Use of osmotically active therapeutic agents in monolithic systems

Journal of Membrane Science, 7 (1980) 319-331 Elsevier Scientific Publishing Company, Amsterdam - Printed in The Netherlands

USE OF OSMOTICALLY ACTIVE MONOLITHIC SYSTEMS*

R. GALE, S.K. CHANDRASEKARAN, ALZA Corporation,

THERAPEUTIC

IN

D. SWANSON and J. WRIGHT

Palo Alto, California 94304

(Received April 24,1979;

AGENTS

319

(U.S.A.)

accepted in revised form May 27,198O)

The functionality of a new class of monolithic systems for the controlled release of drugs is discussed. The systems consist of uniformly dispersed particles of osmotically active therapeutic agents (drugs) in biocompatible polymeric matrices. The drug particles are encapsulated by polymers to form a multiplicity of microcapsules throughout the matrix. These osmotic film systems display zero-order drug delivery kinetics. The principal energy source governing the release of agents is osmotic in nature. When such a film is placed in an aqueous infinite sink, the film imbibes water into the outermost layer of the dispersion at a rate dictated by permeability of the polymer. Water transport into the film continues until volumetric rupture of the drug-containing capsules occurs, after which time saturated drug solution is pumped through channels created by the rupture. This process repeats itself in a serial fashion until the system is exhausted of agent. Due to the osmotic functionality of these systems, reduction of the thermodynamic activity of water outside the system can proportionally reduce the release of agent. In this paper the effects of varying drug particle size, osmotic pressure gradients, system area,

drug type, polymer type, and temperature upon the drug release kinetics are presented. Application of this new technology has allowed the fabrication of several useful drug therapeutic systems.

Introduction The release of chemical agents from macromolecular matrices can be accomplished via several techniques. Polymer membranes placed between a drug-containing reservoir and the external environment yield systems which deliver drug at zero-order kinetics due to the rate-controlling nature of the membranes [l--5]. Agents having favorable partitioning in a polymer phase when dispersed within a polymer matrix are released by diffusion through the matrix to the environment by t- 1’2 kinetics [l, 6, 71. Drugs have been dispersed in specially prepared erodible matrices which displayed zero-order delivery rates [8]. Osmotically active agents can be tabletted and coated with a continuous polymer membrane and drilled to obtain a small orifice in the membrane. *Paper presented at the Symposium March 27,198O.

“Controlled-Release

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1980 Elsevier Scientific

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Publishing Company

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When such a system is placed in an aqueous environment, water is imbibed and the agent is dissolved and pumped through the orifice at a constant rate dictated by the rate of water ingress [9]. Proteins can be placed in a polymer matrix, and under certain conditions will be released in nearly zero-order fashion [lo] . Toxicants can be delivered by diffusion through a porous network created by the osmotic rupture ‘of the matrix surrounding the solid toxicant particles [ll, 121. Recently the release of osmotically active compounds where the agent was dispersed in a polymer phase has been described for inorganic salts [13-151, radionuclides [16] and drug salts [17, 211. In most cases the release of agents from systems with monolithic geometries was time dependent. In our work the goal was to improve upon the previous work to achieve nearly zero-order drug-salt release kinetics of prolonged duration from osmotic film systems. This paper presents the results of several experiments designed to determine the functionality of monolithic systems which successfully delivered osmotic agents at prolonged steady-state rates. Experimental Systems were fabricated using ethylene-vinyl acetate (EVA) copolymers (DuPont). Physical properties of the drug salts used are shown in Table 1. Osmotic pressures of saturated aqueous drug solutions were determined at 37°C using a Hewlett-Packard vapor pressure osmometer, Model 302B. Drugsalt density determinations were made using a Tecam@ Model DC1 density gradient column utilizing non-solvents for the compounds tested. Monolithic drug-salt-polymer dispersions were prepared by first banding the polymer on the rolls of a 15 cm (6 inch) Farrel rubber mill, then adding a preweighed amount of drug slowly until complete incorporation was achieved. The blend was then removed from the mill and passed repeatedly TABLE 1 Physical properties of the drug salts Osmotic pressure, IT,of saturated solution, 37°C (atm)

Weight average drug particle diameter before incorporation (rm)

Weight average drug particle diameter after incorporation (ctm)

Density (g/cm”)

Saturated aqueous solution concentration (mg/ml)

