Controlled release from erod1ble poly(ortho ester) drug delivery systems

JOUnlOl Of Controlled

Release,

Elsevier Science Publishers

l(1984,

23-32

B.V., Amsterdam

23

- Printed

m The Netherlands

CONTROLLED RELEASE FROM ERODIBLE POLY(OR+HO ESTER) DRUG DELIVERY SYSTEMS

Variable ratezeroorder release from surface erosion controlled ercdible poly(ortho ester) deuices was reproducibly attained with the use of latentiated acid catalysts. Vwious chemical and physical characteristics of the drug release system affected its erosion/drug release performance. The greatest effect was achieved with the choice of anhydride catalyst. A range in release rates of over two orders of magnitude was obtained with acid catalysts having a first pK, from 1.8 (maleie) to 4.3 (glutark). The control over the erosion rate was extended by altering the amount of catalyst present in the device. Increasing the anhydride content increased the zero order release up to a point, thereafter having no effect. The physical properties of the polymer, such as thermal and mechanical properties. were a function of the molecular weight and composition of the copolymer. Both had an effect on release rate: increasing either molecular weight or glass transition tempemture or both decreased the rate. Increasing release rates were observed at higher drug loadings, possibly due to plasticization of the matrix by the drug and/or leachbag of the drag by diffusive mechanisms. Release rates urere proportional to the surface area and durations were proportional to thichness of the test slabs, agreeing with the proposed surface erosion mechanism. All of these parameters were capable of being adjusted to giue zero order release deuices coiiering a wide range of useful release rates.

INTRODUCTION

In general, constant release rate drug delivery device systems are based on at least one of three separate designs: control of drug release by diffusion, by osmotic pressure, or by erosion [l]. In the case of parenteral devices, erodible drug delivery systems have an advantage over other controlled release devices in that sequential build up of the material of construction upon repeated dosing is not encountered; thus device retrieval is not required.

0168.3659/84/$03.00

B Elsevier Science

Publishers

Erodible polymers have been designed specifically for surface erosion controlled drug release systems, where the mechanism of release is a chemical breakdown of the solid hydrophobic polymer from the outer surface inward [Z]. The general concept has been to synthesize polymers of low water permeability having potentially easily hydrolysable backbone bonds. This is to favor erosion chemistry only at the surface and not throughout the bulk. The drug may be homogeneously dispersed throughout the erodible polymer matrix and be-

B.V

24

comes available for systemic absorption at a constant rate when polymer dissolution occurs at the erosion front. The water insoluble polymer is altered by chemical or physical action in the physiological environment to facilitate its dissolution and excretion. Poly(ortho carbonate)s and poly(ortbo ester)s have been developed for this purpose [3]. Of special note are the poly(ortho estar)s, which are more prone to acidic hydrolysis than basic hydrolysis [4]. The ALZA Corporation have tested an erodible poly(ortho ester) drug delivery system (CHRONOMERTM) [5] made from 2,2-dialkoxytetrahydrofuran and 1,4-cyclohexanediiethanol. When hydrolysed, the polymer released 1,4-cyclohexanedimethanol and hydroxyhutyric acid as the erosion by-products. Unfortunately, the acidic by-product catalysed the erosion and caused an increasing erosion rate with time. This has been compensated for by using device geometries that decrease in surface area with erosion (e.g., cylinders). Heller et al. [6-91 have synthesized poly(ortho ester)s that do not erode by an autocatalytic mechanism since the hydrolysis by-products are not acidic. The same polymer structures were used in the present study. These poly(ortho ester)s also do not erode under basic conditions. To facilitate erosion at pH 7.4, incorporation of water soluble salts such as sodium carbonate, sodium sulfate or sodium chloride gave prolonged zero order delivery of norethindrone. Their proposed mechanism was a combination of both a slow surface erosion and osmotic uptake of water to produce a moving, swelling front. In addition, Lang@ et al. [lo] have synthesized and tested polyanbydrides that undergo surface controlled erosion. A substantial lag tile followed by a zero order release was noted in this initial study. Here the efforts to produce a versatile erodible nolv(ortho ester) drue delivery svstern are _ presented. Laten da&d acid- catalysts have been physically admixed with

