Week 12 Case Study # 1: Pulmicort Respules

Budesonide is available commercially as a nasal spray, powder for oral inhalation and nebulized suspension. Explain the characteristics of each of these budesonide inhalation and nasal dosage forms? Complete the table

* The dosage form for the first and third products are both pMDI = pressured metered dose inhalers. * For dry powder inhaler - see below

Question 2a) Explain why the inhalation route of administration of Pulmicort Respules® inhalation suspension is chosen for the topical treatment of airway inflammation in asthma ?

1) Because the inhalation route will cause the drug to have negligent to low systemic absorption. 2) In other words, it will not undergo extensive hepatic metabolism like orally administered drugs and hence most of the drug molecules will be available for the lungs to produce a LOCAL anti-inflammatory effect. 3) It is also good to note that when the drug is metabolized, its metabolites will have low potency and will not produce any unwanted side effects. So we're producing a local effect in our target site and the drug won't produce any unwanted side effects.

Question 7: Many different types of nebulizers are available in the US and Europe. For example, the Pari LC® Plus (A), Pari LC® Star (B), and Philips Ventstream® (C) are common nebulizers. (see pictures) Would you tell your patient that these nebulizers are interchangeable for the administration of Pulmicort Respules® inhalation suspension?

1) In terms of particle size produced, the Pari LC Plus had a MMD (mass median diameter) of 5.1um, Pari LC Star produced 4.0um, and Ventstream produced 3.8um. 2) The percentage of drug contained in particles less than 5um is similar for LC Star (about 68%) and Ventstream (about 71%) 3) For LC Plus however whose particle size was bigger than 5 um, less was delivered (about49%) 4) When comparing drug output, the LC Star nebulizer driven by the Turboboy compressor had a slightly smaller maximum output rate than the LC Plus. The ventstream produced the lowest drug output out of the three. (I think drug output here means how much drug came out from the nebuilizer) ***** In conclusion, the study cited found differences between all 3 of these nebulizers and thus they are not interchangeable

Question 4a) Nebulizers are available commercially as 1.) air jet nebulizers (Figure 1); 2.) conventional ultrasonic nebulizers (Figure 2); and 3.) vibrating mesh nebulizers (Figure 3). ******A patient has presented a prescription to your pharmacy for Pulmicort Respules® inhalation suspension (this is the name of the drug). Upon picking up the prescription and counseling, the patient refuses to purchase the recommended nebulizer for that suspension. The name of the inhaler is Pari LC Plus®. Instead, the patient explained that they would like to use a newly purchased Omron MicroAir® VMT nebulizer (NE-U22V1) that they use with their Proventil® inhalation solution (this is another drug that the patient is on). They paid $149 for it. This patient has no insurance. Explain to the patient why this type of nebulizer cannot be used with Pulmicort Respules®.

1)The two nebulizers use two different systems. For Pari LC Plus: it utilizes an air jet system (figure 1) whereas Omron MicroAir that the patient has purchased before for another medication is a passively vibrating-mesh nebulizer (firgure 3). 2) The Pari nebulizer is able to deliver with consistency regradless of the particle size. Whereas the Omron MircoAir nebulizer worked great with small sphere particle size of 1um. However it was unable to nebulise 4.5 or 10um spheres due to its low energy input for atomization. 3) Also The mesh in Omron has precision drilled holes and extrudes the liquid as little droplets due to the vibrations. However this also means that it has the potential to be blocked by the suspended particles. (see below) - that's why it is not going to work for bedonside here because it exists as a suspension and block the particle size.

Corticosteroid definition

A steroid hormone that is produced in the adrenal cortex

Question 6b) As a compounding pharmacist, you can purchase either micronized budesonide powder or spray- dried amorphous budesonide powder from your distributor. The cost of micronized budesonide powder is the same as that of the spray-dried amorphous budesonide powder. For compounding this formulation, considering the images shown, explain why you can or cannot use the spray dried amorphous budesonide powder instead of micronized budesonide powder supplied by your distributor?

According to Ansel's amorphous suspensions and dispersions are stable. However, they have more variable rates of crystallization due to their improved solubility. Risk of crystallization and Ostwald ripening may exceed suitable particle size. This poses the issue of inconsistency from dose to dose and patient to patient. Therefore micronized budesonide is preferred.

Pulmicort Respules®; What's the active component? What's the function

Budesonide; corticosteroid; a cortisol-derivative that will have anti-inflammatory effects to treat asthma (makes sense that it will work on the lungs because its name is Pulmicort - has the prefix Pulmonary in it)

Describe the Pulmicort Respules inhaler

It is an inhaler that contains the drug budesonide in a suspension

Question 1) Water and pH Solubility of Budesonide (how can you remember this?)

