CA2187023A1 - Temporally controlled drug delivery systems - Google Patents

Abstract

A delivery mechanism and device for the passive periodic release of a drug or an active ingredient which avoids the need for external power sources and/or electronic controllers. By taking advantage of oscillating chemical systems, one can change the pH of a solution, a drug, enhancer or solubilizer resulting in oscillating the ability of an active ingredient to be delivered transdermally. The pH of a solution can be oscillated over a range of pH values from 2 to 10 by the reduction and oxidation (redox) reactions of salts, such as permanganates, iodates, sulfates, chlorates, or bromates. Upon activation, the delivery system conditions begin to oscillate and with it, the delivery of the active agent oscillates.

Description

~ W0 95/28144 p~ ~"
2187~3 - '-TemporaUy ControUed Dru~ Deliverv Svstems Field of the Invention This invendon relates to the applicadon of chemical osciUadng reacdons to acdve agent delivery systems so as to modulate the delivery of such actdve agent from the system. The invendon ~ relates to delivery devices in the area of i ' ' delivery systems, infusion pumps, and implants, although virtuaUy any type of delivery system may be udlized in the invendon. The invendon further relates to v . ~
a~ tolerance which may be ~ from condnuous ' The invendon also relates to the field of ' ' )Oy in that the invendon systems can be designed to modulate acdve agent delivery in accordance with biological rhythms.
Back~round of the Invendon The emerging interest in, ' ~ ~y ~ the fact that biological rhythms are an important aspect of clinical ~ ,oY and should be taken into account when evaluadng drug delivery systems (Hrushesky, W., J. Cont. Rel. 19 363 (1992) and Lemmer, B., Adv. Drug Del. Rev. 6 19 (1991)). Studies indicate that the onset of certain diseases show strong circadian temporal d~y~ y. This has led to the need for dmed patterning of drug delivery as opposed to const~nt drug release. Currently, drug delivery moduladon is being ~ by extemal means, such as ultrasonic ' magnedc moduladon and , (Kost, J., Langer, R., Adv. Drug Del.
Rev. 6 19 (1991)). SeLf O ' delivery systems, only recently being discussed, are generally based on the enzymadc triggering of a ~ " ' polymer (Kost et al, above). A theoredcal model of an osciUadng chemical reacdon of a membrane for periodic drug delivery has recently been published by Siegel and Pitt (Siegel, R A. and Pitt, C G., Proceed. Intern. Symp. Control ReL Bioact. Mater. 20 (1993) 49). The present approach is for the passive periodic release of a drug or acdve ingredient utilizing osciUadng chemical reacdons, thus avoiding the need for external power sources and/or electronic controUers. In other words, once the oscilladon reacdon is begun, theoscilladon reacdon, and thereby the delivery of the acdve agent, is driven by the free energy of the system.
Chemical osciL~adng reacdons have been ~nown for about one hundred years. The most WO 95/28144 ,, ) extensively ., 'iv ' oscillator, the Belousov-7 ' ' (BZ) reaction, has been used as a model for studying a wide Yariety of temporal and spatial instabilities in chemical systems (7 ' ' A. M. in Oscillations and Traveling W~avès in Chemical Systems; Field, R. J., Burger, M.~ Eds.; Wil~ ~ New Yorl~;(lg83)). BZ
systems are generally accepted as the metal-ion-catalyzed oxidation and ~ of an organic substrate by acidic bromate. In the classic BZ-reaction, the pH is fairly stable and not a driving force in the reaction.
The family of pH oscillators consist of those oscillating chemical reactions in which there is a large amplitude change im the pH and in which the pH change is an important driving force rather than merely a , or an indicator of the oscillation (Rabai, G. Orban, M. and Epstein, I.R., Acc. Chem. Res. 23 (1990) 258 and Luo, Y. and Epstein, I.R., J.
Amer. Chem. Soc. 113 (1991) 1518). The pH of a solution can be oscillated over a range of pH values from 2 to 10 by the reduction and oxidation (redox) reactions of salts, such as ~ , iodates, sulfates, chlorates, or bromates. The frst pH oscillator, the hydrogen peroxide-sulfide reaction, was discovered only ten years ago. Ap~ 14 pH oscillator systems are now known. These include the ' ' -thiourea system;
the iodate ~ r"4 - r ' system; the ~ ' , '~ rvl-u~ ' sysoem; the iodaoe-i.~vlv~L.ll.lv sysoem; the I ' h~J-u-~' sysoem; the pPn~ u~ltv sysoem; the hydrogen perox'lde-rtllucy ' sysoem; the hydrogen peroxide-thiosulfaoe-copper(ll) sysoem; the hydrogen peroxide-bisulfioe-thiosulfate sysoem, the ~IvlUAO~' r ' -thiosulfaoe-copper(lI) sysoem; the bromite-iodide system; the fv.~u~. ' sysoem; the v., - '~ -thiosulfaoe sysoem; and the - ~)-pedodaoe sysoem. (See Luo and Epsoein, above).
The CIMA reaction (vhlvli~liOdidc/ ' acid) (J. Amer. Chem. Soc. 1990, 112, 9104-9110) is a redox reacdon in whuch the pH of the solution oscillaoes in response to (but does not drive) the oscillation reaction.
U.S. Paoent 4,756,710 (Bondi et al, 1988) describes a pll - ' ~ drug delivery sysoem, in which a weakly acidic or basic unionized drug in a ' -' delivery sysoem may be delivered ~ `~, and at a relatively low rate. The pH control descdbed there is to maintain a stable pH, not an oscillating one.
Other ypical l, ""c ~ sysoems (without mentioning or utilizing oscillation reactions) which can be modified for use in the present invention include those described in: US
. ~ . .

~WO95/28144 2 1 8 ~Q Z 3 . ~ .,~ I

4,781,924; US 3,598,122; US 4,597,961; US 3,996,934; US 4,91 1,707; US 4,743,249; US
4,917,676; US 5,064,654; US 5,073,539 to nart~ a few.
Oral osmotic systems, such æ thoæ embodied in products marketed under the Alza trademark OROS~9, typically have a . ' ' membrane allows fluid into tbe device to dissolve material internal to the device, thereby creating an osmotic pressure and forcing the dissolved material through an orifice to the e~ternal el.~ Theæ
devices are , " ' by, but not limited to, those in US 4,326,525; US 4,439,195; US
4,455,143; and US 3,916,899, which systems can be modified for use in the present invention.
Obiect of the ~ve~L
It is tberefore an objecùve of the preænt inYention to provide a method using chemical oscillators, r ' 'y pH oscillators, to produce the temporal or periodic releæe of a drug or an active ingredient by pæsive means.
It is another objective of the preænt invention to provide a method using a user-activated~ ' ;' . system in which the osciUation reaction are stabilized during storage and activated when desired, to administer a drug in a temporally controlled manner.
It is a further objective of the preænt invention to provide improved efficacy of an active agent by controlling tne temporal releæe of a of the active agent.
It is yet another object of the invention to provide an active agent delivery device which pæsively, periodically, delivers the active agent so æ to avoid or minimize active-agent toleranoe.
It is still another object of the invention to provide an active agent in a temporal manner in a ~J UIIU~D pattern with rhythmic body cycles especially for the treatment of diseææs æsociated with disorders of circadian rhythm.
SummarY of the Invention These and other objects of the invention can be achieved by active agent delivery devices WO 9~118144 ~7~23 _4_ which incorporaoe oscillating chemical reaction reagents therein, provided the oscillation reaction is not initiaoed until desired. At least one of the oscillation reagents i~i separaoed physically from the remainder of the reactant~i necessary to initiaoe the reaction until the r reaction is inoended to begin. The l are brought together by either the action of the user (as in a u~ier activaoed i ' -l) or in a change of C~ (as in the swallowing of an capsule or tablet, insertion of a depot ,r ~ - ' or a . . y, application of a topical or i ' -' bandage, e~posure to light, etc).
Once activated, the oscillating reaction results in changes which alter the active agent's ability to leave the delivery form and reach its inoended target. In one i ' -' b ' t, due to a change in pH (as part of the oscillating reaction, whether or not the pH is the driving force in the reætion), a drug may be rendered charged or uncharged relative to the pKa value of the drug. Since only the uncharged form of a drug can readily permeaoe across lipophilic ' i, a periodic delivery profile may be obtained.
In another '~ the osciliation reaction ~ r are separaoed by a barrier which is r ~ ~ to at least two oscillation reactants (one retained in each of two ), but becomes permeable to at least one of theæ in the user ~llvil~ ~ as in the hydration of a membrane which is . ' '- uniess hydraoed. A recent exampleof such a membrane is seen in Tamada et aL Macromol. Rapid Commun. 16, 47-51 (1995) In a further ~ t ' t, the reactants for a light initiated osciladon reaction are formulated in a suitable form in the absence of initiating actinic radiation. The user exposes the r ~ " to the appropriate light and uses the activaoed system.
In still another form, an A ~ ~~ membrane separate'i two ~ having different porlions of the oscilation reaction . ~, Exposure of the sysoem to moisture may creaoe an osmotic pressure in one portion sufficient to burst the separating membrane thereby causing mixing of the oscillation reactants. Once initiaoed, the reaction oscillaoes according to the deflned ,1- --,., I. . i-~;- ~ of the sysoem.
Brief DescriPtion of the Drawin~s Figure IA - lD illustraoes the d~v~l~r of strategy for temporal drug delivery systems.
Figure 2 shows pH oscillations observed in the semibatch Hydrogen peroxide-Thiosulfaoe reaction under the conditions where Solution A (0.0j M Na2S20~ containing 0.07 M