the poly(ortho ester) to gain an important measure of control over the zero order erosion rate and induction 1% time. This approach extends the utility -of erodible drug delivery systems in that the release rate profile of the drug may be preadjusted through the incorporation of small amounts of these latent acid catalysts. This adds much latitude in the design of specific erodible drug delivery devices where the rate/duration pattern of the given drug must be engineered into the erodible system. Acid anhydrides have been selected as the latentiated catalysts, since they should not act to catalyse the poly(ortho ester) hydrolysis until they themselves are hydrolysed. Thus the addition of the acid anhydride instead of the corresponding free acid has the potential to add hydrolytic stability to the device during fabrication and storage.

MATERIALS

AND METHODS

Poly(ortho ester) samples were milled to
i 10 ym thick and weighed 43 mg. Dissolution kinetics of the erodible discs were determined by a vertical agitation method similar to that described by Heller et al. [X3]. Discs (n = 4) were suspended in stainless steel mesh bags and agitated at 32 strokes/minute in pH 7.4 Soreson buffer at 37°C. Release of the marker dye (e.g., methylene blue, MB) or the drug was monitored continuously via UV spectroscopy with a peristaltic pump and a flow cell. Sample weight loss to indicate polymer erosion was determined by removing a disc from the dissolution medium at a given time, soaking for two hours in deionized water to remove buffer, freeze drying the insoluble disc and comparing the weight to that of the disc prior to dissolution. Determination of [1,4-‘%!I succinic anhydride concentrations was accomplished with a Beckman L56800 liquid scintillation counter; corrections were made for quenching. Anhydride content in the polymer bulk was determined by microtoming 20 gtm sections normal to the cylinder axis and dissolving in an aqueous liquid scintillation cocktail (ScintiVerse Bio-HP, Fisher Scientific Co.) with subsequent counting. Succinic acid content released to the aqueous dissolution medium was assayed by adding 4 ml aqueous aliquots to 10 ml of the cocktail and counting.

RESULTS AND DISCUSSION

The structure of the polymer is shown in Fig. 1. A diketene a&al (3,9-bis(ethylidine)2,4,8,10-tetraoxaspiro[5,5]undecane; DETOSU) and one or more dials were condensed to form hydrophobic linear random copolymers. Typical weight average molecular weights were 35.000 to 60.000. Bv the choice of a mixture of dial ‘co-monomers (l,&hexanediol, HD; tmns-cyclohexanedimethanol, t-CDM), devices were synthesized with a single glass transition temperature (Tg) ranging from 22°C to 122°C. Thus hoth glassy and rubbery materials have been tested. The polymer

hydrolysis ing dials

by-products and

were the correspond-

pentaerythritoi

dipropionate

[=I.

Fig.

1. Poly(orrho ester) repeat strwt~re. Typical dials eopolymerized were M-hexsnediol (HD) and trans.cyclohexanedimethanol (I-CDM).

The greatest control over the erosion of poly(ortho ester) discs was achieved through adjustments in the composition of the device. Thus the acid anhydride catalyst concentration and structure, the polymer molecular weight and chemical structure, and drug loading affected both the magnitude of the constant drug release rate and the lag time. Many acid anhydrides were screened as potential catalysts for the erosion of the poly(ortho ester) devices. It was found that the structure and the acidity of the hydrolysed acid anhydride markedly affected the resulting drug release profile. Figure 2 demonstrates that, based on the anhydride structure, devices have been fabricated with drug release properties rang ing from fast releasing with a very short lag time (650 + 50 pg MB/cm’ h, 0.9 h) to slow releasing with a much longer lag time (11.7 f 0.2 pg MB/cm2 h, 24 h). The variations in the observed lag times were reproducible and were likely a complex function of the intrinsic rate of hydrolysis of the anhydride, and thus its structure and solubility, in combination with the actual concentration of anhydride in the device. Therefore, the lag time decreased with a more acidic catalyst and at higher anhydride concentrations. Increasing the acidity

ester) discs of 65:33 HDiKDM

contained

0.2% MB.

