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Effect of polymer composition on steroid permeation: Membrane permeation kinetics of androgens and progestins
Journal of Controlled Release, 5 (1987) 69-78
69
Elsevier Science Publishers B.V., Amsterdam - Printed in The Netherlands
EFFECT OF POLYMER COMPOSITION ON STEROID PERMEATION: PERMEATION KINETICS OF ANDROGENS AND PROGESTINS Ying Sun*, Musa Ghannam**,
Kakuji Tojo, Yie W. Chien***
Controlled Drug-Delivery Research Center, Rutgers 789, Busch Campus, Piscataway,
MEMBRANE
NJ 08854-0789
The State University of New Jersey, College of Pharmacy, P.O. Box
(U.S. A.)
Chi-long Lee, Katherine L. Ulman and Kent R. Larson Silicone Research Department,
Dow Corning Corporation, Midland, Ml 48684
(Received October 11, 1986; accepted in revised form December
(U.S. A.)
19, 1986)
The permeation rates of 10 androgenic and 7 progestagenic steroids through synthetic membranes fabricated from poly(trifluoropropylmethylsiloxane) (PFMS), poly(dimethylsiloxane) (PDMS) and the copolymer of PDMS with poly(ethylene oxide) (PEO) and poly(methy1 methacrylate) (PMMA) were investigated and found to be profoundly affected by the chemical structure of penetrants and/or the copolymer composition. The permeation rate for both groups of steroids was observed to decrease in the order of PDMS> PFMS > PDMS/PEO/PMMA copolymer. This can be attributed to the increase in membrane polarity, which causes a decrease in the polymer solubility of steroids, and the incorporation of the high-T, glassy polymer segments, which leads to a reduction in the diffusivity in the polymer. The increase in the PDMS block size tends to promote the permeation of steroids, which can be explained in light of the increase in the size of more permeable PDMS domain. Incorporation of PMMA blocks into PDMS drastically decreases the rate of steroid permeation due to the presence of less permeable “hard” PMMA domains, while addition of PEO produces an enhancing effect on the permeation of less lipophilic steroids such as testosterone.
INTRODUCTION Much interest has recently been demonstrated in the application of biocompatible silicone polymers to regulate the rate of delivery of pharmaceuticals and veterinary drugs. A survey of the literature shows that many investigations have been conducted into the permeation of drugs through silicone mem*Present address: Pennwalt Corporation, King of Prnssia, PA 194069018, U.S.A. **Present address: Wyeth Laboratory, Philadelphia, PA 19101, U.S.A. ***To whom all correspondence should be addressed.
0168-3659/87/$03.50
branes, in order to design membrane permeation-controlled drug delivery systems [ l-8 1. Since Fickian diffusion is usually the governing mechanism for membrane-moderated controlled drug release devices, the solubility of drug in the polymer membrane is of great importance, and consequently, so is the lipophilicity or hydrophilicity of the polymer membrane. In accordance with Fick’s Law of Diffusion, a variation in drug solubility, resulting from a change in polymer lipophilicity, will lead to a change in the concentration gradient across the membrane, and therefore to a modification of the drug permeation rate.
0 1987 Elsevier Science Publishers B.V.
70
Block copolymers have been synthesized to achieve this purpose [ 91, and a silicone elastomer was also copolymerized with other organic polymers to improve its physicomechanical properties [ lo]. A block copolymer consisting of polydimethylsiloxane (soft segment block) and an appropriate organic polymer (hard segment block) gives a copolymer with physico-chemical and mechanical properties which are different from those of the homopolymers. Besides improving the permeation characteristics, the presence of a hard domain dispersed in the rubbery matrix ( Tg= - 123’ C for polydimethylsiloxane) will alter the ultimate mechanical properties and make the copolymer superior to silica-filled and unfilled silicone elastomers [ 111. A recent study by Lee and his associates showed that the permeabilities of some steroids through copolymer membranes prepared from poly (ether urethanes) and poly (ethylene/vinyl acetate) were drastically changed by the modification in polymer composition [ 121, They concluded that this change of permeability can be attributed to the variation of solubility and diffusivity of the steroids in the polymers. In this paper, the authors report the results from a systematic investigation of the permeation of a series of steroids across block copolyfrom membranes prepared mer poly ( dimethylsiloxane) , poly ( ethylene oxide ) and poly (methyl methacrylate) . The relationships between the permeation of steroids and the composition of the copolymer membranes, the block size of silicone polymers and copolymers, as well as the molecular structure of steroids will also be discussed.
MATERIALS AND METHODS Materials
Various androgens and progestins were used as the model drugs in this investigation (Tables
SILICONE POLYMER MEMBRANE
Polydimethylsiloxane
(PDMS):
CH3 H3C-
SiI
0
3
CH3
Polytrifluoropropylmethylsiloxane
IPFMS):
CF
I3 I2
CH
H3C-
CH 13 Si -
0
-Si
-
CH
3
’ CH3 Fig. 1. Structure of the silicone membranes used in this study; n is the monomer block size.
