Parenteral Drug Delivery

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Parenteral medications

Back 1

sterile dosage forms administered by injection

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SVP

Back 2

small volume parenterals

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LVP

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large volume parenterals

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Parenteral Drug Requirements

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- safety
- sterility
- stability
- solubility

- must be free from microbes, pyrogens and particulates

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pyrogens

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fever causing molecules from microbial contamination

- major causative molecule is LPS (lipopolysaccharide) from cell wall
- LPS is thermostable and may remain even after steam sterilization or filtration
- requires 250 C for 30-40 min

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Benefits of parenterals

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- most direct access to vascular system
- highly predictable drug levels
- alternative to GI route
- ability to replace fluids, electrolytes, pH balance, blood, plasma
- reliability and controllability

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Disadvantages of Parenterals

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- need for controlled environment and special skills
- pain and discomfort
- reactions and infections
- high cost
- transmission of disease

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tissue granuloma

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hardening of area of repeated injury (i.e. from repeated injections)

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Breast cancer spreads into ______ system

Ovarian cancer spreads into _______

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breast -> lymphatic system

ovarian -> peritoneal cavity

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Water for Injection (WFI)

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the most widely used and important vehicle for injectable preparation; used in manufacture of injectable products which are sterilized after preparation

- distillation or RO
- USP limits amount of anions, cations, solids

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Sterile Water for Injection

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a vehicle for reconstitution

- is free of pyrogens

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Bacteriostatic Water for Injection

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sterile water for injection containing antimicrobial agents

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Drug Injection

Example-

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liquid preparation that are drugs or solutions of drugs

Ex: Insulin Injection USP

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Drug for Injection

Example-

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dry solids that, upon reconstitution, yield solutions for injection

Ex: Cefamandole Sodium for Injection

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Drug Injectable Emulsion

Example-

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liquid preparations of drugs dissolved or dispersed in a suitable emulsion medium

Ex: Propofol

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Drug Injectable Suspension

Example-

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liquid preparations of solids suspended in a suitable liquid medium

Ex: Methylprednisolone Acetate Suspension

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Drug for Injectable Suspension

Example-

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dry solids that, when reconstituted, yield preparations conforming to requirements for Injectable suspensions

Ex: Imipenem

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thrombus

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blood clot formed in blood vessel or heart

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embolus

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clot that circulates in the blood stream

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Intrathecal

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injection into the cerebral spinal fluid

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Intraarticular

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injection into synovial cavity of a joint, usually to obtain local action

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Intracardiac

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Injection directly into the heart chamber

i.e. epinephrine solution for cardiac arrest

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General Requirements of Parenterals

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1. Sterility
2. Pyrogen-free
3. Clarity
4. Isotonicity

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Nosocomial infection

Routes:

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infection acquired in hospital

Routes:
- skin microflora (patients or medical)
- Hub colonisation
- contaminated fluid
- contaminated on insertion

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D-value

goal microbial survival:

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time in minutes required to destroy 90% of microbes exposed under a standard set of conditions

goal: 10exp(-6)

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steam sterilization

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moist heat in autoclave under pressure causes denaturation and coagulation of some microorganism's essential proteins

D= 1 min at 121 C
USP: 120 C at 15 psi for 20 min

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Dry heat sterilization

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- preferred choice for dry items
- method is microbial destruction via dehydration and slow burning or oxidation

D= 0.087 at 160 C
USP: 160-170 C for > 2 hr

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Filtration

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- physical removal of microorganisms by adsorption on a filter or sieving mechanism
- used for solutions that are unstable by thermal, chemical, or radiation sterilization

microbial filters= 0.22um

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size of bacteria

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10 - 100 um

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Gas Sterilization

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- ethylene oxide combined with heat and moisture
- ethylene oxide (alkylating agent) interferes with cell metablolism
- can be used for some heat and moisture sensitive items
- used on medical devices, enzymes, certain antibiotics, other drugs

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Radiation Sterilization

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- ionizing radiation on packaging mat'ls, ointments, implants
- highly reactive ions react with biological macromolecules leading to cell damage and death

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Preparations that are susceptible to microbial contamination

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- aqueous solutions
- emulsions
- suspensions

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bacteriocidal

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kills organisms

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bacteriostatic

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prevents organism growth

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Common contaminants and preferred pH conditions

pH limits of bacterial growth

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bacteria - alkaline media

molds & yeasts - acidic media

few organisms grow below pH 3 or above pH 9

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Preservative modes of action