Fig. 3. The effect of acid strength on the normalized rate of hydrolysis of poly(ortho ester) discsof 60:40 HDlt-CDM containine 0.2% methvlene blue f37”C. pH 7.4). The abscissa-represents th; first p& bf the hydrolysed acid anhydride.

of the catalyst both increased the rate of the polymer erosion and decreased the lag time. The effect on the release rate is snown more clearly in Fig. 3, where the methylene blue release rate was normal-

ized by the equivalent mole fraction of anhydride, fa, and plotted vs. the first pKa of the catalyst. Note that selection of anhydride type covered a release rate range of over two orders of magnitude. This provides the primary source of control over the release characteristics of these devices. Arguments for the slight deviation from linearity observed for the pyromellitic, diglycolic, and succinic anhydrides can be made based on ring size (anhydride hydrolytic stability) or electron withdrawing effects (resulting acid strength). Other than anhydride type, and thus pK,, the overall drug release rate was conveniently adjusted by varying the amount of acid anhydride incorporated in the polytortho ester) disc. Fieure 4 shows that the zero order methylene blue release rate increased linearly with anhydride concentration up until a critical concentration, whereby the release rate was invariant with increasing catalyst content. For devices containing phthalic anhydride or 2,3-pyridine

27 dicarboxylic anhydride tbis occurred above 2 percent by weight anhydride. Presumably, above the critical catalyst concentration the rate of water intrusion into the polymer disc was rate limiting, since the diffusion coefficient of water in 65:35 HD/tCDM poly(ortho ester) was quite low, 3.0 x 10-8 cmZ/src [ 141.

Fig. 4. The effect of anhydride content on the methylenc blue (MB) release rate from 66:35 HD/ t_CDM discs containing 0.2% MB (37’C. pH 7.4).

The physical properties of the polymer also had an effect on the dissolution characteristics of the controlled release device. Glass transition temperat~es, T,, and gross mechanical properties were a kmction of the methvlene blue release rate (Fig. 51. polylorthi ester) copolymer. Alte>i~ the HD/t-CDM ratio affected both the Z’, and the methylene blue release rate (Fig. 5). DETOSUkCDM polymers were glassy at 37’C (Tg = 122”C), while DETOSUjHD polymers were elastomeric at 37°C (Tg = ZZ°C). Two release rate trends were observed: one each for glassy and rubbery discs. The intersection of the two r&we rate vs. dioi compo~~on lines at 37’C

corresponded to a 85:15 DETOSU-HD/ t-CDM copolymer. Faster release rates were expected for the rubbery materials since diffusivity in nonporous rubbery matrices is greater than that in nonporous glassy matrices. i3y X-ray crystallography, no crystallinity was detected in any of these samples.

Fig. 5. The effect of polymer composition on the refease of methylene blue (ME, .) from HD/t-CDM copolymers containing 2.0% pbthdic anhydrids and 0.2% MB (W’C, pH 7.4). The ordinate on the right represents the &WI trmsition temperatures (Tgr k) of each copolymer.

The effect of the mokcuhw weight of the polymer and its distribution on the methyI~e blue release rate is shown in Fig. 6. These sampks were binary blends of low (13,000) and high (51,000) molecular weight 65:35 DETOSU-HD/t-CDM. By decreasing the molecular weight by a factor of four, the release rate increased by a factor of two. The intermediate data ooints were those of blends, and thus bad a pkydispersity very different than that of the 1SK and 51K polymers which represented the end point data. Yet, it is clear that higher average molecular weight polymers gave a significantly slower release rate. This may be due to the fact that loss of polymer mechan-

28

ical integrity and hence drug release was associated with a particular molecular weight. Therefore, it may be that higher molecular weight polymers need to undergo more conversions to allow significant water and drug diffusion. Very low molecular weight discs were quite brittle, whereas high molecular weight discs were ductile and tough. Molecular weights of approximately 30,000 were needed for fabrication of poly(ortho ester) discs with good mechanical integrity. Lag times were relatively unaffected by either polymer molecular weight or copolymer ratio.

as the drug loading increased from 2 to 8% by weight, the lag time decreased sliahtlv and the drun release rate increased. As- expected, doubling the drug loading doubled the drug release rate. This implies that the polymer erosion rate had not been significantly altered by the drug loading, thus supporting a surface erosion mechanism. The decrease in lag times may have been due in part to plasticization of the polymer matrix facilitating faster water intrusion rates, or to leaching of the drug by diffusive mechanisms. Higher loading (>25% by weight) caused a significant Loss in the mechanical integrity of the device for most drug substances. Since very fast release rates were observed for such cases, aqueous channeling may have been prevalent.

