long-acting injectable medications: strategies and ... · “long-acting injectable medications:...

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2016 Drug Design and Delivery Symposium “Long-Acting Injectable Medications: Strategies and Mechanistic Considerations ”

The 2016 DDDS is co-produced with ACS Division of Medicinal Chemistry and the AAPS

Julius Remenar Research Fellow,

Alkermes

Annette Bak Director, Merck Research

Laboratories

© 2016 Alkermes. All rights reserved.


Long-Acting Injectable Medications: Strategies and Mechanistic Considerations

Jules Remenar

ACS Webinar Series

FEBRUARY 25, 2016

2/24/2016

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What is a Long-Acting Injectable (LAI) medication?

Benefits/Risks

Snapshot of LAI technologies

History of LAIs

− Antipsychotics

13

Topics: Background


Molecular Level: Prodrugs to Reduce Solubility

− Traditional esters and LinkeRx®

Materials Level: Physical Barriers to Exposure

− Solutions in oil

− Low solubility crystalline salts

− Polymers (PLGA)

− Particle size

Physiological Level: Foreign Body Response

− pH changes in response to injection

− Immune response and angiogenesis

14

Topics: Strategies and Mechanisms

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A drug/formulation that

forms a depot when

injected into the body

Drug is released slowly

over ≥1 week (up to six

months)

Subcutaneous (sc) and

Intramuscular (im) are

most common sites

15

What is a Long-Acting Injectable?


Oral: Molecule must dissolve within hours

LAI: Release the molecule slowly over weeks

− Reduce aqueous solubility and dissolution rate, and/or

− Use formulation as barrier to escape

16

Typically, an Oral Drug is Converted to an LAI

Remenar J., Mol. Pharmaceutics 2014, 11, 1739.

Pla

sm

a C

on

ce

ntr

ati

on

Time

Tools

Crystals Oils

Prodrugs

Polymers Oral

(Days) (Weeks)

Long-acting

injection

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There are many areas where adherence can be a problem,

especially when consequences are delayed

− Antibiotic resistance, drug/alcohol addiction, HIV therapy,

schizophrenia, depression, etc.

17

Benefit: Adherence

Skip Doses

Stop Taking

Take as Directed

Adapted from

Kaplan, G. et al. Patient Preference and Adherence 2013, 1171

Schizophrenia patients don't always

take their oral medication


LAIs cannot be easily removed after dosing

− Best if patients have already taken a short-acting oral version and

show no adverse events

− Example: penicillin allergies

“Dose dumping” = sudden unexpected release of drug

− Very rare

− Low solubility molecules are less susceptible than strategies using

materials to control release of a soluble molecule

− Some medications don’t have serious liabilities even when overdosed

Risks 18

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Oil solutions Polymeric barriers Crystalline,

water-insoluble

suspensions

Overview of LAI Technologies

In situ

forming gels

Microspheres

Powder for

suspension

Suspension

in vial

Pre-filled

syringe

19


History of LAI Antipsychotics (U.S.)

Number of LAIA drugs on the U.S. market

based on delivery strategy

Reduced solubility

+ “physical barrier”

Physical barrier

Reduced solubility

Remenar J., Mol. Pharmaceutics 2014, 11, 1739.

7

6

5

4

3

2

1

0

Cum

ula

tive LA

IAs o

n the U

.S.

mark

et

1960s 1970s 1980s 1990's 2003 2009 2013 2015

OLZ

APZ

PALI

RISP

HAL

FLP

AP-LAU

OLZ

APZ

PALI

RISP

HAL

FLP

OLZ

PALI

RISP

HAL

FLP

RISP

HAL

FLP

HAL

FLP

HAL

FLP FLP FLP

Aqueous suspensions of crystalline drug

Aqueous suspensions of microspheres

Solutions in sesame oil

20

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Audience Survey Question

Why have the LAI technologies used for antipsychotics changed over time?