~W095/28144 2`1 ~ 7023 : 1. 1 NaOH) is introduced into 300 mL of Solution B (0.10 M H2O2 and 8.8 x 10b M CUSO4) at 0.225 mVmin.
Figures 3A-3B illustrate the model mechanism and schematic diagram for the Iodate-Sulfate-Thiosulfate pH oscillatoL
Figure 4 shows the pH oscillations observed in the semibatch lodate-Sulfite-Thiosulfate oscillator under tbe conditions where Solution A (0.02 M Na2SO37 0.015 M Na2S203 and 0.005 M H2SO4) is introduced into 300 mL of Solution B (0.OSM NaIO3) at 0.225 mVmin.
Figures 5A-5B compare the resultant pH oscillations when poly(2-acrylamido-2-methyl-I-propane sulfonic acid (PAMPS) (Figme 5B) is directly substituted for sulfuric acid (Flgure SA) in a semibatch reactor. In each case, solution A (0.02 M Na2SO3, 0.015 M
NaS2O3 and either H2SO4 (0.0050 M) [Figure 5A] or PAMPS (0.0083 M) [Figure 5B]) is imtroduced at 0.225 mVmin using a peristaltic pump into 300 mL of Solution B (0.05 M
NaIO3) in a 500mL, 3 neck, round bottom flask with magnetic stirfing.
Figures 6A-6H show the results of the Iodate-Sulfite-Thiosulfate-PAMPS æmibatch study. Each of graphs shown report result using a different of the PAMPS
component (6A: 0.0075 M; 6B: 0.0080 M; 6C: 0.0081 M; 6D: 0.0082 M; 6E: 0.0083 M;6F: 0.0084 M; 6G: 0.0085 M; 6H: 0.0086 M).
Figures 7A-7D show the results of the Iodate-Sulfite-Thiosulfate-Nicotme semibatch study using various: of sulfuric acid (7A: 0.01680 M; 7B: 0.01759 M; 7C:
0.01775 M; 7D: 0.01800 M).
Figures 8A-8B show the results of the Iodate-Sulfioe-TI ~r ' Sodium Benzate semibatch study under conditions whete Soludon A (0.02 M Na2SO3, 0.015 M Na2S2O3, 0.005 M H2SO4 and 0.02047 M sodium benzoate) is introduced into 300 mL of Soludon B
(0.05 M NalO3) at 0.225 mL/min (8A: sample 1; 8B: sa nple 2).
Figure 9 shows tie results from the flux study of benzoaoe ion thfough 2 mil, 28% EVA
film at 32C (diffusion of benzoic acid).
Figures 10A-IOB illustfaoe an example of a user acdvated ~ sysoem for the

2 1 8 7 0 2 ~

temporal release of active, ~ ' Flgure IOA is a top view of a i ' ' device (with backing layer removed): I - tne-' device, 2 - an osmotic pump area containing PAMPS, Na2SO3, Na2S2O3 and drug, 3 - a burstable membrane, 4 - a non ' ' ' ~ membrane, 5 - active agent release area containing inert matrb~ and oxidizer solution, 6 - vacuum recepacle pouch, 7 -ultrathin burstable membrane, 8 - layer laminate.
Figure IOB is a side view of device shown in Figure IOA: I - g (see under Figure lOA), 9 -protective liner, 10 - adhesive layer, 11 - protective layer, 12 - backing layer, 13 - release liner, 14 - adbesive.
igures I IA-l lC illustrate changes in periodicity frequency due to changes in iodate resulting from semibatch iodate i , The period frequency increases as the iodate increases (llA: 0.100 M NalO3; llB: 0.050 M
NalO3; 1 lC: 0.025 M NalO3).
Figures 12A-12F show pH oscillation of the iodate system under semibatch conditions using the benzoic acidrL permeant model. Conditions are indicated in Example 5 and Table 3.
Figure 13 illustrates pH oscillations in the presence of benzoate under CSTR conditions using 3 mil 19% EVA film at 24C and a 75mL Crown donor cell. Solution A (containing 0.06 M Na2SO3, 0.045 M Na2S2O3 and 0.01512 M H2SO4) is added to solution B (0.025 M sodium iodate and 3.0 mg/mL of benzoic acid) at 0.190 mL/min using a peristaltic pump, pH = 5.80; Solution B is added at 0.095 mL/rnin.
Figures 14A-14B illustrate pH oscillations under semibatch conditions using a 100 mL, 3 neck, round bottom flask in the presence of additional tbickener, under conditions where Solution A (0.05 M sodium iodate) is introduced into 80 mL of Solution B (0.02 MNa2SO3, 0.015 M Na2S2O3 with either 0.00602 M H2SO4 (Figure 14A) or 0.01175 M
PAMPS (Figure 14B), 0.02047 M sodium benzoate and 0.5% PEO (4,000,000 MW)) at 0.080 mL~min using a peristaltic pump.
Figure 15 .'^ - semibatch flu~ of benzoate and pH variation due to adding iodateto sulfoxide, rather than sulfoxide to iodate utilizing 2 mil 28% EVA film at 32C and a 75 mL donor cell in which Solution A (0.05 M sodium iodate) is introduced to 75 mL of Solution B (0.02 M Na2SO3, 0.015 M Na2S2O3 with 0.00604 M H2SO4 and 0.02047 M
~ , . _ ~W095/2Xl~i 2l87a23 . 1 sodium benzQate) at 0.080 mL/min using a peristaltic pump, Figure 16 illustrates benzoate diffusion under semibatch conditions in response to pH
oscilladons utilizing 2 mil 28% EVA film at 32C and a 75 mL donor cell in whichSolution A (0.05 M sodium iodate) is introduced to 75 mL of Solution B (0.02 M Na2SO3, 0.015 M Na2SlO3 with 0.00604 M HlSO4 aPd 0.02047 M sodium benzoate) at 0.080 mL/min usimg a peAstaltic pump.
Figure 17 illustrates nicotine diffusion under semibatch conditions in response tQ pH
oscillations utilizing 2 mil 28% EVA film at 32C and a 75 mL donor cell in which Solution A (0.05 M sodium iodate) is introduced to 75 mL of Solution B (0.021 M
Na2SO3, 0.015 M Na2S2O3 with 0.037g7 M HlSO4 and 0.75ml nicotine free base) at 0.080 mL~min using a peAstaltic pump.
Detailed DescriPtion ~Jf the InventiQn The present invention is a method using chemical oscillators, preferably pH oscillators, to produce a temporal or periodic release of a drug or an active ingredient by passive meams across a membrane. To achieve oscillating drug diffusion, a strategy was formulated to oscillate the input in order to obt,~in an oscillating output profile This may be , ' ` ' in a variety of manners in a vaAety of delivery systems which are suitable for use in deliveAng ~ c (especially, ~ ' , anticancer drugs, anti-AlDS anti-, ' drugs, . _ 's, Alzheimer's aPd stroke , anti-viral agents, antisenæ peptides, anti-ulcer "~ , PMS
analgesics, ~ '' , birth control general hormone -r ' ih~ r '- , stroke - ' . antibiotics, . addiction treatments, anxiolytics, drugs, and '' , etc.), cosmetics (such as perfumes and fragrances, fif f~lf~ir,rp~ etc.), agricnltural active agents (such as IJII.,.I -P~ ~;r;~ip5 herbicides, or growth regulators), etc.
The balance of this disclosure will be tailored to I ' I products, but the invention disclosed and ~ , ` ' ' can be applied equally wel~ to any other area where temporal control or periodic release of an agent is desired.
For purposes of this invention, "passive delivery~ means that once the osciUation is begun, W0 9!5/28144 2 1 8 7 ~ 2 3 - Y~ --., ~,.
no other source of energy (outside of the system) is needed to drive tbe oscillation reaction and the delivery of active agent follows passive diffusion principles (i.e. flux of a species follows its chemical potential gradient - from biBh to low) depending on the species of the active agent, the pH of the system and/or the oscillation reaction responsive . ~ ;. c of the delivery device per se.
In general, the present invention control of an active agent can be seen with specific reference to pH oscillating reactions. However, any other oscillating species in an oscillating reaction can ad~ , be employed in a similar favhion. For purposes of simplicity, the invention will be described with specific reference to pH oscillating reactions. Other oscillating species in oscillating reactions that can be used in the invention include. but are not limited to, Ce+3, Mn+2, Fe+2, Li+, and Ru~2 complexes in the BZ reaction, s+2-o, ' ~ v blue system, as well as those shown in Table 7.1 in Osrill ~ nc and Traveling Waves in Chemical Systems; Field and Burger, Eds;
Wiley-T New York (lg83), p.230.
In the BZ reaction, which is the catalytic l ' v (preferably 1.. ~ . i i ; ....) and oxidation of an organic substrate, the organic substrate fluctuates bet veen two species, the ' " ' and the, ' ' ~gF ' ' compound. Differences between these two species in any of the parameters needed for effective delivery can be exploited to obtain the desired deliYery control. Typical substrates for use in this reaction include, but are not limited to, citric acid, malonic acid, I ~' acid, malic acid, gallic acid, pyruvic acid, oxalic acid, 2,3-L ' ~, quercetin, morin, acetoacetic acid methyl ester, 4-chloroaceto-acetic acid ethyl ester, ~ LG acid diethyl ester, N J' _'~ _ ' .
~G.r' '.( -chromium complex, 3,4,5-~ i ' ' ' yde, 2,4,5-trimethoxy-benzaldehyde, and (im a water-acetonitrile solution) a mixture of veratric acid and ~. ' ' ' .~ IG. Polymers having these materials L ' therein (typically as pendent groups) in at least 40% of the repeating units of such polymer can also be used in the polymeric ~ - ' described further below.
With reference to pH oscillating systems in L~hall ' contexts, the c..vih, of the acdve agent to be delivered can have its pH altered between a value where tbe active agent shifts between species which more readily and less readily permeates or diffuses tbrough a delivery device barrier (andlor, in the case of a ~ 1, the skin); a membrane barrier through which the active agent must pass or a matrix from which the active agent must be released can have its, ' ' ~.~, altered in response to pH changes;
., _, , _ _ _ . . .

