CA2450366A1 - Controlled heat induced rapid delivery of pharmaceuticals from skin depot - Google Patents

Abstract

The present invention is directed to a method and system for delivering a drug into the systemic circulation. The method comprises establishing a drug depot in a patient's skin and/or sub-skin tissues by applying a transdermal drug delivery system on the patients skin, for a predetermined time so that a drug depot is formed in said user's skin and/or sub-skin tissues. A heating source is placed proximate to the skin area to rapidly release a bolus of the drug from the depot into the systemic circulation when there is a need to rapidly increase the drug's concentrations in the systemic circulation.

Description

CONTROLLED HEAT INDUCIrJD RAPID DELIVERY OF
PHARMACEUTICALS FROM SKIN DEPOT
Field of the Invention: The present invention relates to methods and apparatus for administration of drugs. More particularly, the present invention relates to using controlled heat and other physical means to improve dermal, mucosal, and injection ad111I111St1'at1011 Of drLlgS.
State of the Art: The dermal administration of pharmaceutically active compounds involves the direct application of a pharmaceutically active forlnulation(s) to the skin, wherein the skin absorbs a portion of the pharmaceutically active compoLUdd which is then taken up by the blood stream. Such administration has long been lcrlowll in the practice of medicine and continues to be an important technique in the delivery of pharmaceutically active compounds. For example, U.S. Patent 4,286,592 issued September l, 1981 to Chandraselcaran shows a bandage for administering drugs to a user's skin consisting of an impermeable backing Layer, a drug reservoir layer composed of a drug and a carrier, and a contact adhesive layer by which the bandage is affixed to the skin.
Such dermal administration offers many impol-tallt advantages over other delivery techniques, such as injection, oral tablets and capsules. These advantages include being noninvasive (thus, less risk of infection), avoiding first pass metabolism (metabolism of the drug in the liver when the drug is taken orally and absorbed through the gastrointestinal tract), and avoiding of high peaks and low valleys of concentration Ot phar111aCeL1tlCally aCtlVe C0111pOLllldS 111 a patlellt'S blOOdStrea111.
Ill partlCLllal, hlgh peaks and low valleys of concentration are typical in injection and oral administrations and are often associated with Luldesirable side effects and/or less than satisfactory intended effects.
The term "dermal drug delivery system" or "DDDS", as used herein, is defined as an article or apparatus containing pharmaceutically active compoluld(s) for delivery into the skin, the regional tissues Lender the skin, the systemic circulation, or other targeting sites) ill a human body via shin permeation. The term "DDDS" in this application, Lidless otherwise specified, only refer to those systems in which the main driving force for drug permeation is the drug concentration gradient.
The term ''skin", as used herein, is defined to include stratum cornelun covered shin and mucosal membranes.

