Pharmaceutics Flashcards

Question

What are polymeric matrix water penetration CDDSs?

Answer 1

These are materials made of long polymer chains that swell or dissolve when they absorb water. The drug can be spread throughout the polymer, and as the polymer swells, the drug gradually comes out. Example: A controlled-release pill that slowly lets go of the drug as it breaks down with water.

Answer 2

Reservoir solution diffusion pore diffusion matrix

Answer 3

The drug is dispersed throughout a polymer matrix. As the matrix comes in contact with body fluids, the drug gradually diffuses through the polymer. Example: A tablet or capsule that has the drug spread throughout the polymer, and as the material absorbs fluid, the drug is slowly released.

Answer 4

In this system, the drug is contained in a core (reservoir) surrounded by a semipermeable membrane. The membrane allows the drug to diffuse out at a controlled rate. Example: A drug-filled capsule or implant with a membrane around it that releases the drug slowly over time.

Answer 5

Solution Diffusion-Controlled Drug Delivery Systems release drugs gradually by allowing a drug dissolved in a solution to diffuse out through a membrane or matrix. The system controls the rate at which the drug moves from inside the system to the outside environment, allowing for steady, sustained release over time. These systems are used for extended-release medications and can improve bioavailability and patient convenience by reducing the need for frequent dosing.

Answer 6

Pore Diffusion-Controlled Drug Delivery Systems use tiny pores in a membrane or matrix to allow a drug to gradually diffuse out of the system. The rate of diffusion controls how quickly the drug is released into the body. These systems are often used to provide steady, sustained drug release over time, improving patient compliance and therapeutic outcomes. The design of the system—especially the size and number of pores—determines how fast or slow the drug will be released.

Answer 7

Diffusion-Controlled Release: The drug is released as it diffuses from the polymer matrix through its pores or channels. The polymer matrix does not degrade; instead, it simply allows the drug to diffuse out gradually. Degradation-Controlled Release: Some polymers are designed to degrade over time, releasing the drug as the polymer hydrolyzes or undergoes other types of chemical degradation. This mechanism is often used in biodegradable polymers like PLGA, where the polymer’s degradation rate is controlled to release the drug gradually over a period of time. PLGA breaks down into lactic acid and glycolic acid, which are naturally metabolized by the body. Polysaccharide-based systems (like chitosan or alginate) can also degrade over time, releasing drugs in a controlled manner as they break down.

Answer 8

Natural polymers Polysaccharides: alginate, chitosan, dextran, hyaluronic acid, and starch. Proteins: Albumin, collagen, and gelatin are examples of proteins that can be used to create drug delivery systems.

Answer 9

Poly(lactic acid) (PLA) and Poly(lactic-co-glycolic acid) (PLGA): These are biodegradable and biocompatible, hydrolysedn into non-toxic products Polyethylene glycol (PEG): PEG is used to increase solubility or modify the release rate. PEG can form micelles or nanoparticles for drug encapsulation. Polycaprolactone (PCL): Used in creating slow-release systems due to its slow degradation rate Polylactic acid (PLA): PLA is used in controlled-release systems where slow degradation is needed

Answer 10

- Chemical structure of polymer - Polymer molecular weight - Presence of low MW compounds, e.g., drugs and excipients, residual solvent - Crystalline vs amorphous polymers - Size and shape - Processing method - Porosity - Site of implantation - Degradation mechanism - enzyme vs water

Answer 11

Tablets coated with a polymer that is insoluble in the highly acidic environment of the stomach, but dissolves in the small intestine (>pH 5.5) Can protect the drug from the stomach (e.g. erythromycin) or the stomach from the drug (e.g. NSAIDs) Numerous polymers available, including cellulose derivatives and methacrylic acid co-polymers (Eudragit®) Release area can be tailored depending on pH/solubility profile

Answer 12

3D printed Fused deposition modelling (FDM) is the most accessible type of 3D printing Uses a polymer filament, which is melted and extruded layer by layer to form a 3D print Huge interest in all types of 3D printing, including FDM, for production of personalized dosage forms - tailoring dose and release profile Polymer and drug melted together and extruded to generate a filament Drug matrix printed within enteric coating of different thicknesses

Answer 13

Common polymers used for bulk erosion include polylactic acid (PLA), polyglycolic acid (PGA), poly(lactic-co-glycolic acid) (PLGA), and poly(caprolactone). Bulk erosion occurs when water penetrates the polymer matrix, causing it to degrade from the inside out. As the polymer matrix absorbs water, it begins to break down chemically through processes such as hydrolysis, enzymatic degradation, or chemical cleavage of the polymer chains. The polymer loses its integrity as the degradation progresses, and this allows the active drug to diffuse out of the matrix at a controlled rate.