1 and 2). All androgens and progestins were purchased from Sigma Chemical Company, except testosterone pentanoate, testosterone cyclohexanoate (Pioneer Lab. Inc.), and 17crhydroxycorticosterone (Upjohn Company). These model drugs and polyethylene glycol400 (PEG 400, Fisher Scientific Company) were used as received. The membranes consisting of poly ( dimethylsiloxane ) , poly ( trifluoropropylmethylsiloxane) (Fig. 1) , and the copolymer of silicone elastomer with poly (ethylene oxide) and poly (methyl methacrylate) were customprepared (Dow Corning Corporation ) (Table 3). The average molecular weights of the PDMS block were 1200, 2400 and 3600 and those of PEO were 600 and 1000, respectively. The method of synthesis for these copolymers will be described in a forthcoming paper. Membrane permeation studies
To study the membrane permeation kinetics of testosterone and progesterone and their
71 TABLE 1 Chemical structure
of androgens
investigated
(a)
Code
Androgens
B,
B2
B,
A-l A-2 A-3 A-4 A-5 A-6 A-7 A-6 A-9 A-lo
19-Nortestosterone Testosterone 17cwMethyltestosterone Testosterone acetate Testosterone propionate Testosterone pentanoate Testosterone heptanoate Testosterone cyclohexanoate Testosterone benzoate Testosterone cypionate
H
H H CH, H H H H H H H
H H H CH,CO CH,,CH,CO CH:,(CH,):,CO CH:,(CH,),CO C,H,,CO GHsCO C,H,(CH,),CO
derivatives through silicone and silicone copolymer membranes, a hydrodynamically wellcalibrated membrane permeation system (Bellco Glass Inc.) was used [ 131. After assembling a polymeric membrane between the donor and receptor compartments, a suspension of steroid in 40% (v/v) aqueous PEG 400 solution, which was pre-heated to 37”C, was added to the donor compartment. The same aqueous solution (without drug) was added to the receptor compartment. The use of 40% (v/v) PEG 400 as the diffusion medium was to assure the maintenance of sink conditions in the receptor solution [ 151. At each predetermined time interval, 10 ml of receptor solution was sampled and replaced immediately with the same volume of fresh, drug-free PEG 400 solution. The steroid concentration in the sample was analyzed by UV spectrophotometry (Per-
CH, CH, CH, CH, CH, CH, CHz CH2 CH,
kin-Elmer Corporation) from the peak absorbance at 245 nm. The whole permeation experiment was conducted at 37’ C. The rate of permeation obtained experimentally was then corrected for the effect of hydrodynamic boundary layers by a correction factor (y), which was previously calculated through the calibration procedure of the dimensionless relationship Sherwood-Reynolds-Schmidt [ 131. The value of y depends on both the permeant and polymer membrane used [ 141. In the present study, it led to corrections less than 10% for the rate of permeation in most cases, with a few very lipophilic drugs excepted. For instance, progesterone permeating through a lipophilic membrane (such as that made of
PDMS) necessitated a correction factor as high as 60%. The corrected rate of steroid permeation, called the intrinsic permeation rate, was
12
TABLE 2 Chemical structure of progestins investigated (b)
Code
Progestins
P-l P-2 P-3 P-4 P-5 P-6 P-7
Progesterone Desoxycorticosterone lla-Hydroxyprogesterone 17wHydroxyprogesterone Corticosterone 17wHydroxydesoxycorticosterone Hydrocortisone
H OH H H OH OH OH
H H OH H OH H OH
H H H OH H OH OH
TABLE 3 Composition of copolymer membranes evaluated Membrane No.
PDMS block size
PEO block size
1 2 3 4 5 6 7 8 9 10
1200 2400
-
1200 1200 2400 2400 2400 2400 1200
600 600 600 600 600 1000 1000
then normalized as regards the thickness of the polymer membrane used, so a proper comparison could be made. Only the normalized intrinsic permeation rates are reported throughout this article. The diffusivity of steroids was calculated using the lag-time method [ 161.
PDMS/PEO ratio
100/o 100/o 100/o 50150 50150 66133 66133 66133 55145 38/62
PMMA, %
0 0 0 0
30 0 15 30 45 45
Tensile strength, psi 810 240 230 300 1700 190 110 1900 1620 3020
RESULTS AND DISCUSSION
The results for the permeation of progestins and androgens through PDMS and PFMS polymers and PDMS/PEO/PMMA copolymer membrane are shown in Tables 4 and 5, respec-
73 TABLE 4 Effect of polymer composition on the membrane permeation of progestins Progestins
P-l P-2 P-3 P-4 P-5 P-6 P-7
Normalized permeation rate (,&cm h x 10’) PDMS
PFMS
PDMS/PEO/PMMA”
600 39 2.4 2.4 0.82 0.89 0.60
51 24 2.1 1.8 0.67 0.70 0.39
5.8 3.2 0.82 0.77 0.71 0.70 0.59
“Membrane No. 5 (Table 3). TABLE 5 Effect of polymer composition on the membrane permeation of androgens Androgens
A-l A-2 A-3 A-4 A-5 A-6 A-7 A-8 A-9 A-10
Normalized permeation rate (,&cm h x 10’) PDMS”
PFMS”
PDMS/PEO/PMMAb
89 19 35 210 400 24 6.9 2.9 2.7 2.2
11 3.2 5.4 58 46 11 2.6 1.8 0.95 1.6
4.4 1.7 1.9 6.1 7.1 3.1 1.3 0.85 0.36 0.85
“Ref. [7]. “Membrane No. 5 (Table 3 ) .
