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Copy of INVEGA® SUSTENNA® paliperidone palmitate

Pharmaceutics-Group 1.1
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Katarzyna Rajska

on 1 August 2014

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Transcript of Copy of INVEGA® SUSTENNA® paliperidone palmitate

INVEGA® SUSTENNA®
paliperidone palmitate

Introduced initially as
paliperidone
extended release tablets (Invega®)
-Single daily dosing
-> poor patient adherence-> symptom exacerbation and increased risk of emergency room visits, hospitalisation, relapse and suicide attempts


Need for controlled, extended drug release delivery systems and sustained drug plasma/tissue levels



Paliperidone palmitate
(Invega® Sustenna®)
Manufactured by esterification of paliperidone with palmitic acid
Intramuscular Injection (given every 4 weeks)
-Modified Release Aqueous Suspension (25, 50, 75, 100 and 150mg)

WHY?
Extreme low solubility of paliperidone palmitate that allows formulation of this compound as a long acting product
.



What is INVEGA® SUSTENNA® used for?
It is an antipsychotic drug
To treat the symptoms of
schizophrenia

It works by restoring the chemical imbalance in the brain associated with this condition

Pharmalogical:
Anti-psychotics:
Treat the symptoms of schizophrenia

Non-Pharmalogical:
Psychosocial therapy
counseling with trained therapist

Treatment
Current Treatments
Production of INVEGA® SUSTENNA® using
NanoCrystal™ Technology
Pathophysiology of Schizophernia
The cause is unknown but studies show that schizophrenia may be caused by a
chemical imbalance
in the brain
Dopamine hypothesis
(abnormal levels in the brain)
Other neurotransmitters that play a role include ; glutamate, serotonin , gamma-aminobutyric acid.

Experts claim it may be hereditary related, genetic , environmental and structural or even absence of key genes.

What is Schizophernia?
Severe, chronic and disabling mental illness

Diagnosis is based on clinical symptoms:
Positive symptoms:

Extra feelings or behaviours that are not usually present
Hallucinations
Delusions
Negative symptoms:

A lack of behaviours or feeling that are usually present.

Social withdrawal
Lack of pleasure
Lack of interest
Cognitive symptoms:
Trouble focusing or paying attention
Poor executive function
Problems with working memory
1. paliperidone palmitate -------> paliperidone + palmitic acid

2.

Paliperidone
then travels through the systemic circulation where it
enters the brain via the BBB
3.

Paliperidone
is a substrate for the
P-glycoprotein receptor
, inhibiting its
function.
-> Inhibition leads to an inoperable transport
system, hence allowing the influx of the drug through
the BBB

4 .
Acts as an antagonist on
D2
and
5HT2A receptors
.

INVEGA® SUSTENNA®
Mechanism of Action
NanoCrystal™ Technology

(
Pearl /wet ball milling
)
Nanocrystallization is a technique used to reduce crystalline particles of poorly soluble drugs in the nanometer range.

Objective:
Attain adequate bioavailability of poorly soluble drugs by
surface area
of particles


saturation
solubility of a drug

dissolution rate
of drug particles

Materials used in Pearl/wet bead milling
Paliperidone palmitate:

white crystalline powder contains a racemic
mixture of (+)- and (-)- paliperidone palmitate
PolyMill™ media:

polysterene beads with a diameter of about 0.5 mm
Water
Excipients:
GRAS (Generally regarded as safe) stabiliser:
Polysorbate 20

Due to the high surface energy generated by nanonization, surface stabilizers are needed to establish a steric barrier against
aggregation and precipitation of nanocrystals.

Suspending agent:

Macrogol

(polyethylene glycol)
4000


Chelating agent:

Citric acid

(citric acid monohydrate)
to inhibit the oxidation of the Macrogol

Buffering agent:

Disodium hydrogen phosphate anhydrous

buffers the solution to pH 7.0

Schematic diagram & outline of the nanosizing process using NanoCrystal™ (Pearl/wet milling) technology
Final product is a sterile, isotonic,
aqueous suspension for intramuscular injection


The medication is contained in an assembled, plastic, pre-filled syringe (with plunger rod)

Primary packaging
A kit containing INVEGA
®
SUSTENNA
®
pre-filled syringe and two syringe needles: a 1 ½-inch 22 gauge needle and a 1-inch 23 gauge needle, for gluteal and deltoid administration, respectively.

Secondary packaging
The whole kit is contained inside the
paper carton box, identified by the dosage concentration.