~W095/28144 21 8 7~z3 1 ~
g a barrier separadng a flux enhancer from the acdve agent can be modulated to regulate the ar~ount of flux enhancer delivered to the active agent and as a result modulate the flm~
enhancer dependent active agent delivery; a polymer can be modulated to shift between a more viscous and less viscous form (i.e. poly-~-glutqmate as im C~acenzi et al, Polymer Preprints, August 1994, 407 408) or a more solubilized and less solubilized form or a more swollen and a less swollen form (i.e p~ h)qerylic acid as in Kou et al, P; Research 5(9), 1988, 592-597), thereby altering the amount of water available to tbe acdve agent or another membrane which either needs to be or needs not to be hydrated in order to have proper acdve agent delivery, etc.
Where a lipophilic membrane is involved, either as part of the delivery device or as a membrane of the padent through which tne acdve agent must pass (and is not changed by the l~IIVIl~ ' through which it passes after leaving the device amd before arriving at the lipophilic membrane), the ' of an active agent, preferably a drug, witn a chemical pH oscilladng reaction, may render the active agent charged or uncharged reladve to its own pKa value. Since only the uncharged form of a drug can permeate across lipophilic ' a periodic delivery profile may be obtained by oscillating the pH of the drug solution. The same type of end result cam be achieved by oscilladmg the p~ db;lily of a membrane to either the active agent per se or to a flux enhancer needed for active agent delivery.
Some or all of the above , may also be adapted for use in delivery devices of other types, such as capsules, tablets, etc. These are especially suited for use with active agents which are rapidly cleared from the system and therefore need to be - ' rapeatedly over the course of a day. Any disease state which will be better treated by Iow dosing of the active agent (such as i ' ' I agents) can also benefit from the present invendon. For example, a tablet can be constructed having the oscilladon reaction . . (in which the reaction will be initiated in a low pH
CIIVII~ t) in a core along with a compatible active agent which exists in a diffusible and non ~ ~ form. The core is surrounded by a membrane which is permeable to to the active agent diffusible form. Upon reaching the stomach, the acid ~IIVIIUIIIm~
diffuses into the core and initiates the oscillation reaction which then results in local changes in pH which overide the influences from the g~u~ IIVII~ ' allowing for periodic delivery of the acdve agent. A suitable membrane for use which is permeable to uncharged species of active agents, but not (or at least ' "~, less) permeable to charged species of the active agent and not ( ' "~, not) permeable to W0!~5128144 21 8 7023 . .
osciDation reacaon ~ , is ~Ihjl.,..J~, yl acetate (EVA) copolymer. Other suitable I ' will be apparent to those of ordinary skill in the art. In another variant, the active agent is not contained in the same ~, , with the osciDation reaction . , . but in a æparate . Both , are contained within another membrane which is permeable (or more permeable~ to one form of the active agent. The pH osciDation of the oscillation reaction ' through the EVA membrane to the active agent containing: . In response to the changing pH, the active agent shifts between staoes in which it has greater and lesser ability to diffuse out of its . , and into the outer ~ Other variations adapted from the ' " described concerning the ' ' systems wiD be apparent to those of ordinary skill.
Capsules can be prepared with ~ versions of the above described tablets.
Strategy for Temporal Drug Delivery The key parameter for system design is the ratio of the ~ time for permeation to the "1 ,- t~ time of the osciDating driving force. Tbis ratio must be small (less than one) to produce a temporally controlled delivery profile. As an example, a periodic drug release profile can be obtained by ensuring that the period of oscillation in the drug input through the use of a pH chemical oscillator is longer than the permeation of the drug across all diffusional barriers. The following analysis illustrates how this key parameter controls the delivery of a drug across a membrane. Consider an ideal situation where a drug with a known pKa is in an infinite reservoir, in which the pH of the solution is 'ly changed by a pH chemical oscillator. The ~ of the uncharged form of the drug [C(t)], which can permeate across a h,~ ' ' membrane, is given by:
C(t) = C"""~ sin(~ t) where Cm,,~ is the maximum, , t is time, and ~ is the frequency (or 2tllo) is the period of r,sr~ tirn). The frequency, ~, is controlled by the kinetics of the pH oscillation, and hence by the selection of the chemical oscillator. The flux of the drug across tbe membrane, expressed in a ~' ' form, is then given by:

~WO 9~144 2 1 8 7 ~ 2 3 I
li(t~ )n~ I n2, 2 2 m sin alt ta ( --n-2 3 dimensionless ~ fo~dos~D, A ~ -D t /~
e (n4 + ~2C02 ) diffusion where 1, K, D and ~ (= 12/~2D) are the thickness of the membrane, the partition coefficient, the diffusivity and the ~ ;- time of rPnnPs~inn The permeation ~
time, whicb is theoretically ~ -- ' to the time lag, is governed by tbe diffusivity and the thickness of the membrane, shown in Figures IA-ID. The first term in the right-hand-side of the above equation describes the - to the flux by the imposedperiodic change of the driving force, whereas the second terrn is the dampening of the drug transport by the membrane. C . -'~, if t~te conditions are set up such that the second term dominates (~D 1), then the output flux would always be controlled by the membrane to a const~nt value that reflects the mean driving force for difusion. Mowever, if the conditions are set up such that the frst term dominates (A~ 1), then tie flux of the drug across the membrane would oscillate at the same frequency as the drl-tg in the donor changes from a charged to an uncharged state. Defining this æt of conditions, in which ~ ~ 1, is the underlying principle for the ~ of the temporally controlled delivery system.
Proposed 1~'- ' of Chemical Oscillators The Mixed Landoldt oscillator, which is the iodate o~idation of sulfite with an additional reductant in acid solution, is a well known pH oscillatl~g system. When thiosulfate is chosen as the additional reductant, pH regulated oscillations can occur between the values of 6.5 and 4Ø This system has been extensively studied by Rabai and Beck for batch and Slirred Tank Reactor (CSTR) conditions and Rabai anq Epstein for wo 95128144 21~7~23 semibatch conditions (Rabai, G. and Epstein, I.R., J. Amer. Chem. Soc. 114 (1992) 1529;
Rabai, G. and Beck, M. T., J. Phys. Chem. 92 4831-4835 (1988); and Rabai, G. and Beck, M. T., J. Phys. Chem. 92 (1988) 2804-2807). In oscillating chemical reactions, the of catalyst or " species, such as metal ions, oscillate with time.
They are driven by a decreaæ in free energy of the overall chemical reaction occurring far from i - '~ . "' (æe Luo and Epstein above).
The earliest recogrliæd chemical oscillators are the Belousov-7~ -' ' (BZ) reaction and the Landoldt or "iodine clock reactionn. (Nicholos et al, Chemical Oscillators, Chemical Reviews, 1973, Vol. 73, No. 4, p 365-384.) Neither of theæ are pH driven oscillating systems. The BZ reaction is one of the most extensively studied non-linear reactions known today. Under appropriate conditions, organic materials are oxidiæd by bromine or other halide with the aid of a metal-ion catalyst which leads to ælf-sustained oscillations in the . of the reaction - ' These oscillations can be seen visually by the addition of the reagent ferroin (see Field, Chem Ed., Vol 49, No 5, 1972, p.l08). The accepted Field, Ko}os and Noyes (FKN) mechanism was preænted in 1972 by Field, Koros and Noyes (Tyson, ~ohn; in Ocrill~innc and Traveling Waves in Chemical Systems; Field and Burger Eds.; Wil~ , New York 1983, p.94). In a more simplified form, it is known as the Oregonator (p.108 of this same reference), shown below:
A+Y--X
X+y _ p B+X - ~ 2X+Z

