Osmotically controlled drug delivery systems produced from organic solutions and aqueous dispersions of cellulose acetate

Journal of Controlled Release, 4 (1986) 203-212 Elsevier Science Publishers B.V., Amsterdam - Printed in The Netherlands

203

OSMOTICALLY CONTROLLED DRUG DELIVERY SYSTEMS PRODUCED FROM ORGANIC SOLUTIONS AND AQUEOUS DISPERSIONS OF CELLULOSE ACETATE C. Bindschaedler*, R. Gurny and E. Doelker School of Pharmacy, (Received

University

of Geneva,

June 28, 1985; accepted

CH-127

1 Geneva 4 (Switzerland)

in revised form June 11,1986)

The use of aqueous colloidal dispersions of cellulose acetate instead of organic solutions is proposed as an alternative way to obtain osmotic tablets. At the same plasticizer level, the semipermeable membranes produced from latices were more permeable to water and swelled to a greater extent than those prepared from organic solutions. Consequently, the release rate of the model drug potassium chloride from coated tablets produced from aqueous dispersions was higher and the time delay before constant release was shorter. Generally, the permeability and the solute release rate varied over a wide range, depending on the physico-chemical properties and concentration of plasticizer and on the coating conditions (coating temperature, rate of coating and drying duration). Plasticizers with low vapor pressure gave more permeable films. The mechanical properties of the membranes were also examined and strong films could also be produced from aqueous dispersions, despite the mechanism involved in the formation of such films.

INTRODUCTION

Constant and extended plasma levels may offer a therapeutic advantage for certain drugs in terms of both efficacy and tolerance of the treatment [l] . In addition, from the point of view of patient compliance, once-a-day administration is often desirable. Among controlled-release devices, osmotically driven systems hold a prominent place, because of their reliability and their ability to deliver their contents at predetermined zeroorder rates for prolonged periods [2-61. In their simplest form, called the elementary osmotic pump, such systems consist of a core containing a drug of suitable aqueous solubil*To

whom

correspondence

should

be addressed.

ity and a semipermeable membrane with a micro-orifice drilled usually by a laser beam. In contact with an aqueous medium the core absorbs water, generating a pressure gradient across the membrane. Release of pressure occurs through the orifice and the drug is pumped out of the system at a rate controlled by the thickness and permeability of the membrane. The release rate is constant as long as undissolved solute remains in the core. Upon dilution, the rate diminishes according to the decreasing osmotic pressure, and delivery of drug finally stops [ 7-91. Recent in vivo studies showed that osmotic delivery systems containing metoprolol or oxprenolol, owing to their constant release pattern, produce a more uniform haemodynamic response than conventional slow-release

204

forms, which usually show first-order release [ 10,111 . The versatility of osmotic delivery systems is also demonstrated by the pH independence of the release rate and by the good correlation obtained between in vitro release rate and in uiuo absorption [9,11,12]. The coating of the core of elementary osmotic pumps is usually achieved by spraying an organic solution of cellulose acetate containing a flux enhancer such as polyethylene glycol [13,14]. Recently, we developed an alternative preparative procedure which involves the use of cellulose acetate latices, plasticized with water-soluble additives to form coatings for osmotic delivery systems [15], Such a colloidal dispersion is obtained by dissolution of the polymer in an organic solvent and dispersion of this solution in an aqueous phase which contains emulsifiers. The crude emulsion is then passed through a high-pressure homogenizer and the solvent is finally evaporated under vacuum. The preparation and swelling properties of these latices have been discussed in more detail elsewhere [15,16]. The aim of this paper is to study the effect of the physico-chemical properties of the plasticizer and that of the coating conditions on the release rate of the model drug potassium chloride from osmotic tablets coated with cellulose acetate latex systems. The advantages of the new procedure are also shown by comparison with release profiles of osmotic tablets prepared by spraying organic solutions of cellulose acetate containing different amounts of plasticizer. A detailed study of the water permeation and swelling properties of free films obtained from latices will be published f173.

