PowerPoint implantable drugs

1. IMPLANTABLE DRUGS

2. Contents
• Need for implantable drugs
• Classification
• Methods of development and materials used
• Mechanism of drug release
• Therapeutic uses

3. • Oral
• IV
• Transdermal
• Need for novel drug delivery
systems
To improve delivery of existing
drug compounds
To allow delivery of newly
discovered drugs with less than
ideal properties for oral drug
delivery
Optimize effectiveness and
tolerability of drug compounds
Simplifying their administration

4. • Designed to
Reduce the frequency of dosing
Prolong duration of action
Increase the patient compliance
Reduce the systemic side effects
• Release the incorporated drug in
a controlled manner
• Allowing the adjustment of
release rates over extended
periods of time ranging from
several days to years

5. History
• Deansby and Parkes (1938)
• Subcutaneously (SC) implanted compressed pellets of crystalline
estrone to study their effect upon castrated male chicken
• Folkman and Long (1960)
• Use of silicone rubber (Silastic) for long-term drug delivery at a
systemic level
• Norplant FDA approval in 1990
• Promus (evorolimus) element stent 2015
Revolutionized clinical management practices

6. • Ideal IDDS should be
Designed to substantially reduce the need for frequent drug
administration over the prescribed treatment duration
Environmentally stable, biocompatible, sterile
Readily implantable and retrievable by medical personnel to initiate
or terminate therapy
Enable rate-controlled drug release at an optimal dose
Easy to manufacture
Provide cost-effective therapy over the treatment duration

7. • Subcutaneous or intramuscular tissue
• High fat content that facilitates
Slow drug absorption
Minimal innervation
Good hemoperfusion
Lower possibility of localized inflammation (low reactivity to the
insertion of foreign materials)
• Special implantation devices, needles, or the use of surgery
Rods - most widely used design

8. • Other sites for implantation include:
Intravaginal
Intraocular
Intra-vesicular
Intra-tumoral
Intra vascular
Intrathecal
Peritoneal
Intracranial

9. Advantages
Localized delivery • Drug(s) are released in immediate vicinity of implant
• Action may be diffusion, limited to the specific location of implantation
Improved patient
compliance
• Patient does not need to comply with repeated and timely intake of
medication throughout the implantation period
• Compliance is limited to one-time implantation (and potential removal
in the case of non-biodegradable implants)
Minimized systemic
side effects
• Controlled release for extended periods of time
• Localized dosing possible
• Adverse effects away from site of action are minimized
• Peaks and valleys in plasma drug concentration from repeated
intermediate release dosing are avoided

10. Advantages
Lower dose • Localized implantation of site specific drugs can avoid first-
pass hepatic effects
• Reducing dose required to ensure systemic bioavailability
Improved drug stability • Protection of drug undergoing rapid degradation in the
gastrointestinal and hepatobiliary system
Suitability over direct
administration
• Hospital stay or continuous monitoring by healthcare staff
may not be required for chronic illnesses
Facile termination of drug
delivery
• If allergic or other adverse reaction to drug is experienced,
discontinuation of therapy by implant removal is possible

11. Disadvantages
• Invasive
• Danger of device failure
• Termination
• Limited to potent drugs
• Biocompatibility issues
• Possibility of adverse reactions (even though less)
• Commercial disadvantages
• Periodical refilling

12. Exclusions
• Dental, orthopedic, cardiovascular, and gastric implants
Heart valves
Bare-metal or non-resorbable stents
Dental and bone implants
Artificial joints
Sutures
Ocular lenses
• Microneedle – transdermal drug delivery system

13. Implantable Drug Delivery Device
Classification
1.Passive implants - Polymer depots
2. Active implants
Including Electrometalical systems
Passive can be
Non-biodegradable
implants
Biodegradable
Based on drug delivery method

