Polymeric Delivery Systems - American Chemical Society

Chapter 17

Side-Chain Crystallizable Polymers for Temperature-Activated Controlled Release

Downloaded by UNIV OF GUELPH LIBRARY on October 29, 2012 | http://pubs.acs.org Publication Date: March 5, 1993 | doi: 10.1021/bk-1993-0520.ch017

Larry Greene, Loc X. Phan, Ed E . Schmitt, and Judy M . Mohr Landec Corporation, 3603 Haven Avenue, Menlo Park, C A 94025

A novel controlled release technology based on side chain crystallizable polymers has been developed. The rationale for the use of these polymers in agricultural and medical applications is discussed. The polymer structure and characteristics are described. Laboratory and field data are presented confirming that the release of active ingredients from microcapsule formulations of pesticides can be triggered by increasing soil temperature. This can result in a reduction in pesticide application rates. Temperature activated membranes have been developed to control the release of nicotine in a model transdermal delivery system. The fabrication and release rate characteristics of the membrane system are described. Development of devices that control the release of active ingredients to various biological systems for use in medical, agrichemical and industrial applications has been ongoing for the past two decades. (1,2) Generally, these devices have provided for a constant rate of release over time that is difficult to vary. A unique class of polymers have been developed (Intelimers, a Landec Corporation registered trademark) that exhibit dramatic changes in permeability in response to small temperature changes.(3) This development will allow the design of controlled release systems that can vary the release of active ingredients over time in response to either passive (i.e. atmospheric temperature changes) or active (i.e. heat applied through a resistive film) temperature changes. The synthesis, structure and physical characteristics of these polymers will be described. Devices and formulations have been developed utilizing these polymers to control the delivery of a drug, nicotine, a soil insecticide, diazinon and a proprietary organophosphate insecticide, LL825. The rationale and advantages for utilizing temperature regulated delivery in these type of applications will be discussed. The product form for each area will be 0097-6156/93/0520-0244$06.00/0 © 1993 American Chemical Society

In Polymeric Delivery Systems; El-Nokaly, M., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1993.


17. G R E E N E E T AL.

Side-Chain

Crystallizable

245

Polymers

described and experimental data w i l l be shown that highlights the uniqueness and advantages of using temperature to trigger the delivery of a variety of biologically active molecules. T h e polymers have the generic structure shown i n Figure 1. T h e side chain crystallizable polymers ( S C C ) are composed of a flexible polymeric backbone to which are attached many hydrocarbon chains that are then h e l d i n close conformation for rapid crystallization. A c r y l i c esters are readily prepared f r o m acrylic acid and long chain fatty alcohols. T h e acrylic ester m o n o m e r is polymerized to yield the side chain crystallizable polymer. F i g u r e 1 illustrates the basic synthetic pathway for the production of acrylic polymer. T h e molecular weight of the polymer is controlled by the amount and type of initiator and chain terminator added to the process. T h e S C C polymers have a temperature "switch" built into them. B e l o w a selected switch temperature, the polymer exists i n a crystalline state, but w h e n heated above the switch temperature, conversion to an amorphous or m o l t e n state occurs. This change of state is freely reversible an infinite number of times. T h e switch temperature can be set anywhere between 0°C and 65°C by adjusting the side chain length (4,5,6) and can be controlled w i t h i n 1-2°C. F o r instance a polymer with C side chains w i l l have a melt temperature of 36°C while a polymer with C side chains w i l l have a melt temperature of 2°C. Figure 3 illustrates how we can then mix monomers containing either C or C side chains i n the appropriate ratio to obtain any switch temperature between 2°C and 36°C. D S C analysis has shown that this narrow transition is a result of a very sharp endothermic melting transition with only about 3-5°C between the endotherm onset and the peak. (Figure 2 illustrates this crystal to melt transition.) B e l o w the switch temperature the side chains align through weak hydrophobic interactions that are disrupted above the switch. 1 6

1 2

1 2

1 6

Agricultural Applications In agriculture accurate timing of a pesticide application is one of the keys to an efficient pest control strategy. Ideally, application should coincide with arrival of the pest so that the m i n i m u m amount of pesticide, and fewest n u m b e r of applications w i l l be necessary for effective control. In practice, however, o p t i m u m timing is seldom achieved. O n e way to achieve better timing of pesticide delivery is to utilize the increase i n soil temperature that occurs each spring. T h e r e is a predictable increase i n soil temperature during the growing season which triggers a variety of biological events such as seed germination, egg hatching, and pupation. F i g u r e 4 illustrates a typical soil temperature profile for the N o r t h e r n H e m i s p h e r e through the growing season. A s can be seen, the soil temperature gradually increases during the season and has a daily fluctuation of about 10°C. It is possible to take advantage of this known temperature profile by designing a formulation that releases the chemical only w h e n the specific pest is emerging at a specific temperature.