EXPERIMENTAL Materials

Latices with a mean particle size of 350 nm and a polydispersity index of 4, as measured with the Coulter Nano-SizerTM, were pre-

pared from cellulose acetate with a degree of acetylation of 39.8% (CA 398-10, Eastman Kodak, Rochester, NY). The plasticizers (ethyleneglycol monoacetate, trimethyl phosphate and diethyl tartrate) were supplied by Fluka (Buchs, Switzerland). All agents were of analytical grade, except ethyleneglycol monoacetate which was of technical grade and contained a high proportion of the fully acetylated component ethyleneglyeol diacetate. Preparation of osmotic tablets

Potassium chloride tablets of 10 mm diameter and 667 mg weight were prepared by gr~ulation of the powder with an aqueous gelatin solution and subsequent companion. The punches used had two radii of curvature, of 15 mm and 1.5 mm. The tablets were coated in a fluidized bed (Aeromatic Ktre-1) according to the following procedure. In a typical run, an aqueous solution containing a known amount of plasticizer was added to a cellulose acetate latex with a solid content between 30 and 40%. The final coating dispersion contained usually 8.3% w/w polymer and 13.3% w/w plasticizer (i.e., 160% with respect to the weight of polymer). This exceptionally high amount of plasticizer is required by the physico-chemical characteristics of cellulose acetate. In particular, solutions obtained from this material are known to be very viscous [lS], apparently reflecting highly entangled chains. The rate of spraying was between 5 and 28 ml/min, depending on the plasticizer used. The batch sizes for the coating operation were about 280 g. The outlet air temperature was usually maintained at 60°C and the air-flow rate was between 110 and 130 m3/h. Under these conditions, a major portion of the plasticizer no longer remained in the coatings after completion of the drying. To achieve coating of potassium chloride tablets with organic solutions, mixtures containing 5% cellulose acetate (dichloromethane/ethyl acetate/methanol 60:25:15 w/w) and a preweighed amount of diethyl tartrate

205

were used. Spraying was performed at temperatures of 30 to 35°C. Potassium chloride release experiments

The osmotic tablets were drilled with an electric drilling machine, the diameter of the hole being 250 pm. Release experiments were performed on three tablets per batch in water at 37°C. The tablet was placed in a small basket and suspended in a thermostated beaker. The release medium (500 ml) was gently agitated magneticalIy and was continuously circulated by a peristaltic pump connected to a conductometric cell. The reproducibility of this method is excellent and the release rate was found to be independent of the intensity of agitation. Computation of the release parameters

The mechanical water permeability, L,, of the membranes [9] during the zero-order release period was calculated from eqn. (1): dV

determined to be 39.3 g/100 cm3 water or 33.5 g/100 cm3 final solution. The osmotic pressure An of a saturated solution of potassium chloride was obtained from the equation of Robinson and Stokes [ 191:

sternal

An = v11000

at

where R is the gas constant, T the absolute temperature, Vl the partial molar volume of water, v the number of ions resulting from the electrolytic dissociation, m the molality and Wl the molecular weight of water. The parameter @ is an osmotic coefficient whose values at 25°C can be found in Ref. [19]. Using the previous tables and neglecting the variation of water activity with temperature, a value of cp = 1.0025 at 37°C was calculated for a saturated potassium chloride solution by linear extrapolation of the values of @ for different conc~nt~tions. RESULTS AND DISCUSSION

A - - L, (0. An - AP) dt - h

Release of potassium chloride from osmotic tablets coated with a cellulose acetate latex

Here, dV/dt is the volume flux of water, and A and h are the surface area of the tablet and the thickness of the membrane, respectively. The surface area of the tablets was assumed to be 2.65 cm*. The terms An and AP are the osmotic and hydrostatic pressure differences, respectively, between the inner tablet and the release medium. The reflection coefficient CT,which describes the degree of pe~sel~tivity of the membrane, was assumed to be equal to unity. The hydrostatic pressure built up inside the core is negligible. The water flux, dV/dt, was calculated from:

The release data from osmotic tablets prepared from latices under different coating conditions are shown in Table 1. The table also presents the characteristic parameters of tablets coated with an organic solution (ethyl methyl ketone/dichloromethane) of cellulose acetate without any plasticizer (batch 6). This batch was used as a standard. Figure 1 shows typical release profiles of potassium chloride from single tablets with different formulations. It is seen that the water permeability of the coatings varies strongly with the nature of the plasticizer added to the latex. A very volatile plasticizer, such as ethyleneglycol monoacetate (bp = 182’C), yields membranes which are much less permeable to water than those containing diethyl tartrate which is a much more permanent plasticizer (bp = 280°C). These differences in permeability reflect the effect of the plas-

dm dt=dt

dV

s

(2)

where dm/dt and S are the release rate and the solubility of the osmotic agent, expressed per unit volume of solution. The solubility of potassium chloride in water at 37°C was

206 TABLE 1 Effect of plasticizer on the formulation and transport parameters of osmotic tablets coated by cellulose acetate latices and comparison with a standard batch obtained from an organic solution Batch No.

Formulation parameters Plasticizer

Ethyleneglycol monoacetate Ethyleneglycol monoacetate Trimethyl phosphate Diethyl tartrate Diethyl tartrate Organic solution of cellulose acetate

% plasticizers

Transport parameters Spraying rate (ml/mm)

Outlet air temperature (“C)

Thickness of the coatings (rm) dry

wet

Release rate dmidt

Volume flux dV/dt

(mg KC1 h-‘f

(~1 H,O h-‘)

Mechanical permeability L, (cm’ N-’ s-1) x 10”

320

10.0

60

340

360

4.53 5 0.07

13.52 * 0.22

1.77 + 0.03

160

28.0

60

350

350

3.41 + 0.09

10.18 i 0.28

1.37 * 0.04

160

11.0

60

340

340

7.19 + 0.38

21.46 ?r 1.15

2.81 f 0.15

160 120 -

6.0 5.0 25.0

60 50 35

330 280 300

330 275 310

11.67 t 0.62 29.00 * 2.16 3.39 f. 0.11

34.84 2 1.84 86.57 * 6.46 10.12 f: 0.32

4.42 i 0.23 9.332 0.70 1.17 + 0.04

a% plasticizer by weight of cellulose acetate in liquid coating.

E TI

700

2 $ f

600 A------?-

Time

(h)

Fig. 1. Release profiles of potassium chloride from osmotic tablets prepared by spraying a cellulose acetate latex as a function of the plasticizer type, the amount .of plasticizer in the spraying liquid, and the coating temperature. (I.) Diethyl tartrate 120%, 50” C; (2) diethyl tartrate 160%, 60°C; (3) trimethyl phosphate 160%, 60°C; (4) ethyleneglycol monoacetate 320%, 60°C; (5) ethyleneglycol monoacetate 160%, 60°C; (6) organic solution (no ptasticizer).

ticizer’s physico-chemic~ properties on its residual content in the coatings f15,17]. Diethyl tartrate is retained to a larger degree by the membranes than ethyleneglycol monoacetate because of its lower vapor pressure. Trimethyl phosphate, in spite of having a relatively low boiling point (193”C), is retained to a larger extent than ethyleneglycol monoacetate, probably because of its high affinity for water [15]. It must be noted that all the plasticizers used in this study are miscible in all proportions with water. Furthermore, conventional hydrophobic additives, such as dimethyl phthalate, were unable to give strong continuous films when added to cellulose acetate latices [ 151. As will be discussed elsewhere more thoroughly [17], the water permeability of the films obtained by spraying a cellulose acetate latex onto the tablets is controlled mainly by their plasticizer content. During the soaking of membranes in water, one observes that the plasticizer between the macromolecule