tively. It was found that the effect of the variation in the lipophilicity of steroidal molecules, which is reflected by the drug solubilities in the aqueous diffusion medium, on the permeation across the copolymer membrane is consistent with the results observed earlier [ 6,7]. The change in polymer composition appeared to affect the rate of membrane permeation of a lipophilic steroid, like progesterone, more significantly than that of a hydrophilic steroid, like the hydroxyprogesterones. The membrane permeation rate of progesterone and its monohydroxy derivatives was found to decrease in the order of: PDMS > PFMS > PDMS/PEO/
PMMA copolymer, while the effect on the diand tri-hydroxy progesterone was minimal (Table 4). It can be seen that for a lipophilic steroid, such as progesterone, the permeation rate was reduced remarkably as the silicone membrane became less lipophilic. The rates of progesterone permeation through PFMS and were membranes PDMS/PEO/PMMA approximately only l/lOth and l/lOOth of that across the lipophilic PDMS membrane, respectively. However, the effect of the variation in polymer composition became gradually less significant as steroid hydrophilicity increased. It was observed that the permeation rates of the
14
hydroxy derivatives of progesterone were only slightly dependent upon the polymer compositions as the number of hydroxy groups increased. The permeation rate data for androgens through PDMS/PEO/PMMA copolymer was also found to follow a pattern similar to that observed for PDMS and PFMS membranes. It can be seen from the data in Table 5 that either the variation in the number of methyl groups on the steroidal skeleton or the esterification at the 17 position profoundly affects the magnitude of permeation across the polymer membranes. In general, higher permeation rates were achieved with more lipophilic androgens. However, the permeation rates started to decline as the ester side chain became very bulky, which could be attributed to the drastic decrease in the aqueous solubility of these androgens. The permeation rates of androgens and progestins were reduced as the polymers became more polar, as a result of the introduction of a trifluoropropyl group onto the silicon atom, or by copolymerization of polydimethylsiloxane with polar PEO and PMMA polymer. A rather similar pattern in descending order was noted for the permeation rates of androgens and progestines. Figure 2 shows the effect of PDMS block size on the permeation rates of representative analogs of androgen and progestin. The permeation rates increased as the size of the PDMS block increased from 1,200 to 3,600. This increase in permeation rate can be attributed to the fact that as the size of PDMS block increases, the highly permeable PDMS domain increases, and consequently the permeability increases. A similar phenomenon was reported recently [ 121. The results shown in Fig. 2 also indicate that the effect of block size seems to be dependent upon the chemical structure of the penetrant molecules. Incorporation of PMMA into PDMS/PEO block copolymers markedly reduced the membrane permeation rates of steroid (Fig. 3). This effect may be attributed to the poor drug
loo-
DESOXYCORTlCOSTEl?ONE
3600
2400 PDMS
BLOCK
SIZE
Fig. 2. Effect of PDMS block size on the normalized permeation rate of testosterone ( 0 ) , testosterone propionate ( 0 ) , progesterone ( n ) and desoxycorticosterone (A ).
permeability of PMMA. PMMA is a glassy polymer with a glass transition temperature of 106°C [ 171, whereas PDMS and PEO have glass transition temperatures of - 123 “C and -41°C respectively, and are fluid at room temperature. Incorporation of glassy PMMA into the rubbery PDMS/PEO creates “hard”, less-permeable polymer domains, through which penetrant molecules can diffuse only with great difficulty [ 18,191. This explains the observed reduction in the membrane permeation rates with increasing PMMA content (Fig. 3). On the other hand, incorporation of hydrophilic PEO into the hydrophobic silicone polymer was seen to improve the permeation rate of testosterone through PDMS/PEO/PMMA copolymer (Fig. 4). Apparently, the incorporation of PEO caused an increase in the hydrophilicity of the copolymer and thus facilitated
75
\
TESTOSTERONE
PROPIONATE
PROGESTERONE
PMMAX
0
I
I
15
30
Fig. 4. Effect of PEO content in PDMS/PEO/PMMA copolymer on the normalized permeation rate of testosterone: Key: PDMS/PEO = 38/62 ( 0 ) , PDMS/PEO = 66/33 (0).
PMMAX
Fig. 3. Effect of PMMA content in PDMS/PEO/PMMA copolymer on the normalized permeation rate of testosterone ( 0 ) , testosterone propionate (0)) progesterone (n ) and desoxycorticosterone (A ).
the permeation of testosterone, which has a hydroxy group at the 17 position and is therefore less lipophilic than steroids such as progesterone. However, as the PMMA content of the copolymer was increased, the enhancing effect of PEO on the rate of permeation diminished, as a result of an offset by the negative effect of PMMA. Membrane permeability (P,) is a product of diffusivity (Q,) and solubility (C,,) in the polymer. To understand which is responsible for the experimental results presented above, the permeation of testosterone through the three types of polymer was examined. The results are shown in Table 6. It can be seen from Table 6 that incorporation of PEO into PDMS caused a 47-fold decrease in D, but a 68-fold increase in C,,. As
a result, the permeability increased 45%. The presence of hydrophilic PEO in the copolymer obviously was responsible for the marked increase in C, of testosterone, which is a less lipophilic molecule. It has to be mentioned that, although incorporation of PEO into PDMS increased the permeation rate of testosterone, it reduced the permeation rate of lipophilic steroids such as progesterone. The decrease in D, due to PEO can be interpreted qualitatively in terms of the “free volume” model. That is, the 7’, of PEO ( -41 “C) is higher than that of PDMS ( - 123°C)) therefore the “free volume” of PEO should be lower and hence D, would be lower than that of PDMS. For quantitative interpretation of the experimental results, however, the “free volume” model has to be refined or modified [ 201. Table 6 also shows that incorporation of PMMA into PDMS/PEO block copolymer caused an about 5-fold decrease in D, and a 2fold decrease in C,. The net result was a g-fold reduction in the normalized permeation rate.