246

POLYMERIC DELIVERY SYSTEMS

R I

I

R

R

R

I

I

R I

CH2=C + CH2= C + Initiator-^ [- CH2 - C - CH2 - C - CH2 - C -] I I


OR

I

I

c=o I

c=o

c = o

c=o

Ο ι

Ο ι

OR

(CH2)n CH3

I

(CH2)n CH3

I I

I I

c=o

Ο ι (CH2)n CH3

η = Alkyl Acrylate η = 12 - 22 R = H , CH3 M W = 6,000 to 1,000,000 Figure 1. Side chain crystallizable polymer structure and its synthesis.

Crystalline

Amorphous

Figure 2. T h e transition of Intelimer polymer from crystalline to amorphous activated by a temperature change.



17.

247

Side-Chain Crystallizable Polymers

GREENE ET AL.

Ό

10

20

30

40

50

C16A

60

70

80

90

100

(%)

Figure 3. M e l t i n g point of side chain crystallizable polymers at different C / C ratios. 1 6

1 2

il

Plant Com

(10)

_l

3/1

I

I

I

L I

4/1

I

I

I

1

I

CRW Emerge I

I

5/1 Date

I

if

6/1

I

j

ι

ι

ι

ι

ι

L·

7/1

Figure 4. S o i l temperature at 2" depth i n Y o r k , N e b r a s k a from M a r c h through July.



248


F i g u r e 5 shows how delaying the release of an active ingredient is effective i n the control of a pest such as the corn rootworm. T h e graph o n the left depicts the current practice of applying a large dose of active ingredient at planting to control an insect whose population w i l l not increase until approximately thirty days after planting. W i t h a pesticide encapsulated i n a S C C polymer o n the other hand (right graph), release of the chemical is delayed until the desired temperature is reached, allowing for a significant reduction i n the application rates. Improved pesticide formulations designed to deliver the chemical w h e n and where it is needed w i l l eliminate the need for high rates and therefore reduce or eliminate many of the associated problems. If a pesticide c o u l d be contained and protected i n a microcapsule for extended periods of time and then rapidly released at a preselected temperature, then accurate, automatic delivery w o u l d be possible. This can be achieved using new formulations developed by Landec, where delivery is passively controlled by atmospheric or soil temperature. Medical Applications In drug delivery, controlled release systems were originally developed to address the problems of fluctuations i n plasma concentrations w h e n drugs are administered conventionally. Transdermal therapeutic systems, i n particular, were designed to provide a constant rate of drug release to the circulation system for the lifetime of the device. These topical systems have found m e d i c a l acceptance because they avoid the "first pass effect" and they enable drugs that have short half lives to be administered conveniently. However, constant (or zero-order) release may not always be the best therapeutic regimen due to the development of tolerance for the drug, development of localized irritation, or inconsistency with circadian fluctuations. A n example of the development of tolerance occurs with nitroglycerin transdermal patches. Nitroglycerin is used to reduce ischemia i n the heart tissues which results i n severe chest pain. This reaction is caused by a pressure differential i n the heart. A s nitroglycerin is absorbed into the b l o o d system the ischemia is reduced. Figure 6 illustrates this process. A transdermal patch containing nitroglycerine was applied to the skin. This results i n a n initial high reduction i n ischemia(75%), however it is attenuated (reduction i n ischemia is not as pronounced) w i t h i n 12 hours, even with a n adequate serum level of nitroglycerin, due to the development of tolerance. T h e patch was prematurely removed and after the subjects experienced a 12 hour patch free interval, a new patch was applied and the subjects were retested. T h e reduction i n ischemia rose again (indicating effectiveness) and then fell to levels observed during the previous 12 hour post administration period. O n c e again the effect of nitroglycerine had decreased with time, indicating that the body was b u i l d i n g up a tolerance to the drug. These findings suggest that discontinuous transdermal administration of nitroglycerin, i n which near steady-state b l o o d concentrations are maintained for several hours followed by a p e r i o d i n w h i c h


Side-Chain

G R E E N E E T AL.