The term "dTLlg", aS llSed heTe111, is defined to include any pharmaceutically active compoluld including but not limited to compounds tllat treat diseases, injuries, undesirable symptoms, and improve or maintain health.
The terms ''targeted area" or "targeted areas", as used herein, are defined to include a systemic bloodstream of a h11111a11 body, areas of a ht1111a11 body which can be TeaChed by a SyStel111C bloodStrealn 111C1Lldlllg, bLlt 1101 hllllted t0 111L1SC1eS, bTa111, llVeT, lCld11ey5, etC., and body tissue regions proximate a loCatloll Of an administered drug.
In DDDSs, a drugs) is usually contained in a formulation, such as a hydro-alcohol gel, and may include a r ate limiting membrane between the formulation and slLin 1 O fOT 11211111n1z111g the Var1at1011 112 the permeation of the drug. When a DDDS is applied to skin, the drug begins to transport out ofthe formulation, and transport across the rate limiting membrane (if present). The drug then enters the shin, enters blood vessels and tissues under the slcin, and is taken into the systemic circulation of the body by the blood. At least some DDDSs have certain amount ofphannaceutically active compound in or on the skin side of the rate limiting membrane (if present) prior to use. In those DDDSs, tllat portion of the drug on the sl{in side of the rate limiting membrane will ellteT the S1C1I1 WIthOllt paSS112g thr011gh the rate 111121t1ng membrane. For many drugs, a Slgulf1Ca11t portion of the dermally absorbed drug is stored in the slcin and/or tissues under the skin (hereinafter referred as "depot sites") before being gradually taken into the systemic circulation (hereinafter referred as "depot effect"). This depot effect is believed to be at least partially responsible for the delayed appearance of the drug in the systemic circulation after the application of solve DDDSs and for continued delivery of the drug into the systemic circulation after tile removal of soma DDDSs from the shin.
After placing a DDDS on tile slcin, the d121g concentration in the blood typically remains at or near zero for a period of tune, before starting to gradually increase and r each a concentration deemed to be medicinally beneficial, called tile "tller apeutic level"
(the time it takes to reach the therapeutic level is refelTed to hereinafter as the "onset time"). Ideally, the concentration of the drug in the bloodstream should plateau (i. e., reach a substantially steady state) at a level slightly higher than the therapeutic level and should remain there for extended period of time. For a given person and a given DDDS, the "concentration of the drug in the bloodstream vs. time" relationship usually cannot be altered under normal application conditions.
The onset time and the delivery rate of the drug into the targeted areas) of the body for a typical DDDS are usually determined by several factors, 111C1Lldlllg: the rate of release of the drug from the formulation, the permeability of the drug across the rate limiting membr ane (if a rate lnnltmg membrane is utilized), the permeability of the drug aCTOSS the S1C111 (especially tile Stratl:llll CO111eLlln layer), dTtlg Storage 111 alld release fr0111 the depot SlteS, the peT111eablllty Of tile Walls Of the blood VeSSehS, alld the circulation of blood alld other body felled 111 the tlSSlleS ~111Cllldlllg the skin) Llllder alld aTOlllld the DDDS. Although these primary factors affecting onset time and delivery rate axe lmown, no existing DDDS is designed to have alterable delivery rate in the colu se of the application of the drLlg.
While a DDDS works well in many aspects, current dermal drug delivery teCI11101ogy has 50111e SelloLlS 111111tat1011S, 111Ch1d111g: 1 ) tile 011Set tune belllg LilldeSlTably lOilg for 111a11y DDDSS; ?) the 'late that the,dTllg 1S take11111t0 tile SySte1111C ClrCL11at1011 Or the targeted areas) oftlle body cannot be easily varied once the DDDS is applied onto the skin and, wheel tile steady state delivery rate is achieved, it caanlot be easily changed;
and 3) the shin permeability being so low that many drugs are excluded fiom dermal delivery because the amount of drug delivered is not high enough to reach a therapeutic level. II1 add1t10I1, temperature variations in the skin and the DDDS are believed contribute to the variation of dermal abSOrpt1011 Of dTLlgS.
It is Imo«~ll that elevated tenyecature can increase the absorption 0'r drugs through the shill. U.S. Patent 4,898,592, issued February 6, 1990 to Latzlce et al., relates to a device for the application of heated transdermally absorbable active substances which includes a carrier impregnated with a trallsdermally absorbable active substance and a suppol-t. The support is a laminate made up of one or more polymeric layers alld optionally includes a heat conductive element. This heat conductive element is used for distribution of the patient's body heat such that absorption of the active substance is enhanced. U.S. Patent 4,23-0,105, issued October 28, 1980 to 1-Iarwood, discloses a bandage with a drLlg and a heat-generating substance, preferably intermixed, to enhance the rate of absorption of the drug by a user's skin. Separate drug and heat-generating substance layers are also disclosed. U.S. Patent 4,685,911, issued August 11, 1987 to Komlo et al., discloses a slcin patch including a drug component, alld an optional heating element for melting the drug-containing formulation ifbody temperatlue is inadequate to do so.
Another area of administration involves delivering drugs in eontrohled/extended release tOr111/fOTnlLllat10115 ("fOrill/fOr111L11at1011") 11110 the S1Q11 OT
tlSSlleS 1111der tile Sh111 (tlle residing place for these fornl/fonnulations are hereinafter referred as "storage sites") which results in the drugs being released fiom the storage sites in a controlled/extended fashion. The most connnon technique to deliver the fonn/formulatiolis into the storage 3 5 sites is by inj ection. Other techniques may also be used, such as implalltati0n and fOTC111g the fOT111/fOT111lllat1o11 11110 the skin with high-speed hitting.
However, 011Ce tile form/formulation is delivered into the storage sites, it is usually difficult to alter tile rate, lalown as the "release rate", that the drug is released from the fornn/formulation at the storage sites, and taken into the systemic circulation or the targeted areas) of the body.
Yet another area of administration involves injecting drugs subcutaneously or intramuscularly. In some clinical situations, it is beneficial to accelerate the speed of drug absorption into the systemic circulation or other targeted areas(s) in the body after such injection.
Therefore, it would be advantageous to develop methods and apparatus to improve the drug administration of DDDSs, and, more specifically, to make the use of DDDSs more flexible, controllable, and titratable (varying the drug delivery rate, amount, or period according to the biological effect of the drug) to better accommodate various clinical needs. It would also be advantageous to develop methods and apparatus to make dermal delivery possible for drugs which are currently excluded because of low shin permeability. It would fiuther be advantageous to develop means to alter mainly to increase the drug absorption rate from the storage sites or injection sites in such ways that can accommodate certain clinical needs.
SUMMARY OF THE INVENTION
The present invention relates to various methods and apparatus for improved dermal and mucosal administration of drugs through the use of controlled heat and other ~,0 physical means. The present invention fiuther relates to methods and apparatus for using controlled heat and other physical means to alter, mainly increase, the drug release rate from the storage sites or injection sites in such ways to accolnlnodate certain clinical needs.
In the application of a DDDS, the absorption of the drug is usually determined 5 by a ntunber of factors including: the diffusion coefficient of drug molecules in the drug formulation, the permeability coefficient of the drug across the rate limiting membrane (if one is used in the DDDS), the eoncentr anon of dissolved drug in the formulation, the skin permeability of the drug, drug storage in and release fiom the depot sites, the body flu ld (including blood) circulation in the skin and/or other tissues under the slcln, and 30 permeability of the walls of capillary blood vessels in the sub-shin tissues. Thus, in order to address the limitations of the current dermal drug delivery technologies, it is desirable to have control over and have the capability to alter these drug absorption Factors. It is believed that controlled heating/cooling can potentially affect each one of the above factors.
35 Specifically, increased temperattue generally can increase diffusion coefficients of the dl'LIgS 111 th a fOT111LL1at1011S alld their permeability across the r ate limiting membrane and skin. Increased heat also increases the blood and/or other body f1111d flow 111 the tissues under the DDDS, which sllould carry the drug molecules into the systemic circulation at faster rates. Additionally, increased temperature also increases the permeability of the walls of the capillary blood vessels in the sub-skin tissues.
5 Fur-lhermore, increased tenlperatlue can increase the solubility of host, if not all, drugs 111 thelr foT111L11at1o11S WhlCh, 111 fOr1nL11atrO1lS Wlth L111d1SSOIVed drLlgS, ShoLlld 111CreaSe permeation driving force. Of course, cooling should have substantially the opposite effect. Thus, the pr esent invention uses controlled heating/cooling to affect each of the above factors for obtaining controllable dermal absorption of drugs.
The present invention also uses controlled lleating/cooling in several novel ways to make dermal drug delivery more flexible and more controllable in order to deal with various clinical conditions and to meet the needs of individual patients. More broadly, this invention provides hovel methods and apparatus for controlled heating/cooling (hereinafter "temperature control apparatus") during the application ofthe DDDS, such that heating can be initiated, r educed, increased, and stopped to accommodate the needs.
Another embodiment of the present invention is to determine the duration of controlled lieating on DDDS based on the effect of the drug for obtaining adequate amount of the extra drug and minimizing under-treatment and side effects associated with under and over dosing.
Through the proper selection, based on the specific application and/or the individual patient's need, of the molnent(s) to initiate controlled heating, heating temperature, and monlent(s) to stop the controlled heating, the following control/manipulation of the absorption rates should be achieved: 1) shorten the onset time of the drug in the DDDS without significantly changing its steady state delivery rates; 2) provide proper amolult of extra drug during the application of a DDDS when needed; and 3) increase the drug absorption rate throughout a significant period of duration or throughout the entire duration of the DDDS application.
Shortening of onset time is important in situations where the DDDS provides adequate steady state deliver rates, but the onset is too slow. Providing the proper amount of extra drug is irnportallt where a DDDS delivers adequate "baseline"
alnorult of the drug, but the patient needs extra drug at particular moments) for particular periods) of time during the application of the DDDS. Increasing the drug absorption rate is used for the patients who need higher drug delivery rates from the DDDS.
The first of above approach can be achieved by applying controlled heating at the starting time of the DDDS application, and design the heating to last long enough to cause tile C011Cerltratloll Of tile drug in tile systelnlC CITCLllat1011 Or Other targeted area of the body to rise toward the therapeutic levels, and stops (inay be gradually) shortly after that. The second approach may be achieved by applying controlled lleat when a need to obtain extra drug are rises, and teTilllilat111g the COiltrOlled lleat111g either at a predetermined moment or when the desired effect of the extra drug is achieved.
The third apps oach can be achieved by applying the contr oiled heat at the starting time of the DDDS application. In all those three approaches, temperature of the controlled lleating needs to be designed to control the degree of increase in said that drug delivery rates.
Such embodiments are particularly useful ill situations where the user ofa DDDS
gets adequate drug absorption most of the time, but there are periods of time in which increased or decreased drug absorption is desirable. For example, during the treatment of cancer patients with an analgesic, such as with Duragesic~ dermal fentailyl patches (distributed by Janssen Pharmaceutica, Inc. of Piscataway, New Jersey, USA), "brealctllrough" pain (a suddenly increased and relatively short lasting pain, in addition to a cantinuous ''baseline" pain) may occur. An additional analgesic dose, in the form of a tablet, an oral or nasal mucosal absorption dosage form, or an injection needs to be given to treat tile breakthrough pain. But with the help of controlled heat, one single DDDS may take care of both baseline pain and episodes of breaktllr ough pain.
With the help of controlled heat, a heating patch can be placed on top of the Duragesic"' patch Wllell all eplSOde of bTealCthl Ollgh pain OCCLIr S to deliver more fentanyl into the systemic circulation. The heating duration of the heating patch is preferably designed to be long enough to deliver sufficient extra fentanyl, but not long enough to deliver the extra amount of fentanyl that may pose a risk to the patient. The patient may also remove the heating patch when the brealctllrough pain begins to diminish. Thus, with the help of controlled heat, one single Dluagesic° dermal fentanyl patch may take care of both baseline pain and episodes of breakthrough pain. For another example, a dermal nicotine patch user may obtain extra nicotine for a suddenly increased nicotine craving by heating the nicotine patch.
Due to l ow skin permeability oFthe skin, onset times of conventional DDDSs are usually quite long, and ofl:en undesirably long. Thus, another aspect of the present invention is to provide methods and apparatus for using controlled heat to shorten the onset times of DDDSs, preferably without substantially changing the steady state drug delivery rates. A particularly useful application of this aspect of the present invention is to provide a controlled heating apparatus for use with conventional, commercially available DDDSs t0 ShOrtell tile OllSet t1111eS 111 CI1111CaI llSe, WithOllt haVlllg to re-design the DDDSs or adjust their steady state drug delivery rates.