76 TABLE 6 Effect of polymer composition on the membrane permeation of testosterone
P, (&cmsX10”)
D, (cm’/s x 10’) C, @g/cm” X 10”)
PDMS
PDMS/PEOb
PDMS/PEO/PMMA’
5.6 66 0.09
8.1 1.4 5.8
0.88 0.30 2.9
“Ref. [ 191. bMembrane No. 6: PDMS/PEO = 2/l, PDMS block size = 2400. ‘Membrane No. 8: PDMS/PEO = 2/l, PMMA 30%, PDMS block size= 2400. TABLE 7 Effect of copolymer composition on the membrane permeation of androgens Androgens
A-l A-2 A-3 A-4 A-5 A-6 A-l A-8 A-9 A-10
Normalized permeation rate (pg/cm hx 10’) Memb. 5”
Memb. 6b
Memb. 8
4.4 1.7 1.9 6.1 7.1 3.1 1.3 0.85 0.36 0.85
61 29 31 68 91 6.1 5.4 3.4 2.1 2.2
16 3.2 5.4 58 46 11 2.6 1.8 0.95 1.6
“PDMS/PEO: 50/50; PMMA: 30%; PDMS block size: 1200. “PDMS/PEO: 66/33; PMMA: 0%; PDMS block size: 2400. ‘PDMS/PEO: 66/33; PMMA: 30%; PDMS block size: 2400.
The decrease in II, value was apparently caused by the presence of hard PMMA domains, which are expected to have a lower D, than PDMS or PEO because of its higher Tg (106’ C ) , as mentioned earlier. The data in Table 7 show that the permeation rate first increased with increasing lipophilicity of the steroids and then declined as the ester side chain became very bulky. On the other hand, the diffusivity remained more or less independent of the lipophilicity and the molecular size of androgenic steroids (Table 8). The data in Table 8 also suggest that incorporation of PMMA into the PDMS/PEO copolymer membrane appears to produce a 5- to lo-fold
reduction in androgen diffusivity (comparing Membrane No. 6 with Membrane No. 8)) while there was only a slight increase in membrane diffusivity as the PDMS block size was increased and the PEO content was changed (comparing Membrane No. 5 with Membrane No. 8). Although incorporation of PMMA into the PDMS/PEO copolymer caused a decrease in the permeation rate (Table 7), the presence of hard PMMA domains reinforced the mechanical properties of the copolymer. This is illustrated by the marked increase in the tensile strength shown in Table 3. The copolymers were tough and transparent. The tensile strength increased
77 TABLE 8 Effect of copolymer sivity of androgens Androgens
A-l A-2 A-3 A-4 A-5 A-6 A-7 A-8 A-9 A-10 “PDMS/PEO: “PDMS/PEO: ‘PDMS/PEO:
composition
Diffusivities
on the membrane
(cm*/s~
diffu-
lOa)
Memb. 5”
Memb. 6h
Memb. 8
0.10 0.18 0.17 0.13 0.12 0.14 0.10 0.16 0.20 0.13
1.0 1.4 1.5 2.0 2.0 1.1 1.4 1.3 1.5 2.0
0.10 0.30 0.29 0.20 0.24 0.19 0.11 0.10 0.30 0.17
50/50; PMMA: 30%; PDMS block size: 1200. 66/33; PMMA: 0%; PDMS block size: 2400. 66/33; PMMA: 30%; PDMS block size: 2400.
with increasing PMMA content. the copolymers were shown to toxic. These properties make copolymer ideal for applications drug delivery.
more permeable PDMS domain. Incorporation of PMMA blocks into PDMS drastically decreased the rate of steroid permeation, due to the presence of less permeable “hard” PMMA domains. The addition of PEO produced an enhancing effect on the permeation of less lipophilic steroids such as testosterone.
ACKNOWLEDGEMENTS Y.S. and M.G. gratefully acknowledge port by Dow Corning Graduate Research lowships at the Rutgers University. REFERENCES
Furthermore, be non-cytothis class of in controlled 4
CONCLUSION The rates of membrane permeation of androgenie and progestagenic steroids through a silicone polymer membrane were found to be profoundly affected by the chemical structure of the penetrants and/or the copolymer composition. The permeation rate for both groups of steroids was observed to decrease in the order of PDMS > PFMS > PDMS/PEO/PMMA copolymer. This was attributed to the increase in membrane polarity, which caused a decrease in the polymer solubility of steroids, and the incorporation of high-‘lr glassy polymer segments, which led to a reduction in the diffusivity in the polymer. An increase in PDMS block size tends to promote the permeation of steroids, which can be explained in light of the increase in size of the
supFel-
5
6
7
8
9
10
K.H. Moon and R.G. Bunge, Silastic testosterone capsules, Invest. Urol., 6 (1968) 329-333. F. Kincl, G. Benagiano and I. Angee, Sustained release hormonal preparations, Steroids, 11 (1968) 673-680. K. Sundaran and F. Kincl, Sustained release hormonal preparations. II. Factors controlling the diffusion of steroids through dimethylpolysiloxane membranes, Steroids, 12(4) (1968) 517-524. ’ S.T. Hwang, R.J. Shea, K.H. Moon and R.G. Bunge, Permeation of testosterone through silicone rubber membranes, Invest. Urol., 8 (1970) 245-253. R. Shippy, S. Hwang and R. Bunge, Controlled release of testosterone using silicone rubber, J. Biomed. Mater. Res., 7 (1973) 95. M. Ghannam, K. Tojo and Y.W. Chien, Kinetics and thermodynamics of drug permeation through silicone elastomers. I. Effect of penetrant hydrophilicity, Drug Dev. Ind. Pharm., 12 (1986) 303-326. Y. Sun, K. Tojo and Y.W. Chien, Kinetics and thermodynamics of drug permeation through silicone elastomers. II. Effect of penetrant lipophilicity, Drug Dev. Ind. Pharm., 12 (1986) 327-348. F.S. Rankin, The use of silicones for the controlled release of drugs, in: Proceedings of the 12th International Symposium on Controlled Release of Bioactive Materials, 1985, pp. 143-144. K. Knutson, S.W. Kim and K. Sharma, Design of controlled delivery systems with block copolymers, in: Proceedings of the 12th International Symposium on Controlled Release of Bioactive Materials, 1985, pp. 79-80. R.F. Boyer, Changements de phases, Rubber Rev., 36 (1963) 1303.