that

Fig. 6. The effect of polymer weight average molecular weight on the release of methylene blue (MB) from poly(ortho ester) discs of 65:35 HDltCDM containing 2.0% phthalic anydride and 0.2% MB (WC, pH 7.4). The changes in molecular weight were obtained by physically blending poly(ortho ester)s of 51,000 and 13,000 molecular weight.

Fig. 7. The effect of drug loading on the drug raleaae profile from 50:50 HD/t-CDM poly(ortho ester) discs containing 0.2% poly(sebacic anhydride) (37°C. pH 7.4). Drug loadings: 8% w/w (e), 6% (o), 4% (.), 3% (0).

In most cases a small percentage (0.2% by weight) of a water soluble dye, usually methylene blue, was used in lieu of a drug. By “sing very small amounts of such a marker molecule it was hoped that the erosion prop. erties would reflect only the polymer/anhy dride contributions. Indeed, it was found that increasing the drug loading resulted in faster drug release rates. Figure 7 shows

The injection molding technique of mixing excipients in the poly(ortho ester) melt produced discs with reproducible erosion characteristics. As shown in Table 1, the variability of the zero order release rates within batches was good, within +4.6%; that among batches was somewhat poorer, within +16%, especially at higher anhydride loadings. When the catalyst content

29

was kept low (e.g., 0.5%), it was demonstrated that homogeneous dispersion was evident (Fig. 8). Possibly higher anhydride concentrations in the bd:h resulted in an inhomogeneous mixing throughout the disc by exceeding the solubility limit. The Hildebrand solubility parameters of these anhydrides were generally 12-14, whereas that for the poly(ortho ester)s was 9.0 f 0.5. Thus, the anhydrides are not expected to be appreciably soluble in the polymer matrix, since the solubility parameters differed by more than 1.7. TABLE

1

Reproducibility of methylene blue (MB) release from 65:35 HD/f-CDM containing 2% PA and 0.2% MB WPhthalic

% Standard deviation

anhydride

6.8 2.0 1.7

within batches (n = 4)

among batches

3.7 3.2 4.6

16.0(n = 2) 8.3 (n = 3) 5.8 (n = 3)

The design of an effective constant release rate erodible delivery system requires a rate determining zero order process, such as physical dissolution or chemical hydrolysis. Hopfenberg [15] relates that zero

kinetics will be obtained when the rate determining step occurs at the surface boundary between the dissolution environ-

order

ment and the unaffected polymer interior. This demands that the erodible polymer be relatively hydrophobic, since simultaneous erosion throughout the bulk will likely lead to a diffusion controlled drug release mechanism which is dependent upon time. In addition, surface erosion from a device which does not significantly change its geometry or surface area during the erosion process, i.e., a thin slab, is also a prerequisite. Certainly :be combination of certain time dependent drug release processes, such as bulk erosion and drug diffusion, may offset to result in a nearly constant drug release rate but such systems are difficult to design and potentially difficult to control in viva Since the poly(ortho ester)s utilized in this study were quite hydrophobic, no bulk erosion was expected to occux over the time periods demonstrated. The predominant mechanism of drug release has been perceived as a true surface zone erosion process with little if any contribution from simple drug diffusion. Figure 9 diagrams a proposed mechanism for the surface zone erosion of these poly(ortho ester) drug delivery devices [12]. Water slowly diffuses into a thin reaction zone at the surface of the device, the thickness of which is defined bv the competing series/parallel processes. ” Acid anhydrides are hydrolysed to activate the catalysts, which allow random hydrolysis of the ortho ester backbone linkages in the presence of water. The water soluble polymer hydrolysis by-products, the catalyst, and the incorporated drug are subsequently dissolved from the surface of the reaction zone into the dissolution medium. Under this mechanism, zero order release can be achieved only if hydrolysis of ortho ester linkages or acid anhydride catalyst, or both, are rate limiting [12]. -4 typical drug release profile of an acid anhydride catalysed erodible poly(ortho ester) thin slab (Fig. 10) defines this process in three phases. The