ANSWER THE QUESTION ON BLUE SCREEN IN ONE MOMENT

• An evolution in formulation technology and thinking

• A desire to “Evergreen” existing compounds

• Changes in the properties of drug molecules

• All of the above

• None of the above


Molecular Level: Prodrugs to Reduce Solubility − Traditional esters and LinkeRx®

Materials Level: Physical Barriers to Exposure − Solutions in oil


− Microspheres

− Particle size

Physiological Level: Foreign Body Response − pH changes in response to injection


Reducing Aqueous Solubility/Dissolution Rate 22

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Ester Prodrugs are Commonly Used to Reduce

Aqueous Solubility

Oil Soluble

Prodrug

Water Soluble

Active

Esterases are ubiquitous throughout the body

23


Aripiprazole does not have an –OH

A reversible linker was added to the lactam nitrogen

Fatty acids can be attached to the linker –OH

Fatty acid tail is cleaved by esterases in the body

The linker is hydrolytically unstable at pH 7.4

ARISTADA®

Aripiprazole Lauroxil: 2-step Process to Activate 24

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Concept Behind Poorly Soluble Prodrugs as LAIs 25

Prodrug

in depot

Prodrug

in tissue

Drug

in tissue

Prodrug

in blood

Drug

in blood

Dissolution/

Partition C

on

vers

ion

Transfer

Tissue Plasma

Dissolution

Con

vers

ion

Transfer

Cle

av

ag

e Rate limiting step


Prodrugs Provide Options to Optimize 26

Rat Plasma Stability

Generally, tails shorter than

C10 cleave in <5 minutes

C14–C16, intermediate

cleavage times

− T1/2 <2 hours,

but >5 minutes

Parent molecule affects T1/2

0

25

50

75

100

125

150

175

200

2 4 6 8 10 12 14 16 18

Pro

dru

g T

1/2 (

min

)

Tail Length

APZ

5-CLEO

PIO

Behavior of Fatty Acid Prodrugs

for Three Different Actives

Longer tails cleave more slowly after dissolving

– Positive: reduce the rate of exposure after a “dose dump”

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Melting points vary with tail length

Haloperidol decanoate is always a liquid at room temp

− Too viscous to inject unless diluted in oil

Melting Points Change (unpredictably) With Tail Length

140

120

100

80

60

40

20

0

Meltin

g P

oin

t (

oC

)

20161284

Tail length

ARP

fatty_acid

HAL

Haloperidol Prodrugs

Aripiprazole Prodrugs

Pure fatty acid

27


Most likely explanation:

− C10 esters have higher affinity for the oil and less drive to enter water

28

Dosing Frequency Changes With Tail Length

0

1

2

3

4

Fluphenazine Perphenazine

C7

C10

Do

sin

g F

req

ue

ncy (

we

eks)

Shorter esters need to be dosed more frequently (C7 = enanthate)

2/24/2016

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Materials Level: Physical Barriers to Exposure − Solutions in oil


− Polymers (PLGA)

− Particle size



29

Reducing Aqueous Solubility/Dissolution Rate


Act as diluent and preferred home for drug

Viscous oils (sesame) resist spreading and can persist long

periods without being absorbed (t1/2 = 22 days in rabbits)

Surfactants help oil to spread and emulsify

The oils are taken up by the lymphatic system

If drug is too lipophilic to leave oil, it must wait for lymphatic

uptake of the oil droplets

Surfactant-like properties of the drugs help by

1. Allowing the oil to emulsify or spread to speed uptake by lymphatics

2. Increasing aqueous solubility to partition out of the oil

Materials Level: Oils

See “Remenar J., Mol. Pharmaceutics 2014, 11, 1739.” for original references to these statements.

30

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What could cause a low-solubility crystalline salt to quickly dissolve or change forms after injection?


• pH swings

• Competing counterions

• Diffusion of a water-soluble counterion out of the depot

• Any of the above

• None of the above


Requires salts with low solubility

− Large lipophilic counter-ions

− Bury the charge

Solubility sensitive to pH and competing counter-ions

Lack of control in the body

Materials Level: Salts as LAIs

ppt.