78 11
12
13
14
15
S.B. Hamilton, Jr., Silicone Technology, in: Applied Polymer Symposia, No. 14, Interscience, New York, NY, 1970. E.K.L. Lee, H.K. Lonsdale, R.W. Baker, E. Drioli and P.A. Bresnahan, Transport of steroids in poly (etherurethane) and poly (ethylene vinyl acetate) membranes, J. Membrane Sci., 24 (1985) 125-143. K. Tojo, Y. Sun, M. Ghannam and Y.W. Chien, Characterization of a membrane permeation system for controlled drug delivery studies, AIChE J., 31 (1984) 741-746. K. Tojo, M. Ghannam, Y. Sun and Y.W. Chien, In uitro apparatus for controlled release studies and intrinsic rate of permeation, J. Controlled Release, 1 (1985) 197-203. Y.W. Chien, Novel Drug Delivery Systems, Marcel Dekker, New York, NY, 1982, pp. 490.
16
17 18 19
20
K. Tojo, Y. Sun, M. Ghannam and Y.W. Chien, Simple evaluation method for intrinsic diffusivity for membrane-moderated controlled release, Drug Dev. Ind. Pharm., 11 (1985) 1363-1371. P.C. Hiemenz, Polymer Chemistry, Marcel Dekker, New York, NY, 1984, p. 115. J. Crank and G.S. Park, Diffusion in Polymers, Academic Press, New York, NY, 1968, Chap. 2-3. A.S. Michaels and H.J. Bixler, Membrane permeation: Theory and practice, in: E.S. Perry (Ed.), Progress in Separation and Purification, Interscience, New York, NY, 1968, pp. 143-186. C.L. Lee, K.L. Ulman and K.R. Larson, Kinetics and thermodynamics of drug permeation through silicone elastomers. III. Effect of alkyl substituent (R) in ( MeRSiO) x polymer, Drug. Dev. Ind. Pharm., 12 (3) (1986) 349-368.
69
Elsevier Science Publishers B.V., Amsterdam - Printed in The Netherlands
EFFECT OF POLYMER COMPOSITION ON STEROID PERMEATION: PERMEATION KINETICS OF ANDROGENS AND PROGESTINS Ying Sun*, Musa Ghannam**,
Kakuji Tojo, Yie W. Chien***
Controlled Drug-Delivery Research Center, Rutgers 789, Busch Campus, Piscataway,
MEMBRANE
NJ 08854-0789
The State University of New Jersey, College of Pharmacy, P.O. Box
(U.S. A.)
Chi-long Lee, Katherine L. Ulman and Kent R. Larson Silicone Research Department,
Dow Corning Corporation, Midland, Ml 48684
(Received October 11, 1986; accepted in revised form December
(U.S. A.)
19, 1986)
The permeation rates of 10 androgenic and 7 progestagenic steroids through synthetic membranes fabricated from poly(trifluoropropylmethylsiloxane) (PFMS), poly(dimethylsiloxane) (PDMS) and the copolymer of PDMS with poly(ethylene oxide) (PEO) and poly(methy1 methacrylate) (PMMA) were investigated and found to be profoundly affected by the chemical structure of penetrants and/or the copolymer composition. The permeation rate for both groups of steroids was observed to decrease in the order of PDMS> PFMS > PDMS/PEO/PMMA copolymer. This can be attributed to the increase in membrane polarity, which causes a decrease in the polymer solubility of steroids, and the incorporation of the high-T, glassy polymer segments, which leads to a reduction in the diffusivity in the polymer. The increase in the PDMS block size tends to promote the permeation of steroids, which can be explained in light of the increase in the size of more permeable PDMS domain. Incorporation of PMMA blocks into PDMS drastically decreases the rate of steroid permeation due to the presence of less permeable “hard” PMMA domains, while addition of PEO produces an enhancing effect on the permeation of less lipophilic steroids such as testosterone.
INTRODUCTION Much interest has recently been demonstrated in the application of biocompatible silicone polymers to regulate the rate of delivery of pharmaceuticals and veterinary drugs. A survey of the literature shows that many investigations have been conducted into the permeation of drugs through silicone mem*Present address: Pennwalt Corporation, King of Prnssia, PA 194069018, U.S.A. **Present address: Wyeth Laboratory, Philadelphia, PA 19101, U.S.A. ***To whom all correspondence should be addressed.
0168-3659/87/$03.50
branes, in order to design membrane permeation-controlled drug delivery systems [ l-8 1. Since Fickian diffusion is usually the governing mechanism for membrane-moderated controlled drug release devices, the solubility of drug in the polymer membrane is of great importance, and consequently, so is the lipophilicity or hydrophilicity of the polymer membrane. In accordance with Fick’s Law of Diffusion, a variation in drug solubility, resulting from a change in polymer lipophilicity, will lead to a change in the concentration gradient across the membrane, and therefore to a modification of the drug permeation rate.
0 1987 Elsevier Science Publishers B.V.
70
Block copolymers have been synthesized to achieve this purpose [ 91, and a silicone elastomer was also copolymerized with other organic polymers to improve its physicomechanical properties [ lo]. A block copolymer consisting of polydimethylsiloxane (soft segment block) and an appropriate organic polymer (hard segment block) gives a copolymer with physico-chemical and mechanical properties which are different from those of the homopolymers. Besides improving the permeation characteristics, the presence of a hard domain dispersed in the rubbery matrix ( Tg= - 123’ C for polydimethylsiloxane) will alter the ultimate mechanical properties and make the copolymer superior to silica-filled and unfilled silicone elastomers [ 111. A recent study by Lee and his associates showed that the permeabilities of some steroids through copolymer membranes prepared from poly (ether urethanes) and poly (ethylene/vinyl acetate) were drastically changed by the modification in polymer composition [ 121, They concluded that this change of permeability can be attributed to the variation of solubility and diffusivity of the steroids in the polymers. In this paper, the authors report the results from a systematic investigation of the permeation of a series of steroids across block copolyfrom membranes prepared mer poly ( dimethylsiloxane) , poly ( ethylene oxide ) and poly (methyl methacrylate) . The relationships between the permeation of steroids and the composition of the copolymer membranes, the block size of silicone polymers and copolymers, as well as the molecular structure of steroids will also be discussed.