207

chains is replaced by water, as represented schematically in Fig. 2. It must be noted, however, that a highly water-swollen cellulose acetate film is a thermodynamically unstable system, because water is a poor solvent for this polymer. Indeed, the state of thermodynamic equilibrium corresponds to the water fraction of the unplasticized membranes and consequen~y involves the shrinkage of the highly swollen films. At a temperature of 37”C, however, the wet films, especially when applied on a substrate, contract only slowly and remain in a highly swollen state. For this reason, stable permeability values are observed. A drastic elevation of the temperature brings a rapid shrinkage of the m~~molecu-

0 plasticizer

lar network. In the same way, the membranes irreversibly lose their swelling capacity upon drying, in agreement with the observations of Rosenbaum et al. [20]. The conditions of preparation of the coatings obtained from latices, in particular the initial proportion of plasticizer in the coating liquid, the spraying rate, the coating temperature and the drying time, may strongly affect the amount of plasticizer remaining in the dried films and accordingly their permeability. For instance, lowering the coating temperature from 60 to 50°C results in a strong increase of permeability when a high boiling point plasticizer is used, i.e., diethyl tartrate (Table 1, batches 4 and 5).

*water

@+ polymer

Plasticized membrane

Soaking in water

1

Highly water swollen membrane

of the temperature J

Drying

increase

\ Membrane without water

Soaking in water 1

Membrane swollen ta a low extent by water, in a state of thermodynamic equilibrium

Fig. 2. Schematic representation

of the swelling of plasticized cellulose acetate membranes.

Table 1 and Fig. 1 also show that tablets coated with latices are more permeable to water than those obtained from the spraying of organic solutions of unplasticized cellulose acetate. Release, of potassium chloride from osmotic tablets coatad with organic solutions of cellulose acetate containing diethyl tartrate

To allow a more direct comparison between the release curves of osmotic tablets prepared from latex systems, the coatings of which always contain some residual plasticizer, and those of tablets prepared from organic solutions of cellulose acetate, it is necessary to add a plasticizer to the organic solutions. The release of potassium chloride from tablets coated with organic solutions containing different percentages of diethyl tartrate is shown in Table 2 and in Fig. 3. Table 2 also includes the release parameters of a formulation free of plasticizer (batch 7). The mechanical pe~eab~ity of osmotic tablets of batch 7 is slightly higher than that of tablets of batch 6, probably because of small differences in the processing conditions. In particular, the mixture of dichloromethane, methanol and

z $

5004

5

400

5j;

300.

z B

200.

6 ;

1 oo-

: :

10

*Cl Time

30

40

(h)

Fig. 3. Release profiles of potassium chloride from osmotic tablets prepared by spraying an organic solution of cellulose acetate as a function of the percentage of diethy tartrate in the dried coatings (thickness of the coatings). (1) 50%, 380 grn; (2) 40%, 240 pm; (3) 35%, 350 pm; (4) 30%, 350 Frn; (5) 20%, 340 pm; (6) lo%, 330 rm.

ethyl acetate used as a solvent in all formulations of Table 2 is not optimally balanced and the coatings exhibit a small trend toward phase separation. Table 2 and Fig. 3 show the increase in permeability of coatings prepared from organic solutions, when the amount of diethyl tartrate exceeds the level of 10%. The permeability steadily rises for a plasticizer content between 20 and 35%. A transition is noted for a plasticizer loading between 35 and 40%, which leads to a drastic increase in permeability when the plasticizer content shifts toward 50%. Table 3 gives some additional information about the reasons for this transition, In this table, a comparison is made between the permeabilities calculated from the release curves of osmotic tablets and the relevant permeabilities of membranes of similar compositions obtained from the spraying of organic solutions of cellulose acetate onto potassium chloride disks of 20 mm diameter. The above membranes were removed from the disks and tested for water permeability in an osmosis cell consisting of two chambers filled with pure water and with a saturated saline solution, respectively, and separated by the membrane [ 171. The validity of such a comparison is evident from the good correlation between the two sets of permeabilities, although the values for osmotic tablets are somewhat higher, probably because of solute leakage. The maximal tensile strength and the elasticity modulus in the dry state of the planar membranes detached from potassium chloride disks, determined according to a procedure described in Refs. [ 151 and [21], are shown in columns 4 and 5 of Table 3. It emerges from these data that the elasticity modulus strongly diminishes when the plasticizer content shifts from 35 to 40%. Beyond this level, the films become very plastic and their tensile strength and elasticity modulus approach zero. Most unfo~unately for formulation goals, the decrease in mech~ical strength precedes the increase in pe~eab~ity. For this reason, it may not be possible to exceed the