Crystallizable

100

249

Polymers

100 Pesticide decay profile 75


i 50

t*

Pesticide in Thermal Membrane

25

0 1

30

45

60

0

90

Days after planting

Application

30

45

60

90

Days after planting

1 Application

Figure 5. The left figure shows the current practice of pesticide application. The right figure shows that encapsulated pesticide is applied at the same time as planting for convenience, but it is not activated until the pest emerges.

125

500 Serum Concentration

A 400

H 300

A 200

ο U 6 2

100 fcchemia 10

20

mLm 30

40

50

60

Time (hrs)

Figure 6. A reduction of the ischemic effect due to the development of nitroglycerine tolerance.




250

nitroglycerin concentrations are quite low, may enable 24 hour therapeutic coverage without the development of tolerance. W h i l e the actual time periods cannot be defined at this time, it is clear that a transdermal device that has the ability to turn o n and off w o u l d be highly desired to implement this or variations of this regimen. A s a result of this desire for a pulsatile drug delivery device, a thermally responsive Intelimer membrane transdermal device has been developed that w i l l allow the drug to be delivered i n a pulsatile fashion. T h i s w i l l enable the patient to receive the drug i n a manner that is more closely mimics their n o r m a l biological rhythms and reduce the development of tolerance. Experimental A t a c t i c side chain crystallizable acrylate polymers were prepared f r o m hexadecyl acrylate either by solution or bulk techniques initiated with A I B N or t-butyl peroctoate. M o l e c u l a r weight was controlled with dodecyl mercaptan. Solution polymerization products were precipitated into ethanol, filtered and dried under reduced pressure. B u l k polymerization yielded a product of controlled molecular weight suitable for use directly. Polymers were characterized and compared by D S C by initially heating a l l samples above the melt temperature followed by cooling and a second heating. T h e second heat endotherm was monitored so that a l l polymer samples were compared without adulteration by synthetic processing or annealing. Microcapsules were prepared using a standard emulsion encapsulation process (7). T h e active ingredient was incorporated into the o i l phase, emulsified i n water and crosslinked. T h e microcapsules contained approximately 90 w t % of active ingredient. Microcapsule particles size was monitored using a H i a c R o y c o particle size analyzer and confirmed through optical and electron microscopy. T h e microcapsules were supplied i n a n aqueous m e d i u m with no adjuvants, emulsifiers or other additives. Laboratory release rates of diazinon and trifluralin were conducted i n water and ethanohwater, 1:1, respectively and monitored by U V spectroscopy. A laboratory bioassay was conducted using a d i a z i n o n microcapsule formulation. A capsule formulation with a melting point of 25°C was compared to a commercial formulation of diazinon, 14 G (14 % active granular). Sufficient formulation was mixed with a dry soil to achieve a 2.5 p p m concentration of diazinon. T h e soil was placed i n a chamber at 20°C. A t the end of week 1, 2, and 4, four replicates of 100 g of soil treated with each of the formulations were removed. T h e soil was placed i n cups with a sprouted c o r n (Zea mays L.) seed and 10 larvae of Diabrotica balteata (banded cucumber beetle), a corn insect pest. F o u r replicates of untreated soil were also used for comparison. After four days, the soil was sifted and the number of live larvae were determined. After the four week sample was taken, the temperature was increased to 32°C. S o i l was sampled at week 5, 6, and 8 and were processed the same as described above. T h e data were analyzed by dividing the number



17.

G R E E N E E T AL.