Tertiary packaging
Administration
Note:
When switching from a different long-acting injectable
Invega® Sustenna® is given when next dose is due, as the maintenance dose (in this case the doses of day 1 & 8 are omitted)



Counseling points
Future advancements
Commercial packaging
UTS PHARMACY: Pharmaceutics 96003 Group 1.1
Side effects
Contraindications
For a
dults
(established tolerability with oral paliperidone or risperidone)

Renal impaired patients
Not recommended in patients with moderate or severe kidney function impairment (CrCl <50ml/minute)
For patients with mild kidney function impairment (CrCl 50-80ml/minute)


Invega® Sustenna® is a second generation atypical anti-psychotic.
Risperidone vs. Paliperidone palmitate
Paliperidone ER vs. Paliperidone palmitate IM
Ester hydrolysis
by muscle esterases
Pharmacokinetics
Outline
Schizophrenia and available treatments
INVEGA® SUSTENNA®
Manufacturing of INVEGA® SUSTENNA®
Commercial packaging
Administration
Side effects & counseling
Future advancements
Off-label uses
Therapeutic Goods Administration 2010,
Australian Public Assessment Report for Paliperidone palmitate
, Department of Health and Ageing, Canberra


1. Merisko-Liversidge, E & Liversidge, G. G, 2011, ‘Nanosizing for oral and parenteral drug delivery: A perspective on formulating poorly-water soluble compounds using wet media milling technology’,
Advance Drug Delivery Reviews
, vol. 63, pp. 427-440
2. Sun, B & Yeo, Y. 2012, ‘Nanocrystals for the parenteral delivery of poorly water-soluble drugs’,
Current Opinion in Solid State and Materials Science
, vol. 16,pp. 295-301



NanoCrystal Technology™, 2006, Drug Nanocrystals, viewed 27th April 2014, <http://www.nanopharmaceuticals.org/NanoCrystals.html>

1
2
2
Kesisoglou, F., Panmai, S., Wu, Y., 2007, ‘Nanosizing –oral formulation development and biopharmaceutical evaluation’,
Advance Drug Delivery Reviews,
vol. 59, pp. 631–644.
Möschwitzer, J. P. 2013, ‘Drug nanocrystals in the commercial pharmaceutical development process’,
International Journal of Pharmaceutics,
vol. 453, pp. 142-156

NanoCrystal Technology™, 2006, Drug Nanocrystals, viewed 27th April 2014,
<http://www.nanopharmaceuticals.org/NanoCrystals.html>

Modified
from Merisko-Liversidge, E & Liversidge, G. G, 2011, ‘Nanosizing for oral and parenteral drug delivery: A perspective on formulating poorly-water soluble compounds using wet media milling technology’,
Advance Drug Delivery Reviews
, vol. 63, pp. 427-440


Affect mental alertness and/or coordination
Can
impair psychomotor function
& ability to
drive
a car or carry out other tasks requiring alertnes
s
Alcohol
may cause additive CNS depressant effects

Orthostatic hypotension
Avoid quick standing and sitting movement
In the morning sit on the edge of the bed for couple of
minutes before standing up


 Australian Pregnancy Category C
3rd trimester exposure
—> Extrapyramidal symptoms
Utero Exposure of Neonates
—> Hypertonia and Hypotonia
—> Tremor
—> Somnolence
—> Respiratory distress and feeding disorder
In vivo
studies
—> Excretion in the milk
Not recommended for children <18 year old
Pregnancy and Nursing mothers
➡ Depression
Obsessive-compulsive disorder (OCD)
Post-traumatic stress disorder (PTSD)
Personality disorders
Tourette’s syndrome
Autism
Agitation in dementia
- Increased mortality elderly patients
􂀛->Total 3.1 Million Invega® Prescriptions & 431,000 patients
􂀛-> 334,000 paediatric prescription 0 - 16 yr old
􂀛 ->No of patients aged >17 received Invega® ↓ 13%
􂀛 ->No of patients aged 0-16 received Invega® ↑ 10%

Performance Enhancement
-> Controlled surface modification of the drug nano particles
-> Use of specific surfactants or polymeric stabilisers
-> E.g. folate-chitosan (FA - CS)

MW of Paliperidone palmitate
-> 664 g/molm, slightly larger than 500
Li, L., Y. Liu, J. Wang, L. Chen, W. Zhang and X. Yan (2014). "Preparation, in vitro and in vivo evaluation of bexarotene nanocrystals with surface modification by folate-chitosan conjugates."
Drug Delivery,
(Ahead of print, pages 1-9)
Kusum Mistry, P. D. (2012).
Drug Utilization Review
. D. o. H. a. H. S. P. H. Service. United States.
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Off-Label Use of Atypical Antipsychotics: An Update".
Retrieved 3/05/2012, from http://effectivehealthcare.ahrq.gov/ ehc/products/150/778/CER43_Off-LabelAntipsychotics_20110928.pdf.
Markowitz, M., D. J. Fu, B. Levitan, S. Gopal, I. Turkoz and L. Alphs (2013). "Long-acting injectable paliperidone palmitate versus oral paliperidone extended release: a comparative analysis from two placebo-controlled relapse prevention studies." Ann Gen Psychiatry 12(1): 22.
Clinical trial tables : Markowitz, M., D. J. Fu, B. Levitan, S. Gopal, I. Turkoz and L. Alphs (2013). "Long-acting injectable paliperidone palmitate versus oral paliperidone extended release: a comparative analysis from two placebo-controlled relapse prevention studies."
Ann Gen Psychiatry
12(1): 22.
Aravagiri, M. and S. R. Marder (2002). "Brain, plasma and tissue pharmacokinetics of risperidone and 9-hydroxyrisperidone after separate oral administration to rats."
Psychopharmacology
(Berl) 159(4): 424-431.
Cleton, A., S. Rossenu, H. Crauwels, J. Berwaerts, D. Hough, S. Gopal, M. Eerdekens, A. Vandebosch, B. Remmerie, M. De Meulder and C. M. Fernandez (2014). "A Single-Dose, Open-Label, Parallel, Randomized, Dose-Proportionality Study of Paliperidone After Intramuscular Injections of Paliperidone Palmitate in the Deltoid or Gluteal Muscle in Patients With Schizophrenia."
J Clin Pharmacol.
Hunter, J. (2008). "Intramuscular injection techniques."
Nurs Stand
22(24): 35-40.
Samtani, M. N., A. Vermeulen and K. Stuyckens (2009). "Population pharmacokinetics of intramuscular paliperidone palmitate in patients with schizophrenia: a novel once-monthly, long-acting formulation of an atypical antipsychotic."
Clin Pharmacokinet
48(9): 585-600.