Z--fY
In this model, A and B are reactants, P and Q are products, X, Y and Z are the , of the - ' (bromous acid, bromide ion, and CeaV), the metal-ion catalyst), and f is the Cl. ~ factor, I~,D~ L~1Y (Epstein, I.R.; Orban, M. in ()srill ~innc and Traveling Waves in Chemical Systems; Field, R.J., Burger, M., Eds.;

WO 95128144 2 }. 8 7 ~ 2 3 ~Vil~ T~ New York 1983). The usual practice for the study of oscillating systems has been to use closed (batch) reactors or an open system [. - flow stirred tank reactor (CSTR)]. The recent descripaon of using a "semibatch reactor" as an additional tool, is an appealing and simple - method to study pH oscillating systems (see Rabai and Epstein, J. Amer. Chem. Soc. 114, above).
Initdal l r - '- of pH oscillators st~rted with the Cu(II) catalyzed hydrogen peroxide oxidation of thiosulfate in order to determine ! . ' l Using the ~- - - reported by Rabai and Epstein (J. Amer. Chem. Soc. 114, above), we obtained the same type of pH -- - with the exception of a longer period length due to a differing residence time of the reactor (Figure 2). Even though a detailed mechanism has not been suggested for this system, the oscillations can be explained by the fact that the oxidation of thiosulfate by hydrogen peroxide can occur through two reaction routes:
2S2032 +H202 ~ S4062-+20H (I) S2032~ + 4H202 ~ 2SO42- + 2Hf + 3H20 (2) This ~ between the productdon of OH- and of H~ has generally been assumed to be the driving force responsible for the pH ocr~ nc, at least under CSTR conditions (Orban and Epstein, J. Amer. Chem. Soc. 109 (1987) 101). When hydrogen peroxide is in excess, as it is in the æmibatch reactor, the hydrogen ion producing reacdon (eq 2) - As the peroxide falls with respect to thiosulfate, the hydroxy producing reacdon begins to take over and pH climbs. Once the peroxide c..~
drops ~ig ~ , reladve to thiosulfate, the hydrogen ion producing reacaon again Iciclcs in and the the pH again falLc. The addidon of hydroxide is essentdal m order to make reacdon (I) coln~ , (Rabai and Epstein, J. Amer. Chem. Soc. 114, above). The mixed Landoldt reacdon (iodate- ~ ) oscillates the pH between 6.5 and 4Ø
With this oscilladng system there is a ~ "spilce" where the pH minimum is just above 4Ø If the pH falls below 4.0 for any length of dme, the iodate-iodide (Dushman) reacdon 1~. ' and the soludon turns brown in color. The model mechanism for this reacdon is as follows:
A+B --Y
A+B+ X --Pl W09~/28144 2t 8 7~23 - P~

. .
A+Y+X ~ 2X+P2 where in this skeleton model, A ~ , ' to (but does not stand for) iodate, B to thiosulfate, Y to hydrogen sulfite, X to hydrogen ion, Pl to t~ and P2 to sulfate.
The basis for the oscillatory behavior is the alternation of the I~D;D of sulfioe and the . . of hydrogen ion and tbe formation of sulfite (Rabai and Beck, above), (see Figure 3).
The known oscillating reactions include, but are not limited to:
the .c ' ~ thiourea system;
the i ~ r ' system;
the i~ WIU~ ' system;
the I -~uLt~, f~lu~,~ . system;
the ~c ' -h.~u~ system;
the ~-iu~t~ ~,VdlVA~' ' system;
the phenol-bromite-ll.~dl~ ' ~ system (pH 3-7) Orban. J. Phys. Chem. 1994, 98, 2930-2935;
the periodate-thiosulfite system;
the hydrogen peroxidc C~lu~ system;
the hydrogen peroxide-;' r ' copper(II) system;
the hydrogen peroxidc '~ f~ ...;~ Sysoem (pH 4.5-7) Rabai et al. J. Phys.Chem., 1994, 98, 2592-2594;
tbe chlorite-thiocyanate system (pH 14) Chinake et al, J. Phys. Chem. 1994, 98, 2908-2916;
the chlorite-ic ' -' ~ acid system;
the ~ rr~ system (pH 2.5-4.5) Epstein t al, J. Phys. Chem. 1992, 96, 5852-5856;
Any of these can be used in the practice of the invention, depending upon the use to which the product will ultimately be put. Generally, where one halogen is used, it may be substituted with the ~ull. r ' g species of another halogen, for example bromatereplacing iodate or bromite replacirlg chlorite.

~W095/28144 2 f 8 70 2 ~ ~

Preferably, for l - ' uses, the pH oscilluors of the ;c -h~u~
system, the ' ~ - system. the ' ~ f~ ' system, and the hydmgen peroxidc ;- ~ copper~) system are uæd.
Each of the pH oscillators has a defined range of pH through which it will oscillate, making the choice of oscillator dependent upon the ~ ' ;-, of the other materials chosen in the u.,lio.l of the delivery device. Some ûf the pH oscillation reaction pH
ranges are shown below in Table l. Others will be readily determined by tboæ of ordinary skill in the art using known techniques.
TABLE I
pH REGULATED OSCILLATORS (1990) SYSTEM PH RANGE
1) IODATE-SULFITE-THIOUREA 7.5-3.5 2) IODATE-SULFITE-THIOSULFATE 6.5-4.1

3) IODATE-SULFITE-FERROCYANIDE 2.5-8.0

4) IODATE-HYDROXYLAMINE 2.8-5.5

5) PERIODATE-HYDROXYLAMINE

6) PERIODATE-THIOSULFATE 4.0-6.0

7) HYDROGEN PEROXIDE-FERROCYANIDE

8) HYDROGEN PEROXIDE-THIOSULFATE-COPPER(II) 6.0-8.0

9) HYDROGEN P~ROXIDE-BISULFITE-THIOSULFATE

10) PEROXODISULFATE-THIOSULFATE-COPPER(II) 2.3-3.0 WO 95/28144 21 8 7 ~ 2 ~

1 1) BROMITE-IODIDE
12) BROMATE-SULFlTE-FERROCYANlDE
13) BROMATE-SULFITE THIOSULFATE
14) MANGANESE(D~)-PERIODATE 3.5 4.5 TABLE I is contulued on next page with: pH OSC~LATORS

~1~70 951~ 2 1 8 7 ~ 2 3 ~ r~-,. T

W095/28144 2 1 8 7 0 2 ~

The delivety devioes into which the oscillating reactions can be ~ ' include tablets, capsules, implants, . ,, ' bandages, and trPnc~ l delivery devioes.
With specific referenoe to pH oscillating systems. the delivery devices have at least one barrier layer, which is a membrane coat through which the active agent must pass or a matrix from which the active agent must be released. ~n tbe simplest systems, this membrane or matrix is permeable to one species of the active agent, but not another species of the active agent, and the active agent changes between these species in response to the pH changes in the oscillating reaction. Such a i ' ' system is ' by a cavity formed by an ~ 1 aoetate membrane to which is laminated a silicone based ~ , adhesive. heat sealed to a polyester I ' ' backing. Inside the cavity is a reærvoir containing the active agent and pH oscillator reactants. In this , since there is no separation of the oscillator reactants, tbe system is acdve upon assembly. This is suitable for a so-called "fillable" i ' -' system in which the one or more of the oscillator reactants are left out of the system until it is ready for use. At that time, the final reactants are added and the system is active. In a slightly more complex system, multiple . are present with at least one oscillation reaction reactant separated from the rest of the reactants. The separation barrier between these is burstable by the user, thereby activating the oscillation reaction, just before applying the i ' -' Alternatively, if tbe oscillation reaction is either initiated by light one of the reactants is converted to an active form by light, then all of the reactants can be combined in a single lj L provided tbe initiating radiation is ecxcluded until one desires to initiate the osciallation reaction. Examples of actinic radiation initiated oscillation reactions include, but are not limited to those disclosed in:
DD 146864 (puWished 314/81) (~ Fe(m) . ' bromate-organic acid-dipyridyl complex former); Mori et al, J. Phys. Chem 1994, 98,12968-12972 (fbll~uy -peroxide-sulfuric acid); Rabai et al, J. Phys. Chem. 1994, 98, 10550-10553 (chlorite-cloride-i ' ' acid); and Vanag et al, J. Phys. Chem. 1994, 98. 8392-8395 and Mori, J. Phys. Chem. 1992, 96, 9083-9Og7 (peroxide-sulfite-rtllu~ ' ).
The various dosage forms which are suitable for use in the present invention include tablets, capsules, depot rl for insertion into the body, topical 1.. ~, ,. I ;. . ~, tr~nc~Prn~olc ~ ' bandages, infusions, etc. In each case, the delivery device must either have a means for preventing the initiation of the osciliation reaction until it is desired that the reaction begin, or the device is capable of having at least one component added by either the user or the r ' '( of tbe device so as to activate the oscillation reaction. Beyond these criteria and that the device ~ 1~ be compatible with tbe .

