intra tumoral drug delivery
DESCRIPTION
interstital chemotherapyTRANSCRIPT
INTERSTITAL CHEMOTHERAPY
A NOVEL INTRATUMORAL DRUG DELIVERY SYSTEM FOR SOLID TUMOURS
Dr. V.Lokesh M.D*, B.S.Praveen Kumar** ,
Dr.P.P.Bapsy, Dr. .K.P.R.Pramod
*Associate Professor, Department of Radiation Oncology
Kidwai Memorial Institute of Oncology
**Former Student, Govt College of Pharmacy, Bangalore
Introduction
administration of Chemotherapy – systemic chemotherapy : orally, Intravenously,
Subcutaneously, intramuscularly, or Intraosseously.
– Regional chemotherapy : Intrathecal, Intraarterial, or intracavitary administration including intraperitoneal, intrapleural and intravesical.
• steep dose response curve. • modest reductions in doses lead to substantial
reduction in tumor cell kill. • intensive therapy - assumption - close to a total
cell kill using present drugs, if a small additional log kill can be achieved we may obtain many more cures.
• based on Skipper Curve to the tumor stem cell population, as we approach total cell kill, the cure rate moves rapidly from very low to very high because it moves along a semilog curve.
Intratumoral Chemotherapy
Implantable polymeric devices• The polymer device is loaded with the desired
chemotherapeutic agent and then implanted within the tumor, surgically or by special implanting devices.
• Implantable polymeric systems utilize various types of polymers and polymeric membranes to control the release kinetics of drugs from the delivery systems.
• The implantable polymeric system can be further subdivided into two different classes:
Biodegradable systems. Non-biodegradable systems.
CHEMO-BRACHYTHERAPY DEVICES For solid tumors - Selected Cancer Chemotherapy drugs can be delivered similar to Radiation – Brachytherapy using. i) Interstitial Chemotherapy Devices ii) Intra Cavitary / Luminal Chemotherapy Devices These Chemo-drug delivery systems can be further grouped as a) Temporary(Removable) b) Permanent Implants The rate of drug delivery can further be controlled via various manipulation and grouped as 1. Delayed release 2. Sustained releasei. Controlled releaseii. Prolonged release The system of implant can be in the form of 1. Single Plane 2. Double Plane3. Volume implant The System for Intracavitary / Intraluminal a. Osmotic Systemsb. Ion Exchange resinsc. Reservoir / Matrix devices.
The potential advantages
a) Avoids patient compliance problems b) Employ less total drug
i. Minimize or eliminate systemic side effectsii. Minimize or eliminate local side effects
c) Minimize cumulative drug toxicities d) Improve control of condition, i.e., reduced fluctuations of drug level. e) Improve bioavailability
f) The problem of Drug resistance can be circumvented - cells that are resistant to a particular dose level of drug may be sensitive at higher level.
f) Economy g) Within the tumor tissue
i. Higher drug concentration can be achieved ii. Homogenous drug distribution
h) Improved radiosensitization for concurrent chemo-radiotherapy regimensi) Potential use in
i. Salvage Treatments for Post Radiotherapy failures ii. Unresectable and advanced primary disease
j) Potential dissemination of drug via lymphatic to the site of lymphatic emboli. k) In patients where systemic drug dose reduction is needed due to various restricting factors. l) Avoids interventional investigations required in Regional Chemotherapy, there by decreasing the patient
discomfort.
AIMS AND OBJECTIVES
1. To device newer Chemo Brachytherapy (intratumoral) drug delivery systems for Anti- cancer drugs
2. To study kinetics of such applications and design a sustained – release system to deliver drug at a rate necessary to achieve and maintain a constant anti-tumor drug level.
3. To study the feasibility of application in human subjects following Animal Experiments, Phase I to III Trials as indicated.
MATERIAL and METHODS
The development of the new drug delivery system requires systematic planning, experiments and in vitro / in vivo studies in the following order.