Answer 14

The chemical composition of the polymer, The degree of cross-linking within the polymer, The molecular weight of the polymer chains, The hydration properties of the polymer

Answer 15

In surface erosion systems, the drug is usually encapsulated in a polymer that degrades from the surface inward. The degradation occurs at the outer surface first, forming a degradation front that moves inward as the polymer erodes. The polymers used in surface erosion are often hydrophobic (water-repelling) and are designed to degrade via chemical breakdown when exposed to water or body fluids. Common polymers for surface erosion include polylactic acid (PLA), poly(lactic-co-glycolic acid) (PLGA), polycaprolactone (PCL), and polyethylene glycol (PEG).

Answer 16

More Predictable Drug Release Linear Drug Release Less Risk of Residual Material Control Over Release Duration Targeted Delivery

Answer 17

the drug is covalently attached to a polymer backbone through pendant groups or side chains. The drug is released through, linker degradation, diffusion, or cleavage, offering a controlled and sustained release profile.

Answer 18

Numerous applications for drug release throughout the body (e.g., dressings, implants), plus tissue engineering and regenerative medicine. They are highly customizable, allowing for precise control over drug release rates, matrix structure, and fiber morphology. Drug is mixed with polymer and electrospun to give matrix or chemically-controlled DDS PEVA does not degrade - diffusion-controlled matrix release Effectively created a reservoir system, with the PCL layers acting as a rate-controlling membrane Electrospinning is a process where a polymer solution or melt is subjected to a high voltage, causing the polymer to stretch into fine fibers.

Answer 19

Drug release controlled by: - pH - Chemicals (metabolites) - Enzymes - Ultrasound - Magnetism - Light Predominantly used in implantable devices or parenterally delivered DDS

Answer 20

Changes in ionization or cleavage of functional groups due to altered pH can affect sol-gel behaviour e.g. Poly(propylene imine) dendrimers: They are particularly useful in areas where the pH varies, such as in the gastrointestinal tract (GI tract), tumor microenvironment, or inflammatory sites. Polymeric hydrogels that swell and release the drug at low pH

Answer 21

The tumour microenvironment can be 0.5 to 1.0 pH units lower than normal tissues Acid-sensitive linkers are designed to release drug in the acidic conditions in tumours, endosomes and lysosomes Binds to circulating albumin following administration Does not accumulate at non-specific sites (heart, marrow GI tract) Reduced side effects, improved efficacy and quicker to reach the tumour than doxorubicin alone

Answer 22

Ulcerative colitis, Crohn’s, etc These systems use the presence of specific enzymes (either endogenous or exogenous) to trigger drug release. Enzymes like proteases, lipases, or hydrolases can break down the polymeric matrix or cleave a drug-linker to release the therapeutic agent. Polymers with peptide linkers that are cleaved by specific enzymes, such as matrix metalloproteinases (MMPs), which are often overexpressed in tumor tissues. Polysaccharides like chitosan, which can degrade in the presence of specific enzymes (e.g., chitosanase).

Answer 23

Magnetism can be used for both targeting and release of drugs Drug can be attached by a chemical bond or embedded in the polymer matrix Release by diffusion, pH change, magnetic field or interaction with cellular component Can directly kill or remove cancer cells These systems respond to magnetic fields and can be used for targeted drug delivery. Magnetic nanoparticles or carriers loaded with drugs can be directed to specific sites in the body using an external magnetic field, and drug release can be triggered by the field. Magnetic nanoparticles that can be loaded with drugs and directed to a tumor site using a magnetic field. The magnetic field can also induce local heating (hyperthermia), which facilitates drug release.