It is believed that an important cause for variation in drug absorption in DDDSs is variation in ten -Iperatt~re of the DDDSs and the adjacent slcin caused by variations in aIllbIellt telllper atllr a alldlOr physical COlldlt1011 Of the peTS011. ThlS
temperature variation can, of course, potentially affect all of the factors that collectively determine the ultimate drug delivery rates of the DDDSs. Thus, the present invention ofproviding methods and apparatus to use controlled heating/cooling also minimizes the variation in temperattue of the skin and the DDDSs applied on the shin. It is also contemplated that an insulating material can be incorporated with the controlled temperature apparatus to assist 111 Ilot Ollly 1n11111nlzlllg the temperature variation, btlt also increasing the temperature of the DDDS and the skin under it (by decreasing heat loss), each of which tend to increase dermal drug absorption.
The present invention also relates to methods alld apparatus for using an insulating device, such as a cover made of insulating material (such as closed-cell foam tape) with adhesive edges, and a size slightly larger than the DDDS or the area over an injected drug, to cover the DDDS/injected drug when the DDDS and/or the skin of the user is exposed to extreme temperature (such as a hot shower or bath, direct sunlight, etc.).
An important area in modern anesthesiology is patient controlled analgesia (hereinafter "PCA"), in which the patient gives himself a dose of analgesic when he feels the need. The ranges of the dose and dosing frequency are usually set by a care giver (i. e., caring physician, muse, etc.). In many PCA situations, the patient receives a baseline rate of analgesic, and gets extra bolus analgesic when he feels that it is needed. The technology in the present invention may be used for a PCA in which the patient gets the baseline dose by a regular dermal analgesic patch and the extra ("rescue") dose by heating the dermal analgesic patch. The heating temperattue and duration needs to be designed to deliver a proper amount of extra dose.
Drugs in controlled or extended release forms or formulations may be delivered into depot/storage sites in the Sh111 aild/Or the tissues under the skm wlth methods such as inj ection, implantation, hitting the dr ug/drug formulation on the skin with supersonic 3 0 speed, and embedding the drug/drug formulation onto the skin. The controlled/extended fonn/formulation allows the drug to be released gradually into the sturounding tissues and/or systemic circulation over an extended period of time. ror instance, extended release insulin (such as Ultralente° zinc insulin - Eli Lilly and Co.) can be injected subcutalleously to deliver insulin into the patient's systemic circulation over an extended period of tinge. However, once the drug in the controlled/extended form/fonnulation is delivered to the storage sites, it is usually difficult to alter or control the course of drag release. The apparatus and methods of the present invention allow controlled heat to 111C1eaSe alld controlled cooling to decrease, the drug release from the conirolled/exfiended forln/formulation after it is delivered into the depotlstorage sites.
For example, many diabetic patients need additional insulin shol-tly before meals to suppress the blood sugar increase resulting from the meals. However, the release rate of tile subcutaneously injected extended release insulin is relatively constant. With the 111et110d5 alld appaTatLlS 111 tile lnVelltloll, a diabetic patient 111ay 111~eCt a subcutaneous extended release insulin in the morning and apply cozltrolled heat on the skin of the injection site for a dtuation of time shortly before ingestion of a meal to obtain additional insulin to suppress the sugar from the meal. The contr olled heat increases the flow of blood and other body fluid surrounding the storage sites and is believed to increase the dissolution rate of insulin. It is, of course, understood that whether a given controlled/extended release formulation in the depot/storage sites call actually release extra drug with increased temperatLUe depends on the nature of the drug forl/formulation. However, since heat is lalown or expected to increase the diffusion speed of drugs in their formulations, increase the permeability of blood vessel walls, and increases the circulation of body fluid surrounding the depot sites, each of which tend to favor increased drug release, the heat-induced extra drug release is expected to take place for many, if not most, controlled/extended drug fonn/forlnulation delivered into sub-shin storage sites.
One important aspect of the present invention is to properly choose the temperature of the controlled heat and the moments) to initiate and stop the controlled heat in the applications with injected drug formulations, especially extended/controlled release formulations, to accommodate the needs of different therapies and individual patients, in ways similar to the applications with DDDSs discussed above.
Many biodegr adable polymers lnay be used to make contr olled/extended release fOr111L11at1011S. Of particular note are the biogradable lactic/glycolic acid polymers described in Chapters 29 and 33 of >Jncyclopedic Halldboolc of Biomaterials and Bioen ineerin~, edited by Donald L. Wise, et al., publ. Marcel DelclLer, 1995, hereby incorporated herein by reference. It is one important aspect of the present invention to use controlled heat, as discussed above, to control/regulate drug release rates from controlled/extended release formulations made with such polymers, and preferably, prepared using the methods described in the IJncvclopedic Handbook of Biomaterials and Bioen~ineerin~.
For drugs where quick systemic absorption is important, the present invention may be beneficial. For example, it is generally agreed that to successfully treat a migraine headache, concentrations of an anti-migraine drug, such as dihydroergotalnine, in the bloodstream must reach a therapeutic level within a certain time from the onset of migraine headache. In such situations, the heating devices, as discussed.
above, may be used with normal injection of drugs. Since heat can usually increase the diffilsion speed of drugs in their formulations, increase the permeability of blood vessel walls, and increases the circulation of body fluid sul-rounding the injection site, the drug will enter the system circulation more quickly.
One of the more important aspects of the present invention is the apparatus for generating and providing controlled heating. These controlled heat generating appar atus generally comprise a heat generating pol-tion and a means to pass the heat generated by the heat generating portion to the DDDSs, the slcin, and/or the sub-shin depot and storage sites. These controlled heat generating apparatus generally fiuther include a mechanism (such as tape, adhesive, and the like) for affixing apparatus onto the DDDSs and/or the skin. Preferably, the affixation mechanism securely holds the controlled heat generating apparatus in place while in use, but it also allows relatively easy removal after use. Additionally, these controlled heat generating apparatus may further include a mechanism for terminating the generation of heat. The shape and size of the bottom of the controlled heat generating apparatus are generally specially made to accommodate the DDDSs with which they are to be employed.
One embodiment of a controlled heat generating apparatus is a shallow chamber 111C1Lldlng non-air permeable side wall(s), a bottom wall, and a non-air permeable top wall which has as ea(s) with limited and desired air permeability (e.g. , holes covered with a microporous membrane). A heat generating medium is disposed within the shallow chamber. The heat generating medium preferably comprises a mixtLUe of iron powder, activated carbon, salt, water, and, optionally, sawdust. The controlled heat generating apparatus is preferably stored in an air-tight container from which it is removed prior to use. After removal from the air-tight container, oxygen in the atmosphere ("ambient oxygen") slows into heat genes ating medium tluough the areas on the non-air permeable top with desired air-permeability to initiate a heat generating oxidation reaction (s. e., an 3 0 exothermic reaction). The desired heating temperature and duration can be obtained by selecting the air exposlue of the top (e.g., selecting the right size and number of holes on the cover and/or selecting the microporous membrane covering the holes for a specific air permeability), and/or by selecting the right quantities and/or ratios of components of the heat generating medium.
3 5 This embodiment of the controlled heat genes ating apparatus pr efer ably includes a 111echa111S111 for affixing the controlled heat generating apparatus onto the slcin or a DDDS that is applied to the skin. For applications where the removal or termination of the heating 1111ght be necessary, the heat generating apparatus may also have a mechanism for allowing easyrenloval from the DDDS and/or the slcin or for termination of the heating. One mechanism for allowing easy removal ofthe shallow chamber from 5 a DDDS without removing the latter fT0111 the SIC111 COI11pr1S2S a layer of adhesive on the side walls of the heat generating apparatus with an non-adhesive area or less adhesive area (less adhesive than the adhesive affixing the DDDS to the skin) at the bottom of the shallow chamber, with the non- or less adhesive area having a shape similar to that of the DDDS. When such a heat generating apparatus is applied onto the DDDS which is 10 on the slcin, the adhesive at the bottom of the side walls of the heat generating apparatus adheres to the shin, and non- or less adhesive part is on top of, but not adhered or not strongly adhered to, the DDDS. This allows for removal of the heat generating apparatus without disturbing the DDDS.
Although one application of such a heat generating apparatus is to be used in conjunction with a DDDS, it is understood that the heat generating apparatus can also be applied directly to the skin to increase the release of drugs fro111 depot sites or sites of injection or implantation of controlled released drugs (storage sites), or to accelerate the absorption of subcutaneously or intramuscularly injected drugs.
The heat generating mechanism of the present invention for the controlled heat generating apparatus is not limited to the preferred exothermic reaction mixture of iron powder, activated carbon, salt, water, and, optionally, sawdust, but may include a heating tllllt whose heat is generated by electricity. The electric heating unit, preferably, includes a two dimensional surface to pass the heat to the DDDS and/or the skin. The electric heating unit play also include a temperature feedbaclosystem and a temperature S2IISOr that Call 17e placed OIl the- DDDS Ol' the Slilll. The tel11pe1'atllle 5eIlSOr 1110n1tOI'S
the temperature at the DDDS or skin and transmits an electric signal based on the sensed temperature to a controller which regulates the electric clu-rent or voltage to the electric heating unit to keep the temperature at the DDDS or skin at desired levels.
Preferably, a double sided adhesive tape can be used to affix the electric heating lulit onto the slcin.
The heat generating mechanism may also comprise an infrared generating Lllllt alld a 111eCha111S111 t0 direct the infiared radiation onto the DDDS Or tile skin. It may also have a temperature feedback system and a temperature sensor that call be placed on the DDDS Or the skin to C011trOI the intensity Of the lllfTaled e1111SS1011 t0 lllall1ta111 tile temperature at the DDDS or skin at desired levels.
The heat generating mechanism may fiuther comprise a microwave generation trait and a mechanism to direct the microwave radiation onto the DDDS or the skin.