Side-Chain

Crystallizable

Polymers

251

of dead larvae/cup by the number of live larvae that had survived i n the n o n treated soil and multiplying by 100. A n analysis of variance was conducted o n the data with the means compared by L S D at the 0.05 level of probability. A field trial using an experimental organophosphate insecticide, L L 8 5 2 , was conducted i n Y o r k , Nebraska. In experiments conducted i n 1989 and 1990, the biological activity of encapsulated L L 8 5 2 (a L a n d e c formulation) was compared to a L L 8 5 2 granule and commercially available granule of C o u n t e r insecticide. B o t h experiments were conducted i n a field containing a Sharpsburg silt l o a m soil ( fine, montmorillonitic, mesic T y p i c A r g i u d o l l ) to evaluate the damage to corn roots of each formulation at different concentrations. C o u n t e r was applied at 1.0 lb ai/ac (active ingredients per acre), L L 8 5 2 1 0 G at 0.5 and 0.25 lb ai/ac, and L L 8 5 2 Capsule at 0.5 and 0.125 lb ai/ac. T h e capsule treatments were applied i n 165 L of water/ha w i t h a hand held spray b o o m that was powered by C 0 . T h e granule formulations were applied using a standard granule applicator. Plots were 3 by 9 m and the treatments were replicated three times i n a randomized complete block design. A l l formulations were lightly incorporated after the corn seed had been planted and covered. Eight weeks after planting, three corn plants i n each replicate were p u l l e d from the ground, their roots cleaned and a root rating conducted. O n the root rating scale, a 5.0 is m a x i m u m damage and a 0 is no damage. Release of nicotine through S C C polymer membranes was accomplished by preparing either a free standing f i l m of polymer or a porous polypropylene supported film. Nicotine was allowed to permeate the f i l m f r o m an aqueous solution to water that was continually monitored by an automatic sampling U V spectrophotometer. T h e cell was thermostated and designed to increase the temperature i n one degree increments from 5°C to 40°C. 2

Results a n d discussion Pesticide M i c r o c a p s u l e s . D i a z i n o n was microencapsulated with Intelimer polymer that has a melt temperature of 30°C. T h e formulation had a particle size of 9 0 % less than 10 microns and contained 2 5 % active ingredient. T h e release profile i n water compared to a standard polyurethane microcapsule is shown i n Figure 7. A t 20°C both formulations had the same release profile; however, at 30°C the release rate of the Intelimer increased dramatically, while the standard capsule release rate did not increase with temperature. The release profile shown here is typical of all microcapsule Intelimer formulations. Figure 8 illustrates the results of the laboratory biological efficacy of the L a n d e c formulation compared to a commercial d i a z i n o n granule (14G) w h e n tested against corn rootworm. This test was designed to demonstrate reduced efficacy at low temperature when the microcapsules are below the transition temperature and commercially acceptable efficacy above the transition temperature when the microcapsules are turned on. T h e 1 4 G (commercial granule product) exhibited the greatest efficacy at 20°C with a significant decrease i n efficacy at 32°C. Because the 1 4 G granule formulation releases a l l of its active over a short p e r i o d of time, the



252


100

2.5 ppm AI 20°C

32°C — •

Time (Wks.)

Figure 8. Bioefficacy testing of corn root w o r m ( C R W ) using a L a n d e c formulation a n d a commercial 1 4 G formulation.



17.

G R E E N E E T AL.

Side-Chain

Crystallizable

253

Polymers

chemical is readily available for any environmental degradation. T h i s is seen i n the rapid decrease i n efficacy during the 32°C test period. A f t e r eight weeks, the efficacy of the granule had dropped to 5 0 % control. T h e L a n d e c formulation o n the other hand gave significantly less control at 20°C, but control increased to 9 0 % when the temperature was increased to 32°C. T h i s higher level of control continued for 4 weeks at 32°C after which time the experiment was terminated. A t 2.5 p p m , this formulation was superior to the granule i n its duration of control. These data suggest that for the commercial granule to achieve equivalent efficacy to the L a n d e c formulation, amounts greater than 2.5 p p m of active ingredient w o u l d have been required. C o r n rootworm field trials were conducted using a n experimental organophosphate insecticide, L L 8 5 2 . Table I shows the results of testing i n 1989 and 1990.

Table I.

Corn Rootworm 1989 & 1990 Field Trial Results using LL852 Granules and Capsules

Treatment

Rate (lb ai/ac)

Root Rating 1990 1989

Control

None

3.9

4.6

Counter 15G

1.0

1.8

2.4

LL852 10G

0.5

1.5

2.9

L L 8 5 2 10G

0.25

--

2.7

L L 8 5 2 Capsule

0.5

1.6

2.8

L L 8 5 2 Capsule

0.125

1.8

2.9

Counter 1 5 G is the commercial standard and the L L 8 5 2 1 0 G is a standard clay based granular formulation, and the capsule formulation contained the active plus Intelimer polymer. In the root rating system used here, the higher numbers indicate less insect control. E c o n o m i c control is achieved at a root rating of less than 3. In both 1989 and 1990, the L L 8 5 2 capsule formulation gave equivalent control at 0.125 lb ai/ac to the standard granule formulation at 0.25 lb ai/ac (the lowest rate tested), and also gave equivalent control to the Counter formulation. This demonstrates that a significant reduction i n application rates is possible under field conditions using temperature responsive microcapsule formulations. Nicotine Transdermal Delivery. T h e r e are two components to the Intelimer transdermal system, the temperature sensitive membrane and a mechanism to activate the membrane. T h e transdermal patch is comprised of the drug reservoir and the temperature sensitive polymer membrane. T h e patch must



