Extended drug delivery through Thermosensitive Naltrexone HCl for the treatment of Drug addiction.

1. Design and Development Of
Thermoresponsive Hydrogel Of
Naltrexone HCl Injectable Formulation-
Pharmacotherapy For Drug Abuse
Prepared By-
Harshit Joshi
1

2. • Hydrogels
• Natural Vs. synthetic hydrogels
• Advantages & disadvantages
• Types of hydrogels
• Drug release mechanism
• Explanation of the LCST
• Method of preparations
• Characterization of hydrogels
• Common uses
• Application of the hydrogels
• Drug abuse treatment
• Alcoholism treatment
• Naltrexone HCl drug
information
• Formulations available in the
market
• Proposed hypothesis
• Plan of work
• Clinical trial reports
2
List of contents

3. Hydrogels
 Hydrophilic polymeric networks that can
absorb water without dissolving.
 Can be composed of natural or synthetic
polymers.
 First suggested for use in biomedical
applications in 1960.
Injectable, mixed natural-synthetic polymer hydrogels with modular properties.
Patenaude M, Hoare T.
Author information- Department of Chemical Engineering, McMaster University, 1280 Main
Street West, Hamilton, Ontario, Canada L8S 4L7 3

4. HYDROGELS
Ahmed Enas M, Aggor Fatma S, Awad Ahmed M, El-Aref Ahmed T. An innovative
method for preparation of nanometal hydroxide superabsorbent hydrogel.
Carbohydr Polym 2013;91:693–8. 4

5. Natural vs. Synthetic Hydrogels
Natural
– Most closely resemble the
tissues they are meant to
replace
– Almost always
biocompatible
– Biodegradable
– Difficult to isolate from
biological tissues
– Restricted versatility
Synthetic
– Can be reliably produced
– Greater control over
polymer structure
– May not be biocompatible
– Not always biodegradable
– Use of toxic reagents a
problem
5

6. Hydrogels
• Advantages
– Aqueous environment for
cells
– Porous to allow for
nutrient transport
– Easily modified
– Usually biocompatible
• Disadvantages
– Hard to handle
– Physically weak
– Difficult to sterilize
6

7. Types of Hydrogels
Classification : On the basis of-
 Method of preparation
Homo-polymer,
Copolymer,
Multi-polymer,
Interpenetrating polymeric
 Ionic charge
Neutral,
Catatonic,
Anionic,
Ampholytic
 Physical structure
Amorphous,
Semi-crystalline,
Hydrogen-bonded
Maolin Z, Jun L, Min Y, Hongfei H. The swelling behaviour of radiation prepared semi-
interpenetrating polymer networks composed of polyNIPAAm and hydrophilic polymers.
Radiat Phys Chem 2000;58:397–400.
7

8. Preparation of Hydrogels
8

9. Method Of Preparation Of Hydrogels:
Crosslinking
Isostatic Ultra High Pressure
Nucleophilic Substitution Reaction
Using Gelling Agents
Use Of Irradiation
Freeze Thawing 9

10. Linear polymers
Crosslinking
Chemical
compounds
Irradiation
Monomers used in the preparation of the
ionic polymer network contain an ionizable
group, gets ionized, or undergoes
substitution after the polymerization is
completed.
10
By using Cross Linkers:

11. By using Cross Linkers:
Purpose
 To impart sufficient mechanical
strength to these polymers
Examples
 Cross linkers prevent burst release of
the medicaments.
 Glutaraldehyde, Calcium chloride
Presence of residue.
Advantage
Drawbacks
11

12. Drug release mechanism
Diffusion Controlled Release Systems :
-Reservoir devices.
-Matrices devices
Swelling Controlled Release Systems
Chemically Controlled Release Systems
Stimuli-sensitive Swelling-controlled Release Systems :
-pH-Sensitive Hydrogels
-Temperature-sensitive Hydrogels:
-Other Stimuli-sensitive Hydrogels:
http://www.sid.ir/en/VEWSSID/J_pdf/81320090106.pdf 12