~WO 9~i/28144 2 1 8 7 ~ 2 3 ~11 s chosen oscillation reachon, any standard delivery device materials may be used.
With specific reference to the h ' ' area. a typical device is shown in Figure IA. It has an . ' ' bscking layer o} laminate which is sealed to a cont~ol membrane, and together define a reænoir area On hhe control membrane, distal to the backing layer, is an adhesive. Figure IA shows hhe device as applied to the skin of the user. Prior to applying the device to hhe skin, hhe typical i ' ~' device has a removable layer or laminate in place of tbe skin in Figure lA. The reænoir may contain the drug to be delivered, or the drug may be within either the conuol membrane or the adhesive. The osciUation reaction reactants are placed in the reservoir area by any suitable means (such as a resealable enhry port for inserhng the reactants).
Once the oscillation reaction reactants are al present, hhe oscillahon reaction stans. The oscillations obtained can modulate the drug itself or a needed fiux enhance} (such as , azone, limonene, etc) to effect delivery; modulate the membrane to open and close the conhrol membrane "gate" to either the drug or to a needed flu,c enhancer (i.e. pore size modulation and/or chemical ~ of the membrane fo} the species which must diffuse i' ,, - see Islam et al, Journal of Applied Polyme}
Science, vol. 45, 1485-1490 (1992) - pc~ h,L,l.~" Israels et al, ~ 1994, 27, 6679-6682; Lee et al, J. of Conh~olled Release, 6, (1987) 3-13); modulate hhe viscosi~y of the resenoir o} adhesive (such as PAMPS, pc~ ud~,D~ poly(meth)acrylic æid, polyvinyl alcohol, pol~ poly-~-glutamic æid etc.) to enhance or impede drug or flux enhancer travel i' ' J~ , or alter the available solvent (such as pol~ ' gels, polyvinyl ~ ." ' PAMPS gels, etc.)to modulate the of drug and/o} enhance}, A more typical i ' ' device is shown in Figure lO. This device has an ' ' - bæking and a releaæ line} or memb}ane o} laminate. These two layers are sealed togethe} so as to define between them at least three separate ~c , In one~ , is the bulk of oscillation reætion , In the case shown, this is PAMPS, Na2SO3, Na2S203, and the drug desired to be delivered. This is adjacent to a æcond ,~ l, having a matrix and the oxidize} solution contained therein. In the specific example in Figure 10, the oxidize} would be 103. This ~
to hhe ætive agent release area. Distal to the first . t, but adjacent to the second t, is a third , which is a væuum }ecepticle , To p}event drug migration , ~ . L I and 3 have an ove}layer on the WO 95/28144 ~ / 5 .
2~ 87023 release layer (distal to the , themselves) which is . ' to the drug.
Further distal to the . . and covering the overlayers as well as the remainder of the release layer is an appropriate: ' ' adhesive. The final covering on ~he adhesive is a removable protecdve layer which is removed by the user or am r ~ -of the device just prior to its applicaaon to the body to be treated.
In this ~ ' t, . 1 and 2 are separated by a burstable . ' ' membrane. This burstable membrane is broken by the ætion of the user or - ' just before or just after (preferably before) removal of tbe release layer.
The following non-limiting e~amples further describe the present invention.
C . ' that were used: All chemicals were of reagent grade and used without further ~ Sodium iodate, sulfuric acid (volumetric standards 0.5 N and 0.1 N), poly(ethylene oxide)- MW 4,000,000 and 900,000 and poly(2-acrylamido-2-methyl-1-propane sulfonic acid) 10 wt.% in water (PAMPS), were obtained from Aldrich Chemical Co., Milwaukee, Wl. Sodium tbiosulfate, sodium sulfite, sodium iodate, (-)-nicotine (free base), cupric sulfate, malonic acid, citric acid, ceric ammonium nitrate and hydrogen peroxide (30% w/w solution) were obtained from Sigma chemical Co., St.
Louis, MO. r~ly(dcljl;c acid)- MW 450,000 and 250,000 was obtained from rOI.y~.,;~,.,~c., Inc., Warrington, PA. Potassium bromate, sulfuric acid (18 M), pH buffer standards (4.00 and 7.00) and 1, 10 1 ' ', ' ~ ferrous sulfate complex (Ferroin 0.025 M solution) werç obtained from Fisher Scientific, Pittsburgh, PA. pH oscillator - -r werç carried out irl a simple semibatch reactor or a custom made super cell diffusion cell apparatus obtained from Crown Bio-Science. The reactor, a 500 mL, 3 neck, round bottom flask, was fed by a Rainin Rabbit peristaltic pump usirlg an Elkay pump tube (i.d. 1.14 mm). The rçactor was stirred ~.y with a magnetic stirreL
The pH of the reactor solution was monitored using a ROSS . ' pH electrode connçcted to an Orion 520A pH meter. For .~ ;. ,., potassium hydrogen phthalate buffers (pH 4.0 and 7.0) wçrç used. Data acquisition was a . ' - ' using an Apple Macintosh computer with Rr~ ' ,, . ' software to produce the pH plots. Additional PC
data acquisition software, HT BASIC, was uæd and the plots werç produced using PS
PLOT plotting program.
Examnlç 1: pH Oc~ nc in a Semibatch Reactor ~W0 9!~/28144 2187~2~3 -2 -Cu(ll) catalyzed hydrogen peroxide oxidation of thiosulfate - The pH semibatch ~, followed the conditions described by Rabai and Epstein a.A.C.S 114, 1529 (1992)) for the semibatch reactor. The reactions were run using stock solutions of 0.10 M
hydrogen peroxide (H22)~ 0.1O M sodium thiosulfate (Na2S203), 0.14 M sodium hydroxide (NaOH) and 8.83 x 10-6 M cupric su]fate (CuS04) which were prepared with deionized, distilled water. Briefly, 50.0 raL aliquots of the two stock solutions (sodium thiosulfate and sodium hydroxide) were combined into a 125 mL F ,~ flask This solution was then introduced, at 0.225 mL~min. using a peristaltic pump, into a 500 rnL 3 neck round bottom flask containing 300 mL of 0.10 M hydrogen peroxide solution and 1.0 mL of the cupric sulfate solution. The reactor was used at room ~ . and the solution was mixed by magnetic stirling.
Iodate-Sulfite-Thiosulfate - The reactions were run using stock solutions of 0.05 M
sodium iodate (NalO3), 0.045 M sodium thiosulfate (Na2S203), 0.06 M sodium sulfite (Na2SO3), 0.015 M sulfuric acid and several water soluble polymers which were prepared with deionized, disalled water. The soluaons of NalO3, Na2S2O3 and Na2SO3 were made fresh every week and protecoed from light during storage. The pH æmibatch ! .
followed the conditaons described by Rabai and Epstein a. Amer. Chem. Soc. 114, above) for the æmibatch reactor with only minor changes. Briefly, 40.0 mL aliquots of the tbree stock solutions (sodium sulfite, sodium thiosulfate aud sulfuric add or water soluble polymer) were combined into a 125 mL F ' ~. flask. To avoid addic ~L . "' of thiosulfate, the add and sulfite solutaons were measured first and then the thiosulfate soluaon was added. This soluaon was then introduced, at 0.225 mL/min. using a peristaltic pump, into a 500 mL 3 neck round bottom flask containing 300 mL of 0.05 M
sodium iodate. Again, the reactor was used at room i ~ and the solutaon was mixed by magnetac stirring. pH oscillaaons were obtained when sulfuric acid (0.005 M) was used as the acid component in the addiaon soluaon (Figure 4). The pH was found to oscillate eight times between the values of 65 and 4.0 after an extended minimuminduction period. Each cycle was . . '~, 30 minutes in length and towards the end of the . t, the damped osci~tions decreased m amplitude and increased in cycle time. This reacaon was found to b~ repeatable and not sensiave to r~ in room i . Additaonally, the reactant, were found to be ,'~ ' For example, when the thiosulfate c was reduced 7% or more, the pH decRases to below 4.0 during the inducaon period and the presence of elemental iodine appears. When thiosulfate r is increased 16% or more, the pH stays above 5.5 and the number of oscillaaons is reduced. The same effects were seen , _ , . . . . . . . .. . _ _, , _ wo 95128144 r~
2~8~23 -22-when the sulfuric acid . were vatied.
ExamPle 2: pH Ocri~ ionc in a Semibatch Reactor with Polvmer lodate-Sulfite-Thiosulfate and PAMPS - Several water soluble polymers were tested as potential candidates for a viscosity enhancer witbin the iodate oscillator system.
Poly(acrylic acid) gave: _ g results, but oscillations were not produced.
Poly(2-acrylamido-2-methyl-1-propane sulfonic acid) 10 wt.% in water, (PAMPS) was found to be readily available from Aldrich Chemical Co. and in the free acid form. Other polymeric sulfonic acids are only available irl the sodium salt form which wouldnecessitate l ~ and ~ ; ThiC polymer has a pendent sulfonic acid group and recently has been studied by Gooda and Huglin (Gooda, S. R and Huglin, M.
B. J. of Polym. Sci. Part A, 30 1549-1557 (1992) and Gooda, S. R. and Huglin, M. B.
r ' , ' ' Vol. 25, No. 16, 4215-4217 (1992)). Tnitial, . revealed that pH oscillations were possible substituting PAMPS for sulfuric acid in the iodate oscillator (Figures SA-SB). Therefore, a study was conducted in order to identify oscillations as a function of the . of PAMPS, the results of which are shown in Figure 6. The pH oscillates between 65 and 4.0, however, the pattern of oscillation is very sensitive to the, of PAMPS. This type of behavior is not uncommon in nonlinear systems. The amplitude and periodicity of the pH value changed ,i~
as the, of PAMPS was varied from 0.0075 M to 0.0087 M in increments of 0.0001 M. Molarity of PAMPS was calculated based upon the repeat unit. When the PAMPS ~ was below the critical acid the pH stayed above 5.5 and oscillations could not be started. Conversely, when the PAMPS C ~ t~ was increased too much, the pH fell to 4.0 or below, stimulating the iodate-iodide reaction to occur and~or inhibiting the pH to return to 5.5. Therefore, at a of 0.0080 M.
there is enough available acid to allow When the is increased, the number of oscillations increase. Above the of 0.0083 the reactor solution becomes acidic and oscillations are damped. In order to develop a usable drug delivery system, a viscosity modifier is recluired. Several synthetic and natural water soluble polymers are now under ;~lV~Dti~;~li;Oll. When poly(2-acrylamido-2-methyl-l-propane sulfonic acid) or PAMPS was directly substituted for sulfuric acid, pHoscillations of the same period and amplitude were observed. This is the f~rst polymeric ' ' that we know of in a chemical oscillating system where the polymer actively participates in the reaction instead of serving as an inert reaction medium. Recently, 2 articles by Prem Mohan [Drug Dev. Res. 29 (1993) 1-17 and Drugs of the Future 18(4) , ~wo gsirl44 2 1 8 7 ~ 2 3 (1993) 351-358] discuss the potential use of sulfonic acid derivatiYes as selective anti-HIV-l agents. PAMPS, the polymeric sulfonic acid that can be substituted for sulfuric acid irl the iodate oscillator reaction, shows anti-HIV-I activity. Other smaller sulfonic acids, wbich may be , ' into the osciDator system, also show anti-HIV-1 activity.
Example 3: pH Oscillations in a Semibatch Reactor with a Dru~
Iodate-Sulfite-Thiosulfate and Nicotine - The procedure used for the (-)-Nicotine . ~ was a slightly modified version of the procedure above, in order to account for the sensitivity of nicotine free base to oxidation. A 40.0 mL aliquot of sulfuric acid stock soludon was frst measured into a 125 mL r ~. flask. 0.50 mL of (-)-rlicotine free base was then measured using a disposable glass pipette and added to the sulfuric acid solution. It was assumed that the nicotine sulfate salt was formed - '~,. Dry argon gas was used to flush the nicotine reagent bottle in order to avoid oxidative ~' , of the nicotine free base. 40.0 mL aliquots of the remaining two stock solutions (sodium sulfite, sodium thiosulfate) were then added to the 125 mL F ' ,~,. flask. This clear, colorless, l ~ solution was then introduced, at 0.225 mLlmin. using a peristaldcpump, into a 500 mL 3 neck round bottom flask containing 300 mL of 0.05 M sodiumiodate. The reactor was at room , and the solution was mixed by magnetic stirring. F, ' towards the . ~ of a ~ active compound into the iodate pH oscillator was then initiated. Nicotine was suggested as a model compound because: I) it is miscible in water, 2) it fomms stable salts with almost any acid, 3) the pKa's are 3.4 and 7.9 1~DIJ~ V~d~/ for the ~ ", of the protonated pyridine and pyrrolidine nitrogens, 4) a vast amount of - r " is readily available conceming IJh~ ' ' properties and analytical techniques, and 5) nicotine pemmeation across synthetic and biological membranes is welD'- ' Nicotine (free base) was found to be compatible in tbe iodate system. It was assumed that the free base fommed the sulfate salt upon addition to sulfuric acid. There was no ~ l. .. rl ;U~ of either the addition solution or reactor solution which indicates a minimum of nicotine oxidation. pH oscillations are shown in Figure 7. It was assumed that the free base fommed the sulfate salt upon addition to sulfuric acid. ~f nicotine is oxidized during the oscillator ~ ~r- -- t, the most probable products are S-Cotinine and S-Nicotine-N'-Oxide, which are reported to be colorless Shown in Figure 7, are the results of a study illv~ ~ _ the addition of nicotine free base to the iodate oscillator.
When nicotine is added, the system becomes even more sensitive to variation in species W09~i128144 21 8 7~23 - In this study only the acid ~ was varied. pH (lC~ innC were observed, but are very sensitive to the amount of each component and laboratory techniques, which seem to accoumt for the difficulty in achieving nc~ innC Additional ci r ' ' with the of nicotine free base and PAMPS revealed no solution .l -- . .l. .. nl ;~ ~ or polymer l A ' '- in the iodate oscillator system. This suggests that both PAMPS and nicotine (free base) are compatible.
Iodate-Sulfite-Thiosulfate and Sodium Benzoate - Benzoic acid has been L.~. i" ' as a model compound to !' ~he application of pH oscillators to modulate the delivery of the ingredient. F, revealed the repeatable production of pH oscillations when sodium benzoate is added m the iodate oscillator system (see Figure 8). Tbis suggests that benzoic acid is compatible in the iodate system and benzoic ac~d can be released in a temporal fashion.
Example 4: D of Permeated Benzoate lon at Constant pH Values Following the methods described by Morimoto et al. (Morimoto et al., Chem. Pharm. Bull.
39(9) (1991) 2412-2416), a modified a~csay method was developed for the ~' of benzoic acid permeation across EVA ' at const~nt pH values. Additional ~ . J~ n~y has been taken from Maurin (Maurin, M.B., Ditoert, L.W., Hussain, A A., J.
Pharm. Sci. Vol. 81, No. 1 (1992)). The permeation of a model compound (benzoic acid) across a model membrane (28% EVA, 2 mil thick, 32 C) was ~ at discrete pH
values. Table 2 expresses the actual - of permeaoe through the membrane and the cul.. r " ~ flux. The donor solution was 0.05 M sodium iodaoe with 0.02047 Msodium benzoaoe. The pH was adjusted with the addition of sulfuric acid. The receiver solution wæ 0.05 M phosphate buffer (pH 2.4). The resulting flux was greaoer than expecoed owing to the fact that the r . was increased and a higher vinyl acetaoeconoent (EVA, 28% vinyl acetaoe conoent, film of 2 mil tbickness was used rather than 25% EVA). This agrees with Maurin (1992). Figure 9 shows the soeady staoe flux of benzoaoe that diffu~ed through the 5 cm2 of 28~ EVA film at different pH values.

