Parenteral drug delivery

Question 1

what is Parenteral delivery?

Answer 1

1) A method to deliver the drug directly to the blood (IV)
- “par” = Outside
- “Enteral” = gastrointestinal tract

Question 2

There are a large number of factors influencing the onset, intensity and duration of action of a drug. state 4 of the major factors

Answer 2

1) (Liberation)
2) Absorption
3) Distribution
4) Metabolism
5) Excretion

Question 3

outline the Advantages of Parenteral delivery

Answer 3

1) Rapid & complete absorption
2) predict the PK profile of drug → control dose & frequency
3) For the unconscious patient, uncooperative patient, nausea /vomiting; unable to swallow
4) Useful for giving very small dose

Question 4

outline the diadvantages of Parenteral delivery

Answer 4

1) Aseptic precautions must be followed
2) Manufacturing of PD is more
3) Once administered cannot be removed from bloodstream
4) Pain & infection at site of injection can occur

Question 5

parenteral preparations can be classified according to volume and formulation. outline both the volume and formulation classification

Answer 5

1) volume:
- Small Volume <10ml
- Large volume >10ml
2) According to formulation
- emulsions
- Suspensions (not for IV)
- solutions

Question 6

the Angle used to inject depends on the route required to deliver the drug . state the different types of Injection techniques

Answer 6

1) intramuscular: 90 degrees
2) subcutaneous : 45 or 90 degrees
3) intradermal: 15 degrees

Question 7

describe the characteristics IV (into vein) administration.

- volume injected

Answer 7

1) Large (up to 500ml) or small volumes (<10ml) can be administered
2) Not to administer larger volume at fast rate-sudden osmotic pressure/electrolytes- risk of shock or acute renal failure
3) Solutions or emulsions (droplet size below 1uM)
- e.g. Gentamicin IV

Question 8

discuss the Complications associated with intravenous delivery

Answer 8

1) Air embolism, or the injection of air into a vessel.
- larger amounts (a few ml) fatal, if it reaches the brain
2) Thrombosis- dangerous if the clot circulates in the bloodstream. can be caused by irritant formulations which are injected too rapidly.
3) Haemolysis, the breakdown of red cells with the release of haemoglobin, can cause kidney damage if severe. A problem with strongly hypotonic injections
4) Phlebitis is the inflammation of the vein wall due to irritation-can be caused by the formulation, or may be due to precipitation of the drug if injection is too rapid
5) Extravasation, or the leakage of the injection from the vein into the surrounding tissue, can lead to extensive damage s. This is a particular problem for cytotoxic materials, (e.g. methotrexate or mitomycin) as it can lead to ulceration and necrosis which is slow to heal

Question 9

describe the characteristics of the muscle (IM) route of administration.

• volume injected
• typical sites

Answer 9

1) small volumes (<10ml) can be administered
2) Commonly used for sustained release-onset not important
3) Typical sites : deltoid, gluteal or vastus lateralis
4) Onset of IM is alower than IV but choice depends on desired onset & mw
- NSAIDS, e.g. Flu vaccine

Question 10

describe the characteristics of the Subcutaneous (SC) route of administration.

Answer 10

1) Into the fat layer, beneath dermis and epidermis and above muscle tissue
2) Slower absorption, usually low volume (1mL) but larger volumes can also be used in exceptional cases
3) Typical sites: arm, abdomen, legs
- Insulin, local anaesthetics lidocaine 5%

Question 11

what is the difference between a subcutaneous injection and an intradermal injection and what are the consequences?

Answer 11

1) A subcutaneous injection (SC) is made into the connective tissue beneath the dermis,
2) intradermal injection is made into the dermal layer, often between the dermis and the epidermis
3) the subcutaneous tissues have a significant volume of interstitial fluid into which the drug can diffuse, while the epidermal tissue has relatively little available fluid, nor is it well perfused by blood

Question 12

Drugs injected subcutaneously dissolve in the interstitial fluid and gain entry to the bloodstream by two routes.

1) outline these two routes
2) comment on the relative speed of these two pathways

Answer 12

1) They may be absorbed directly into blood vessels, but the subcutaneous tissues are often adipose and poorly perfused
2) the interstitial fluid is collected by lymphatic capillaries and these drain into the regional lymph nodes and then into the bloodstream
3) These pathways are both relatively slow and depend on the local vasculature, so absorption from subcutaneous sites can be slow and unpredictable.