13. Explanation of the LCST
• LCST = Lower Critical
Solution Temperature
• The temperature at which a
phase transition occurs from
a solution to a gel.
• Phase transition -interaction
between polymer chain &
solvent molecule at shrunken
and swollen state.
Gel + Water
Solution
Weight fraction solute
T
(1.) https://en.wikipedia.org/wiki/Lower_critical_solution_temperature
(2.) "IUPAC Compendium of Chemical Terminology". Retrieved 2009-03-05
13

14. Morphology
• Indicative of their porous structure.
Swelling
Property
• Determines the release mechanism of the drug from the
swollen polymeric mass.
Elasticity
• Affects the mechanical strength of the network.
• Determines the stability of drug carriers
Characterization Of Hydrogels:
14

15. Atomic Force Microscope
Atomic Force Microscopy (AFM):
A Multimode Atomic Force Microscope form Digital
Instrument is used to study the surface morphology of
the hydrogels.
15

16. Used to understand whether the
polymers retain their crystalline
structure or they get deformed
during the pressurization process.
X-ray Diffraction:
16

17. FTIR (Fourier Transform Infrared Spectroscopy)
Any change in the morphology of
Hydrogels changes their IR absorption
spectra.
Formation of coil or helix which is
indicative of cross linking is evident by
appearance of bands near 1648 cm-1 .
FTIR
17

18. Rheology:
Hydrogels are evaluated for
viscosity under constant
temperature (4°C) by using
Cone Plate viscometer.
Cone plate viscometer
18

19. Swelling Behavior:
The Hydrogels are allowed to immerse in aqueous
medium or medium of specific pH to know their
swellability of these polymeric networks.
These polymers show increase in dimensions
related to swelling.
19

20. Swelling Behavior:
The SD was calculated as follows:
W0 = Weight of the original Hydrogel
Wt = is the weight of hydrogel at various
swelling times
SD (%)= (Wt/Wo)×100
Picture of a
swollen
Hydrogel 20

21. In-vitro Release Study For Drugs:
Since Hydrogels are the swollen polymeric
networks, interior of which is occupied by drug
molecules, therefore, release studies are carried out
to understand the mechanism of release over a
period of application
21

22. In-vitro Release Study For Drugs:
Dissolution media:
Buffer solution with various pH values.
R.P.M: 90 rpm.
Temperature : 370C.
Sink condition is maintained by replacing the buffer
periodically.
22

23. Common Uses For Hydrogels:
MISCELLANEOUS
• Used as Medical electrodes in ECG.
• Used as Breast implants.
BIOTECHNOLOGY
• Used as Biosensors that are responsive to specific
molecules, such as glucose or antigens.
SANITARY
PURPOSE
• Used in disposable diapers.
23

24. Applications of Hydrogels in Drug Delivery
- Diffusion controlled Drug Delivery
(1) Polymer matrix
Water-insoluble
Polymer matrices
(2) Reservoir system
time
Water-insoluble
Polymer membrane
time
24

25. Applications of Hydrogels in Drug Delivery
 Environment-Sensitive Hydrogels
• Respond to environmental change
: temperature, pH, specific molecule
• Reversible volume phase transition or sol-gel phase
transition are called an “Intelligent” or “smart” hydrogel.
Drug-loaded gel
Change in pH
for gel swelling
Drug release
through the
swollen
network
Drug release by
the squeezing
action
Change in
temperature for
gel collapse
25

