NANO 243/CENG 207 Course Use Only

Transcription

1 L6. Drug Administration & Transport by Fluid Motion April 19, 2018

2 Part I: Drug Administration

3 Routes of Drug Administration Topical: local effect, substance is applied directly where its action is desired. Enteral: systemic effect, substance is given via the gastrointestinal (GI) tract. Parenteral: systemic effect, substance is given by routes other than the gastrointestinal (GI) tract.

4 Topical Drug Delivery Epicutaneous directly onto the surface allergy testing local anesthesia Eye drops Inhalational asthma medications of the skin antibiotics for conjunctivitis acute infection in upper airway Intranasal route decongestant nasal sprays

5 Enteral Drug Delivery Any form of administration that involves any part of the gastrointestinal tract Oral: many drugs as tablets, capsules, drops Rectal: various drugs in suppository or enema form Gastric feeding tube: many drugs, enteral nutrition

6 Parenteral Drug Delivery Intravenous: into a vein (many drugs, total parenteral nutrition ) Intramuscular: into a muscle (many vaccines, antibiotics ) Subcutaneous: under the skin (insulin ) Intraarterial: into an artery (vasodilator drugs in the treatment of vasospasm ) Intradermal: into the skin itself (skin testing some allergens, tattoos ) Transdermal: diffusion through the intact skin (transdermal opioid patches in pain management, nicotine patches for treatment of addiction ) Transmucosal: diffusion through a mucous membrane (insufflation of cocaine) Inhalational: e.g. inhalational anesthetics

7 Topical: Drug Administration Routes - Summary Epicutaneous (allergy testing, local anesthesia ) Inhalational (asthma medications ) Eye drops (antibiotics for conjunctivitis ) Intranasal route (decongestant nasal sprays ) Enteral: any form of administration that involves any part of the gastrointestinal tract Oral (many drugs as tablets, capsules, drops ) Rectal (various drugs in suppository or enema form ) Gastric feeding tube (many drugs, enteral nutrition ) Parenteral: Intravenous: into a vein (many drugs, total parenteral nutrition ) Intramuscular: into a muscle (many vaccines, antibiotic ) Subcutaneous: under the skin (insulin ) Intraarterial: into an artery (vasodilator drugs in the treatment of vasospasm ) Intradermal: into the skin itself (skin testing some allergens, tattoos ) Transdermal: diffusion through the intact skin (transdermal opioid patches in pain therapy, nicotine patches for treatment of addiction ) Transmucosal: diffusion through a mucous membrane (insufflation of cocaine, Inhalational, e.g. inhalational anesthetics

8 Contact lenses for eye delivery Micro-needle patch Novel Administration Routes Controlled-release microchip Drug eluting stent And many many more...

9 Advantages: Convenient - portable, no pain, easy to take. Disadvantages: Oral Administration Cheap - no need to sterilize, compact, multi-dose bottles, produced in large quantities. Variety - fast release tablets, capsules, enteric coated, layered tablets, slow release, suspensions, et al. Sometimes inefficient - high dose or low solubility drugs may suffer poor bioavailability. First-pass effect - drugs will be metabolized in the liver during absorption. Food - Food and GI motility can effect drug absorption. Local effect - Antibiotics may kill normal gut flora and allow overgrowth of fungal varieties. Unconscious patient - Patient must be able to swallow solid dosage forms. stomach duodenum jejunum ileum

10 Advantages: Rapid - A quick response is possible Disadvantages: Intravenous Injection Total dose - The whole dose is delivered to the blood stream. Large doses can be given by extending the time of infusion. Veins insensitive - irritation by irritant drugs at higher concentration in dosage forms. Suitable vein - It may be difficult to find a suitable vein. Maybe toxic - Because of the rapid response, toxicity can be a problem. Requires trained personnel - Trained personnel are required to give intravenous injections. Expensive - Sterility, pyrogen testing and large volume of solvent means great cost for preparation, transport and storage. First intravenous injection (1667)

11 Advantages: Disadvantages: Can be painful Subcutaneous Injection Can be given by patient, e.g. in the case of insulin. Absorption is slow but usually complete. Improved by massage or heat. Irritant drugs can cause local tissue damage Maximum of 2 ml injection thus often small doses limit use.