Question 13

list Insulin Delivery Methods

Answer 13

1) Insulin Syringe
2) Insulin Pen
3) Insulin Pump or Pod
4) Jet Injector

Question 14

state the common sites insulin can be injected

Answer 14

1) Common sites: abdomen, thigh buttocks, upper arms

2) Inject into fat layer under skin and Rotate sites

Question 15

list the different types of insulin

Answer 15

1) Rapid-acting - Humalog ®, Novolog ®, Apidra
- preffered in insulin pumps
2) Short-acting - Regular
3) Intermediate - NPH
4) Long-acting - Glargine (Lantus), Detemir (Levemir)

Question 16

What is basal bolus insulin therapy?

Answer 16

A basal-bolus routine involves taking a longer acting form of insulin to keep blood glucose levels stable through periods of fasting and separate injections of shorter acting insulin to prevent rises in blood glucose levels resulting from meals.

Question 17

what is a bolus dose?

Answer 17

1) A bolus dose is insulin that is specifically taken at meal times to keep blood glucose levels under control following a meal.
- “cover” carbs in meals and snacks.
- Used to “correct” high blood glucose levels

Question 18

what is the role of basal insulin?

Answer 18

1) background insulin, is to keep blood glucose levels at consistent levels during periods of fasting.
2) Matches Glucose Released by Liver
3) Meets Body’s Basic Energy Needs
- May Need Different Settings at Different Times of Day

Question 19

what is an Intradermal injection?

Answer 19

1) Intradermal: dermal tissue (0.1ml). Minimal absorption hence reserved for detection of antibodies (allergy to penicillin or tuberculin test).

Question 20

what is an Intrathecal and Epidural injection?

Answer 20

1) Intrathecal: injection into the subarachnoid space to reach cerebrospinal fluid, e.g. IT baclofen to treat spasticity in multiple sclerosis
2) Epidural: into the dural membrane surrounding the spinal cord, e.g. epidural steroid injections for back pain and sciatica

Question 21

what are the requirements for parenteral drug delivery PDD?

Answer 21

1) Sterile: free from living microorganisms
2) Pyrogen free: pyrogen is fever inducing substance (endotoxin) such as lipopolysaccharide (cell wall) remaining after deactivation of bacteria
3) Homogenous and delivers reproducible dose, physically and chemically stable

Question 22

what are the Pharmaceutical considerations for a Parenteral formulation?

Answer 22

1) viscosity
2) pH
3) solubility
4) preservatives

Question 23

outline the formulation considerations for Intravenous delivery

Answer 23

1) sterile in order to avoid causing an infection
2) Particulate material, glass, or pieces of rubber closures, must also be rigorously excluded
3) Small volume parenterals, below 100 ml in volume, can be formulated at a pH ranging from 4 to 10, and be considerably hypotonic or hypertonic. Large volume parenterals must be more closely matched to the properties of the blood, and the pH is rarely outside the limits 6–8.
4) IV parenterals to be infused through a peripheral vein are closely matched in tonicity

Question 24

what should the tonicity of parenteral nutrition mixtures be?

Answer 24

parenteral nutrition mixtures may have a tonicity up to around twice that of blood (infused into subclavian vein) In this case the infusion is very rapidly diluted, so that variations in its properties are of lesser importance
- (Plasma extenders, which are often infused through a peripheral vein, are closely matched in tonicity)

Question 25

one of the vehicles used for injections is water. what are the key specifications of water for injections

Answer 25

1) Appearance
2) Purity
3) Sterility (water for injections BP is sterile)
4) Absence of pyrogens and particulates

Question 26

outline some Non-aqueous vehicles used in injections and their purpose

Answer 26

1) Used for water-insoluble APIs- must be inert and safe
2) Typically oils (corn oil, cottonseed oil) or water miscible solvents (propylene glycol/ethanol for digoxin)
3) Issues (pain/irritation on injection; patients sensitivity)

Question 27

Solubility is a determining factor for the type of formulation chosen. discuss how we can manipulate solubility

Answer 27

1) Co-solvents can be used such as ethanol, PEG, glycerine, soybean oil and castor oil
2) Poorly soluble drug more likely be emulsion or suspension
3) Surfactants can be used, but toxicity profile should be carefully evaluated, Polyoxyethylene sorbitanmonooleate

Question 28

outline the use of Preservatives in parenteral formulations

Answer 28

1 Preservatives should be avoided in single dose IV and now allowed in IT and ED
2) If desired (multidose) phenolic compounds, e.g. phenol (0.25–0.5% w/v) or chlorocresol (0.1–0.3% w/v), methylparahydroxybenzoic acid