~ W0 95128~44 ~1 8 7 ~ 2 3 TABLE 2: FLUX OF BENZOATE ION THROUGH 2 mil EVA (28%) MEMBRANE
pH I CONCENlRATlON(mglmL) I F~UX
6.S l 0.17 l 0.008 6.0 l 0.44 l 0.020 5.5 l 1.50 l 0.070 5.0 ~ 3.90 l 0.195 4.5 l 9.50 l 0.480 ExamDle 5: r~ of Permeated Benzoate lon at Oscillatin~ pH Values A. The periodicity of the pH osciDations im an iodate system (the mixed Landolt system) were first evaluated for further use in evaluating benzoate ion permeation under semibatch conditions, Steady and repeated osciDations were obtained. The results, shown in Figure

11, indicate that the periodicity of the pH oscillations is a function of the iodate and that the freqnency of the oscillation increases with increasing iodate Based on this data, 0.025 M lodate: was used for the balance of this B. For these ~, . a 2 mil, 28~ e~ ";l acetate (EVA) membrane was employed. The model active agent (benzoic acid, 0.02047 M) was placed in an iodate solution and the pH was adjusted to a value of 5.8 using sodium hydroxide. A sulfoxide addition solution containing sulfuric acid, sodium sulfite, and sodium thiosulfate in a ratio of 1:4:3 was added at a rate of 0.225 mL/min. The specihc of the sulfoxide component are shown in Table 3 below.
TABLE 3: CONCENTRATION OF REACTANTS USED TO OBTAIN CRAPHS

