1. Microcapsule-Based Drug Delivery
CH E 4273 – Advanced Process Design
Leann Johnson
Mark McClendon
Miguel Bagajewicz

2. Oral Drug Delivery Blood Concentration after multiple oral doses
Target Blood Concentration
This is not optimal because drug concentrations go above and below the Target Blood Concentration.
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3. Extended Release Injection
Blood Concentration after a single extended release injection
Target Blood Concentration
Constant drug concentrations produce optimal results in the patient.
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4. Extended Release
There are currently over 10 drugs on the market that use microspheres. Those include Haloperidol, Naltrexone, and Piroxicam.
We predict that in the future many orally administered drugs will be converted to an extended release formulation.
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5. Extended Release
Doctors will need a method of prescribing extended release injections to individual patients.
Input Patient Info
Prescription Program
Output Prescription
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6. Mission Statement
Create a computer simulation that will calculate drug prescriptions for a patient in the form of extended release injections.
The extended release injection must result in a drug concentration profile that looks like this:
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7. Microcapsule-Based Drug Delivery Overview
Extended Release Mechanisms
Microspheres as extended release forms
Drug Metabolism
Prescription Calculation Program
Microsphere Production and Pricing
Conclusions
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8. Extended Release Injection
After the microsphere injection has been administered, the individual microspheres will release the medicine at a rate that will achieve the target blood concentration in the body for the required number of days. This is how microsphere injections work.
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9. Microcapsule-Based Drug Delivery Overview
Extended Release Mechanisms
Microspheres as extended release forms
Drug Metabolism
Prescription Calculation Program
Microsphere Production and Pricing
Conclusions
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10. Microspheres are one type of drug delivery vehicle for extended release formulations
Other extended release forms are small rods surgically implanted under the skin and oral slow release capsules.
100 μm
Microspheres are composed of a biodegradable polymer, typically PLGA
Many things affect the release rate from microspheres:
Size
Drug Concentration
PLGA molecular weight
Polymer type
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11. Modeling Drug Diffusion
Microspheres injected into a patient form a round pocket of densely packed microspheres.
Pocket of microspheres injected into a mouse hamstring.
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12. Modeling Drug Diffusion
Microspheres injected into a patient form a round pocket of densely packed microspheres.
Microsphere
Capillary
Muscle
Tissue
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13. Modeling Drug Diffusion
This is an enlarged view of the pocket of microspheres.
Laminar Blood Flow
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14. Modeling Drug Diffusion
Fick’s Law of Diffusion x1 x2 x3
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15. Modeling Drug DiffusionC4 C3 C2 C1 x1 x2 x3
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16. Modeling Drug Diffusion
Capillary
Interstitial Fluid
Microsphere
Total Resistance
Capillary + Interstitial Resistance << Microsphere Resistance

17. Modeling Drug Diffusion
A more accurate view of drug diffusion from the microspheres
Laminar Blood Flow
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18. PLGA Molecular Weight (Kda)
Drug Release Rate
Microsphere Type
Type 1
Type 2
Type 3
Type 4
Type 5
Type 6
Type 7
Type 8
Type 9
Diameter (μm) 10 50
PLGA Molecular Weight (Kda) 6 20 35 70
These nine different types of microspheres were used to prescribe medication in our prescription program.
These release profiles were found in the literature and their form is related to PLGA disintegration
Raman et al. Modeling small-molecule release from PLG microspheres Journal of Controlled Release.   - Vol. 103. - pp