14. Passive implants
• Relatively simple, homogenous and singular devices
• Simple packaging of drugs in a biocompatible material or matrix
• Do not contain any moving parts
• Depend on diffusion-mediated phenomenon / degradation to
modulate drug release
• Delivery kinetics are partially tunable Choice of drug
Concentration
Overall implant morphology
Matrix material
Surface properties

15. Non-Biodegradable Polymeric Implantable
Systems
• Passive diffusion
• Commonly prepared using polymers such as
Poly siloxanes (Silicones)
Poly urethanes
Poly acrylates
Copolymers such as poly ethyelene vinyl acetate
• Can be reservoir or monolithic (matrix-type system) type implant

16. Reservoir
• Implants contain a compact drug
core covered by a permeable
non-biodegradable membrane
• The membrane thickness and
the permeability of the drug
through the membrane will
govern the release kinetics
Monolithic
• Implants are made from a
polymer matrix in which the
drug is homogeneously
dispersed
• Release from these systems are
directly proportional to the
volume fraction of the
encapsulated drug within the
matrix

17. Examples
• Norplant
• contraceptive system
• Six thin, flexible silicone capsules
(silastic tubing)
• Each loaded with 36 mg of the
hormone levonorgestrel
• Implanted SC, typically on the
inside upper arm of female users
• Contraceptive protection for up
to 5 years
• Implanon
• Single-rod implant
• PEVA core (reservoir)
• 68 mg of etonogestrel
• Releases the drug over 3 years
• Rate of drug release is controlled
by a PEVA membrane covering
the rod
• Easier subcutaneous insertion
and removal than Norplant

18. DES
• Reduce restenosis
• Standard of care in the treatment of stenotic CAD
• Deployed for opening blockages and maintaining patency in a
coronary artery
• Three-component system
Scaffold (or stent) for ensuring vascular luminal patency
Matrix or coating (polymer) to control drug release
Drug to inhibit neo-intimal restenosis
• Release of drugs from these coatings is typically diffusion-controlled

19. • Vitrasert
• Treatment of cytomegalovirus (CMV) retinitis
• Releases ganciclovir
• Intravitreal implantation of a compressed tablet of the drug
• Tablet is coated with polyvinyl alcohol (PVA)
• Partially over-coated with PEVA
• Finally affixed to a PVA suture

20. Drawbacks of non-biodegradable implant
• Robust and structurally resilient over their intended lifetime
• After depleting their drug load, they need to be removed
• The materials used to prepare these devices can cause
Infections
Tissue damage
Cosmetic disfigurement

21. • How to overcome this?
• Shape and size
• Availability of specialized devices for easy implantation and extraction
• X-ray visible tracer material - for detection of the embedded implant
prior to extraction by imaging

22. Biodegradable Polymeric Implants
Developed to overcome drawbacks of non-
biodegradable implants
Brocken down in to safe metabolites
(degradation)
Subsequently absorbed or excreted by the
body

23. Biodegradable Polymers
• Poly lactic acid (PLA)
• Poly glycolic acid (PGA)
• Poly lactic-co-glycolic acid (PLGA)
• Poly caprolactone (PCL)
Most commonly used
biodegradable polymers for
biomedical applications
• Biocompatibility
• Mechanical strength
• Ease of formulation
Degradation periods for these polymers
range from one month to over six months

24. • Ideally, any chosen biodegradable polymer should be
Highly reproducible
Easily metabolized and excreted by physiological pathways
Degradable to non-toxic products
Free from an inflammatory response in vivo

25. • Examples
• Gliadel wafer (carmustine - brain tumors)
• Zoladex (goserelin - advanced prostate cancer and advanced breast
cancer)
• Profact or Suprefact Depot (buserelin - hormone-responsive cancers -
prostate cancer or breast cancer and in assisted reproduction)

26. Mechanism of Drug Release from Biodegradable
Implants
Hydrolysis Enzyme degradation
Oxidation
Physical degradation
Drug will be released at a
pre-determined rate as
the polymer degrades
Degradation of the
polymer and
subsequent drug release
may occur by

