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(Received 8 June 2013; accepted 20 August 2013; published online 1 October 2013)
Intravaginal devices composed of polyhydroxybutyrate/polycaprolactone blends incorporating
progesterone were used over eight days in crossbred cow ovariectomized, and then analyzed with
photoacoustic methods, measuring the absorption spectra, thermal diffusivity, and inspecting its
degradation by means of scanning electron microscopy. The characteristic time found for
progesterone release was TR 53 h, and the typical time found for biodegradation was TB 30 h.
Morphological analysis complements the study showing that release of progesterone and
C 2013 AIP Publishing LLC.
biodegradation of the blend occurs on sample surface. V
[http://dx.doi.org/10.1063/1.4823986]
The artificial insemination is essential in livestock to be
a biotechnical that provides the genetic improvement of cattle. One of the protocols makes use of intravaginal devices
for progesterone releasing. Most systems delivery of veterinary drugs is based on silicone, polyurethane, vinyl acetate,
or ethylene, which are cheap and biocompatible.13
The biodegradable products have various applications,
with significant advances in the biomedical implant and drug
delivery system. For animal health care, for example, often
the duration of drug release should be extended.1 In this context, some positive results have been obtained with drug
incorporation in biopolymers, which permits a better release
control of the drug from the biodegradation of the
material.46
One of physiological effects of progesterone is to inhibit
the growth of epithelial cells of human breast.7 Progesterone
produces its effect on target cells by enhancing the synthesis
of new structural proteins or enzymes.8 Among the steroids,
progesterone is the most attractive to regulate fertility and
treat infertility. The P4 occurs in high concentrations in the
body and has no toxicity problems, as usually happens with
synthetic progestins. However, progesterone is not active
orally, except in high doses, and have a relatively biological
short lifetime. In an attempt to reduce production costs and
environmental impacts, Nascimento et al.9 developed intravaginal devices for sustained release of progesterone composed by polyhydroxybutyrate (PHB) and polycaprolactone
(PCL) containing amount of P4.9
This paper reports the study of parenteral delivery of
P4 by biodegradation of the intravaginal device by
a)
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few samples for a better view: D0; D1; D3; D5; D7; D8 and
the PHB/PCL-base sample, where one can see a gradual
decrease in the absorption band of the hormone P4 and its
relation with time of insertion. One may note that sample D8
tends to the blend PHB/PCL-base but still presents remains
of P4 in the range 270300 nm.
The typical exponential decay of OPC amplitude after
linearization undergoes to best fit what gives parameter b,
corresponding to the individual slope (Dj) related to time
releasing, slopes were obtained from 36 to 100 Hz in a semilog plot.
Table I summarizes the main results, giving the samples
thicknesses, the fitted parameters b and its confidence band,
also the calculated value for thermal diffusivity a of each
PHB/PCL blend. Errors for a is calculated from single fittings of b and comprises both, thickness error dL 1 lm
(1/5000.2%) and db 0.006 (0.006/0.9000.7%). One
can evaluate the error da from derivative of a p2s =b2 ,
which gives da 2adb=b d= and one can estimate
it close to 2%. Nevertheless, a major error is found from fitting b using more than one single sample. Then one can estimate statistically an averaged value from measuring one
sample at a time of a triplicate set in such way errors could
be overestimated reaching higher values like those in Table I
for a, figuring in percentage about (da/a) 7.4%.
Figure 2(a) shows the in time variation to the integrated
areas of the curves like those presented in the Figs. 1(a) and
1(b). The band 270380 nm was used in the integration of
hormone absorption areas. The time to decrease the amount
of P4 in the sample to a value of 1/e of the sample D0 was
denominated as the characteristic time of release (TR). The
fitted data to an exponential decay revealed a TR 53 h,
which is the best adjusted time for the releasing process, in
which 63% of the total amount of P4 is released when device
is intravaginally implanted.
Time evolution of thermal diffusivity of PHB PCLblends is shown in Fig. 2(b) for each sample Dj. The main
picture is the exponentially growing of thermal diffusivity
along the time of intravaginal insertion. A rapid releasing of
P4 is found at about two days and a slow growing till the
thermal diffusivity finding a plateau and a steady value
around to a8 6.5 103 cm2/s. The typical time needed for
the diffusivity grow over 63% of its steady value (sample
D8) is evaluated as the typical time of biodegradation of
TABLE I. Calculated thermal diffusivity of P4-doped blend of PHB/PCL
using blend thicknesses and slopes of OPC fittings.
Blend
D0
D1
D2
D3
D4
D5
D6
D7
D8
PHB PCL-base
Thickness
ls (104 cm)
Parameter:
b (s1/2)
Thermal diffusivity
a (103 cm2/s)
405 6 1
454 6 1
420 6 1
418 6 1
413 6 1
503 6 1
409 6 1
395 6 1
410 6 1
415 6 1
(0.922 6 0.007)
(1.006 6 0.007)
(0.925 6 0.005)
(0.922 6 0.005)
(0.907 6 0.005)
(1.101 6 0.006)
(0.892 6 0.007)
(0.860 6 0.008)
(0.897 6 0.006)
(1.011 6 0.007)
6.06 6 0.45
6.39 6 0.47
6.48 6 0.48
6.45 6 0.48
6.51 6 0.48
6.55 6 0.49
6.60 6 0.49
6.62 6 0.49
6.56 6 0.49
5.29 6 0.46
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Filho et al.
indicates that granular characteristic occurs only on the surface and it extends up to a 20 lm depth approximately.
The ultimate characteristic found from SEM analysis if
depicted in Fig. 4, where one can find an evident block size
reduction when it is compared Fig. 4(a) against Fig. 3(c) that
shows sample D0 surface. Moreover, it is worthy to note the
reduction of block size from approximately 20 lm5 lm, if
one compares sample D1 (Fig. 4(a)) to D8 (Fig. 4(c)). The
cross-section of samples D1 and D8 shown in Figs. 4(b) and
4(d) indicates a typical depth of 20 lm where degradation
and consequently progesterone releasing may be found.
Here, a polymer and the active agent have been mixed to
form a homogeneous system, also referred to as a matrix system (PHB PCL-blend). Mass diffusion occurs when the
drug (progesterone P4) passes from the polymer matrix
(PHB PCL-blend) into the external environment (intravaginal medium). As the hormone release continues, its rate normally decreases with this type of system, since the active
agent has a progressively longer distance to travel and therefore requires a longer diffusion time to release. Thus, aside
releasing the drug, degradation also may occur and SEM
micrograph looks to be well correlated with microstructure
of the blend and to thermal diffusivity evolution with time.
There are some known theoretical models of drug
release in the literature,1113 but the case of the drug delivery
followed degradation has been studied recently in a device
silk-based for oral administration.8 It is presented here an alternative way to relate the kinetics of progesterone release
in vivo using the integrated areas of the PAS spectra and
measuring the evolution of thermal diffusivity in time.
In reservoir systems, the release rate is well established,
and it is independent on environment, with advantage of
keeping constant the concentration of drug inside the host
body.3 The drug delivery from bulk-eroding or surfaceeroding biodegradable or layer-by-layer14 systems are named
of Chemically Controlled Systems, the drug may be uniformly distributed and immobilized in the matrix, and the
release occurs by erosion of the matrix of the biomaterial.
When there are covalent bonds between the drug and the biopolymer, the release will occur through the divisions of the
connections formed through chemical reactions, usually enzymatic or hydrolytic degradation of the matrix.3
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