254


also contain a material that warms i n response to a stimulus (e.g. electrical impulse) i n order to raise the temperature of the polymer membrane, w h i c h i n turn allows for permeation of the drug. Figure 9 shows a m o d e l of such a system. A typical transdermal type system is shown which consists of a drug reservoir and a backing. A n Intelimer membrane that can be heated is p l a c e d between the drug reservoir and the adhesive. W h e n the membrane is i n the crystalline phase no drug is released. A s the membrane is heated, the polymer becomes amorphous, and drug is delivered to the adhesive, then to the s k i n and eventually to the circulatory system. T h e second component of the transdermal system is the electronics and the power source to provide the stimulus to the receiving material. B o t h components of the transdermal therapeutic system have been developed. D r u g release was demonstrated using nicotine as the probe molecule. M e m b r a n e release through a n Intelimer f i l m was effectively controlled i n response to temperature where the slope of the release rate vs time exhibits a dramatic increase at the switch temperature as shown i n Figure 10. H e r e , over a 2.5°C temperature change a 1000 fold increase i n release rate was observed. I n a separate experiment, nicotine diffusion was switched o n a n d off i n response to resistive heating of a membrane, yielding greater than two orders of magnitude difference i n drug release i n the o n versus off state. (Figure 11) T h e feasibility of constructing a transdermal device that is capable of delivering a drug i n response to a n external stimulus has been shown. B o t h a transdermal patch containing Intelimer polymer and a heater that c a n be programmed and miniaturized have been produced.

PRODUCT DESIGNCONCEPT

Backing Dmg Reservior Intelimer Switch

•

»

188888888888888888881 i v - - -····· ···:·· ν - · ^ · · : · -

·

·:·:·==··· · a

Adhesive

Figure 9. M o d e l of L a n d e c transdermal delivery system.

Conclusions Side chain crystallizable polymers have been developed that c a n control the release of a variety of active agents i n response to changes i n temperature. H e a t activated membrane based devices have been constructed that can deliver drugs through a transdermal patch i n a pulsatile fashion. Pesticide containing microcapsules have been formulated that can deliver the active to the soil i n


17.

Side-Chain

G R E E N E ET AL.

Crystallizable

255

Polymers


10

20

25

30

35

40

Temperature

45

50

55

(°C)

Figure 10. T h e release of Nicotine through an Intelimer polymer membrane. 100000 Ε

*~0

•

2

4

6

8

10

1

12

14

16

18

20

Time (hours)

Figure 11. Pusatile release of Nicotine. E a c h spike of drug release occured after applying 1.8 watts for 5.6 minutes. response to temperature changes. This w i l l allow for significant reductions i n application rates of insecticides and herbicides. N e w applications are being developed for other medical, agricultural and industrial uses. Acknowledgments T h i s work was supported i n part by S B I R grant N o . 88-39410-4710 f r o m the U n i t e d States Department of Agriculture and S B I R grant N o . 1 R 4 3 G M 4 6 1 5 6 01 from the U n i t e d States Department of H e a l t h and H u m a n Services. L a n d e c gratefully acknowledges the assistance of D o w - E l a n c o , G r i f f i n C o r p . and C i b a Geigy, L t d . i n providing active ingredients.


256



Literatures C i t e d

1. Plate, N. A. and Shibaev, V. P. Comb Shaped Polymers and Liquid Crystals; Plenum Press, 1987. 2. Jordan, E. F.; Feldeisen, D. W. and Wrigley, A. N. J. Polym. SCi. 1971, Part A-1, 2, pp 1835. 3. Stewart, R. F.; U.S. Patent 4,830,855 4. Greenberg, S. A. and Alfrey, T. J.Am. Chem. Soc. 1954, 76, pp 6280. 5. Kyodnieus, A. F. Controlled Release Technologies: Methods, Theory, and Applications, 1, CRC Press, Inc., 1980. 6. Ruppel, R. F. J. Econ. Entomol.,1984, 77, pp 1084. 7. Stewart, R. F. Stewart; Greene, C. L. and Bhaskar, R. K. U.S. Patent 5,120,349. RECEIVED September 24,

1992


Polymeric Delivery Systems - American Chemical Society

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