26. Environmental
Factor
Typical polymers Main Mechanism Applications
Temperature PNIPAAm, PDEAAm, PEO-PPO
block copolymers
Competition between
hydrophobic interaction and
hydrogen bonding
On/off drug release,
squeezing device
pH Polyelectrolytes, PAA,
PDEAEM
Ionization of polymer chains
upon pH change
pH-dependent oral drug
delivery
Glucose pH-sensitive hydrogels;
Concanavalin A-grafted
polymers; polymers
containing phenylborate
groups
pH change caused by glucose
oxidase; reversible interaction
between glucose-containing
polymers and Concanavalin A;
reversible sol-gel transformation
Self-regulated insulin
delivery
Electric signal Polyelectrolytes (pH-sensitive) Reversible swelling & deswelling
in the presence of electric field
Actuator, artificial muscle,
on off drug release
Light Copolymer of PNIPAAm and
light sensitive chromophore,
such as triphenylmethane and
leuco derivatives
Temperature change via the
incorporated photosensitive
molecules; dissociation into ion
pairs by UV irradiation
Optical switches,
ophthalmic drug delivery
Antigen Semi-IPN with grafted
antibodies or antigens
Competition between polymer-
grafted antigen and free antigen
Modulated drug release in
the presence of a specific
antigen; sensor for
immunoassay and antigen
Environmental-Sensitive Hydrogels used for Drug Delivery
26

27. Pharmaceutical Applications Of Hydrogels:
Peroral Drug Delivery
Drug Delivery In the
Oral –Cavity
Drug Delivery in the
G.I.T
Ocular Delivery
Transdermal Delivery
Subcutaneous Drug
Delivery
Hydrogels To Fix Bone
Replacements
Tissue Engineering
Protein Drug Delivery
Topical Drug Delivery
27

28. Drug Abuse Treatment
Drug Abuse
Alcoholism
Naltrexone Disulfiram
Opioids
Opioid
antagonist
Naltrexone
28

29. Alcoholism Treatment
• Most of alcoholism treatments use a combination of psychological
means (such as CBT- Cognitive behavioral therapy (CBT) is a form of
psychotherapy. It was originally designed to treat depression, but is
now used for a number of mental illness. It works to solve current
problems and change unhelpful thinking and behaviour) in
combination with aversion therapy aided by drugs.
• Most drugs used in treating alcoholism are aimed at creating adverse
reaction to imbibing alcohol.
• Currently in the market, there are a limited number of drugs to treat
alcoholism.

30. Naltrexone
• Naltrexone is metabolized in the
liver into a variety of
metabolites, with the 6-β-
naltrexol being the metabolite
useful in treating alcoholism.
• The mechanism of action is not
quite fully understood.
• Approved for use in the
treatment of alcoholism in April
2006.
http://en.wikipedia.org/wiki/Naltrexone

31. Naltrexone
Proposed Mechanisms of Action
• After metabolizing into the 6-β-naltrexol, the
metabolite is believed to act as a competitive
antagonist at opioid receptors.
• It is because of this reaction that Naltrexone is
believed to interact with the dopaminergic
mesolimbic pathway, which is alcohol activates,
thereby causing pleasurable feelings.

32. Naltrexone Actions
• Naltrexone is aimed at reducing
the psychological need or craving
for alcohol.
• Naltrexone can be administered in
a 50 mg tablet with some
nauseating side effects.
• Various Naltrexone preparations,
administered by IM route, is also
available.
• Naltrexone has been shown to be
effective for up to 30 days.

33. Naltrexone Safety
• Naltrexone is considered a relatively safe drug for the treatment of
Alcoholism.
• Injectable naltrexone appears to be well tolerated.
• Like oral naltrexone, the injectable formulation carries a black-box
warning (A black box warning is the strictest warning put in the labeling
of prescription drugs or drug products by the Food and Drug
Administration (FDA) when there is reasonable evidence of an
association of a serious hazard with the drug) regarding liver toxicity .
• However, because of its lack of first-pass metabolism, injectable
naltrexone significantly reduces liver exposure to the drug, reducing the
risk of potential liver toxicity.

34. Formulations available in the market
Naltrexone HCl Tablet
Tablet
formulation
Limitations
-Nausea & vomiting
-IR dosage form
requires frequent
drug administration
-Patient non-
compliance
Vivitrol, Naltrel, and
Depotrex
(Naltrexone for extended-
release injectable suspension)
is supplied as a microsphere
formulation of naltrexone for
suspension, to be administered
by IM injection.
Limitations
-High cost of medication
-Complex manufacturing
-Stability issues with the
microsphere.
-Pain at the site of
injection
34
Other medications
Implants
Limitations
- Although prolong release
of medication but implants
involve surgical
interventions for
administration & removal.
- Patient non- compliance
- High cost of medication
- Hospitalization required.