Pilocarpine nitrate, USP

1.36

270

37

44

2.2-4.7

Epinephrine, bitartrate, USP

1.50

670

78

42

5.2

Sodium chloride, USP

2.17

310

345

Drug

>300

7.5

321

between the mill rolls until satisfactory dispersion of the drug particles was obtained. We found that the degree of drug particle attrition was a function of the number of passes. The best results were obtained when the number of passes was kept constant. The blend was then cornminuted and extruded through a 0.75 mm slit die attached to an extrusion barrel heated to approximately 65°C. Discrete systems were formed by die cutting the extruded ribbon of film with an oval die measuring 6 X 14 mm, except when systems of other areas were desired. Drug release rate profiles were determined by placing systems in polyester mesh containers affixed to the end of a stirring rod which was attached to a reciprocating stirrer. The systems were submerged in aqueous media containing various concentrations of either glycerin, USP or sodium chloride, USP. With this test method the drug was released from both sides of the matrix. Usually osmotic pressures were maintained in the external sink by fixing the NaCl concentration at 9 mg/ml or the glycerin concentration at 26 mg/ml. The temperature of the thermostatted water bath surrounding the media-containing tubes was maintained at 37 + 0.5%. The medium was exchanged for fresh solution frequently. The release medium was subsequently assayed for drug concentration using a spectrophotometer for UV absorbing compounds or a Perkin-Elmer flame emission spectrophotometer in the case of sodium chloride. Agent release rates were calculated knowing the medium volume, V, drug concentration, C, and medium exchange interval, At, using eqn. (1): dMt cv Release rate = ~ = ~ dt At

(1)

Release rate values were plotted as the base form of the drug at the midpoint of the changing interval. Particle diameters were calculated from BET nitrogen adsorption determinations [22], assuming spherical particles, which results in a weight average diameter. The BET analyses of drug particle were performed after separating the particles from the polymer matrix by dissolving the osmotic films in toluene, a non-solvent for the drug crystals. Results A typical release rate profile for the drug-salt pilocarpine nitrate dispersed in a monolithic EVA matrix is depicted in Fig. 1. The data in Fig. 1 have been divided into three temporal regions which typify the kinetics of drug delivery from these systems. The first region (A) illustrates the initially high drug release rate due to drug particles dissolving from the system surface and the apparently facilitated rupture of drug-containing capsules nearest to the surface. After the initial decline in drug release rate, steady-state release of drug is observed for a prolonged period of time (region B). The duration of the steady-state portion of the release rate profile was approximately one week, during which time 60 percent (nominal) of the pilocarpine nitrate contained in

322

Temporal

Regions

of

Drug

Release

C

B Steady

Rate

Decline

state

0 0

50

150

100 Time

200

250

300

(hours)

Fig. 1. Release of pilocarpine nitrate from a matrix containing

27% by volume of the

osmotic agent.

the system was released. During this period a dynamic balance between the osmotic imbition of water and the release of drug from the system is achieved. After the steady-state release region a monotonic decline in release rate occurs (region C), the start of which coincides with the time after the migrating drug fronts meet. Of importance is the fraction of drug delivered at nearly zeroorder rate. It is possible to fabricate systems which will deliver up to 75% of the encapsulated drug with time-independent kinetics. Since it has been hypothesized that the release of agent from the dispersed drug matrix is osmotic in nature, the release rate should depend upon the difference (An) in osmotic pressure between the medium (next) and a saturated solution of agent (7~~)as expressed by eqn. (2): ANT= n, - next

(2)

When the osmotic pressure of the external medium was varied by addition of NaCl or glycerin, the dependence of release rate of pilocarpine nitrate on An as shown in Fig. 2 was observed. The linear relationship between release rate

323

60

50

40

30

20

10

l

NaCl

A

Glycerin

0 0

10

Osmotic Fig.

20

Driving Force,

30

40

An (atmospheres)

2.Dependence of pilocarpine nitrate release rate on the osmotic driving force.

60

SO

40

30

20

10

0 0

0.50 Bilateral

Fig. 3. Pilocarpine

System Area

nitrate release rate as a function

(cm*)

of system area.

324

and An confiis that osmotic pressure in the driving mechanism that controls the release of drug-salt. Interestingly, the release of drug could be prevented entirely when the external sink osmotic pressure exceeded that of a saturated solution of the dispersed agent. In this experiment when the osmotic pressure of the release medium was greater than 37 atmospheres (the osmotic pressure of a saturated solution of pilocarpine nitrate), essentially no drug release was detected. The dependence of drug release rate on the area available for release was investigated by die cutting systems from osmotic films containing 27 vol.% pilocarpine nitrate. The bilateral area of these systems was varied between 0.4 and 1.85 cm*. Subsequent release rate determinations of these systems revealed a linear dependence of drug release rate on area as shown in Fig. 3. By varying the system surface area, it was possible to vary over a five-fold range the release rate of drug from systems die cut from a single intermediate film. The effect of pilocarpine nitrate loading on the steady-state release rate is presented in Fig. 4. In this experiment, the volume fraction of pilocarpine Drug Loading Svmbol

a

7.0 9.4 14.9 18.0 22.9 27.0

A . :

l

l

0

0

0

l

v v

.