Answer 24

Mesoporous silica nanoparticles (MSNs) are inorganic nanoparticles. They are made from silica (SiO₂) and characterized by uniform pores typically 2–50 nm. These give MSNs a high surface area, allowing them to hold a large amount of drug. Thermally stable, easy to functionalize, controlled particle size, great potential for controlled delivery of traditional drugs, proteins and nucleic acids. Following drug loading, pores can be capped with nanoparticles that can be selectively be removed by pH, light, magnetism, antigen, S-S reduction or saccharide

Answer 25

Convenience Compliance Control

Answer 26

Surgery Failure Potency Reactions/compatibility

Answer 27

Contraception Pain management Diabetes Incontinence Systemic infection

Answer 28

Ocular Dental Contraception Pain Vasculature

Answer 29

Jadelle®: Used from late 1990s 75 mg drug per rod 100 µg/day → 40 µg/day → 30 µg/day

Answer 30

52 mg levonorgestrel PDMS 20 µg/day → 14 µg/day Local delivery Easily reversible

Answer 31

Flexible, drug-containing polymer rings (usually silicone-based) which are seated around the cervix Numerous products on the market, in trials or development for the delivery of: Contraceptive therapy HRT IVF therapy microbicides (HIV, herpes, etc) Different types of ring with release of drug from 3 weeks to 3 months NuvaRing® 2” diameter ethylene-vinyl acetate copolymer ring Controlled release of contraceptive for 3 weeks 99% effective

Answer 32

Chronic noninfectious uveitis Approx. 3 mm x 2 mm x 5 mm 0.59 mg tablet of fluocinolone acetonide Silicone elastomer cup PVA membrane and suture tab 0.6 µg/day → 0.3 to 0.4 µg/day 30 months total Age-related Macular Degeneration (AMD) Diabetic Macular Edema (DME) Glaucoma BravoTM polymer matrix Drug release up to 2 years 15 minute procedure Sub-conjunctiva

Answer 33

Drug-eluting stents (DES) help to prevent narrowing of the artery by delivering drugs that inhibit cell proliferation and reduce inflammation. While they offer improved long-term outcomes compared to bare-metal stents, DES come with increased risks (e.g., stent thrombosis, longer need for antiplatelet therapy) and higher costs. The choice of drug and biocompatibility of the coating play a crucial role in their effectiveness and safety. Polylactic acid backbone, stent is bioabsorbed in 2 years by bulk erosion

Answer 34

~150 µl drug formulation Zero-order release up to 12 months Drug protected Subcutaneous implant

Answer 35

For treatment of high-grade malignant gliomas After surgery, residual glioma cells can double in number every 10 days, treatment usually starts 14 days after surgery Typical life-span post-surgery < 1 year GLIADEL wafers contain 7.7 mg of the chemotherapeutic carmustine Systemic delivery can cause low blood count and lung toxicity 14.5 x 1 mm wafers erode over 2 to 3 weeks Combined with radiotherapy

Answer 36

Used for: Chronic intrathecal or epidural infusion of morphine sulphate for chronic, intractable pain Chronic intrathecal infusion of ziconotide sterile solution for the management of severe chronic pain Chronic infusion of baclofen for severe spasticity of spinal or cerebral origin Chronic intravascular infusion of floxuridine or methotrexate for the treatment of cancer

Answer 37

Requirements: 1. A shape and size that can be ingested by a subject 2. The ability to adopt a conformation in the stomach the prevents passage to small intestine 3. Ability to carry large drug load 4. Controlled drug release for weeks or months with little or no potential for burst release 5. Maintain long-term drug stability in low-pH 6. Degrade/dissolve or dissociate into forms in a predictable manner that can exit the stomach and pass through the GI lumen with no potential for obstruction or perforation 7. Safety mechanisms enabling dissociation of the device if it accidentally passes into small intestine

Answer 38

Always “wearing” a device Change the set every three days Skin irritation/infection Some poor skin insert sites Peripheral insulin delivery

