation

Polymers in solid dosage forms

* Superdisintegrants are used to help dosage form with proper disintegration
* Ex: cross-linked poly (vinyl pyrrolidone) (Crospovidone), and cross-linked sodium salt of carboxymethyl cellulose (Croscarmelose)

Polymers in Osmo-c Tablets and Pumps

* Based on osmosis concept
* Oros provides 24 hr controlled drug release that is independent of many factors such as diet status

Polymers in liquid dosage forms

* Used as viscosity inducing agents and suspension stabilizers
* Ex: in oral or ophthalmic suspensions/ solutions MC or HPMC (cellulose ethers) are widely used
* Gums (Guar gum or Xanthan gum)
* Obtained from natural sources with different assay and qualities
* Natural gums, batch-to-batch consistency and quality is major challenge
* Good platform for bacteria growth, thus limiting their shelf life and requires sterilization

**Polymers in drug delivery**

* Used to achieve taste masking, controlled release, enhanced stability, and improved bioavailability
* Non-bioerodible or non-biodegradable
* Polymethylmethacrylate (PMMA)
* Ethylene vinyl acetate copolymer (EVA)
* **Controlled release of steroids**
* **Ex: Nexplanon is non-bioerodible delivery system for delivery of etonogestrel contraceptive**
* **Bioerodible or biodegradable**
* **Polylactic acid**
* **Polylactic/glycolic acid (PLLA, PLGA)**
* **Polycaprolactone (PCL)**
* **Polyanhydride**
* **Use: Poly Anhydrides**
* **Sebacicacid (SA)**
* **Bis (p-carboxyphenoxy) propane**

Hatefi Slide 24

* Glycoside - sutures
* Di-lactide - fracture
* E-caprolactone - antibiotics