. A l 0

20

v

v

.

.

A

A

0,

?

40

A

1.

60

A0

Time

v

v

v

a

a

.

A

A

1. 100

I

120

l

A I

140

(hours)

Fig. 4. Pilocarpine nitrate release rate profile from osmotic films containing several volumetric loadings of drug.

l 160

325

nitrate in the polymer matrix was varied between 7 and 27 percent by volume, while all other variables were held constant. Notably, zero-order drug release kinetics were maintained over the drug loading range studied. For this drug-polymer system, drug release rates varied from 1.5 to 40 pg/hr. above 30 vol.% drug loading, the release rate profiles tended to lose the timeindependent character, possibly suggesting that a new mode of release, such as simple leaching, began to be significant when neighboring drug particles were not sufficiently separated to behave independently. In another series of experiments, the average drug particle diameter of pilocarpine nitrate in the systems was varied by either of two methods. One method was to decrease the distance between the rolls of the mill during the dispersing process, which resulted in significant particle attrition. The other method used was to simply increase the number of passes between the mill rolls. In these experiments all parameters such as system area, drug volume loading, temperature of release rate determination, the osmotic pressure of the release medium, and the copolymer used were held constant. The particle size of incorporated drug was determined using the BET specific surface area technique. This area is inversely proportional to the weight average particle diameter. Figure 5 presents the results of this work where the steady-state release rate of drug is plotted as a function of the drug specific

50

40

1.00

1,20 BET

1.40

1.60

Specific

Surface

1.60 Area

2.00

2.20

(m2/~)

Fig. 5. Relationship between pilocarpine release rate and BET specific surface area of the drug for osmotic films containing 27 vol.% drug.

326

l

125

c

‘I;

2

zl

Temperature

z 60

l

37oc

A

3ooc

0

23OC

I

l

8

A

0

8

A

A

A

A

A

A

0

l

0

l

0

0

0 0

20

40

60

80 Time

100

120

140

160

180

(hours)

Fig. 6. Temperature dependence of the release rate of pilocarpine nitrate from osmotic films containing 27 vol.% drug.

surface area. A linear regression analysis of these data revealed a correlation coefficient, r2, of 0.907 and a coefficient of variation of 8.1% at the 95% confidence level. At a given drug volume loading, the specific surface area analysis has been found to be a necessary process tool for the prediction of the final steady state drug release rate from these osmotic films [18]. The temperature dependence of the release rate of pilocarpine nitrate was determined with the results shown in Fig. 6. In this experiment systems which contained 27 vol.% drug were tested for drug release rate profile at temperatures of 23”, 30”, and 37°C. As shown in the figure, steady-state drug release rate decreased with decreased temperature. An Arrhenius plot of the release rate data as a function of reciprocal temperature in degrees Kelvin was linear. The apparent activation energy of the overall process for drug release was 18.0 kcal/mole. This value is similar to those determined in separate water permeability experiments using dense EVA membranes. These data indicate that the controlling aspect of drug-salt release is osmotic imbibition of water into the system.

327

When micronized sodium chloride was dispersed in a polymer network using the method described above, the salt release rate profile of this system into isotonic glycerin also was zero-order as depicted in Fig. ‘7. Because the release rate of salt was relatively high, the duration of the steady-state release portion was shorter, on the order of one day versus one week observed with the pilocarpine nitrate-containing films of the same thickness. The net osmotic driving force (An) for sodium chloride was approximately eleven times greater than for pilocarpine nitrate (337 vs. 30 atm), which had the effect of elevating the steady-state release rate proportionately. In spite of the magnitude of An in this experiment, essentially zero-order release rates were still obtained over a large fraction of the system lifetime. Further evidence of the utility of the osmotic film technology developed was generated when two osmotically active drugs were incorporated in the same polymer matrix, namely pilocarpine nitrate (14 vol.%) and epinephrine bitartrate (6.5 vol.%). The data in Fig. 8 show that both drugs were released from the matrix following zero-order kinetics. In this experiment the drug600

0

500 -z 2 ;1

400

0

0 0

a

s !z $

300

z d 8 200 5' S! 100

0

0 0

I

I

1

I

I

I

5

10

15

20

25

30

Time

(hours)

Fig. 7. Sodium chloride release rate profile from osmotic films containing 14 vol.% micronized salt.