Answer 39

Drugs with poor solubility: The rate constant for dissolution is smaller than the rate constant for absorption A very slow dissolution process can limit the rate of the following steps When this occurs, dissolution becomes the “rate-limiting step”. Modified-release formulations: Sustained and extended forms which release the drug slowly over an extended period of time The rate constant for release is smaller than the rate constant for absorption The slow release process limits the rate of the following steps and becomes the “rate-limiting step”. When an increase/decrease in the dissolution rate leads to faster/slower absorption. E.g., drug in solid dosage form compared to drug in solution When an increase/decrease in the release rate leads to faster/slower absorption. E.g., immediate versus slow-release formulations. Either dissolution or release is slow. Any drug dissolved/released is readily absorbed. But absorption cannot proceed faster than dissolution/release. Thus: The systemic input of the drug (absorption) is rate-controlled by either the dissolution or the release process. Changes in dissolution rate or in the release rate will modify profoundly the rate of absorption of the drug

Answer 40

Dissolution and release are fast, but absorption is limited by poor permeability. Most of the drug is dissolved before a significant fraction of the drug is absorbed. Thus: The systemic input of the drug is absorption (permeability) rate-limited. Modifying the dissolution and release rates will have little effect on the rate of absorption of the drug.

Answer 41

The most frequent case. When the absorption rate constant is greater than the elimination rate constant. Or in other words, when the absorption half-life is shorter than the elimination half-life: The absorption process is faster than the elimination process and the elimination step controls the decline of the drug concentration during the terminal phase. Most of the drug has been absorbed and little has been eliminated when the peak is reached. The decline of the drug in the terminal phase is primarily determined by the elimination (disposition) of the drug. The rate constant (half-life) obtained from the terminal phase corresponds to the elimination rate constant (elimination half-life).

Answer 42

Less frequently, the absorption process is slower than the elimination process. The absorption rate constant is smaller than the elimination rate constant. Or in other words, the absorption half-life is longer than the elimination half-life. A very slow absorption will rate-limit all subsequent processes including the drug elimination and therefore, the terminal phase of the PK-profile. At any time, most of the dose of a drug is: either at the absorption site or has been eliminated. A considerable amount of drug has not yet been absorbed when the peak (tmax,Cmax) is reached. The decline (elimination) of the drug during the terminal phase is rate-controlled by the absorption process: The drug is eliminated as fast as it is absorbed. The rate constant (half-life) obtained from the terminal phase corresponds to the absorption rate constant (absorption half-life).

Answer 43

Look at the properties of the drug: good or poor solubility/permeability? Type of formulation: immediate or sustained or controlled release Which step is controlling the kinetics: - dissolution/release - absorption - elimination (most frequent case) Absolute certainty requires an IV Bolus/infusion to estimate either the elimination rate constant (k) or elimination half-life (t1/2) in the absence of absorption.

Answer 44

Usually patch based Good patient compliance - painless - easy to apply - multiple dose ease Can be used for all ages Avoids first-pass metabolism Continuous supply of drugs locally and into systemic circulation Able to maintain drug level within therapeutic window for longer Relatively easy to stop treatment (peel off patch)

Answer 45

Intercellular: In between cells (predominant pathway) Intracellular: Through cells Follicular: Through hair follicles

Answer 46

- molecule size - hydrophilic + hydrophobic - potency important - sensitization & irritation - patch size

Answer 47

Bricks: Corneocytes (terminally differentiated flat keratinocytes filled with keratin) Corneodesmosomes link the ‘bricks’ Mortar: Lipid matrix (a mixture of ceramides, cholesterol and free fatty acids) Hydrophobic drugs can travel through the ‘mortar’ while hydrophilic drugs travel mainly via the ‘bricks’ (though they still have lipid-rich mortar to navigate through) Hair follicles only cover approx. 0.1% of skin surface therefore not ideal

Answer 48

Oral absorption rapid (faster rate of absorption than rate of elimination), topical absorption is slow(slower rate of absorption than rate of elimination- ‘flip-flop’ kinetics) Oral: quick rise of Cp to maximum with t1/2 corresponding to kinetics of elimination, topical: slow rise of Cp to maximum with t1/2 (decay) longer than ODD Oral: high Cp but repeated doses needed to maintain, topical: Cp not as high but sustained (reduced dosing frequency and increased control)

Answer 49

Cp can be somewhat controlled (or rather fluctuating Cp levels avoided) by: - patch size - skin site - adjuvant/ skin penetration enhancers - easily controlling the lag time between patches