Again, the heat generating mechanism rnay have a temperature feedback system and a temperatlue sensor to regulate the intensity of the microwave emission to maintain the tenlperatLlre at the DDDS or slcin at desired levels.
The heat generating 111eCha111S111111ay yet further comprise a container containing supercooled liquid which generates heat from crystallization ("exothermic").
The crystallization is initiated Wlthlll the COlltalller, SLICK aS by bending a metal piece in the supercooled liquid, and the container is placed on a DDDS or on the skin. The heat which is released from the crystallization process is passed to the DDDS
and/or the skin.
However, heat generated by crystallization usually does not maintain a constant level over extended tinge. Thus, such a heat generating mechanism is not ideal for applications where elevated temperature in a narrow range over an extended tilde is necessary, but is useful where only a short heating duration is needed, such as with a DDDS that would benefit from short heating duration to minimize the onset time.
Although, in general, most benefits for DDDSs are realized from increased drug absorption and .release rates by heating, tllere are circtunstances where it may be desirable to be able to both increase and decrease the drug absorption and release rates.
It is understood that for a more complete control in dermal and controlledlextended release drug administration that a 111eCllarlls111 for providing both heating or cooling, depelld111g 011 deed, WOLlld be adValltageOLls. ThLlS, a nOVel approach of thl5 111Ve11tr011 is to provide methods and apparatus for providing heating or cooling to the DDDSs, the skin and/or the tissues under it, or the controlled/extended release drug fornl/formulation 111 the Slilll OT the tISSLIeS Llllder tile Skrll, SLICK that the drug absorption and/or release call be controlled. The lleating/cooling mechanism comprises a thermoelectric module which functions as a heat pump wherein the power supply may be reversed depending on whether heating or cooling is desired. A cooling mechallisln can include an endothermic crystallization mechanism similar to tile exothermic crystallization mechanism discussed above.
It is, of course, understood that the use of controlled heating and/or cooling to control drug absorption and/or release are equally applicable to controlled/extended forlnlformulations after they are delivered into the skin and/or tissues Lender the skin.
However, physical mechanisms other than heating and/or cooling may also be used for the same purpose. Thus, it is novel approach of this invention to provide methods and apparatus to use ultrasound, electric clurent, and mechanical vibration to induce extra drug release from controlled/extended release form/formulations which are already delivered into the body and that are responsive to these physical lrldLlCtrOrl lllearl5.