2l87023 26 GRAPH IODATE SULFURICACID SULFl~E THIOSULFATE
A (lX) 0.025M 0.00504M 0.020M 0.0150M
B 0.025M 0.00533M 0.021M 0.0160M
C 0.025M 0.00600M 0.024M 0.0180M
D (2X) 0.025M O.OlOOOM 0.040M 0.0300M
E (2.5X) 0.025M 0.01250M 0.050M 0.0375M
F (3X) 0.025M 0.01500M 0.060M 0.0450M
pH oscillations were ~o~l~t~ tl~ obtained. The results, shown in Figure 12, indicate that the amplitude as well as the periodicity of the pH oscillations are a fimcdon of sulfoxide ,""r,.,t,,.l;~.,\ in this case. At three times (Table 3, F) the normal (Table 3,A), the system was overloaded amd the rate of addition reduced.
C. In tbe flux ~ r t, a 2 mil, 28% EVA film was used at 32C with semibatch conditions. a 75mL donor cell was used. The sulfoxide solution contained 0.02M sodium sulfite, 0.015M sodium thiosulfate amd 0.005 M sulfuric acid, with 0.02047M sodium benzoate and was added to a 0.025M sodium iodate solution at the rate of 0.225 mL!min using a peristaltic pump. The results indicate that the flux of benzoate responds to pH
changes, increasing as pH decreases while decreasing when pH increases.
D. A variation of the experiment C above (results shown in Figure 14), began with 20% of the benzoate added to the iodate solution. Upon this addition, the pH of the iodate solution rose to 7.6, which was adjusted to 5.84 with a small amount of sulfuric acid. The addition rate of the iodate solution was 0.1 ImLlmin, but otherwise the conditions were the same as in C above. The profile obtained shows a shorter lag time and a clearer response of active agent diffusion to pH oscillation is seen.
E. The variation in this experiment was basically the inclusion of all of the benzoaoe in the iodate solution. This differed from C above in that the sulfoxide solution contained 0.06M
sodium sulfite, 0.045M sodium thiosulfate and 0.015M sulfuric acid, while the iodate soludon contained 0.025M sodium iodate and 0.02047M benzoic acid. The iodate solution was added to the sulfoxide solution at a rate of 0.175mL/min using a peristaltic pump. The results show elimination of the intial time lag (seen in C and D above) and benzoate diffusion responding to pH (increasing diffusion when pH decreases and ~WO 95/28144 2~ ~ 70 2 3 - -A ~
decreasing when pH increases).
Example 6: pH oscillations under CSTR Conditions 4 trials of the same system were run utlder CSTR conditions using a 3 mil, 19% EVA
membrane and a 75mL Crown Donor Cell. The and rate of addition are specified in Table 4 below. The results obtained with sample D are reported in Figure 13.
In all cases, solution (a) below is added to solution (b).

SAMPLE: A B C
REACTANT
TEMP. 24C 21.5C 20C 24C
a.) Na2SO3 0.05M 0.05M O.O~M 0.06M
Na2S2O3 0.0375M 0.0375M 0.0375M 0.045M
H2SO4 0.0126M 0.0132M 0.01322M 0.01512M
b.) NalO3 0.025M 0.025M 0.025M 0.025M
benzoic acid 3.0mg/ml 3.0mg/ml 3.0mg/ml 3.0mg/ml rate of (a) added to (b) o I ~n ' O.l90ml/min O.l90ml/min O.l90ml/min rate of (b) addition 0.015ml/min 0.095ml/min 0.095mllmin 0.095ml/min Wo 95/28144 A ~
2~n2~ -28-ExamDle 7: Effect of reversal of order of addin~ reactants This e~periment was run using semibatch condidons with a 2 mil, 28% EVA fllm at 32C
and a 75ml donor cell. 0.05M sodium iodate (soludon A) was introduced into 75ml of a sulfoxide soludon containing 0.02M sodium sulfite, 0.015M sodium thiosulfate, 0.00604M sulfuric acid and 0.02047M sodium benzoate at a rate of 0 08n " using a peristaltic pump. The results are shown in Figure 15. The reversal of the order of addition results in a single period. The preænce of all of the benzoate in the solutdon which is added, allows all of the bellwate present to react to tbe changes m ~.. , t, which is that as pH decreases, the benzoate flux increases, and æ pH increases, the benwate flux decreases. A 20 minute diffusional lag is also seen which is relatdve to the permeation of benzoate tbrough EVA membrane.
E~mDle 8 - -This experiment was run using semibatch condidons with a 2 mil, 28% EVA film at 32C
and a 75ml donor cell. 0.05M sodium iodate (soludon A) was imtroduced into 75ml of a sulfoxide solutdon containing 0.021M sodium sulfite, O.OI5M sodium thiosulfate, 0.03797M sulfuric acid and 0.75ml of nicodne free base at a rate of 0.080ml/min using a peristaldc pump. The results are shown in Figure 17. In this experiment the donor soludon is aUowed to stand for 60 minutes in order for the nicodne to passively diffuæ
across dhe membrane. After this dme period, the iodate soludon is added and the oscilladon reaction begun. The reversal of the order of addition results in a single period.
The presence of all of the nicodne in the soludon which is added, allows all of the nicotine preænt to react to the changes in ~ , which is that as pH decreaæs, the nicodne flux decreaæs, and as pH increases, the nicodne flux increaæs. A 30 minute diffusional lag is also æen which is reladve to the permeadon of nicodme tbrough EVA membrane.

~ _ , ~

Claims (35)

claims:

1. A method of using a chemical oscillating reaction having an initial oscillation frequency, which method comprises activating said oscillating reaction within an active agent delivery system, said delivery system comprising an active agent to be delivered, wherein the delivery of said active agent is sensitive to at least one reactant or product of said oscillating reaction and said oscillation frequency corresponds to an oscillation period which is no less than 1.5 times the time period necessary for a deliverable species of said active agent to be delivered under the conditions of the oscillating reaction which permit such species delivery, said delivery occurring passively once said oscillating reaction is activated.

2. The method of claim 1 wherein said oscillation reaction is a pH oscillation reaction.

3. The method of claim 2 wherein said pH oscillation reaction is selected from the group consisting of iodate-sulfite-thiourea, iodate-sulfite-thisulfate, iodate sulfite-ferrocyanide, iodate-hydroxylamine, periodate-hydroxylamine, periodate-thiosulfate, hydrogen peroxide-ferrocyanide, hydrogen peroxide-thiosulfate-copper (III), hydrogen peroxide-bisulfite-thiosulfate, peroxodisulfate-thiosulfate-copper (II), bromite-iodide, bromate-sulfite-ferrocyanide, bromate-sulfite-thiosulfate, and manganese(II)-periodate.

4. The method of claim 1 wherein said active agent is selected from the group consisting of pharmaceutically active agents, cosmetic active agents and agriculturally active agents.

5. The method of claim 4 wherein said pharmaceutically active agents are selected from antiasthmatics, antiarrhythmics, anticancer drugs, anti-AIDS medications, anti-parkinsonian drugs, anti-anginals, Alzheimer's and stroke medications, somatomedins, anti-viral agents, antisense peptides, anti-ulcer medications, PMStherapeutics, analgesics, endocrine/reproductive therapeutics, birth control medicaments, general hormone replacement therapeutics, stoke medications, antibiotics, immunizations, addiction treatments, anxiolytics, antisensitization drugs, antiirritants and antiinflammatories.

6. The method of claim 5 wherein said pharmaceutically active agent is selected from LHRH, PTH, PTH fragments, PTH analogs, somatistatin, somatistatin analogs, melatonin, insulin, IGF-I, nicotine, nitrosoureas, antiarrhymics, gastric acid inhibitors, nitrates, beta-blockers, progesterone, and aldactone.

7. The method of claim 1 wherein said agriculturally active agents are selected from pheromones, herbicides, insecticides growth regulators.

8. The method of claim 1 wherein said active agent delivery system is selected from the group consisting of tablets, capsules, implants, impregnated bandages, and transdermals, said active agent delivery system further comprising a means for maintaining the initial reactants of said oscillating reaction separated until activation of said oscillating reaction is desired.

9. The method of claim 1 wherein said active agent delivery sensitivity to said oscillating reaction is the result of at least one of:
a) said active agent changing a deliverable species and a significantly less deliverable or non-deliverable species in response to said oscillation reaction oscillations;
b) said delivery system further containing a barrier to said active agent delivery and said barrier changing between an active agent transmissable or releasable form and a substantially less transmissible or releasable form in response to said oscillation reaction oscillations;
c) said delivery system containing a viscosity enhancer, said viscosity enhancer changing between species which are more and less soluble, swellable, or viscous in response to said oscillation reaction oscillations whereby available solvent for dissolution of said active agent is altered correspondingly, so that transportability of said active agent and/or concentration of active agent are modified in response to said oscillations of said oscillating active agent;
d) said delivery system optoionally further comprises a flux enhancer or delivery aid which flux enhancer or delivery aid changes between an enhancing form (delivery-aid form) and a non-enhancing (non-delivery-aid form) in response to said oscillation reaction oscillations whereby the delivery of active agent is modified in response to said oscillation reaction oscillations; and e) said delivery system further comprises i) a flux enhancer or delivery aid and ii) a separation barrier which separates said flux enhancer or delivery aid from said active agent, wherein said separation barrier changes between an enhancer/delivery-aid transmissable form and an enhancer/delivery-aid non-transmissable form in response to said oscillations of said oscillating reaction.

10. The method of claim 9 wherein said viscosity enhancer is a polymer selected from the group consisting of those polymers having at least 40% of the monomeric units thereof having a pendent group selected from the group consisting of carboxylic acid, sulfonic acid, acrylamide, hydroxylamine, phosphonic acid, amino acids, vinyl alcohol, and N-vinyl-2-pyrrolidinone.