Answer 50

Glyceryl trinitrate (GTN) Vasodilatory drug: relief from anginal chest pains Sublingual tablet or spray, IV, ointment and transdermal patch Decreasing angina attacks where sustained drug delivery is useful Many side effects: dizziness, palpitations, vertigo, severe headaches, nausea and vomiting log P ~2, MW ~300 and liquid at room temperature Avoiding tolerance: drug-free intervals of 10-12 hours needed

Answer 51

Low MW (<500 Da) Lipophilic log P/ partition coefficient (octanol-water): 1-5 for optimal permeability Solubility in water (pH 6-7.4) Half-life in hr (<10) Dose <10mg/day Non irritating and nonsensitizing Patch size <50 cm2………

Answer 52

Backing: Impermeable side facing clothes (flexible polymers) Adhesive: Binds patch parts together and adheres patch to skin Liner: Peelable part to protect patch during storage Membrane: Added control of drug release profile (polymers/ elastomers)

Answer 53

Transderm-Scop: motion sickness and post-operative recovery Patch behind the ear (postauricular), releases drug over 3 days (approx. 5 µg/hr) Based on the reservoir system

Answer 54

Catapres-TTS: ‘Transdermal Therapeutic System’ vasodilator for hypertension Usually applied every 7 days (upper, outer arm or upper chest). Issue with adhesion Drug held in reservoir, membrane to control rate of delivery (steady state obtained in ~3 days). Sensitization issues, multiple wear difficult (patch size small)

Answer 55

Estradot/ Vivelle/ Evorel…: Post-menopause hormone replacement therapy Highly potent, delivered via reservoir system (was ethanol which diffused into skin) or matrix system (either twice weekly or once weekly) Log P < 3 and MW ~230, high clearance, short t1/2 Oral: high first-pass effect in liver (high dose of conjugated equine estrogens with elevated estrone/ estradiol ratio- and therefore side-effects) Transdermal patch - restores ratio in post-menopausal women (see plot) - sustains plasma levels (better outcome)

Answer 56

Opioid drug for managing severe and persistent post-operative/chronic cancer pain Requires monitoring (side-effects include breathing difficulties) (0.3-2.4 mg/ day) - reservoir initially to adhesive matrix Replacement of patch every 72hrs (12-24 hrs for Cp to stabilise; habit forming (therefore controlled decrease needed + careful disposal) Good hydrophilic and hydrophobic properties (+ low MW and high potency) Adhesive can peel (extra adhesive dressings sometimes)

Answer 57

Butrans/Transtec: another opioid analgesic (semisynthetic with both agonistic and antagonistic receptor-binding) Better safety profile (lower opioid dependency than fentanyl) but some studies report better pain management with fentanyl 7-day patch via matrix adhesive

Answer 58

Well-known for smoking cessation (and remains most popular TD patch) ~20 mg/ day (16hr/24hr) Adhesive/layered/reservoir systems (gum, tablets, inhaler, spray also available) ‘Invisibility’ and size important to users (smaller than credit card + clear or ‘skin’ colour)

Answer 59

Hypogonadism Review of other drugs used (not with licorice: reduces Cp blocks conversion of androstenedione to testosterone) 24 hr (reservoir and matrix adhesive). Testoderm was originally applied to scrotum (compliance low, moved to upper arm, thigh, abdomen, site rotation/irritation). Neither popular (gel more conventional)

Answer 60

Ortho Evra/ Evra…: contraceptive impacting ovulation (combination drug: progestin and estrogen) 28 days cycle. New patch applied each week for 3 weeks, and week four is patch-free (recommended 7-day adjustment period- steady-state) Abdomen, upper body, upper outside of arm, buttocks (adhesive matrix) 150 μg/day of norelgestromin and 20 μg/day of ethinyl estradiol

Answer 61

For incontinence Anticholinergic: blocks acetylcholine preventing ‘urgency’ of urination (inc. uncontrolled release) Adhesive matrix system- very thin! (rapid absorption, steady-state ~1 hr). 3.9 mg delivered/ day Extensive 1st-pass effect (metabolised by CYP3A4) Twice weekly (abdomen, hip or buttock). Changed every 3–4 days to different site