32

2/24/2016

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Salts as LAIs: Olanzapine Pamoate

Crystallizes as monohydrate of 1:1 salt

~58X higher in human plasma

Solubility in buffer

33


Materials Level: Polymeric Barriers: Microspheres

Microsphere suspension

Hypodermic needle

SC or IM

Dry Powder microspheres

+ Diluent

34

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2/24/2016

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Drug Release from Polymeric Microspheres

Initial Release (diffusion) Sustained Release (polymer erosion)

d d d

0

10

20

30

40

50

60

70

80

90

100

0 10 20 30 40 50

Days

Pol

ymer

Mw

(kD

)

0

20

40

60

80

100

120

% R

elea

se

Formulation: 37.1% loaded 75:25 PLG 91.6kD

35


Physical Barriers: Gelling Formulations

Leuprolide acetate

30 mg API

258 mg NMP

211 mg PLGA co-polymer with hexanediol

Inject once every 6 months to reduce

testosterone levels

Source: Product label

Se

rum

co

nce

ntr

atio

n

Time (months)

API concentration

Testosterone concentration

36

2/24/2016

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PS 50% um

Specific Surface

Area m2/g Cmax (ng/mL) Tmax (days) AUC0-t (ng.h/ml)

6.03 1.3 41.2 (± 22.1) 12 (± 5) 19487 (± 7697)

1.38 6.5 86.4 (± 30.5) 7 (± 3) 25769 (± 9782)

0.74 13.5 139 (± 33) 1.8 (± 1.5) 28603 (± 4305)

0.52 >15 132 (± 60) 6.3 (± 1.5) 34852 (± 14055)

Materials Level: Particle Size

Particle size/Surface area and PK for

Paliperidone palmitate i.m. suspensions in dogs

Smaller particles = more surface area + higher/faster

exposure in general

Complex – tables don’t give a realistic picture

PS has to be controlled in any LAI suspension

37



Materials Level: Physical Barriers to Exposure − Low solubility crystalline salts

− Solutions in oil

− Microspheres

− Particle size



38

Reducing Aqueous Solubility/Dissolution Rate

2/24/2016

20

39


How does local pH of tissue when damaged?


• It doesn’t. The body is well buffered.

• Increase up to pH 8

• Decrease as low as pH 6.5

• Any of the above

• Decrease as low as pH 4.5


Slow initial dissolution rate

Release accelerates over 5-10 days

40 Low-Solubility Crystals can show

Lag Phase Behavior

• 21% of Cmax reached in 24 hrs

• Release slows for several days, then increases

Paliperidone palmitate (Rat PK data)

N. Darville, et al., Pharmaceutics, Drug Deliv., and Pharm. Technology, 2014

2/24/2016

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The immune system responds to foreign materials − There are commonalities and differences in the response to different materials

Immune Response/Encapsulation

Aripiprazole monohydrate Olanzapine pamoate

1d 1d 7d 7d

21d 21d 14d 14d

S.M.Paquette, Pharm Res. 2014

41


The typical signs of acute inflammatory response are observed:

− Mild hemorrhage, muscle damage, vascular edema, recruitment of leukocytes

Large volume of liquid means full release potential of the crystals can be

achieved during this 24 hour period − Formulation and particle size effects dominate release in this stage

42

0-24 Hours Post Injection


2/24/2016

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“A marked inflammatory cell layer…consisting of macrophages

from vascular origins surrounded the entire remaining formulation”

Main driving force is presence of foreign materials

24-48 Hours Post Injection 43



Radial angiogenesis of new capillaries into depot

Infiltration of macrophages

Uptake of crystalline drug into macrophages

− (for particles 0.2-5 um)

pH can drop in macrophages, and they also express esterases

Hypothesized that the macrophages themselves act as a source

of sustained release

2-7 Days Post Injection 44


2/24/2016

23


Beyond Day 7: Long Steady Release is possible 45

What can a long term human profile look like after repeat dosing?


ARISTADA™: PK Profile at Steady State with

Monthly Administration 46

Monthly Injection

2/24/2016

24


ARISTADA™:

Levels maintained following missed dose 47


Limited excipients

Needles: Viscosity and potential for clogging

Sterility

Solid for dispersion or pre-made suspension

Patents, etc.

New technologies offer new opportunities

48

Practical Issues

2/24/2016

25


Long-acting injectables are most useful in diseases where adherence to therapy is important

Daily oral therapies are converted to LAIs by reducing their

solubility and/or dissolution rate

− Prodrugs

− Physical barriers such as oils or polymers

− Low solubility crystal forms (including salts)

− Particle size

Physiological response influences release rate

− Formulation and particle size have largest impact on first day release

Low aqueous solubility is essential but there is no correlation

that says “if solubility = X, then release will take Y weeks”

Lessons Learned 49



50

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Alkermes


Laboratories

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long-acting injectable medications: strategies and ... · “long-acting injectable medications:...

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