MATERIALS AND METHODS Materials
Various androgens and progestins were used as the model drugs in this investigation (Tables
SILICONE POLYMER MEMBRANE
Polydimethylsiloxane
(PDMS):
CH3 H3C-
SiI
0
3
CH3
Polytrifluoropropylmethylsiloxane
IPFMS):
CF
I3 I2
CH
H3C-
CH 13 Si -
0
-Si
-
CH
3
’ CH3 Fig. 1. Structure of the silicone membranes used in this study; n is the monomer block size.
1 and 2). All androgens and progestins were purchased from Sigma Chemical Company, except testosterone pentanoate, testosterone cyclohexanoate (Pioneer Lab. Inc.), and 17crhydroxycorticosterone (Upjohn Company). These model drugs and polyethylene glycol400 (PEG 400, Fisher Scientific Company) were used as received. The membranes consisting of poly ( dimethylsiloxane ) , poly ( trifluoropropylmethylsiloxane) (Fig. 1) , and the copolymer of silicone elastomer with poly (ethylene oxide) and poly (methyl methacrylate) were customprepared (Dow Corning Corporation ) (Table 3). The average molecular weights of the PDMS block were 1200, 2400 and 3600 and those of PEO were 600 and 1000, respectively. The method of synthesis for these copolymers will be described in a forthcoming paper. Membrane permeation studies
To study the membrane permeation kinetics of testosterone and progesterone and their
71 TABLE 1 Chemical structure
of androgens
investigated
(a)
Code
Androgens
B,
B2
B,
A-l A-2 A-3 A-4 A-5 A-6 A-7 A-6 A-9 A-lo
19-Nortestosterone Testosterone 17cwMethyltestosterone Testosterone acetate Testosterone propionate Testosterone pentanoate Testosterone heptanoate Testosterone cyclohexanoate Testosterone benzoate Testosterone cypionate
H
H H CH, H H H H H H H
H H H CH,CO CH,,CH,CO CH:,(CH,):,CO CH:,(CH,),CO C,H,,CO GHsCO C,H,(CH,),CO
derivatives through silicone and silicone copolymer membranes, a hydrodynamically wellcalibrated membrane permeation system (Bellco Glass Inc.) was used [ 131. After assembling a polymeric membrane between the donor and receptor compartments, a suspension of steroid in 40% (v/v) aqueous PEG 400 solution, which was pre-heated to 37”C, was added to the donor compartment. The same aqueous solution (without drug) was added to the receptor compartment. The use of 40% (v/v) PEG 400 as the diffusion medium was to assure the maintenance of sink conditions in the receptor solution [ 151. At each predetermined time interval, 10 ml of receptor solution was sampled and replaced immediately with the same volume of fresh, drug-free PEG 400 solution. The steroid concentration in the sample was analyzed by UV spectrophotometry (Per-
CH, CH, CH, CH, CH, CH, CHz CH2 CH,
kin-Elmer Corporation) from the peak absorbance at 245 nm. The whole permeation experiment was conducted at 37’ C. The rate of permeation obtained experimentally was then corrected for the effect of hydrodynamic boundary layers by a correction factor (y), which was previously calculated through the calibration procedure of the dimensionless relationship Sherwood-Reynolds-Schmidt [ 131. The value of y depends on both the permeant and polymer membrane used [ 141. In the present study, it led to corrections less than 10% for the rate of permeation in most cases, with a few very lipophilic drugs excepted. For instance, progesterone permeating through a lipophilic membrane (such as that made of
PDMS) necessitated a correction factor as high as 60%. The corrected rate of steroid permeation, called the intrinsic permeation rate, was
12
TABLE 2 Chemical structure of progestins investigated (b)
Code
Progestins
P-l P-2 P-3 P-4 P-5 P-6 P-7
Progesterone Desoxycorticosterone lla-Hydroxyprogesterone 17wHydroxyprogesterone Corticosterone 17wHydroxydesoxycorticosterone Hydrocortisone
H OH H H OH OH OH
H H OH H OH H OH
H H H OH H OH OH
TABLE 3 Composition of copolymer membranes evaluated Membrane No.
PDMS block size
PEO block size
1 2 3 4 5 6 7 8 9 10
1200 2400
-
1200 1200 2400 2400 2400 2400 1200
600 600 600 600 600 1000 1000
then normalized as regards the thickness of the polymer membrane used, so a proper comparison could be made. Only the normalized intrinsic permeation rates are reported throughout this article. The diffusivity of steroids was calculated using the lag-time method [ 161.