Step 1 : Structural Designing of Implantable Devices
Step 2 : Selection of Drugs Suitable for Implantable devices
Step 3 : Pharmaco kinetic evaluation of Drug Delivery System
Step 4 : Invitro and In vivo Experimental Studies
Step 5 : Human Clinical trials Phase I / II / III
Step 1
• In the form of Needles or Tubes containing
• These devices are proposed to be implanted into Solid tumors (Localized and Advanced). The implantation procedure is akin to implanting radioactive needles (Brachytherapy) in Single plane or Double plane or Volume implants depending on the volume of tumor to be treated.
The dimensions of the Needles and Tubes are varied as per requirements, for preliminary studies the Dimensions are
• a. Needles : Length 4 to 5cms x thickness 0.2 to 0.3 cms
• b. Tubes : Length 2 to 3cms x thickness 0.2 to 0.3 cms
• c. Capsules : Length 2 to 3cms x thickness 0.5 to 0.7 cms
Step 2
• CDDP
• Delivery System : Matrix - biodegradable
H3N
H3N
Cl
Cl
Pt
The ideal goal of a sustained release delivery system is to maintain a constant level of drug in target tissue. The release from the dosage form should follow zero-order kinetics
Molecular formula Cl2H6N2 Pt
Molecular weight 300.1
Normal state Crystalline solid
Colour Deep yellow (crystalline solid)
Clear (reconstituted solution)
Structure Tetragonal (square) Planar
Symmetry C2V
UV absorption In 0.1 N HCl max = 301 + 2nm,
Water
< 1 mg /ml at 190 C
= 2.53 mg/ ml at 250 C
Saline solution = 1mg / ml at 190 C
95 % ethanol < 1 mg / ml at 190 C
Acetone < 1 mg / ml at 190 C
Dimethylsulphoxide > = 100mg/ml at 190 C
N, N, dimethyformamide = 24 mg / ml
BASIC CONCEPTS
BSA
1 mtr2
100mg Pt/m2
1cm3 Tumour:
0.00147mg
1.47 gm Pt
1470 ngm Pt
5.88 gm Pt for 4 cycles
8.820 gm Pt for 6 cycles
Avr Adult
70Kg
Ht:160
1.73m2
70% water
0.00346mg
3.46 gm Pt
3460 ngm Pt
Cisplatin as a model drug for Intratumoral Chemotherapy
Diffusion of Cisplatin in the tumor
g Pt/g
Kroin & penn 1982, RAT BRAIN,micro infusion. 0.9mg/h – 7 days
UPTO 10mm
• Tumor [Pt] – did not predict antitumour activity or survival (Troger et al 1991-92)
• Prolonged accumulation with repeated dosing may be relavent (Tothill et al 1992)
• CDDP Co-valently binds to plasma protein irreversibly > impermeable to cell / loose cytotoxicity (Melvik et al).
• In the cell – only activate hydrolysed Pt compount & intact drug are cytotoxic (DNA/enzymes)
• 1 hr after infusion: Cytosol – several LMW metabolitesof CDDP (6 species) (mistry et al 1989)
• Resistance to Pt – over come by Dose intensification (Ozol et al, 1985)
Polymeric Matrix systems
• uniformly distributed drug through out a solid polymer
• rely on the diffusion of drug particles through fibrous network of the polymer to obtain sustained release of the drug
Time = 0
Drug dispersed in the polymer
Time = t
Drug dispersed in the polymer.
Remaining polymer 'Ghost'
Biodegradable polymer • the drug release rate is also determined by
polymer degradation rate • the kinetic release of drug from these formulations
differs • kinetics depend on polymer erosion / degradation,
diffusion of the drug in the matrix and physicochemical properties of the drug
• drug loaded matrix itself undergoes dissolution
Time = 0
Drug Dispersed in the matrix
Time = t
Drug Dispersed in the matrix
Biodegradation of Polymers
• The biodegradation mechanisms are
Enzymatic degradation.
Hydrolytic degradation.