19. Microcapsule-Based Drug Delivery Overview
Extended Release Mechanisms
Microspheres as extended release forms
Drug Metabolism
Prescription Calculation Program
Microsphere Production and Pricing
Conclusions
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20. Drug Metabolism
The metabolic consumption of drugs differs widely among individual patients.
Therefore every patient needs a different dose of extended release drugs.
Slow Metabolism
Dose 1
Fast Metabolism
Dose 2
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21. Prescription Process
Step 1: Patient is injected with the desired drug intravenously.
Step 2: The Blood Concentration of that drug is measured for a period of 1 to 24 hours.
Step 3: The doctor obtains the patients metabolic rate by the blood concentration levels.
Step 4: The doctor inputs all information into our program and receives a calculated prescription.
Step 5: The patient is injected with the extended release prescription.
These steps will be eliminated in the future when patient metabolism can be predicted based on patient info
Step 5
Step 1
Step 2
Step 3
Step 4
Prescription Program
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22. Metabolism Modeling
Drug blood concentration decreases as the body metabolizes the drug. This decrease is in an exponential decay.
Heeb et al. Single dose pharmacokinetics of piroxicam in cats [Journal] // J. Vet. Pharmacol. Therap..   - Vol. 26. - pp
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23. Metabolism Model
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24. Microcapsule-Based Drug Delivery Overview
Extended Release Mechanisms
Microspheres as extended release forms
Drug Metabolism
Prescription Calculation Program
Microsphere Production and Pricing
Conclusions
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25. = + Prescription Model metabolic model prescription model Microsphere
Drug Release
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26. Prescription Model Outputs Inputs Input Patient Info
Prescription Program
Output Prescription
Inputs
Patient Weight
Desired Concentration of Drug
Medicated Period
Patient’s Metabolic Rate
Outputs
Microsphere Mass Distribution
Blood Concentration vs. Time Plot
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27. Medicated Period (days)
Prescription Model
Patient's Weight (lbs)
Tgt Blood Conc (g/L)
Medicated Period (days)
Initial Ramp Period
Final Ramp Period
150
0.0001 35 5 30
INPUT D
delta
E-07
Microsphere Type
Type 1
Type 2
Type 3
Type 4
Type 5
Type 6
Type 7
Type 8
Type 9
Microsphere Mass (mg)
0. 5
3.4 .6 .1 .7
1.3
Total Microsphere Mass (mg)
6.6
OUTPUT
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28. Prescription Model 1st Injection 2nd Injection
Microsphere Type
Type 1
Type 2
Type 3
Type 4
Type 5
Type 6
Type 7
Type 8
Type 9
Microsphere Mass (mg)
1.5 .9 1
2.7
1st Injection
Total Microsphere Mass (mg)
7.6
Microsphere Type
Type 1
Type 2
Type 3
Type 4
Type 5
Type 6
Type 7
Type 8
Type 9
Microsphere Mass (mg)
1.1 1
4.8 .6 .2
2.4
2.3
2nd Injection
The second injection requires more microsphere mass because the medicated period is 10 days longer.
Total Microsphere Mass (mg)
12.4
Drug
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29. Conclusions
We have created a computer simulation that models the drug concentration in the blood stream
With this program a doctor can specify a target blood drug concentration
The computer simulation will then calculate the correct dosage of microspheres that will achieve this target blood drug concentration
We predict that this method of prescribing microspheres will become essential for future medications

30. Microcapsule-Based Drug Delivery Overview
Extended Release Mechanisms
Microspheres as extended release forms
Drug Metabolism
Prescription Calculation Program
Microsphere Production and Pricing
Conclusions
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31. Economic Analysis Overview
Production of Microspheres
Raw Materials and Equipment Needed
Utility Maximization
Budget and Demand Constraints
Demand Model
Parameters within the model
Net Present Value
Optimal price of new drug delivery system
Comparing Values of Beta

32. Production of Microspheres
Emulsion-solvent extraction/evaporation
Most common method used to produce microspheres
Compatible with many common polymers
Most often used in drug delivery research studies

33. Production of Microspheres
Step One
Emulsification (stirring) of a solution containing polymer, drug, and a small amount of stabilizer
For PLGA polymers, ethyl acetate is used as a solvent and poly (vinyl alcohol) is a stabilizer
Homogenizer: $4,000
PLGA: $6/gram
Ethyl Acetate: $7/L
PVA: $100/kg
Drug: Vary ($92/g)