27. • Advantage
Do not need to be extracted
after implantation
Degraded completely by the
body of the patient
Increasing patient acceptance
and compliance
• Drawback
More complex to develop
Degradation kinetics is highly
variable in each patient
Lack of availability of polymers
with the exact physical
properties needed
Regulatory requirements are
stricter
Pre-approval of the
implant material

28. Dynamic or active implants
• Positive driving force to enable and control drug release
• Able to modulate drug doses and delivery rates much more precisely
than passive systems
• Higher cost - complexity and actual device price
• Implantable pump systems

29. Implantable pump systems
• External control of dosing
• Provide the higher precision
• Remote control needed in these situations
• Advantages
• Evasion of the GI tract
• Avoidance of repeated injections
• Improved release rates (faster than diffusion-limited systems)

30. • Implantable pumps primarily utilize
Osmosis (osmotic pumps)
Propellant-driven fluids (Propellant infusion pumps)
Electromechanical devices
to generate pressure gradients
enable controlled drug release

31. Osmotic pumps
• Drug reservoir surrounded by a semipermeable membrane
• Allows a steady inflow of surrounding fluids into the reservoir through
osmosis
• Hydrostatic pressure built on the drug reservoir
• Steady efflux of the drug then ensues via the drug portal, an opening
in the membrane
• Nearly constant or zero-order drug release is maintained until
complete depletion of the drug packaged in the reservoir

33. • Examples:
• The DUROS - leuprolide implant
• ALZET pump - opioid hydromorphone
• No “initial burst effect”
volume of drug that
they can release
limits them

34. Propellant infusion pumps
• Utilizes propellant gas instead of an osmotic agent
• Generate a constant positive pressure for zero-order release
• Use of a compressible medium (gas)
• Allows for a larger volume of drug to be stored and released
Example:-
• Infusaid - fully implantable fixed-rate pump
Utilized for insulin delivery, anticoagulant therapy, and cancer
chemotherapy

35. Electromechanical systems
• Osmotic and propellant-driven constant pressure pumps work well for
small volumes of medication
• Severe limitation for certain chronic diseases requiring daily infusion
of medication, precluding their use over long timespans.
• Larger implants
• Storage capacity of the pump may be replenished from time to time
• Pumping mechanisms stay implanted
• Electrically powered mechanical pumps, typically with moving parts
and advanced control systems

36. • Examples:-
• Medtronic Inc
Pain management using intrathecal delivery of opioids
Treatment of severe spasticity using baclofen

37. Implant manufacturing
• Implants can be manufactured using a variety of techniques including
Compression
Solvent casting
Hot melt extrusion (PLA, PGA and PLGA)
Injection moulding (PLA, PLGA)
3D printing (more recent)

38. • Manufacturing technique
• Polymer degradation - Drug release from the resulting implants
• Hot moulding and compression as techniques to make intra-ocular
implants
• Compressed implants showing an increased rate of drug release than
their moulded counterparts.

39. Current Therapeutic Applications
• Wide variety of clinical applications
Women’s health
Cardiovascular disease
Oncology
Ocular disease
Pain management
Infectious disease
Central nervous system disorders

40. Women’s health
• Large impact
• Use for contraception
• Norplant (1990) – first implantable contraceptive device to be
approved
• Implantable long acting contraceptives – most effective form of
contraception
• Annual pregnancy rate of less than 1% for women

41. Norplant® Jadelle® - Sub-cutaneous – Silicone - Levonorgestrel Contraception
Estring®- Intra-vaginal – Silicone – Estradiol - Menopausal symptoms
Nuvaring® - Intra-vaginal – PEVA - Etonogestrel, Ethinyl estradiol -
Contraception
Implanon® Nexplanon® - Sub-cutaneous – PEVA – Etonogestrel - Contraception