Question 29

Osmolarity and pH are important in parenteral formulations. discuss how Osmolarity and pH can be corrected

Answer 29

1) slow IV infusion render hypertonic liquids isomolar, however hypotnicity should be corrected by dextrose, glycerine or NaCl
2) To maintain pH, to ensure drug stability and prevent possible ppt. Examples of commonly used buffers include acetic acid/sodium acetate, citric acid/sodium citrate and sodium phosphate/disodium phosphate

Question 30

define when a solution is considered to be isotonic

Answer 30

A solution is considered to be isotonic if it has a freezing point of -0.52ºC (freezing point of plasma water)

Question 31

The freezing point depression of a 1% w/v solution of morphine sulfate is 0.08ºC and that of 1% w/v sodium chloride solution is 0.576ºC . How many grams each of morphine sulfate and sodium chloride are required to prepare 50ml of a 1% w/v morphine sulfate solution isotonic with blood plasma?

Answer 31

1) The freezing point of (a 1% w/v solution of) morphine sulfate is −0.08ºC. The required freezing point is 0.52ºC, therefore the freezing point must be lowered by: 0.52ºC - 0.08ºC = 0.44ºC.
2) W = (0.52 − 0.08)/0.576= 0.7638g/100ml
- W morphine = 0.5g
- W NaCl= 0.7638/2= 0.3819g

Question 32

Calculate the concentration of (%w/v) of sodium chloride (mw=58.5g/mol) to be added to water to produce an isotonic solution.

Answer 32

1) Sodium chloride is ionic so 1 mol of NaCl when added to 100grams of water will produce a gram molecular concentration of 2% (2 moles of ions in 100ml).
2) Based on freezing point depression, 0.03% (0.03 mole per 100ml) of any dissolved solute should produce freezing point depression = 0.52ºC (colligative property!)
3) 0.03 mole/100ml* (58.5/2 g/mol) -> ~ 0.9g/100ml= ~ 0.9%w/v

Question 33

discuss how the viscosity of a parenteral formulations can be modified

Answer 33

1) Viscosity may change when adding polymeric stabilizer or to increase solubility, e.g. PVP or aluminium stearate
2) Oil based formulations may have higher viscosity
3) Minimum polymer Mw should be selected, ~ <10000
4) Increasing viscosity may be essential for stability, stearic hindrance or to decrease flocculation of suspensions, DLVO!

Question 34

outline the most significant advantage of Intramuscular delivery

Answer 34

The most significant advantage of intramuscular delivery is the ease with which a wide range of drugs can be administered in a variety of dosage forms, which not only provide rapid absorption, but can also be used for sustained therapy

Question 35

summarise the Steps involved in intramuscular delivery

Answer 35

1) release of the drug from the dosage form into the intercellular fluid (ICF)
2) absorption from the ICF into the blood and lymphatics
3) transport from the local blood volume into the general circulation
4) metabolism

Question 36

comment on the Formulation considerations for Intramuscular injections

Answer 36

1) Since the formulation does not have to be miscible with water (one phase), it is possible to inject a much wider range of materials than those which can be administered intravenously.
2) aqueous solutions, aqueous suspensions, oily solutions, oil in water emulsions, oily suspensions…
3) If the drug is extremely hydrophobic it will not dissolve in the ICF
4) If it is strongly ionized or extremely water soluble it will not be able to cross the capillary membrane
5) Drugs which are strongly protein-bound will also be slowly absorbed since their activity in solution will be reduced

Question 37

discuss the perfusion limited absorption of drugs from intramuscular injections

Answer 37

1) Injection of a bolus of soluble drug. the drug is immediately available in the ICF and is rapidly absorbed into the capillaries
2) the rate-limiting absorption step is the perfusion of the muscle by the blood. Any factor which influences muscle perfusion (such as movement or exercise) will change the rate of absorption
3) In particular, if cardiac failure has occurred, absorption will be extremely low since the muscle perfusion rate will be small. For this reason intramuscular delivery is contra-indicated if cardiac function is poor

Question 38

comment on the Device limited absorption of drugs from intramuscular injections

Answer 38

1) Injection of the drug in sustained-release form (e.g. a solid depot or crystal suspension). In this case release from the formulation is slower than absorption or perfusion, and so the behavior of the device becomes the rate-limiting step, and the effects of muscle perfusion are not evident
2) Under these conditions the concentration of drug in the plasma remains approximately constant until the delivery device is exhausted, a period which can be designed to last from several hours to several months.