11. The method of claim 10 wherein said viscosity enhancer is a polymer selected from the group consisting of poly(sulfonic acid), poly(acylamide), poly(carboxylic acid), poly(hydroxylamine), poly(phosphonic acids), poly(amino acids), poly(vinyl alcohol), and poly(N-vinyl-2-pyrrolidinone).

12. The method of claim 9 wherein said viscosity enhancer is selected from the group consisting of poly(meth)acrylates, cellulosics, alginates, chitosan, starches, hyaluronic acid, collagen, and poly(ethylene oxides).

13. The method of claim 9 wherein said barrier and said separation barrier are each independently selected from the group consisting of those polymers having at least 40% of the monomeric units thereof having a pendent group selected from the group consisting of carboxylic acid, sulfonic acid, acrylamide, hydroxylamine phosphonic acid, amino acids, vinyl alcohol, and N-vinyl-2-pyrrolidinone.

14. The method of claim 13 wherein said barrier and said separation barrier are each independently selected from the group of polymeric membranes consisting of poly(carboxylic acid), poly(sulfonic acid), poly(acylamide), poly(hydroxylamine), poly(phosphonic acids), poly(amino acids), poly(vinyl alcohol), and poly(N-vinyl-2-pyrrolidinone).

15. The method of claim 9 wherein said barrier and said separation barrier are independently selected from the group consisting of poly(meth)acrylates, cellulosics, alginates, chitosan, starches, hyaluronic acid, collagen, and poly(ethylene oxides).

16. The method of claim 1 wherein said active agent exists in a deliverable form and in a non-deliverable variation and converts between said deliverable form and non-deliverable variation as a result of interactions with one or more chemical species which are consumed or generated in the course of said oscillations of said oscillation reactions, where such interaction is other than a change of pH.

17. An active agent delivery device for the passive temporal or periodic control of delivery of said active agent comprising:
a) a first species, which is an active agent, to be delivered from said device or a second species to be modified in situ into said first species;
b) some or all of the initial reactants of an oscillating reaction such that said oscillation reaction is not initiated until desired; and c) means for separating at least one of said initial reactants from the remaider of said initial reactants prior to activation of said oscillation reaction within said device (when all of said reactants are contained within said device in b prior to activation) or means for introducing any of said initial reactants of said oscillation reaction which are not otherwise present in said device prior to activation;
whereby said oscillation reaction can be suitably activated by bringing together all of said initial reactants or exposing said initial reactants to an activating condition and said delivery of said first species is passively controlled in response to said oscillations of said oscillation reaction.

18. The device of claim 17 wherein said oscillation reaction is a pH oscillation reaction.

19. The device of claim 18 wherein said pH oscillation reaction is selected from the group consisting of iodate-sulfite-thiourea, iodate-sulfite-thiosulfate, iodate sulfite-ferrocyanide, iodate-hydroxylamine, periodate-hydroxylamine, periodate-thiosulfate, hydrogen peroxide-ferrocyanide, hydrogen peroxide-thiosulfate-copper(II), hydrogen peroxide-bisulfite-thiosulfate, peroxodisulfate-thiosulfate-copper(II), bromite-iodide, bromate-sulfite-ferrrocyanide, bromate-sulfite-thiosulfate, and manganese (II)-periodate.

20. The device of claim 17 wherein said active agent is selected from the group consisting of pharmaceutically active agents, cosmetic active agents and agriculturally active agents.

21. The device of claim 17 wherein said pharmaceutically active agents are selected from antiasthmatics, antiarrhythmics, anticancer drugs, anti-AIDS medications, anti-parkinsonian drugs, anti-anginals, Alzheimer's and stroke medications, somatomedins, anti-viral agents, antisense peptides, anti-ulcer medications, PMStherapeutics, analgesics, endocrine/reproductive therapeutics, birth control medicaments, general hormone replacement therapeutics, stoke medications, antibiotics, immunizations, addiction treatments, anxiolytics, antisensitization drugs, antiirritants, and antiinflammatories.

22. The device of claim 21 wherein said pharmaceutically activeagent is selected from LHRH, PTH, PTH fragments, PTH analogs, somatistatin, somatistatin analogs, melatonin, insulin, IGF-I, nicotine, nitrosoureas, antiarrhythmics, gastric acid inhibitors, nitrates, beta-blockers, progesterone and aldactone.

23. The device of claim 17 wherein said active agent is an agriculturally active agent selected from pheromones, herbicides, insecticides and growth regulators.

24. An active agent delivery device according to claim 17 which is selected from the group consisting of tablets, capsules, implants, impregnated bandages, and transdermals, said active agent delivery system further comprising a means for maintaining the initial reactants of said oscillating reaction separated until activation of said oscillating reaction is desired.

25. The device of claim 17 wherein said active agent delivery sensitivity to said oscillating reaction is the result of at least one of:
a) said active agent changing a deliverable species and a significantly less deliverable or non-deliverable species in response to said oscillation reaction oscillations;
b) said delivery system further containing a barrier to said active agent delivery and said barrier changing between an active agent transmissable or releasable form and a substantially less transmissible or releasable form in response to said oscillation reaction oscillations;

c) said delivery system containing a viscosity enhancer, said viscosity enhancer changing between species which are more and less soluble, swellable, or viscous in response to said oscillation reaction oscillations, whereby available solvent for dissolution of said active agent is altered correspondingly, so that transportability of said active agent and/or concentration of active agent are modified in response to said oscillations of said oscillating active agent;
d) said delivery system optoionally further comprises a flux enhancer or delivery aid which flux enhancer or delivery aid changes between an enhancing form (delivery-aid form) and a non-enhancing (non-delivery-aid form) in response to said oscillation reaction oscillations whereby the delivery of active agent is modified in response to said oscillation reaction oscillations; and e) said delivery system further comprises i) a flux enhancer or delivery aid and ii) a separation barrier which separates said flux enhancer or delivery aid from said active agent, wherein said separation barrier changes between an enhancer/delivery-aid transmissable form and an enhancer/delivery-aid non-transmissible form in response to said oscillations of said oscillating reaction.

26. The device of claim 25 wherein said viscosity enhancer is a polymer selected from the group consisting of those polymers having at least 40% of the monomeric units thereof having a pendent group selected from the group consisting of carboxylic acid, sulfonic acid, acrylamide, hydroxylamine, phosphonic acid, amino acids, vinyl alcohol, and N-vinyl-2 pyrrolidinone.

27. The device of claim 26 wherein said viscosity enhancer is a polymer selected from the group consisting of poly(sulfonic acid), poly(acylamide), poly(carboxylic acid),poly(hydroxylamine), poly(phosphonic acids), poly(amino acids), poly(vinyl alcohol), and poly(N-vinyl-2-pyrrolidinone).

28. The device of claim 25 wherein said viscosity enhancer is selected from the group consisting of poly(meth)acrylates, cellulosics, alginates, chitosan, starches, hyaluronic acid, collagen, and poly(ethylene oxides).

29. The device of claim 25 wherein said barrier and said separation barrier are each independently selected from the group consisting of those polymers having at least 40% of the monomeric units thereof having a pendent group selected from the group consisting of carboxylic acid, sulfonic acid, acrylamide, hydroxylamine, phosphonic acid, amino acids, vinyl alcohol, and N-vinyl-2-pyrrolidinone.

30. The device of claim 29 wherein said barrier and said separation barrier are each independently selected from the group of polymeric membranes consisting of poly(carboxylic acid), poly(sulfonic acid), poly(acylamide), poly(hydroxylamine), poly(phosphonic acids), poly(amino acids), poly(vinyl alcohol), and poly(N-vinyl-2-pyrrolidinone.

31. The device of claim 25 wherein said barrier and said separation barrier are independently selected from the group consisting of poly(meth)acrylates, cellulosics, alginates, chitosan, starches, hyaluronic acid, collagen, and poly(ethylene oxides).

32. The device of claim 17 wherein said active agent exists in a deliverable form and in a non-deliverable variation and converts between said deliverable form and non-deliverable variation as a result of interactions with one or more chemical species which are consumed or generated in the course of said oscillations of said oscillation reactions, where such interaction is other than a change of pH.

33. A device according to any one of claims 17 to 32 which is a transdermal device for use with an oscillation reaction to regulate delivery of an active agent comprising:
a) a backing layer or laminate which is impermeable to the components of the device with which it comes in contact;
b) a membrane or matrix layer through which the active agent must migrate;
c) an oscillation reaction area in which an oscillation reaction can take place, once initiated;
d) necessary oscillation reaction reactants; and e) a transdermally suitable adhesive layer.

34. The device of claim 33 wherein at least one of said oscillation reaction reactants is added by a user or administrator of said device.

35. The device of claim 33 wherein all of said oscillation reaction reactants are present within said device, but at least two of said reactants are physically separated by a separation means so as to prevent said oscillation reaction from ocurring, said device further comprising a means for modifying said physical separation by the action of a user or administrator of said device to allow said oscillation reaction to initiate.