42. Cardiovascular disease
• DES

43. Oncology
• Systemic delivery of chemotherapeutic agents
• Often involves delivery of the agents at their maximum tolerated dose
• Severe side-effects (neutropenia and cardiomyopathy)
• Implantation of a drug delivery device close to the site of action may
allow
Reduced systemic exposure
Reduce the damage caused to healthy tissue

44. Zoladex® - Sub-cutaneous – PLGA – Goserelin - Prostate cancer
Prostap®SR - Sub-cutaneous – PLGA – Leuprolide - Prostate cancer
Gliadel/Wafers® - Intra-tumoral – Silicone – Carmustine - Primary malignant glioma
Oncogel® - Intra-tumoral - PLGA-PEG-PLGA – Paclitaxel - Oesophageal cancer
Vantas® - Sub-cutaneous - Methacrylate based hydrogel - Histrelin - Prostate Cancer
GemRIS® - Intra-vesical -ND – Gemcitabine - Non-muscle invasive Bladder Cancer

45. Ocular disease
• Challenges in ocular drug delivery
• Drug delivery to the posterior segment of the eye is difficult
• Poor drug permeation and poor drug retention in the eye
• Poor patient compliance
• Implantable drug delivery devices
• Challenges including: burst release, the possibility of dose dumping,
and low bioavailability

46. Ocusert® - Intra-ocular – PEVA - Pilocarpine, Alginic acid -
Open angle glaucoma
Retisert® - Intra-ocular - Microcrystalline cellulose, PVA,
Magnesium stearate – Fluocinolone - Non-infectious uveitis
Vitrasert® - Intra-ocular - PVA, PEVA – Ganciclovir - CMV
retinitis in AIDS patients

47. Pain management, infections & CNS disorders
Chronic pain - difficult to
treat - associated with a
high risk of addiction or
death from overdosing
• Use in infectious diseases (particular
tuberculosis)
• The treatment for TB is long - drugs used are
associated with side-effects
Poor patient compliance with the treatment
regimen
Treatment failure
Development of resistance
 Ensure patient compliance
 Completion of the treatment

48. • Poor patient compliance to antipsychotic therapy
• High risk of relapse, hospitalization and other negative
outcomes
• Parenteral administration of antipsychotics offers
advantages such as:
Increased bioavailability
Lower drug serum levels
Decreased variation in drug plasma levels
Use of a long-acting implantable drug delivery device - 100%
patient compliance

49. Pain
ND (Axxia Pharmaceuticals) - Sub-cutaneous - PU, PEG/PPG/ PTMEG –
Hydromorphine - Chronic neuropathic pain
LiRIS® - Intra-vesical – Silicone – Lidocaine - Interstitial cystitis/bladder pain
syndrome
Probuphine® - Sub-cutaneous – PEVA – Buprenorphine - Opioid abuse

50. Infectious Diseases
PLGA – Isoniazid - TB
PLGA - Isoniazid, Pyrazinamide - TB
CNS disorders
Med-Launch - Sub-cutaneous – PLGA – Risperidone – Schizophrenia
ND - Sub-cutaneous – PU – Risperidone – Schizophrenia
Risperdal consta® - Intra-muscular – PLGA – Risperidone - Schizophrenia

51. Challenges
• Biocompatibility-related issues
• Patient compliance
• Regulatory aspects
• Cost-effectiveness

52. References
• Implantable Drug-Delivery System - Perry J. Blackshear
• Implantable Polymeric Drug Delivery Devices: Classification,
Manufacture, Materials, and Clinical Applications:
Sarah A. Stewart , Juan Domínguez-Robles, Ryan F. Donnelly and Eneko
Larrañeta
• Implantable Drug Delivery System: A Review :
Mohammad Zaki AJ, Satish K. Patil, Dheeraj T. Baviskar, Dinesh K. Jain
• Implantable drug delivery systems: An overview:
Anoop Kumar and Jonathan Pillai

53. Summary

54. THANK YOU