Microbial degradation• The polymer compounds are cleaved by
hydrolysis to monomeric acids and are eliminated from the body through the Krebs cycle, primarily as carbon-dioxide and in the urine
Properties of Drug Relevant to Sustained Release Formulation The physiochemical properties of the drug
1. Aqueous Solubality and pKa 2. Partition Coefficient 3. Drug Stability4. Protein binding5. Molecular size and diffusivity
Biological Properties of the Drug 1. Absorption: 2. Distribution:3. Metabolism4. Estimation and Biological Half life5. Side effects and safety considerations6. Dose Size
Step 3: Pharmaco-kinetic evaluation of Drug Delivery System (IN vitro - Experimental STUDIES)
Concept for the release of a drug from Dosage forms
In determining the dissolution rate of drugs from solid dosage form, several physiochemical processes will have to be taken into consideration
1. Wetting characteristics of solid dosage forms
2. Penetration ability of the dissolution medium into the dosage forms
3. The swelling process
4. Disintegration
5. Deaggregation
Factors affecting the rate of Dissolution
1. Physio chemical properties of the drug
Particle size on Solubality (S=S∞.e α/r) Solid-Solution/Molecular Dispersion
Crystalline state of drug on dissolution rate - Solid phase characteristics
- Amorphicity, Crystallinity, State of Hydration, Polymorphic Structure
Factors relating to the Solid Dosage Form
Effect of Formulation Factors
Effect of Formulation Factors on Devices Dissolution Rate
Effect of Compression force on Dissolution Rate
Modified release dosage forms
1. Delayed release dosage forms
2. Extended release Dosage forms
• Polycaprolactone as a biodegradable material for polymeric implants.
• Degradation of Polycaprolactone occurs by non-enzymatic bulk hydrolysis of unstable ester linkages followed by fragmentation and release of Oligomeric species. Fragments are, ultimately scavenged by macrophages and giant cells.
Plan of Work.
Preformulation studies to confirm the stability, and suitability of the drug and polymer for the proposed formulation.
Development of suitable analytical method for the estimation of the
drug in the formulation. Formulation of Polymeric implants in a suitable form to facilitate
Intratumoral implantation. Characterization and study of in vitro drug release behavior of the
formulation. Short time stability studies to evaluate the effect of storage at
elevated temperature on the stability of the formulation.
In vitro Tissue Permeation study of Cisplatin
Total amount of Cisplatin permeated v/s Time
y = 0.0894x - 0.0128
R2 = 0.9968
0.0
0.2
0.4
0.6
0.8
0 5 10
Time in hours
Am
ount
of C
ispl
atin
in m
g
Actual line
Fitted line
CDDP tissue salineThickness of the tissue : 0.24mm
The average Permeability constant 0.854 cm / hour (SD = 0.0378)
Formula CDDP Drug load
Amount of Cisplatin added
Amount of Polycaprolactone added
1234
10%20%30%
10%Pt +10%Nacl
0.2G0.4G0.6G0.2G0.2G
1.8G1.6
1.4G1.6G
Drug-polymer ratios used for the formulation of Implants
Sl no
Formulation code Shape % drug loading Dimension
Diameter Length
1 SFL Cylinder 10 1 mm
3 cm
2 SFM Cylinder 20
SFH Cylinder 30
3 SFN Cylinder 10
BFL Cylinder 10 1.5 mm
3 cm
4 BFM Cylinder 20
5 BFH Cylinder 30
6 BFN Cylinder 10
• Determination of Cisplatin content in the Implants -- UV Spectroscopy
• Physicochemical Characterization of Cisplatin in the implants -X-Ray diffraction method
– Cisplatin was present in the same crystalline pattern in both physical mixture and in the mold.
– This explains that Cisplatin is not soluble in Polycaprolactone and was dispersed in the polymer as a crystalline network.
In vitro Drug release studies:
• 370C in 10 ml normal saline for a period of 1 month
• samples were analyzed spectrophotometrically for platinum content and the amount of Cisplatin released in to the medium
Drug release profile of BFL-1, BFL-2 & BFL-3.
Cumulative Drug Release v/s Time
0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1
0 5 10 15 20 25 30 35Time in days
CD
R in
mg
Average CDR in mg
Drug release profile of SFL-1, SFL-2 & SFL-3.