It is insoluble in water (which means a logP >1) ; and has no pH dependent solubility. By remembering the fact that the drug exists as a suspension inside the inhaler.

How does a jet nebulizer work? It is based on what principal?

It is powered by a battery or other means. When the device is turned on, a stream of air passes through a compressor which causes the air passes to pass with very high velocity to the container containing the liquid medication to turn into an aerosol which exits through a mouthpiece or face-mask that the patient wears; based on Bernouli's principal: increase in the fluid velocity simultaneously when we decrease the pressure (which is the purpose of the compressor)

Question 3) Discuss general differences between pMDI, nasal spray and a nebulized suspension

Nasal spray: will be administered to the nose pMDI: pressured metered-dose inhaler: will be administered to the nose nebulizer suspsension: usually mouth but can be mouth and nose if person is wearing a face mask.

Question 5b) As a compounding pharmacist, explain if you can or cannot extemporaneously compound the Pulmicort Respules suspension formulation without polysorbate 80 or a similar surfactant for a prescription.

No, you cannot compound the suspension without a surfactant. The surfactant is necessary to maintain stability and increase solubility of the drug. This is because it decreases the surface tension between the particles and hence prevents the drug particles from aggregating together. Otherwise the drug particles will aggregate and not be effectively released.

Question 2b) Identify the dosage strength (i.e., the amount of drug per dosage unit) and administered dose (i.e., total amount of drug given at each administration time) of Pulmicort Respules® inhalation suspension .

PULMICORT RESPULES is available in three strengths: 0.25 mg/2 mL, 0.5 mg/2mL, and 1 mg/2 mL. The actual amount of drug that gets administered is 17% of the amount of drug per dosage unit. Therefore the total amount of drug at each administration is .0425 mg/2 mL, or .085 mg/2 mL, .17 mg/ 2 mL

Question 8: Drug products for inhalation must meet the sterility criteria of the USP- NF (U.S Pharmacopoeia - National Formulary - who cares?) ........ US patent 7524834 describes a suitable method for sterilizing budesonide powder which involves heat treating budesonide at a temperature of 110°C to 120°C for up to 24 hours. You compounding pharmacy does not have suitable apparatus for performing heat sterilization. He/She wants to use sterile filtration instead. Explain why or why not sterile filtration is a suitable sterilization method for budesonide inhalation suspension

Sterile filtration (with 0.2 micron filter) would not be a suitable method of sterilization. Because the drug particles are larger than .2 microns and hence most of the drug product would remain on the filter.

Why is OMron MicroAir nebulizer suitable for a solution and NOT a suspension?

The Omron could have been used for solution since it is a solution therefore particle size is not a factor since it is all dissolved. the solution particles can then pass through the holes of the nebulizer to be extruded form the other side. However since Pulmicort Respule is a suspension the particle size has to be taken into account and Omron would not be able to efficiently deliver the drug as needed since large particle sizes can very well block the mesh

What is dosage strength

The amount of drug given per dosage unit (like per mL)

Question 6a) As a compounding pharmacist, you can purchase either *micronized* budesonide powder or *bulk* (i.e., nonmicronized) budesonide powder from your distributor. The cost of micronized budesonide powder is more than 10times that of the bulk budesonide powder. Explain why you can or cannot use the bulk budesonide powder instead of micronized budesonide powder (which is more expensive)

The bulk budesonide powder cannot be utilized in any inhalant formulations. According to Ansel's, the required particle size for reaching the bronchioles need to be less than 6 microns; for alveoli the required particle size needs to be less than 2 microns. The bulk budesonide powder is too large, therefore it will deposit in the upper airways and be swallowed

What is administered dose?

Total amount of drug given at each administration time

Question 4b) The patient also just recently purchased a Veridian Healthcare SonicMist TM ultrasonic nebulizer for $128. Explain to the patient why this type of nebulizer cannot be used with Pulmicort Respules®

Ultrasonic nebulizers such as SonicMist TM are generally unsuitable for delivering suspensions due to the heat generated during atomization, causing instability of the processed material. This heat generated due to the high frequency vibrating piezoelectric crystals in the device might solubilize the drug particle or change the particle size in the suspension which can then affect the stability of Pulmicort Respule as a suspension.

A device for producing a fine spray of liquid, used for example for inhaling a medicinal drug.

a nebulizer

For alveoli the required particle size needs to be

less than 2 microns.

The required particle size for reaching the bronchioles need to be

less than 6 microns;

Dry powder inhaler:

used as an atlerenative to metered dose inhalers. The drug is literally administered as powder not in aerosol cloud. The patient inhales in the mouth piece and the air pulls the drug particles.