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1. microorganism cannot grow in hypertonic solutions (i.e. 67% sucrose)
2. addition of + charge molecule will react with - charge of bacterial surface, leading to cell death
3. Irreversible coagulation (denaturation & precipitation)
4. Inhibition of cellular metabolism, oxidation of constituents, and hydrolysis

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Rabbit febrile reaction test

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for pyrogens;

- sample is injected into ear vein of rabbit, temp elevation of >0.6 C in 3 hr is basis for failure

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Limulus amebocyte lysate test

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for pyrogens;

- sample incubated for one hour at 37 C with the lysate of horseshoe crab blood. A gel forms in the presence of pyrogens

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phlebitis

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inflammation of the vein

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USP particle limit

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limit of 50 particles of 10 um and larger per mL for large volume infusions

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Clarity testing for particulates

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swirl solution and look at it against light and dark backgrounds

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hypertonic
vs
hypotonic

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hyper - too much salt in solution

hypo - too little salt in solution

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osmolality

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number of osmols per kg of solvent

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osmolarity

isotonic =

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number of osmols per liter of solvent

isotonic is 252-265 mOsmols/L

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where can you administer hypertonic parenterals?

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through the superior vena cava

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characteristics of ideal injectable formulation

- most common solution when drug is not soluble in these condition

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- isotonic
- neutral pH

- use ionized/salt form to increase solubility and buffer to maintain pH

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pH limits for IM

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pH 3 - 11

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pH limits for SC

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ppH 3 - 6

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cosolvents

Examples-

Possible problems-

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reduces polarity for increased solubility

- propylene glycol, ethanol, glycerol, polyethelene glycol, dimethyacetamide

problems: precipitation, phlebitis

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Cremophor-EL

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the most widely used nonionic surfactant in IV formulations
-inhibits P-glycoprotein

- used for paclitaxel, an anticancer drug
- limited by serious hypersensitivity

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cyclodextrins

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relatively nontoxic cyclic oligomers of dextrose that form inclusion complexes with drugs due to hydrophobic interaction

- can be toxic, are associated with cholesterol
- size and shape of drug may require > 1:1 ratio

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propofol

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the only marketed oil-in-water emulsion for injection

- droplets must be very small, causes pain on IV injection

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prodrugs

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pharmacologically inactive compounds that are converted to an active drug by enzymes or hydrolysis

- molecules containing hydroxyl, carboxyl, or amine have potential
- affect pharmacokinetics due to time to convert

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nanoparticles

Methods (2)

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small enough to not cause embolism unless they aggregate

1. grind, grind, grind
2. supersaturate to get fine crystals
- both cases require a surfactant

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antioxidants effect on drug stability

Examples (3)

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enhance drug stability from oxidation

- tocopherol, EDTA, sulfites

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container effect on drug stability

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container can absorb or adsorb to the container
or
container can leech into drug

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lyophilization

3 stages and result

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freeze-drying

1. freezing an aqueous solution of drug
2. 1 drying: sublimation of ice by reduced pressure
3. 2 drying: sublimation of water bound to solutes

Result: a solid cake with same shape as the frozen liquid, but with a honeycomb appearance

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Advantages of Freeze Drying

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- enhanced drug stability
- reduced oxidation
- reconstitutes rapidly
- fewer particles than dry-filled

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Disadvantages of Freeze Drying

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- risks associated with reconstitution
(e.g. spillage, spray)
- drug degradation

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admixtures

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combined parenteral dosage forms

- must consider compatability, excipients, preservatives, surfactants

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physical incompatibility

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results in a change in the solution's appearance

- color, clarity, turbidity
- precipitation of solid
- evolution of gas

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sorption

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plastic and rubber may absorb lipophilic drugs

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problem with prolonged storage of frozen parenteral admixtures

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polymorphic crystal changes -> less soluble

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chemical incompatibility

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a drug degrades more rapidly as a result of being combined with other drugs or formulations

- arise from hydrolysis, oxidation, photolysis

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factors affecting chemical stability

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- pH
- solubility/clarity
- concentration
- complexation
- UV light
- temperature
- time

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techniques to prevent chemical instability of admixtures

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- administer drugs separately at staggered time intervals
- use a heparin lock
- use alternative route of administration
- flush line between drugs

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order of lability to hydrolysis

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lactams/cyclic amides
esters
imines
amines (slowest)