Cumulative drug release v/s Time
0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
0 5 10 15 20 25 30 35Time in days
CD
R in
mg
Average CDR w ith SD
The cumulative drug releaseObservations:• CDR - dependent on drug loading in the polymer.
• The total amount of drug released - was found to be maximum from the implants with 30% drug load. • The cumulative amount of Cisplatin decreased in the order of 30% (BFH), 20% (BFM), and 10%
(BFL)drug loading. • Cisplatin Implants containing 10% Sodium Chloride showed higher Cumulative drug release . • The Percentage drug released varied inversely with % drug loading. Implants with 10% Cisplatin and
10% Sodium chloride showed maximum %CDR whereas Implants Containing 30% showed least percentage cumulative drug release.
• The effect of diameter on the drug release profile was also studied. The results indicated decrease in diameter increased the cumulative drug release.
In vitro degradation profile of Polycaprolactone
• The in vitro degradation profile showed decrease in the dry weight of the polymer indicating slow surface erosion or degradation of Polycaprolactone cylinders.
• The surface erosion or degradation may contribute to the drug release from the formulation.
Polymer Degradation in 0.9% Sodium chloride
98.498.698.8
9999.299.499.6
99.8100
100.2
0 5 10 15 20 25 30
Time in daysw
eig
ht%
of d
eg
rad
ed
p
oly
me
r r
em
ain
ing
Trial -1
Trial-2
Scanning Electron Microscopic (SEM) studies of implants
• The external surfaces of the implants that were kept for release studies were rough and pitted.
• The external surface of sodium chloride containing implant was more rough and pitted than that of implant containing only Cisplatin.
• Sodium chloride along with Cisplatin showed comparatively more roughness, indicating faster surface degradation of the polymer implants due to the dissolution of Cisplatin, Sodium chloride crystals and surface erosion of the polymer.
• The faster surface degradation of the implant may contribute to the faster dissolution and diffusion of the drug from the polymer.
Mechanistic study of Cisplatin release from the Biodegradable Polymer implant
• The data indicated the increase in drug release constant with the increase in drug loading. – The release rate constant was found be highest in case of
10% drug loaded implants containing 10% Sodium chloride as release modifier. This was followed by implants containing 30%, 20% and 10% Cisplatin.
• Sodium chloride crystals present on the surface of the implant dissolve that may lead to the formation of channels through which the release medium can interpenetrate the matrix and increases the dissolution and diffusion of Cisplatin through the polymer.
Formulation Stability Studies • Thin Layer Chromatography - to confirm the Drug-Polymer
compatibility and stability of the formulation at elevated temperatures
• The results proved that there is no chemical degradation of Cisplatin due to the polymer and elevated temperatures.
• Cisplatin Content by UV Spectroscopy at elevated temperature for stability studies were sampled after a period of 1 month and analyzed Spectrophotometrically for Cisplatin content.
• Implants maintained at 370 were slightly soft due to the low melting point of the polymer (500C - 600C), indicating that 370C and higher temperatures are not suitable conditions for long time storage of implants
• Absorption, fate and excretion.• After rapid intravenous administration of usual doses, the drug
has an initial elimination half life in plasma of 25-50 minutes; concentrations of total drug, bound and unbound, fall thereafter, with a half life 24 hours or longer. More than 90% of the platinum in the blood is covalently bound to plasma proteins.
• High concentrations of Cisplatin are found in the kidney, liver, intestine and testis, but there is poor penetration in to the CNS. Only, a small portion of the drug is excreted by the kidney during the first 6 hours; by 24 hours upto 25% is excreted, and by 5 days up to 43% of the administered is recovered in the urine. When given by infusion instead of rapid injection, the plasma half-life if shorter and the amount of drug excreted is greater. Biliary or intestinal excretion of Cisplatin appears to be minimal.