30

lag phase is indicative of the finite dependence of the observed drug release upon the initial slow water intrusion and activation of the catalyst, and its subsequent initial erosion of the polymeric matrix. The zero order phase occurs during the steady state erosion of the device as the reaction zone and erosion front move to the unreacted core of the device. The depleting phase is a departure of the steady state erosion from zero order kinetics due to frequently unavoidable change in the surface area (i.e., edge effects). Fig. 10. Demonstration of the three phases of drug release which may occur during the acid catalysed dissolution of poly(ortho ester) discs. The test sampies were 65:35 HD/t-CDM containing 2.0% phthslic anhydride and 0.2% methylene blue (MB) (37’C, pH 7.4).

Fig. 9. Surlace reaction zone model for the acid catalyred erosion of poly(ortho ester) thin slabs: (1) permeation of H,O into the reaction zone, (2) hydrolysis of the acid anhydride to the corresponding acid, (3) hydrolysis of the poly(ortho ester) backbone linkages, and (4) dissolution of the polymer erosion products and the drug into the external aqueous medium.

Evidence to support a surface zone erosion for these poly(ortho ester)s is shown in Fie. 11. The release of the methvlene blue marker and the succinate catalyst appeared in the dissolution medium at the same rate as the polymer was eroding. One would expect polymer erosion to lag behind drug release if drug diffusion from the matrix was significant. It appears that at least for 50:50 HD/tCDM discs (Z’, = 62’C) eroding within 20 days, excipient diffusion prior to erosion was minimal if the excipient loading was not more than about ZO-25% by weight. As expected, diffusional considerations are more important for discs of lower Tg, i.e., below 37°C. Further support process

Fig. 11. The appearance of methylene blue (MB, o) and (1.4.“C]sucoinic acid (0). and the disc weight loss (e) as they were recorded from the erosion of SO:50 HD/L-CDM containing 0.1% [1,4~“Clsuccinic anhydride and 0.3% MB (37”C, pH 7.4).

of this mechanism was found in the predictable release rates which were observed when the device geometry was changed. As the disc thickness increased the duration of the erodible device increased linearly (Fig. 12). When the thickness remained increased surface area due to constant, an increase in the disc diameter resulted in a proportional increase in the drug release rate (Fig. 13).

of eradible devices containing acid anhydride catalysts. Altering the amount of anhydride catalyst in these devices has been shown to provide a convenient method for tailoring their erosion characteristics. Zero order release has been reproducibly achieved by a surface reaction zone machanism, following a rational design for contemporary erodible drug delivery systems. Erosion of these systems leads to by-products of anticipated low toxicity, suggesting clinical testing for efficacy. The preceding has described how the composition of these devices affected the dissolution of erodible poly(ortbo ester)s. Other factors affecting the erosion kinetics, such as device fabrication and the dissolution environment, were important but will be discussed in subsequent publications.

ment

Fig. 12. The effect of poly(ortho ester) disc thickness an the duration of drug release from 50:50 HCI t-CDM containing 0.2% poly(sebacic anhydride) and 4% drug (37-C, pH 7.4).

The authors wish to thank Dr. Jorge Heller and SRI International (Menlo Park, CA) for poly(ortho ester) synthesis, molecular weight determinations, and X-ray crystallography.

Fig. 13. The effect of paly(ortha ester) disc surface area on the drug release rate from 50:50 HD,r-CDM containing 0.2% poly(sebacic anhydride) and 4% drug (STC, pH 7.4).

R.W. Baker and H.K. Lonsdale, An emerging use for membranes, Chemtech, 5 (1915) 668. J. Heller, Synthesis of biodegradable polymers for biomedical utilization. Amer. Chem. Sac. symp. Ser., 212, 1983, pp. 373-392. N.S. Chai and J. Heller, Dnrg delivery devices manufactured from poly(ortho ester@ and poly(ortho carbonates), U.S. Patent 4,093,709,

June 6.1978.

CONCLUSIONS

Erodible poly(ortho ester)s have been designed specifically for controlled ralaase applications. Their instability in an aqueous acidic environment has led to the devalop-

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