34. Production of Microspheres
Step Two
Solvent is extracted from the “continuous phase” and allowed to evaporate
This leaves the polymer-rich phase droplets that begin to harden
Extraction System: $1,700

35. Production of Microspheres
Step Three
Harden Microspheres are then filtered, washed and lyophilised (freeze dried)
This leaves only the desired polymer with encapsulated drug throughout
Lyophilizer: $5,000
Filters: $540/pkg of 5

36. Patient Utility Maximization
The patient will attempt to maximize their utility subject to their budget constraint
p1 is the price for the microsphere injections
p2 is the price for the daily oral medication
Y is the budget constraint for the market of interest
d1 is the demand for our delivery system
d2 is the demand for the existing delivery system

37. Budget and Demand Constraints
There are an estimated 14 million Americans that have problems with alcohol addiction
Only 5% of these Americans will seek treatment for their disability
The total demand for our market (D) should not be greater than 5% of 14 million or 700,000
The total amount of money spent on treatment programs for alcoholics in 1987 was approximately $1,700,000
This amount in 2008 is estimated to be $3,400,000

38. Demand Model
Used to determine number of units demanded at different prices
The Constant Elasticity of Substitution model with hedonic parameters was used for u
The market is contrained by the budget and the total demand of the market (D) is not binding
M. Bagajewicz. On the Role of Microeconomics, Multi-scale Planning and Finances in Product Design.

39. Demand Model Parameters
Alpha: A measure of how well the consumer knows the product
Our consumers are patients seeking treatment
This value will increase over time as patients gain more knowledge of the drug delivery system
Perfect knowledge of the product alpha = 1.0
Previous research has shown this trend is typical for new drugs entering the market*
*Clemente-Harl E and Martin, M Financial and Technological Risk Analysis for the Development of New Drugs [Report] : Undergraduate Capstone Paper / CBME ; University of Oklahoma. - Norman : [s.n.], 2006

40. Demand Model Parameters
β: Describes how much a consumer will prefer one product over another
At a time of 30 days, the proportion of the sample NOT relapsing was found to be approximately 0.29
This value corresponds to a rating of 0.09 on a utility graph.
H. Roozen, R. Waart, W. Brink. Efficacy and Tolerability of Naltrexone in the Treatment of Alcohol Dependence: Oral versus Injectable Delivery.

41. Demand Model Parameters
Two factors (Proportion NOT Relapsing and Convenience) were used to determine the beta value
The value of β was determined to be 0.72
This means the microsphere delivery will be preferred 1.4 times more than the daily oral pill delivery system

42. Demand Model Market Budget Constraint (Y) = 3.4 million
Price of Pill Delivery System (P2) = $150
Alpha increases over time from a value of
0.14 to 0.91 over a five year time period
These graphs show the amounts demanded over a five year time period for varying prices.

43. Net Present Value
A positive Net Present Value (NPV) indicates that the process is profitable
NPV was calculated for different prices and was used to determine the optimal price of our delivery system

44. Net Present Value
Between years 5 and 6 of production, the $75 price overtakes the $50 price in NPV
Increasing the price during year 5 will produce a higher total NPV
Over a 10 year production life the NPV for the $50 and $75 price are 42.6 and 42.9 million, respectively

45. Comparing β Values The value of β affects NPV more as price increases
Ideally, we would like to have the lowest possible value of beta
The lower the value of β, the higher the total NPV over the production life
Consumers will prefer our drug deliver system (extended release injection) more than the competition (daily oral pill)

46. Economic Conclusions Microsphere production IS a profitable investment
An initial price of $50 then a price increase to $75 during the fifth year of production will produce the greatest Net Present Value
Holding the patent for a new drug and delivery system will create a more monopolistic market
The microsphere manufacture could increase the price beyond the $75 optimal price
Other considerations such as pharmaceutical market structure, additional beta factors and insurance plans should be investigated

47. Acknowledgements
Sam Noor
Rufei Lu
Warren Yates
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