PDMS/PEO ratio
100/o 100/o 100/o 50150 50150 66133 66133 66133 55145 38/62
PMMA, %
0 0 0 0
30 0 15 30 45 45
Tensile strength, psi 810 240 230 300 1700 190 110 1900 1620 3020
RESULTS AND DISCUSSION
The results for the permeation of progestins and androgens through PDMS and PFMS polymers and PDMS/PEO/PMMA copolymer membrane are shown in Tables 4 and 5, respec-
73 TABLE 4 Effect of polymer composition on the membrane permeation of progestins Progestins
P-l P-2 P-3 P-4 P-5 P-6 P-7
Normalized permeation rate (,&cm h x 10’) PDMS
PFMS
PDMS/PEO/PMMA”
600 39 2.4 2.4 0.82 0.89 0.60
51 24 2.1 1.8 0.67 0.70 0.39
5.8 3.2 0.82 0.77 0.71 0.70 0.59
“Membrane No. 5 (Table 3). TABLE 5 Effect of polymer composition on the membrane permeation of androgens Androgens
A-l A-2 A-3 A-4 A-5 A-6 A-7 A-8 A-9 A-10
Normalized permeation rate (,&cm h x 10’) PDMS”
PFMS”
PDMS/PEO/PMMAb
89 19 35 210 400 24 6.9 2.9 2.7 2.2
11 3.2 5.4 58 46 11 2.6 1.8 0.95 1.6
4.4 1.7 1.9 6.1 7.1 3.1 1.3 0.85 0.36 0.85
“Ref. [7]. “Membrane No. 5 (Table 3 ) .
tively. It was found that the effect of the variation in the lipophilicity of steroidal molecules, which is reflected by the drug solubilities in the aqueous diffusion medium, on the permeation across the copolymer membrane is consistent with the results observed earlier [ 6,7]. The change in polymer composition appeared to affect the rate of membrane permeation of a lipophilic steroid, like progesterone, more significantly than that of a hydrophilic steroid, like the hydroxyprogesterones. The membrane permeation rate of progesterone and its monohydroxy derivatives was found to decrease in the order of: PDMS > PFMS > PDMS/PEO/
PMMA copolymer, while the effect on the diand tri-hydroxy progesterone was minimal (Table 4). It can be seen that for a lipophilic steroid, such as progesterone, the permeation rate was reduced remarkably as the silicone membrane became less lipophilic. The rates of progesterone permeation through PFMS and were membranes PDMS/PEO/PMMA approximately only l/lOth and l/lOOth of that across the lipophilic PDMS membrane, respectively. However, the effect of the variation in polymer composition became gradually less significant as steroid hydrophilicity increased. It was observed that the permeation rates of the
14
hydroxy derivatives of progesterone were only slightly dependent upon the polymer compositions as the number of hydroxy groups increased. The permeation rate data for androgens through PDMS/PEO/PMMA copolymer was also found to follow a pattern similar to that observed for PDMS and PFMS membranes. It can be seen from the data in Table 5 that either the variation in the number of methyl groups on the steroidal skeleton or the esterification at the 17 position profoundly affects the magnitude of permeation across the polymer membranes. In general, higher permeation rates were achieved with more lipophilic androgens. However, the permeation rates started to decline as the ester side chain became very bulky, which could be attributed to the drastic decrease in the aqueous solubility of these androgens. The permeation rates of androgens and progestins were reduced as the polymers became more polar, as a result of the introduction of a trifluoropropyl group onto the silicon atom, or by copolymerization of polydimethylsiloxane with polar PEO and PMMA polymer. A rather similar pattern in descending order was noted for the permeation rates of androgens and progestines. Figure 2 shows the effect of PDMS block size on the permeation rates of representative analogs of androgen and progestin. The permeation rates increased as the size of the PDMS block increased from 1,200 to 3,600. This increase in permeation rate can be attributed to the fact that as the size of PDMS block increases, the highly permeable PDMS domain increases, and consequently the permeability increases. A similar phenomenon was reported recently [ 121. The results shown in Fig. 2 also indicate that the effect of block size seems to be dependent upon the chemical structure of the penetrant molecules. Incorporation of PMMA into PDMS/PEO block copolymers markedly reduced the membrane permeation rates of steroid (Fig. 3). This effect may be attributed to the poor drug
loo-
DESOXYCORTlCOSTEl?ONE
3600
2400 PDMS
BLOCK
SIZE
Fig. 2. Effect of PDMS block size on the normalized permeation rate of testosterone ( 0 ) , testosterone propionate ( 0 ) , progesterone ( n ) and desoxycorticosterone (A ).
permeability of PMMA. PMMA is a glassy polymer with a glass transition temperature of 106°C [ 171, whereas PDMS and PEO have glass transition temperatures of - 123 “C and -41°C respectively, and are fluid at room temperature. Incorporation of glassy PMMA into the rubbery PDMS/PEO creates “hard”, less-permeable polymer domains, through which penetrant molecules can diffuse only with great difficulty [ 18,191. This explains the observed reduction in the membrane permeation rates with increasing PMMA content (Fig. 3). On the other hand, incorporation of hydrophilic PEO into the hydrophobic silicone polymer was seen to improve the permeation rate of testosterone through PDMS/PEO/PMMA copolymer (Fig. 4). Apparently, the incorporation of PEO caused an increase in the hydrophilicity of the copolymer and thus facilitated
75
\
TESTOSTERONE
PROPIONATE
PROGESTERONE
PMMAX
0
I
I
15
30
Fig. 4. Effect of PEO content in PDMS/PEO/PMMA copolymer on the normalized permeation rate of testosterone: Key: PDMS/PEO = 38/62 ( 0 ) , PDMS/PEO = 66/33 (0).