Janssen-Ortho Inc 2010, Summary Basis Of Decision (SBD) Invega Sustenna, Health Canada, Canada, viewed 20th April 2014, <http://www.hc-sc.gc.ca/dhp-mps/prodpharma/sbd-smd/drugmed/sbd_smd_2010_invega_sustenna_127385-eng.php#a3.3.1>

U.S Department of Health & Human Services 2013, Agency for Healthcare Research and Quality, viewed 18th April 2014, <http://effectivehealthcare.ahrq.gov/index.cfm/search-for-guides-reviews-and-reports/?productid=1458&pageaction=displayproduct>
WebMD 2005, Mental Health Centre, Schizophrenia Medications, viewed 18th April 2014, < http://www.webmd.com/schizophrenia/guide/schizophrenia-medications>.

Janssen-Ortho Inc 2010, Summary Basis Of Decision (SBD) Invega Sustenna, Health Canada, Canada, viewed 20th April 2014, <http://www.hc-sc.gc.ca/dhp-mps/prodpharma/sbd-smd/drugmed/sbd_smd_2010_invega_sustenna_127385-eng.php#a3.3.1>
Psychopharmacology Institute, 2014,
First verses Second Generation Antipsychotics,
viewed 1st May 2014, <http://psychopharmacologyinstitute.com/antipsychotics-videos/first-second-generation-antipsychotics/>

Zhu, H. J., J. S. Wang, J. S. Markowitz, J. L. Donovan, B. B. Gibson and C. L. DeVane (2007). "Risperidone and paliperidone inhibit p-glycoprotein activity in vitro." Neuropsychopharmacology 32(4): 757-764.
Therapeutic Goods Administration 2010, Australian Public Assessment Report for Paliperidone palmitate,
Department of Health and Ageing, Canberra


MIMS 2014,
Invega Sustenna
, viewed 18th April 2014, Australia, <http://www.google.com.au/urlsa=i&rct=j&q=&esrc=s&source=images&cd=&cad=rja&uact=8&docid=M2vIHPymcp50TM&tbnid=QzeQ3NIIfB09M:&ved=0CAUQjRw&url=http%3A%2F%2Fwww.mims.com%2Fthailand%2Fdrug%2Finfo%2FInvega%2520Susten%2F&ei=ac9sU7TkF4jOkQWI34CIDg&bvm=bv.66330100,d.dGI&psig=AFQjCNEsP4rjxCV80leJGdkaO-RFr Z_2A&ust=1399725896640633>
MIMS 2014,
Invega Sustenna
, viewed 18th April 2014, Australia, <http://www.google.com.au/urlsa=i&rct=j&q=&esrc=s&source=images&cd=&cad=rja&uact=8&docid=M2vIHPymcp50TM&tbnid=QzeQ3NIIfB09M:&ved=0CAUQjRw&url=http%3A%2F%2Fwww.mims.com%2Fthailand%2Fdrug%2Finfo%2FInvega%2520Susten%2F&ei=ac9sU7TkF4jOkQWI34CIDg&bvm=bv.66330100,d.dGI&psig=AFQjCNEsP4rjxCV80leJGdkaO-RFr Z_2A&ust=1399725896640633>
Modified from: Osherovich, L. 2009. “Cover Story- Drug Platforms: Beating the brain’s bouncer”,
Science-Business eXchange
, Vol. 2, Issue 19, pg. 1-3
Janssen Pharmaceuticals, Inc. 2014,
INVEGA® SUSTENNA®

Product Information
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INVEGA® SUSTENNA® Product Information
, Invega Sustenna, viewed 25 April 2014, <http://www.invegasustenna.com/important-product-information>
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INVEGA® SUSTENNA®

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INVEGA® SUSTENNA®

Product Information
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Full transcript