Transcript Drug Delivery using 3M`s Hollow/Solid Microstructured Transdermal

3M Drug Delivery Systems
Drug Delivery using 3M’s Hollow/Solid Microstructured Transdermal Systems
John K. Simons, Kris J. Hansen, Tim A. Peterson
Introduction
Results and Discussion - hMTS
6.000
Experimental Methods
DOP – The results of the hMTS, DOP studies are reported in table below.
Number of MSs
6 arraysx18 MSs/array=
108 MSs
DOP in Pigs
6 arraysx18MSs/array=
108 MSs
Average DOP (µm)
210
250
Standard Deviation (µm)
30
40
On average the MS arrays penetrated more deeply in pigs as compared to HGPs.
The photograph shown below (left side) illustrates how the HGP skin looked
following the application of the hMTS patch coated with rhodamin B. Marks from all
18 MSs can be seen.
Infusion of Placebo Formulations - Several infusions of up to 1mL were conducted
using a sterile 5% dextrose or 0.001% methylene blue solution. Once the
formulation had been delivered, the device was allowed to stay in place for up to 10
minutes. The photograph shown below (right side) shows the results of an 800µL
intradermal infusion of a 0.001% methylene blue formulation into pig. The skin was
dry to the touch after patch removal; the deep blue of the infused formulation
provides a visual assessment of the treatment. Each blue spot on the skin
corresponds to one of the eighteen hollow microstructures on the array.
The sMTS arrays (~1200 MSs/array, 250 µm) were coated with naloxone formulation. For the time release studies (~16 µg/array), the naloxone contents of the
MS arrays were determined before and after specified wear times on the HGPs
(T=0, 0.5, 1. 2, 3, and 10 minutes). The amount of naloxone removed from the
array provided an indirect measure of how much drug had been delivered. For the
systemic delivery studies on pigs (270 µg/four arrays), blood samples were drawn
before and at specified times following patch application. The higher dose/
mulitiple arrays were used to ensure an adequate concentration of naloxone in the
blood to be accurately quantified. Arrays were also analyzed post application to
determine an upper limit of how much naloxone was actually dosed (224 µg).
Naloxone, sera (pg/mL)
DOP in HGPs
hMTS: 200 µL Infusion
4.000
3.000
2.000
1.000
Naloxone Infusion - Four different animals were used for the study comparing the
PK profiles generated after hMTS infusion, subcutaneous (SQ) injection and IV
injection. The pigs weighed between 10-22 kg at the time of dosing and ranged in
age from 1.5-3 months. Similar volumes of the same naloxone formulation were
administered to three pigs to directly compare the PK profiles associated with hMTS,
SQ, and IV administration. In the fourth case, 200 µL of formulation were delivered
via hMTS using a faster infusion profile to evaluate the effect of infusion rate on the
PK profile. Naloxone levels detected in the sera were normalized to approximate the
blood volume of the dosed animal based on a conversion of 62mL of blood per kg of
pig. All results are shown at the top of the next column. The results indicate
comparable delivery and bioavailability of naloxone via hMTS infusion and SQ
injection. As expected, both Tmax and Cmax are affected by the hMTS infusion rate. In
the case of the 200 µL hMTS infusion, Tmax is comparable to the SC injection. In the
case of the 435 µL hMTS infusion (slower infusion rate), Tmax is delayed by ~25
minutes.
Avg SQ Injection (250 µg, n = 2)
1.4
1.2
1
0.8
0.6
0.4
0.2
0.000
0
20
40
60
80
100
120
140
0
0
Time (minutes)
20
40
60
80
100
120
140
Time (minutes)
As the results show, delivery of naloxone via a sMTS patch is comparable to a SQ
injection with regard to bioavailability and PK profile.
Results and Discussion - sMTS
DOP – When applied to pigs, the average DOP for the sMTS arrays was 109 ± 9
µm when applied to the ham and 93 ± 8 µm when applied to the abdomen.
Naloxone Time Release - The graph below shows the results of the time release
study where the array content values are plotted against the time the array patches
were worn. The initial (T=0 min) array content of 15.6 µg/array drops to ~1.6
µg/array within 30 seconds. The results confirm that very fast, efficient delivery is
possible with coated MSs. Although this data set does not demonstrate that the
dose was actually delivered versus being simply wiped off on top of the skin, the
systemic delivery study (data discussed below) clearly demonstrates that the
formulation is being delivered efficiently.
25.00
With domestic pigs, a red, array-sized blotch was observed immediately after patch
removal, but faded to be non-perceptible within 5 minutes. A small wheal was also
observed on the pig skin immediately following patch removal but was resolved
visually and to the touch within 40 minutes.