BRIEF DIJSCRIPTION OF THIJ DRAWINGS
While the specification concludes with claims particularly pointing out and distinctly claiming that which is regarded as the present invention, the objects and advantages of this invention may be more readily ascertained from the following description of the invention, when read 111 C011JLll1Ctlo11 Wlth tile accompanying dr aW111g5 lIl W111C11:
FIG. 7 is a side cross-sectional view of an embodiment of a temperature control apparatus according to the present invention;
FIG. 2 is a side cross-sectional view of another embodiment of a temperature control apparatus according to the present invention;
FIG. 3 is a side cross-sectional view of an embodiment of a dermal drug delivery system according to the present invention;
FIG. 4 is a side cross-sectional view ofthe temperature control apparatus of FIG. 2 in conjunction with the dermal drug delivery system of FIG. 3 according to the present invention;
FIG. 5 is a graph of time versus temperature for a temperatlue control apparatus according to the present invention;
FIG. 6 is a graph ofthe mean fentanyl concentration of nine volunteers verse time For a folu hotu contact of a fentanyl containing DDDS with heating and without heating according to the present invention;
FTG. 7 is a graph of time versus temperature for a ten lperatlue control apparatus accarding to the present invention;
FIG. 8 is a side cross-sectional view of another embodiment of a temperature control apparatus according to the present invention;
FIG. 9 is a side cross-sectional view of another embodiment of a dermal drug delivery system according to tile present invention;
FIG. 10 is a side cross-sectional view of the temperature control apparatus of FIG. S in conjunction with the dermal drug delivery system of FIG. 9 according to the present invention;
FIG. 11 is a side cross-sectional view of still another embodiment of a dermal drug delivery system according to the present invention;
FIG. 12 is a side cross-sectional view of the temperature control apparatus of FIG. H 111 CO11~L111Ct1o11 Wlth the dermal drug delivery system of FIG. 11 according to the present invention;

FIG. 13 is a side cross-sectional view of yet another embodiment of a temperature control apparatus having tluee cover layers over an oxygen activated temperature regulating 111eCha111S111 Cha111berS aCCOTdlllg t0 the present invention;
FIG. 14 is a side cross-sectional view of the temperature control apparatus of FIG. 13 having a first cover layer removed according to the present invention;
FIG. 15 is a top plan view of the temperature control apparatus of FIG. 14 along line 15-15 according to the present invention;
FIG. 16 is a side cross-sectional view of the temperature control apparatus of FIG. 14 having a second cover layer removed according to the present invention;
FIG. 17 is a top plan view of the temperature control apparatus of FIG. 16 along line 17-17 according to the present invention;
FIG. 18 is a side cross-sectional view of the temperature control apparatus of FIG. 16 having a third cover layer removed according to the present invention;
FIG. 19 is a top plan view of the temperatlue control apparatus of FIG. 18 along line 19-19 according to the present invention;
FIG. 20 is a side cross-sectional view of another embodiment of a dermal drug delivery system having a rate limiting membrane according to the present invention;
FIG. 21 is a side cross-sectional view of an electric temperature control mechanism according to the present invention;
FIG. 22 is a side cross-sectional view of a temperatlue control apparatus comprising a flexible bag felled with a supercooled liquid according to the present invention;
FIG. 23 is a side cross-sectional view of a temperature control apparatus capable of both heating and cooling applied to a DDDS according to the present invention;
FIG. 24 is a schematic for a closed loop temperature controller for the temperature control apparatus of FIG. 23 according to the present invention;
FIG. 25 is a side cross-sectional view of a temperatlue control apparatus applied directly to a patient's skin according to the present invention;
FIG. 26 is a side cross-sectional view an electrical mechanism for increasing drug absorption according to the present invention;
FIG. 27 is a side cross-sectional view a vibrational mechanism for increasing drug absorption according to the present invention;

FIG. 28 is a side cross-sectional view of a temperature control apparatus capable of both heating alld COOIIIlg applied directly to a patlellt'S SICII1 aCC01'dlllg t0 tile pleSellt IIIVeIltloll; alld FIG. 29-32 is a side cross-sectional view an insulative material over a DDDS
and inj ected or depot drug sites fOr 11111111111z111g temperature variation and/or increasing the temperature of the DDDS and the skin thereunder according to the present invention.
DETAILED DESCRIPTION OF THE ILLUSTRATED EMBODIMENT
FIGs. 1-32 illustrate various views oftemperatllxe control or other apparatuses and dermal drug delivery systems. It should be understood that the figures presented 111 CO11Jt111Ct1011 Wlth this de5Cr1pt1011 are IlOt llleallt t0 be illustrative of actual views of any particular apparatus, but are merely idealized representations which are employed to more clearly and fully depict the present invention than would otherwise be possible. )J1e111eI1tS COIllllloll between the figures retain the same numeric designations.
FIG. 1 illustrates a temperature control apparatus 100 of the present invention comprising a chamber defined by a bottom wall 102, a top wall 104, and side walls I06 wherein a temperature regulating mechanism 108 is disposed Wlth111 the chamber. The temperature regulating mechanism 108 can include a heat generating oxidation reaction mechanism, electric heating unit, exothermic crystallization 111eCha111S111, elldOthel'1111C CTyStalllZatloll 111eCha111S1n, heatlllg/COOllllg 111eCha111S1n, cooling mecllanisnl, or the like.
FIG. 2 illustrates a temperatwe control apparatus 100 comprising a temperature regulating mechanism 108 surrounded by a bottom wall 102, a top wall i 04, and side walls 106. The bottom wall 102 is preferably a plastic material and the side walls 106 are preferably made of a flexible non-air permeable material, such as non-air permeable closed-cell foam material. A pol'tian or all of tile bOtt0111 wall I02 of the temperature control apparatus 100 includes an adhesive material 1 I2 for attaclnnent to a DDDS or to the skin of a patient. The temperature regulating mechanism 108 preferably comprises a composition of activated carbon, iron powder, sodium chloride and water in a proper ratio. Optionally, saw dust Inay be added to the composition to facilitate the airflow within the composition and/or provide ''body" to the C0111poS1t1011. Tlle top wall 104 is preferably also a flexible non-air permeable material having holes 114 therethrough. An air permeable membrane 116 is, preferably, disposed between the top wall 104 and the temperature regulating IlleCha111S111 108 to regulate the amolult of air reaching the temperature regulating mechanism 108 through the holes 114. The air permeable membrane 116 is preferably a porous flhll (such as No. 9711 1111crOp01'OtlS polyethylene film CoTranTM, 3M Corporation, Milmeapolis, Minnesota, USA).
FIG. 3 illustrates a dermal drug delivery system 120 (hereinafter 5 "DDDS 120") comprising a housing 122 made of a flexible material(s). The housing 122 preferably comprises side walls 124 and a top wall 126 with a dlmg farmlilation 128 disposed within the housing 122. Preferably, the bottom of the DDDS side walls 124 include an adhesive 132 to affix the DDDS 120 to the shin of a patient. , FIG. 4 illustrates the temperature control apparatus 100 of FIG. 2 attached to 10 the DDDS 120 of FIG. 3. The DDDS 120 attached to a portion of the skin 134 of a patient. The area of the temperature regulating mechanism 108 is preferably slightly larger than that of the drug formulation 128. The temperature control apparatus 100 and the DDDS 120 are preferably stored in separated compartments of an air tight container (or in separate air tight containers).
15 Exan mle 1 One example of LlSlllg the embodiment of the present invention illustrated in FIGS. 2-4 for administering analgesic material for relief of pain consists of a patient or care giver placing the DDDS 120 on the shin 134 of the patient, which preferably adheres to the skin 134 with DDDS adhesive 132. The patient or care giver then attaches the temperature control apparatus 100 on top of the DDDS 120, which adheres to the DDDS 120 with temperature control apparatus adhesive 112.
Oxygen in ambient air flows into the temperature regulating mechanism 108 through Roles 114 and air permeable membrane 116. Of course, it is understood that the rate at which oxygen contacts the temperature regulating mechanism 108 is determined by the size and nlunber of the holes 114 on the top wall 104, as well as the air permeability of the air permeable membrane 116. A heat generating (exothermic) chemical reaction occurs in the temperature regulating mechanism 108. Heat from this reaction passes tlllough the temperate re control apparatus bottom wall 102, tluough the DDDS top wall 126, through the drug formulation 128, and increases the temperature of the patient's skin 134 under the DDDS 120.
In actual experimentation, the temperatlue control apparatus 100 comprised the side walls 106 defined by a 1/8 inch thick rectangular foam tape (2 layers of No.1779 1/16" white fOalll tape, 3M Corporation, Mimieapolis, Milmesota, USA) with an outer dimension of about 2.25 inches by 4 inches with an opening therein having an inner d1111e11Slon Of about 1.75 inches by 3.5 inches, the bottom wall 102 comprising rectangular medical tape (No. 1525L plastic medical tape, 3M