209

TABLE 2 Effect of diethyl tartrate concentration on the formulation with organic solutions of cellulose acetate Batch No.

7 8 9 10 11 12 13 14

and transport parameters of osmotic tablets coated

Formulation parameters

Transport parameters

% (w/w) of diethyl tartrate in the dry coatings

Thickness of the wet coatings (pm)

Release rate dmldt (mg KC1 h-l)

Volume flux dV/dt (~1 H,O h-‘)

Mechanical permeability L, (cm4 N-l s-l) x k0”

0 5 10 20 30 35 40 50

278+ 6 307 * 8 317 f 23 340 355+ 5 350 240 387 + 12

5.00 4.59 4.67 7.91 10.98 12.60 21.44 51.11

14.93 13.69 13.94 23.60 32.77 37.60 81.91 152.58

1.60 1.62 1.68 3.09 4.48 5.07 7.57 22.68

* f + + f f f +

0.17 0.28 0.87 0.74 0.42 2.09 1.65 4.01

f f * f f * + f

0.51 0.83 2.59 2.22 1.24 6.25 4.91 11.96

f + + ? * r * *

0.03 0.14 0.18 0.29 0.22 0.85 0.45 1.36

TABLE 3 Comparison between the water permeabilities of osmotic tablets and those of membranes of the same composition, prepared by spraying an organic solution of cellulose acetate onto potassium chloride disks and tested with a bicompartmental osmosis cell Amount of diethyl tartrate in the dry films (% w/w)

0

5 10 20 30 35 40 50

Mechanical permeabilities L, (cm” N-’ s-‘) x 10” Osmotic tablets Bicompartmental osmosis cell 1.60 1.62 1.68 3.09 4.48 5.07 7.57 22.68

* * f f * r * +

0.03 0.14 0.18 0.29 0.22 0.85 0.45 1.36

Maximal tensile strength urnax (MPa)

Elasticity modulus E (MPa)

0.04 0.16 0.15 0.22

64.7 f 5.5 _ _ _

1944 * 48 _

3.21 + 0.71

23.0 * 1.2 16.3 f 0.4 6.9 + 0.4

876 ? 76 707 * 25 192 + 16

1.19 1.14 1.32 2.06

f t + f

5.56 * 0.58 16.42 f 4.08

loading of 35% plasticizer without violating the strength requirements that ensure integrity of the coatings in the gastro-intestinal tract. Comparison

between the release curves of osmotic

tablets prepared from latex systems and the release curves of solutions

osmotic tablets

Mechanical properties

produced from

organic

Since the use of latex systems for coating purposes is more complex than that of organ-

_

ic solutions from a technological standpoint, it is worthwhile comparing the advantages and disadvantages of both procedures. Figures 4 and 5 show the release of potassium chloride from both types of tablets during the first ten hours. As we see, the curves representing tablets coated with latex systems (Fig. 4) are usually more linear than those of samples coated with organic solutions (Fig. 5). However, the run including diethyl tartrate performed at 60°C (Fig. 4) is an exception to this rule. The profiles corresponding to for-

210

mulations produced from organic solutions and with a plasticizer content between 20 and 35% are curved upward, in contrast with those of higher diethyl tartrate loading (Fig.

Time

(h)

Fig. 4. Initial release of potassium chloride from osmotic tablets prepared from cellulose acetate iatices as a function of the plasticizer type, the amount of plasticizer in the spraying liquid and the coating temperature. (1) Diethyl tartrate 120%, 50” C; (2) trimethyl phosphate 160%, 60” C; (3) diethyl tartrate 160%, 60°C; (4) ethyleneglycol monoacetate 320%. 60°C; (5) ethyleneglycol monoacetate 160%, 60” C.