Avg sMTS (224 µg, n = 3)
1.6
hMTS: 425 µL Infusion
The DOP studies were conducted on both hairless guinea pigs (HPGs) and
domestic pigs. The DOP was determined using a water soluble dye (rhodamine
B) coated on the MSs which were assessed microscopically both before and after
application. The micrograph to the right shows the array
after application. Prior to application the MSs are uniformly coated along their full length with rhodamine B.
The hMTS array consisted of a MS disk (18 MSs/array)
connected to a commercial syringe pump through
which up to 1mL of liquid formulation was administered
intradermally. The hollow MSs were applied to the
skin to a depth sufficient to penetrate the stratum corneum and the epidermis and
create direct access to the dermis. With domestic pigs, the hMTS device was
used to deliver up to 1000 µL of formulation in about 18 minutes. Blood samples
were drawn prior to infusion and at specified time points during and post infusion
from the ear vein of the pigs and analyzed by LC/MS.
1.8
SQ: 425 µL
5.000
Residual Naloxone (ug/array)
To fully characterize the performance of the hMTS device, three sets of experiments
were conducted: depth of penetration (DOP) studies, infusion of placebo formulations,
and infusion of a naloxone solution. The DOP studies were conducted to determine
the average penetration depth of the MSs into the skin. The infusion studies with
placebo formulations were conducted to evaluate site reactions and visualize the
delivery of the formulation. Finally, the naloxone infusion was conducted to establish
the pharmacokinetic (PK) profile of a molecule delivered intradermally via the hMTS
device. To characterize the performance of the sMTS device, DOP studies, release
studies of coated naloxone formulations from the sMTS array, and systemic delivery
studies were all completed.
IV: 300 µL
Naloxone, sera (µg)
3M Drug Delivery Systems has designed proof of concept (POC) devices that utilize
either hollow (hMTS) or solid (sMTS) microsturctures (MSs) for intradermal delivery of
molecules not typically compatible with traditional transdermal delivery technologies.
The use of MS devices has long been proposed as a minimally invasive method for
drug delivery.(1-3) MSs, usually less than 2 mm in length, can penetrate the stratum
corneum with minimal patient discomfort(4), providing a delivery route for drugs typically
available only via injection. In this work, 3M characterizes the in vivo performance of
the hMTS and sMTS technologies to deliver naloxone, a small, molecular salt,
systemically.
Individuals
20.00
Mean
Conclusions
Relative to traditional passive transdermal technologies, 3M’s hMTS and sMTS
technologies can provide rapid transdermal delivery of liquid (1000 µL) or solid
formulations. Intradermal delivery of a small molecular salt (naloxone), not
compatible with traditional transdermal delivery, was achieved with both
technologies with measured PK profiles similar to those obtained with SQ
injections. The hollow, polycarbonate MSs penetrate the stratum corneum and
provide infusion up to 1 mL in less than 20 minutes, at approximately 250µm
beneath the surface of the skin. The PK profile resulting from the naloxone
infusion can be affected by the infusion profile. Coated sMTS arrays demonstrates
fast (<1 minute) and efficient transdermal delivery of solid, dried API formulations.
ACKNOWLEDGEMENTS
The authors acknowledge the contributions of A. Determan, G. Prochnow, H. Lewin, N.
Johnson, S. Burton, R. Simmers, K. Brown, T. Fenn, C. Moeckly, P. Sackett,
D.
Brandwein, J. Gysbers, K. Puckett, J. Oesterich, K. Siebenaler, L. Robinson, R. Krienke, D.
Heidebrink, J. Moseman, P. Johnson and B. Haldin
15.00
10.00
5.00
0.00
0
2
4
6
8
10
12
Wear Time (minutes)
Systemic Delivery - The results of the naloxone systemic delivery studies are
shown in the graph at the top of the next column. The results are plotted with
those obtained with a SQ control. To ensure adequate sensitivity of the assay, the
arrays were coated with ~68 µg/array and four arrays were applied per animal.
Higher loadings can be achieved but are dependent on the physical properties of
the API. As an example 325 µg/array of ovalbumin have been successfully coated.
For direct comparison, 250 µg of naloxone were delivered subcutaneously.
REFERENCES
1. S.R. Rosenthal, Multiple Injector Puncture Device. US Patent 3,675,766 (1972).
2. J.B. McConnell, H.E. Zangenberg, and M.S. Cooper, Intracutaneous Injection Device.
US Patent 3,034,507 (1962).
3. M.R. Prausnitz, Microneedles for Transdermal Drug Delivery. Advanced Drug Delivery
Reviews. 56: 581-587 (2004).
4. S. Kaushik, D.D. Denson, D.V. McAllister, S. Smitra, M.G. Allen,
M.R. Prasunitz. Lack of Pain Associated with Microfabricated
Microneedles. Anesthesia and Analgesia. 92:502- 504 (2001).