Corporation, Minneapolis, Minnesota, USA) of a dimension of about 2.25 inches by 4 inches with a non-adhesive side attached to the bottom of the side walls 10G, and a top wall 104 COLI117TLSlllg a rectangular 1/32111011 thick foaln tape (No.
9773 1/32" tan foam tape, 3M Corporation, MiIlIIeapolis, Milmesota, USA) with forty-five holes 114 S (diameters approximately 0.9 IIlIll, IIl a 5 by 9 pattern with about 7.S
I11I11 t0 8.0 IInl1 center spacing) thereth rough. The side walls 106, the bottom wall 102, and the top wall 104 defined a chamber. The holes 114 of the top wall 104 were covered by an air permeable membrane 116 comprising a porous membrane (No. 9711 microporous polyethylene film - CoTranTM, 3M Corporation, Milllleapolis, Minnesota, USA) disposed between the top wall 104 alld tile temperature regulating 111eCha1115111 108.
The side walls lOG, the bottom wall 102, and the top wall 104 all had 1/8"
rounded corners. The temperature regulating mechanism 108 disposed in the chamber comprised a mixture of activated carbon (HDC grade - Norit Americas, Inc., USA), iron powder (grade 81430 - ISP Technologies, USA), saw dust (Wood Flour, Pine -Pioneer Sawdust, USA), sodilun chloride and water in tile weight ratio of approximately S:1G:3:2:G weighing approximately 1G.5 grams. The temperattue control apparatus 100 was sealed in an air-tight container innnediately after fabrication.
The temperature control apparatus 100 was tested on a vohulteer with a temperature probe placed between the temperature control apparatus 100 and the volunteer's skin to measure the temperature. The results of this temperatlue experiment is illustrated in FIG. S and Table A, which shows that the temperatlue control apparatus 100 is capable of keeping the shin temperature to a narrow, elevated range of about 41 ° C to 43 ° C for extended period of time (at least about 240 minutes).
TABLE A
Time (minutes) Temperatur a ( C) 0 30.G

1 31.8 2 33.G

3 35.2 4 3G.G

S 38.0 G 39.1 7 39.9 8 40.5 9 41.1 10 41.5 S 11 41.9 12 42.3 13 42.5 14 42.5 1 S 42.5 1 G 42.5 17 42. S

18 42. S

19 42.5 20 42.5 1 S 22 42.4 24 42.4 2G 42.3 28 42.2 30 42.5 3 S 42.5 40 42. G

4S 42.G

60 42.5 75 42.8 90 42.7 .

120 42. G

1 SO 42.3 180 42.0 210 41.8 240 41.0 2SS 40.4 Nllle hLllllall VOlLlllteel'S reCelVe a dose of fentanyl 111 a DDDS 120. The DDDS 120 C0111p1'lSed a C0111111e1'Clally aVallable del'lllal felltallyl patch, DLll'ageSlC-50~ (designed to deliver an average of 50 1111CrOgTa111S Of felltallyl per hour), distributed by Janssen Pharmaceutics, Inc. of Piscataway, New Jersey, USA. The experiment was conducted to determine fentanyl cO11ce11trat1011S Wlth111 the volunteers' blood (over a 12 hour period) without heating the DDDS 120 and with heating the DDDS 120 (with the temperature control apparatus 100 described above).
The experiments were conducted with at least a two week time period between the heated and unheated sessions. In the unheated session, the DDDS 120 was applied 011t0 the VO1L111teeT'S Chest S1C111 alld re1110Ved after abOLlt 240 111111L1teS. I11 the heated session, the DDDS 120 was applied onto the subject's chest skin and immediately cover by the temperatlue control apparatus 100. Both the DDDS 120 and the temperatLUe control apparatus 100 were removed after about 240 minutes. In both sessions, blood samples were taken at various intervals for IZ hOLlrs alld the fentanyl concentrations in serLlm samples were determined by radioilnlnunoassay.
rIG. 6 alld Table B illustrates the mean serum fenta11y1 concentrations produced by the heated and unheated Duragesic-50° patches, respectively, over a 720 minute duration (The lowest standard used in the assay was 0.11 ng/ml.
Concentrations lower than 0.11 ng/ml were obtained using an extrapolation method.).
With heating by the temperature control apparatus 100, it was foluld that fentalryl began to enter the systemic circulation earlier, and at faster rates. At 240 minutes, the end of the heating and fentanyl patch application, the average serum concentrations of fentanyl in the volLUlteers with the heating of the Duragesic-50°
patch was about 5 times that of the unheated Duragesic-50 "'. These results demonstrates that controlled heat can siglliflcalltly increase the speed of dermal fentanyl absorption and shorten the onset time.
TABLE B
T1111e ~111111L1teS)Se1L1111 FelltallylSeTL1111 Featanyl CO11C. Conc.
Without Heat With Heat (ng/nll) (nglnll) 0 0.04 0.01 10 0.03 0.01 20 0.03 0.02 30 0.03 0.03 0.03 0.0G