12 Advantages: Disadvantages: Intramuscular Injection Larger volume, than SC, can be given by IM. A depot or sustained release effect is possible with IM injections. The site of injection will influence the absorption, generally the deltoid muscle is the best site. Trained personnel required for injections. Absorption is sometimes erratic, especially for poorly soluble drugs. The solvent maybe absorbed faster than the drug causing precipitation of the drug at the site of injection.

13 Advantages: By-passing the liver Disadvantages: Inhalation Fastest method, 7-10 seconds for the drug to reach the brain User can titrate (regulate the amount of drug they are receiving) Most addictive route of administration because it hits the brain so quickly Difficulties in regulating the exact amount of dosage Absorption of gases is relatively efficient, but not solids or liquids

14 A Comparison of Different Administration Routes Administration of Human Immunoglobulin G (IgG) IgG, ~150 kda Adapted from Lancet 1972, i, 1208

15 Drug Administered via Different Routes Will Have Different Consequences The route and method of drug administration will influence: Pharmacokinetics: what the body does to the drug Absorption Distribution Metabolism Excretion Pharmacodynamics: what a drug does to the body Effectiveness of the drug

16 Intravenous Injection for Systemic Drug Delivery Notorious and fatal diseases usually require direct treatments with fast response and large dosage.

17 Part II: Drug Transport by Fluid Motion

18 Basic Concept Diffusion: molecular movement within 100 µm; driven by concentration gradient Bulk flow & convection: long distance movement in the body; driven by hydrostatic and osmotic pressure How blood flow is regulated? How to measure molecule concentration in blood?

19 1. Blood Movement in the Circulating System Cylindrical vessel model P: hydrostatic pressure V z : fluid velocity along the z axis (function of radial distance from the tube centerline) r θ z

20 1. Blood Movement in the Circulating System Hagen-Poiseuille flow

21 1. Blood Movement in the Circulating System Equation for conservation of momentum: Parabolic dependence of local velocity on radical position.

22 1. Blood Movement in the Circulating System Overall rate of blood flow Overall resistance of a cylindrical vessel to flow Vessel cross section r dr dθ When blood vessel becomes smaller, the resistance to flow increases dramatically. The majority of the overall resistance to blood flow resides in the smallest vessels.

23 1. Blood Movement in the Circulating System Blood supply to tissue Local blood flow to tissue is controlled by constriction and dilation of the arterioles delivering blood to the tissue. Individual arterioles have muscular walls which allow them to adjust their diameter, and hence resistance.

24 1. Blood Movement in the Circulating System Flow distribution in branching networks can be regulated by resistance If one branch changes its resistance: R ½ R One arteriole size drops by a factor of ½, Flow rate in the large artery drops to ml/min

25 1. Blood Movement in the Circulating System Efficient mixing For highly toxic drug (e.g., chemotherapy drug), they need to be injected to large vein/artery. - High flow velocity (15~20 cm/s) - Extensive branching of the cardiovascular circuit

26 2. Monitoring Drug/Nanoparticle Concentration in Blood (1) Radioisotope labeling e.g., docetaxel-loaded PLGA nanoparticles Docetaxel- 14 C (half-life: 5730 years) PLGA- 3 H (half-life: 12 years) e.g., liposomal nanoparticles lipid-chelated 111 In (indium, 2.8 days) 153 Gd (gadolinium, 240 days) 45 Ca (calcium, 163 days) 51 Cr (chromium, 27 days) 32 P (phosphorus, 14 days) 109 Cd (cadmium, 464 days) Advantages: trace amount; very accurate Disadvantages: dangerous; trained person Science, 1994, 263, 160.

27 2. Monitoring Drug/Nanoparticle Concentration in Blood (2) Fluorescence labeling Challenge: interference from blood Solutions: (1) high loading of blue, green, or red probes (2) using far red fluorescent probes: Alexa 647, Cys 5.5, etc (3) No labeling Chemical characterization of drug/material itself. - high performance liquid chromatography (HPLC): UV absorbance - mass spectroscopy: elemental composition - electrochemical analysis: Redox reaction