35

328

60

-

0

20

n

Pilocarpine

0

Epinephrine

l

n

m

l

l

0

40

60 Time

80

100

120

140

160

(hours)

Fig. 8. Drug release rate profiles of an osmotic film containing both pilocarpine nitrate and epinephrine bitartrate.

salts exhibited osmotic pressures within a factor of two (Table 1). In other work, where two salts with quite different osmotic pressures were combined in the same matrix, usually one or both agents displayed time-dependent release rate kinetics. In these cases the detailed mechanism governing the zero-order release of agent(s) was not readily apparent. Discussion Marson, Narkis, and Fossey have each suggested that the release of osmotic agent dispersed within a matrix is preceded by water imbibition into capsules and subsequent rupture of the capsules [ll, 13, 231. After rupture, agent is released to the environment by diffusive leaching through the waterfilled interconnecting channels created by the rupturing. In each case the release rate of agent was time-dependent, a phenomenon we have not found with the present systems. Significant differences between the previous and present results are perhaps attributable to the loading of osmotic agent, the state of the matrix material, and the system thickness. Most workers have incorporated agents in a range exceeding 30 vol.%. Our work concentrated on loadings between 7 and 30 vol.%; however, our data

329

indicate that steady-state drug release rate is difficult to obtain above this loading, which agrees with the results of Marson, Yoshida, and McGinity [ll, 14,171. The tensile properties of the polymeric matrices in our systems differed from previous authors in that the EVA copolymer exists in the rubbery state at ambient temperatures (Z’s = -40°C). Hence the polymer surrounding a drug particle could be extended significantly prior to capsule rupture. A measureable swelling of the entire system was observed because the polymer extended prior to capsule rupture. In contrast, the previous authors used polyethylene, polystyrene, or polyesters as matrix materials [13-161. These polymers all exhibit relatively high transition temperatures (Z’s or Tm at least 50°C) and hence are glassy or crystalline. Systems made from these polymers apparently did not swell appreciably during operation, nor did they collapse as evidenced by the photomicrographs of the porous structure of the exhausted films of Marson 1121 and Yoshida et al. [15]. We attempted to obtain similar pictures but without success. This in part could be due to the collapse of the extended polymer network during sample preparation for the photomicrographic work. Nonetheless, we conclude that the extensibility of the polymer played a large role in the functionality of our systems. Another notable difference between this and other work is the thickness of the systems studied. Marson used films of only 50 E.tm,where ours were nominally 15 times thicker. We have postulated a serial rupture mechanism for these systems involving the osmotic imbibition of water, subsequent swelling of individual capsules, followed by the rupture of agent-containing capsules. The rupture causes a small fissure in the polymer wall through which drug solution is pumped into the water-filled channels leading to the system surface. Once the concentration of drug within the capsule falls below saturation, the water activity will increase and water will partition into a subsequent layer of capsules. The process will be repeated until the drug fronts meet. After the fronts meet, drug solution will continue to be pumped from the system until the water activity is everywhere constant. This latter temporal region in system lifetime is shown in Fig. 1, region C. Using the data we have generated, a theoretical model has been formulated which allows a semi-quantitative prediction of the steady-state release rate of osmotic agent. The model correlates release rate with a number of important properties, namely the particle size, loading, density, and osmotic pressure of the osmotic agent; the polymer water permeability and extensibility; and the system area. The effect of most of these properties has been described in this paper. The complete mathematical model describing the release of osmotic agents from monolithic dispersions will be published shortly [19].

330

Conclusions The incorporation of osmotic agent particles into polymeric matrices represents a novel method for achieving controlled release of substances, as evidenced by the zero-order release rate profiles presented in this work. The steady release of osmotic agents from the monolithic systems under study has been found to be dependent on volumetric loading, osmotic agent particle size, system area, and the osmotic properties of the agent itself. While the initial and final portions of the release rate profile are time-dependent, it has been shown that a significant fraction (> 50%) of the osmotic agent incorporated in the polymeric matrix can be delivered with zero-order kinetics. It is envisaged that the osmotic agent release technology presented herein should be applicable to the controlled delivery of a wide variety of agents. Acknowledgements The authors are indebted to the is not intended to be limiting: A.S. Theeuwes, K. Smith, P.S.L. Wong, Ben-Dor, R. Baker, M. Guillod and

following co-workers, the roster of which Michaels, F. Landrau, S.I. Yum, F. H.M. Leeper, S. Johnson, P. Wilder, M. D. Hutchison.

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