Other Experiments
Animal Studies
• Mouse Tumour Model (RIF-1)
• Polymer rod(CPP:SA; 80:20) 17%CDDP
• 8x0.5mm
• RT v/s no RT
• T – [Pt] (Period)
• Response : Superadditive , > Implant & # RT
Yapp et al, IJROBP, Sep 1:39(2) 1997, 497-504
• Rat (n=344)
• 92 Gliosarcoma Cell
MST (Days) Day60
0.5mg/m2
CDDP Polymer 51+/- 14 63%
Control 24+/- 4
Placebo 24+/-4
p=2.5x10-9
Kong Q. J.Surg Oncol.1997.Apr:64(4), 268-273.
• CPP:SA - hydrolytic stability, T1/2, period of drug release
• BCNU:Polymer: 20:80 v/s 50:50
• 50:50 – improved survival 40 fld (p<0.001)
• 20:80 – achieved best balance of toxicity / antitumour efficacy, yeilding 75% long term survival rate in Recurrent Brain Tumor in Rats.
Sipos E P et al. Cancer Chemotherapy Pharmacol.1997.39(5),383-9
9L gliosarcoma rat model Polymer alone Free CDDP infusion CDDP Polymer Systemic CDDp
0.5 5.0 25 mg/m2
0.5 5.0 25 mg/m2
50 100 mg/m2
Local toxicity nil Min Significa Nt Neuro toxcicity
1/100th STD Dose
Day 60Survivors Survival improvement CDDP 50mg v/s Infusion Infusion v/s CDDP polymer
3/13 0.00059
8/12 p 0.00004 0.128Day 60: p<0.01
0/13 0/11
Kevin O Lillehi et al.Neurosurgery.Vol 39,No-6,Dec 1996.
Pt Implant
Pt Micro Infusion
50100
• Rabbit Brain• Radiolabled Polymer
implant BCNU• Measured Concn
profile-drug diffusion & elimination
• 30-40Ci 3H label
J.F.Strasse et al. TJofPharmacol Expt Theraptics.Vol275,No:3.1995
Penetration Distance• CDDP upto 1cms• Pd =0.8mm (morrison et al,1986), point wher concn
drops to 10% of Max conc.• For BCNU pd 2mm, Only 10-15 M of BCNU is
required for anti cancer activity. Mathematical models – anti cancer effect extends upto 5mm. (Hunter et al 1990)
• Mol Wt BCNU v/ CDDP : 214 v/s 300Our Expt:Permeability Co-efficient of CDDP - 0.854cms/hr
Phase I Trial• N =222
• Recurrent Brain Tumour – 2nd Surgery
Median GBM 6mnth
Survival Survival Mortality
• Placebo (n=112) 23 - 64%(47/73)
• Carmustine (n=110) 31 50% 44%(32/72)p=0.006
p=0.02
Poly Carboxy phenopropane & sebacic acid 20/80 ratio
Disk 1.4 cms x 1 mm thick.
Loading: 50 g Carmustine/mm3(3.85%Loading)
7.7mg/wafer. Max pt dose62mg
Systemic Use: 200 –240mg/m2 every 6-8wks
Henry Brem et al.The Lancet.Vol 345, April 22,1995.1008-1112.
• Adult dog
CDDP iv v/s Intra Arterial CDDP
(g Pt/ml) Albumin Microsphere
1 hour 1.65 0.42
4 week 0.15 0.1
mean 0.1 g Pt/ml/week
Yutaka Nishoka et al.Chem Pharm.Bull:37(5),1399-1400 (1989).
i.a Pt solution
Future Perspective
• Collaborative Programmes– Body volume rendering – dose prescription– Formulation – other agents/combinations/additive– Diffusion : radiolabled/others
• Planning System Development• Animal Studies• Clinical Studies• others
recurrent HNSCC
randomized, double-blind, phase III .
• intratumoral cisplatin/epinephrine injectable gel (CDDP/epi gel) x 4
• T < or =20 cm(3)• DOSE: 0.25 mL CDDP/epi gel/cm(3)
• CDDP v/s Placebo
• (CR or PR): 34% (21 of 62) v/s 0% (0 of 24) (p <.001).
• palliative benefit (37% v/s 12%, p =.036).
• side effects : local pain and local cutaneous reactions, which resolved over 3-12 weeks.
Castro DJ et al. Head Neck. 2003 Sep;25(9):717-31