PMMAX
Fig. 3. Effect of PMMA content in PDMS/PEO/PMMA copolymer on the normalized permeation rate of testosterone ( 0 ) , testosterone propionate (0)) progesterone (n ) and desoxycorticosterone (A ).
the permeation of testosterone, which has a hydroxy group at the 17 position and is therefore less lipophilic than steroids such as progesterone. However, as the PMMA content of the copolymer was increased, the enhancing effect of PEO on the rate of permeation diminished, as a result of an offset by the negative effect of PMMA. Membrane permeability (P,) is a product of diffusivity (Q,) and solubility (C,,) in the polymer. To understand which is responsible for the experimental results presented above, the permeation of testosterone through the three types of polymer was examined. The results are shown in Table 6. It can be seen from Table 6 that incorporation of PEO into PDMS caused a 47-fold decrease in D, but a 68-fold increase in C,,. As
a result, the permeability increased 45%. The presence of hydrophilic PEO in the copolymer obviously was responsible for the marked increase in C, of testosterone, which is a less lipophilic molecule. It has to be mentioned that, although incorporation of PEO into PDMS increased the permeation rate of testosterone, it reduced the permeation rate of lipophilic steroids such as progesterone. The decrease in D, due to PEO can be interpreted qualitatively in terms of the “free volume” model. That is, the 7’, of PEO ( -41 “C) is higher than that of PDMS ( - 123°C)) therefore the “free volume” of PEO should be lower and hence D, would be lower than that of PDMS. For quantitative interpretation of the experimental results, however, the “free volume” model has to be refined or modified [ 201. Table 6 also shows that incorporation of PMMA into PDMS/PEO block copolymer caused an about 5-fold decrease in D, and a 2fold decrease in C,. The net result was a g-fold reduction in the normalized permeation rate.
76 TABLE 6 Effect of polymer composition on the membrane permeation of testosterone
P, (&cmsX10”)
D, (cm’/s x 10’) C, @g/cm” X 10”)
PDMS
PDMS/PEOb
PDMS/PEO/PMMA’
5.6 66 0.09
8.1 1.4 5.8
0.88 0.30 2.9
“Ref. [ 191. bMembrane No. 6: PDMS/PEO = 2/l, PDMS block size = 2400. ‘Membrane No. 8: PDMS/PEO = 2/l, PMMA 30%, PDMS block size= 2400. TABLE 7 Effect of copolymer composition on the membrane permeation of androgens Androgens
A-l A-2 A-3 A-4 A-5 A-6 A-l A-8 A-9 A-10
Normalized permeation rate (pg/cm hx 10’) Memb. 5”
Memb. 6b
Memb. 8
4.4 1.7 1.9 6.1 7.1 3.1 1.3 0.85 0.36 0.85
61 29 31 68 91 6.1 5.4 3.4 2.1 2.2
16 3.2 5.4 58 46 11 2.6 1.8 0.95 1.6
“PDMS/PEO: 50/50; PMMA: 30%; PDMS block size: 1200. “PDMS/PEO: 66/33; PMMA: 0%; PDMS block size: 2400. ‘PDMS/PEO: 66/33; PMMA: 30%; PDMS block size: 2400.
The decrease in II, value was apparently caused by the presence of hard PMMA domains, which are expected to have a lower D, than PDMS or PEO because of its higher Tg (106’ C ) , as mentioned earlier. The data in Table 7 show that the permeation rate first increased with increasing lipophilicity of the steroids and then declined as the ester side chain became very bulky. On the other hand, the diffusivity remained more or less independent of the lipophilicity and the molecular size of androgenic steroids (Table 8). The data in Table 8 also suggest that incorporation of PMMA into the PDMS/PEO copolymer membrane appears to produce a 5- to lo-fold
reduction in androgen diffusivity (comparing Membrane No. 6 with Membrane No. 8)) while there was only a slight increase in membrane diffusivity as the PDMS block size was increased and the PEO content was changed (comparing Membrane No. 5 with Membrane No. 8). Although incorporation of PMMA into the PDMS/PEO copolymer caused a decrease in the permeation rate (Table 7), the presence of hard PMMA domains reinforced the mechanical properties of the copolymer. This is illustrated by the marked increase in the tensile strength shown in Table 3. The copolymers were tough and transparent. The tensile strength increased
77 TABLE 8 Effect of copolymer sivity of androgens Androgens
A-l A-2 A-3 A-4 A-5 A-6 A-7 A-8 A-9 A-10 “PDMS/PEO: “PDMS/PEO: ‘PDMS/PEO:
composition
Diffusivities
on the membrane
(cm*/s~
diffu-
lOa)
Memb. 5”
Memb. 6h
Memb. 8
0.10 0.18 0.17 0.13 0.12 0.14 0.10 0.16 0.20 0.13
1.0 1.4 1.5 2.0 2.0 1.1 1.4 1.3 1.5 2.0
0.10 0.30 0.29 0.20 0.24 0.19 0.11 0.10 0.30 0.17
50/50; PMMA: 30%; PDMS block size: 1200. 66/33; PMMA: 0%; PDMS block size: 2400. 66/33; PMMA: 30%; PDMS block size: 2400.
with increasing PMMA content. the copolymers were shown to toxic. These properties make copolymer ideal for applications drug delivery.
more permeable PDMS domain. Incorporation of PMMA blocks into PDMS drastically decreased the rate of steroid permeation, due to the presence of less permeable “hard” PMMA domains. The addition of PEO produced an enhancing effect on the permeation of less lipophilic steroids such as testosterone.
ACKNOWLEDGEMENTS Y.S. and M.G. gratefully acknowledge port by Dow Corning Graduate Research lowships at the Rutgers University. REFERENCES
Furthermore, be non-cytothis class of in controlled 4
CONCLUSION The rates of membrane permeation of androgenie and progestagenic steroids through a silicone polymer membrane were found to be profoundly affected by the chemical structure of the penetrants and/or the copolymer composition. The permeation rate for both groups of steroids was observed to decrease in the order of PDMS > PFMS > PDMS/PEO/PMMA copolymer. This was attributed to the increase in membrane polarity, which caused a decrease in the polymer solubility of steroids, and the incorporation of high-‘lr glassy polymer segments, which led to a reduction in the diffusivity in the polymer. An increase in PDMS block size tends to promote the permeation of steroids, which can be explained in light of the increase in size of the
supFel-
5
6
7
8
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