GO 0.04 0.09 75 0.03 0.1 G

90 0.04 0.28 120 O.OG 0.45 180 0.14 0.85 240 0.2G 1.29 300 0.47 1.04 360 0.40 0.98 420 0.33 0.88 480 0.35 0.67 540 0.38 O.G3 G00 0.37 0.51 GGO 0.33 0.50 720 0.2G ~ 0.49 ThllS, it is believed that the increased temperature increases the shin permeability (compared with a DDDS without such a heating mechanism), which results in the fentanyl entering the patient's systemic circulation faster.
This should result ill serum fentanyl concentrations reaching steady state quicker. The heating is also believed to increase the body fluid circulation and blood vessel wall permeability in the sub-skin tissues, and cause fentanyl to spend less time in the sub-slcin depot site. As a result, the patient receives the analgesic compoluld more quickly and receives improved pain relief.
In yet another experiment, the temperatlue control apparatus 100 comprised the side walls l OG defined by a 3/16 inch thick rectangular foam tape (3 layers of No.
1779 1/1G" white foam tape, 3M Corporation, Minneapolis, Minnesota, USA) with all OLltel d1I11e11S1O11 Of about 2.25 111CheS by 4 inches with an opening therenl havnlg an ilnler d1111e11S1011 Of about 1.75 inches by 3.5 inches, the bottom wall COl11pT1Slllg rectangular medical tape (No. 1525L plastic medical tape, 3M
Corporation, Mimleapolis, Mimlesota, USA) of a dimension of about 2.25 inches by 4 inches with a non-adhesive side attached to the bottom of the side walls 106, and a top wall 104 COIIIprISlIlg a rectangular 1/32 lIlCh thlClC fOalll tape (NO.
9773 1/32" tall foam tape, 3M Corporation, Mimleapolis, Milnlesota, USA) with seventy-eight holes 114 theretllrough (diameters approximately 1/32 inch, in a G by 13 pattern with about a 6 tnm center spacing). The side walls 106, the bottom wall 102, and the top wall 104 define a chamber. The holes 114 of the top wall 104 are covered by an air peTllleable lllelllblalle 116 C0111p1'lSlllg a porOLlS 111elllbralle (I~10.
9711 COTTaIITM
membrane, 3M Corporation, Milllleapolis, Minnesota, USA) disposed between the 5 top wall 104 and the temperature regulating 111eCha1115111 108. The side walls 106, the bottom wall 102, and the top wall 104 all had 1/8" rotulded corners. The temperature regulating mechanism 108 disposed in the chamber comprised a mixture of activated carbon, iron powder, saw dust, sodiLUn chloride and water in the weight ratio of approximately 5:16:3:2:6 weighing approximately 25 grams. This temperature 10 control apparatus 100 was tested on a vohulteer's stomach with a temperature probe placed between the temperature control apparatus 100 and the volunteer's slcin to measure the temperatwe. The results of this temperature experiment is illustrated in FIG. 7 and Table C, which shows that the temperatLUe control apparatus 100 is capable of keeping the skin temperature to a narrow, elevated range at between about 15 41 and 44°C for extended period of time (at least about 450 minutes).
TABLE C
Tinge (minutes)Temperature (C) 0 29.6 1 31.9 20 15 39.3 16 39.9 17 40.6 18 41.0 19 41.4 20 . 41.9 22 42.7 24 43.2 26 43.6 28 43.7 30 43.5 35 43.5 40 43.3 45 43.3 60 43.1 75 42.9 90 43.0 120 43.0 150 43.2 l 80 43.0 210 42.6 240 42.5 270 42.3 300 43.0 33O 43.0 360 42.6 390 42.6 420 42.5 450 41.9 FIG. 8 illustrates another embodiment of a temperature control apparatus 150 comprising a temperature regulating mechanism 108 su mounded by a bottom wall 102, a top wall 104, and side walls 152. The side walls 152 extend a distance below the bottom wall 102 to define a cavity 154. The bottom wall 102 is preferably made of plastic tape material and the side walls 152 are preferably made of a flexible non-air permeable material, such as non-air permeable closed-cell foam material. A
portion of the bottom of the temperature control apparatus 150 includes an adhesive zmaterial 112 on the bottom of the side walls 152 and, preferably, includes a second adhesive material 156 in the bottom of the bottom wall 102, wherein the second adhesive material 156 is preferably less adhesive than the adhesive material 112.
Again, the temperature regulating 111eCha111S111 108 preferably comprises a composition of activated carbon, 1r011 powder, sodium chloride, water, and, optionally, saw dust. The top wall 104 is preferably also a flexible non-air permeable material having holes 114 theretluough. An air permeable membrane 116 is disposed between the top wall 104 and the temperatlue regulating mechanism 108 to regulate the amount of air reaching the temperatlue regulating mechanism 108 tluough the boles 114.