Answer 62

ADHD in children 6-12 years Adhesive matrix system (multipolymer: acrylic and silicone). Delivery rate affected by time worn (9 hrs on alternating hip) and size of patch Avoids 1st pass metabolism: better Cp than oral formulation (and higher Cmax) therefore lower dose required

Answer 63

EMSAM…: Depression in adults and Parkinson’s disease Matrix adhesive system (potent: 6-12 mg/ day) Higher Cmax than oral: extensive 1st-pass metabolism avoided, sustained Cp Decreased metabolite production (therefore decreased side-effects)

Answer 64

Parkinson’s disease and moderate-severe restless leg syndrome Dopamine receptor agonist 24 hr patch with Cp similar to IV infusion (steady-state within 1-2 days of daily application) Polymer matrix with a permeation enhancer

Answer 65

Parkinson’s disease-associated dementia 24 hr patch (drug-loaded matrix) to upper torso Starting with low dose and increased to 9.5 mg/ day over 4 weeks to build tolerance

Answer 66

Prevention of nausea/ vomiting due to chemotherapy (blocks serotonin) Up to 7-day patch (large patch size on abdomen or upper arm) delivering 3.1 mg/ 24 hrs Side-effects complicated by chemotherapy: decreased appetite, dry mouth etc.

Answer 67

Alzheimer’s dementia. Donepezil is reversible inhibitor of the enzyme acetylcholinesterase 7-day patch (drug in matrix with a rate controlling membrane). 5 mg/ day. Increased to 10 mg/ day if required after 4-6 weeks) Applied to back (avoid using same site for 2 weeks after removal of patch) Mild skin irritation reported

Answer 68

Metabolites can be: Inactive waste products that could be used to: - measure bioavailability of the parent compound and assess bioequivalence - detect exposure to illicit drugs. The active compound: - a prodrug is administered that depends on metabolism to be activated. Pharmacologically active and modify the response to the parent compound - sum to the effect of the parent drug - have a different effect than the parent compound - cause toxic effects. Modify the disposition of the parent compound.

Answer 69

Potential properties of the metabolite: Activity Toxicity Alter binding of the parent compound or other drugs Alter response to parent drug Concentration and PK profile of the metabolite

Answer 70

Metabolism of a drug results in a metabolite that is eliminated faster than the parent compound. Typical examples: Metabolites such as glucuronide, sulphate and glycine conjugates are more polar and water soluble than the parent compound and are eliminated faster than the parent compound. The elimination of the metabolite is rate-limited by its formation (or parent drug elimination). Thus, the slope of the terminal phase reflects k

Answer 71

Metabolism of a drug results in a metabolite that is eliminated more slowly than the parent compound. Typical examples: Acetylated or other metabolites which are less polar / less water soluble than the parent compound and are eliminated more slowly than the parent compound. The elimination of the metabolite is rate-controlled by its own elimination (kME) Metabolite accumulation occurs. Preferable scenario for pro-drugs Active metabolite from several 7-chloro-benzodiazepine drugs with long t1/2 Nordazepam Css ~ twice diazepam Css following oral multiple doses (see also the different slopes for drug and metabolite terminal phase) Nordazepam kinetics independent of parent drug administered as they are controlled by its own elimination (see parallel terminal phase decline)

Answer 72

ABSORPTION Slowly but completely orally absorbed Low solubility (14 mg/L) and weak acid (pKa = 8.3) DISTRIBUTION Distribution equilibrium in 30-60 min. Vss = 0.6-0.7 L/kg Rapid distribution to brain; Cbrain  Cp Crosses placental barrier and distributes into breast milk fu~0.1 in plasma for usual 0.65 mM albumin. fu constant as far as Cphen < 0.1 mM ELIMINATION Mostly metabolized, 1-5% renal clearance. Inactive hydroxylated metabolites, some further metabolized (glucuronides) 60-90% of a dose recovered in urine as p-HPPH and glucuronide p-HPPH CYP2C9 predominant. PGx variation up to 10-fold in vivo. CYP2C19 also involved

Answer 73

C and AUC are not directly proportional to the dose Small changes in dosage cause a large, disproportionate difference in Cp Narrow therapeutic window: 10-20 mg/L and poor correlation between dose and Cp Difficult dose adjustments “Do not switch brands” advice Need for therapeutic drug monitoring (TDM)

Pharmaceutics Flashcards

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