Time

(h)

Fig. 5. Initial release of potassium chloride from osmotic tablets prepared by spraying an organic solution of cellulose acetate as a function of the percentage of diethyl tartrate in the dried coatings (thickness of the coatings). (1) 50%, 380 pm; (2) 40%, 240 pm; (3) 35%, 350 pm; (4) 30%, 350 ym; (6) 20%, 340 pm.

5). This curvature reflects the relatively long time necessary for these coatings to reach equilibrium when the plasticizer percentage is not high enough to allow rapid diffusion of the water. As the membranes produced from latices have approximately the same thickness as those produced from organic solutions, we conclude that the tablets coated with latices tend to absorb water and reach equilibrium more rapidly. This point may be specially important for oral forms, since the g~tr~intestinal transit time is limited [l J . Such influence would however be reduced for thinner membranes. Another significant difference between the two kinds of coatings lies in the ratio of plasticizer content to permeability. The overall concentration of diethyl tartrate and emulsifier in the coatings of tablets of batch 5 (Table 1) is 36.5% (i.e., ca. 35.5% plasticizer), whereas the permeability is 9.33 X 10-l ’ em4 N-l s-l. A comparison with representative data of tablets coated with organic solutions (Table 3) reveals that in this last case it is necessary to add more than 40% plasticizer to obtain similar permeation properties. The difference in plasticizer concentrations may appear minimal. This is not the case, however, if allowance is made for the mechanical strength of the coatings, which decreases sharply when the plasticizer content shifts from 35 to 40%. Thus, one observes that the coatings of batch-5 tablets are harder (Omax 2 20 MPa, E N 700 MPa) than those of batch 13. The higher permeability at the same plasticizer loading of membranes prepared from latices versus those prepared from organic solutions is consistent with the tendency of the first kind of film to swell to a larger extent in contact with a concentrated saline solution, like that in the osmotic tablets [15].

CONCLUSION

We have developed a new technique with minimum environmental pollution for the

211

coating of osmotic tablets involving the use of cellulose acetate latices containing a more or less volatile plasticizer. This approach makes it possible to obtain mechanically strong films. The water permeability of these membranes is determined by the following factors: - the physico-chemical properties of the plasticizer, in particular its boiling point, or more exactly its partial vapor pressure, - the initial content of the plasticizer in the spraying blend, - the coating temperature, and - the rate of spraying. With the use of a plasticizer of relatively low volatility, a small mod~i~ation of either the coating temperature, the rate of spraying or the initial plasticizer content of the latex gives rise to big changes in the drug release rate. Apart from the technological versatility of the new procedure, membranes obtained from latices show the following advantages with respect to those produced from organic solutions: - the elapsed time before constant release, which corresponds to the swelling of the coatings, is usually shorter for the latex-prepared systems, at the same plasticizer level, - the membranes prepared from Iatices swell to a greater degree and are more permeable at the same plasticizer levels. The first point is important for thick coatings and for oral forms, since it is desirable for the coatings to reach an equilibrium swelling state rapidly, facilitating quick establishment of a zero-order release rate. The second point is also of great significance, since the requirements for high permeability and for sufficient mechanical strength (to ensure no cracking of the coatings) are to some extent ~ontr~icto~. The use of latex systems results in films that are stronger in the dry state, at the same permeability level, than those produced by spraying organic solutions. Further investigation of the mechanical properties of the coatings in the wet state would be an interesting goal, At the present

time, the new latex is not yet suitable for industrial applications since the stability studies showed hydrolysis of the polymer.

ACKNOWLEDGEMENTS

This work was supported by a grant from Ciba-Geigy Corp., Basle, Switzerland. The authors are indebted to Drs. H. Hess, P. Fankhauser and S. Khanna (Ciba-Geigy) for helpful discussions.

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