35. 35
Formulations available in the market
Naltrexone HCl IR formulations
Naltrexone HCl ER formulations

36. Proposed hypothesis
• A Thermosensitive hydrogel shall be prepared for the
delivery of Naltrexone HCl for the treatment of drug abuse
and will be given subcutaneously that will act as a depot
system for its prolonged release.
36
Composition
Ingredients Uses
Naltrexone HCl Used in the treatment of drug abuse.
Pluronic f-68 Thermosensitive polymer used for
gelation.
TAbCD As a carrier & complex forming agent
with the hydrophilic drug thereby
controlling drug release.

37. Plan of work
• Review of literature
• Selection & procurement of drug & excipient
• Identification & characterization of Drug
 Identification
 Solubility determination
 Melting point determination
 Residue on ignition
 Water content
 Limit of total solvent
 Assay
 Drug- Excipient compatibility
37

38. • Post Formulation
 Appearance
 Viscosity
 Gelation time
• In vitro Drug release
 Effect of different temperature on drug release
 Effect of Pluronic F-68 concentration on drug release
 Effect of pH of polymeric solution on drug release
 Effect of inorganic salts on drug release
 Effect of complexation of Naltrexone with TAbCD
Plan of work
38

39. Clinical Trials
The status of naltrexone in the treatment of alcohol dependence:
specific effects on heavy drinking.
Pettinati HM1, O'Brien CP, Rabinowitz AR, Wortman SP, Oslin DW, Kampman KM,
Dackis CA.
Abstract
BACKGROUND:
In almost 2 decades of naltrexone research for treating alcoholism, there have
been 29 published randomized placebo-controlled trials of opioid antagonists,
primarily naltrexone, for the treatment of alcohol dependence. The present review
builds on prior systematic reviews while maximizing the number of included
studies to date, for the purpose of resolving inconsistencies in naltrexone's
reported efficacy across trials. Clinical trial results in this article are evaluated by
the type of outcome measure used to determine naltrexone's treatment advantage,
that is, measures related to reducing heavy drinking versus those related to
increasing abstinence.
39

40. Clinical Trials
Naltrexone vs Placebo for the Treatment of Alcohol Dependence: A
Randomized Clinical Trial.
Oslin DW1, Leong SH2, Lynch KG3, Berrettini W3, O'Brien CP3, Gordon AJ4, Rukstalis M5.
Abstract
IMPORTANCE:
Alcohol use disorder is one of the leading causes of disability worldwide.
While effective pharmacological treatments exist, they are efficacious only
in certain individuals, contributing to their limited use. Secondary analysis
of clinical trial data suggests that a functional polymorphism (rs1799971,
Asn40Asp) of the µ-opioid receptor gene (OPRM1) is associated with the
risk of relapse to heavy drinking following treatment with the opioid
antagonist naltrexone.
40

41. Clinical Trials
Naltrexone in alcohol dependence: a randomised controlled trial of
effectiveness in a standard clinical setting
Noeline C Latt, Stephen Jurd, Jennie Houseman and Sonia E Wutzke
Abstract
Objectives: To determine whether naltrexone is beneficial in the
treatment of alcohol dependence in the absence of obligatory
pyschosocial intervention.
ClinicalTrials.gov
A service of the U.S. National Institutes of Health
41

42. Included reports on treatment effects and
tolerability by various author and year of
publication
42

43. Included reports on treatment effects and
tolerability by various author and year of
publication
Naltrexone Depot Formulations for Opioid and Alcohol Dependence: A Systematic
Review Philipp P. Lobmaier, Nikolaj Kunøe,Michael Gossop & Helge Waal.
43