FIG. 9 illustrates a DDDS 160 COlllpl"lslllg a housing made 122 of flexible materials. The housing 122 preferably comprises side walls 124 and a top wall Wlth a dTllg f01111111at1011 128 disposed Wlthlll the hO115111g 122, alld may 111Chlde a lllelllbralle 13O WhlCh play be a rate-111111t111g lnelnbTalle.
FIG. 10 illustrates the temperature control apparatus 150 of FIG. 8 attached to the DDDS 160 of FIG. 9. The DDDS 160 is placed on (or attached with an adhesive, not shown) a pol-tion of the skin 134 of a patient and the temperature control apparatus 150 is placed over' the DDDS 160, such that the DDDS 160 resides within the cavity 154 (see FIG. 8). The adhesive material 112 attaches to the skin 134 and holds the temperature control apparatus 150 in place. If the DDDS 160 is not attached to tile skin 134, the temperature control apparatus 150 holds the in place. Preferably, the DDDS 160 is attached to the skin 134 with an adhesive material (not shown) with the temperature control apparatus 150 placed over the DDDS 160. The temperatlue control apparatus 150 is attached to the skin 134 with the adhesive material 112 and the second adhesive Material 156 (less adhesive than any attaclslnent adhesive (not shown) between the DDDS 160 and the skin 134 and less adhesive than the adhesive material 112 between the temperature control apparatus 150 and the skin 134) attaches the temperature control apparatus 150 to the DDDS 160. Such an arrangement results in secure adhesion of the temperatlue control apparatus 150 and the DDDS 160 to the shin 134, yet allows for the removal of the temperature control apparatus 150 without removing the DDDS 160.
PIG. 11 illustrates an alternate DDDS 165 comprising a housing 123 made of flexible material(s). The housing 123 preferably comprises top Wall 125 and a i11e111bTalle 103, VV171Ch 117 ay be a rate-h1111t111g 111e111bTa11e, Wlth a drug fOr111111at1011 12g disposed within the housing 123. FIG. 12 illustrates the temperatlue control apparatus 150 of FIG. 8 attached to the DDDS 165 of FIG. 1 l, similar that described for FIG. 10.
Example 2 An example of using the embodiment of the present invention illustrated in FIGS. 8-12 for administering analgesic material to treat brealCthrough pails consists of a patlellt Ol' Cal'e glVer plaClllg the DDDS 160, 165 011 tile S1C111 134 Of tile patient with the temperature control apparatus I50 placed thereover. By way of example, when the DDDS 160, 165 is a commercially available fentanyl patch, Duragesic-50°, it talces several holes after the application of the DDDS 160, 165 to obtain a sufficient steady state level of fentanyl in the patient's bloodstream to control baseline pails.
However, such as with the treatment of cancer patients, a patient will front time to time suffer breakthrough pain, which is a suddenly increased but usually not long lasting pain. When a patient feels that a breakthrough palls eplSOde 1S
1111111111e11t, the patient places the temperatlue control apparatus 150 over tile DDDS 160, 165.
The heat from the temperature control apparatus 150 increases'the temperature of the fentallyl patch, the skin, and tissues lender the skin. As a result, more fentanyl is abSOlbed aCl'OSS the skin. FLlTtherlllOre, felltallyl already 111 the skill and Sllb-Sklll depot SlteS (l.c?., felltal7yl 111oleCLIIeS that have ah'eaCly pei'111eated aCTOSS the S1C111 bllt were Sl;Ored 111 the S1C111 allCl Sllb-510111 tISSLIeS~ Starts t0 be released lllt0 the systemic circulation at faster rates because of increased blood/body fluid flow in the tissues under the fentanyl patch and increment blood vessel wall permeability caused by heat from the temperatlue control apparatus 150. The overall result is that fentanyl concentration in the patient's bloodstream is significantly increased shol'tly after the heating patch is applied (compared with no temperature control apparatus 150 being used), and the increased fen tanyl in the bloodstream alleviates the brealctllrougll pails in a timely manner. It is believed that for lipophilic compounds, such as fentanyl, that usually have significant dermal depot effect (storage in depot sites in the skin and sub-shin tissues and gradual release from the depot sites), the increased drug release from the depot sites due to the heating may make a snore rapid and a more significant contribution to increasing bloodstream drug concentrations than the contribution from increased skin permeability caused by the heat. The patient can leave the heating patch on for a pre-determined length of time, based on l7is previous experience of brealctlll'ough pain, before he stops the heating by removing the patch or placing all air impermeable tape to cover all the holes on the top wall 104. The patient may also stop the heating when he feels the clurent episode of brealctllrough pain is over or begimling to end.
Preferably, the heating patch is designed to have a predetermined heating duration that is sufficient to treat most patients' breakthrough pain, bLlt not long enough to cause serious side effects associated with fentanyl aver dose.
However, if a particular patient has a higher tolerance to fentanyl, the patient can use two or more of the heating patches consecutively so that the patient gets just enough extra fentallyl to treat the breakthrough pain.
Exalnule 3 Another example of using the embodiment of the present invention illustrated in FIGS. 8-12 for dermally administering nicotine for suppressing nicotine craving consists of a user placing a nicotine DDDS 160, 165 on the skin 134. After a few hours, the user should obtain a steady state nicotine concentration in the bloodstream that is sufficient to suppress a "baseline" nicotine craving. When the user starts to have an episode of increased nicotine craving, the user puts the temperattwe control apparatus 150 on top of the DDDS 160, 165. The temperature control apparatus preferably heats for at least 15 minutes before the exothermic reaction exhausts the temperature regulating mechanism 108. The heat increases the transport of nicotine across the skin, and increases the blood flow in the tissues under the DDDS
160, 165 which carries nicotine stored in the tissues order the DDDS 160, 165 into the systemic circulation at increased rates. As a result, the user gets a rapid increase in his blood nicotine concentration to treat the surge of the nicotine craving.
After the heating, the nicotine absorption rates gradually Co111e back to normal to deliver the steady state nicotine concentration in the bloodstream.
Example 4 Another example of using the embodiment of the present invention illustrated in FIGs. 8-I2 for dermally administering testosterone to increase and optimize the amount of drug delivered consists of a user placing the DDDS 160, 165, such as a once a day dermal testosterone patch, for example Androderm~ produced by Theratech, Inc. of Salt Lake City, Utah, USA, on the skin 134. The DDDS 160, is generally applied to the skin 134 at night, for example at 10 PM. However, if the user does not get a sufficient dosage of testosterone the next day, the user puts the temperature control apparatus 150 on top of the DDDS 160, 165. The increased teanperature in the DDDS 160, 165, the slcin 134 and tissues under the slcin significantly increase the dermal absorption of testosterone. In addition, if the DDDS
I 60, 165 has permeation eWancer, such as glycerol monooleate, the heat should also make the enhancer permeate the skin faster, thus making it more effective. The ultimate result is that the user gets sufficient testosterone from the DDDS
160, 165.
Furthermore, the user may also place the temperature control apparatus 150 on the DDDS 160, I65 in the morning to deliver more testosterone from morning to the evening when the user needs the higher dosage the 1110St. The increased absorption of testosterone by the controlled heating may allow the reduction of a permeation eWancer concentration which is used in the DDDS 160, 165. h1 a testosterone DDDS, a permeation eWancer is usually necessary for delivering sufficient testosterone, however permeation eWancers may cause serious skin irritation, such as glycerol monooleate in Androderm~.
Example 5 It is, of course, understood that the DDDS 160, 165 and the temperature control apparatus 150 can be with athletic injuries. For example, if a person injures au elbow in a sporting event Or such, the user can apply a DDDS 160, 165 containing an analgesic, such a dexamethasone, wintergreen oil, or the like, wherein the DDDS 160, 165. The heat generated by the temperature control apparatus 150 drives more drug into the elbow and the increased the blood flow induced by the heat takes 5 the drug deeper into the elbow.
Examine 6 Yet another example of using the embodiment of the present invention illustrated in FIGs. 8-I2 comprises using the temperature control apparatus 150 for administering analgesic materian to treat pain when the diffusion coefficient of the I O active ingredients in the formulation 128 and/or permeability coefficient across a rate limiting membrane 130 is so Iow that it dominaatly determines the overall absorption rate of analgesic material from the DDDS 160, 165 into a patient's body. By way of example with the use of a DDDS I60, 165, the patient or care giver places the DDDS 160, I65 on the skin 134 of the patient. If after a time of wearing the 15 DDDS 160, 165, it is determined that for this particular patient and his conditions a higher concentration of fentallyl in the bloodstream is required to properly treat his pails, the temperature control apparatus 150 is placed on top of the DDDS 160, 165 to heat the DDDS 160, 165.
The increased temperatlue increases diffusion coefficient of the active 20 ingredient in the formulation ill the DDDS 160, 165 and increases the permeability coefficient across the rate limit membrane 130 in the DDDS 160, 165, and, thus, tile overall rates at which the active ingredient enters the patient's body. This, in turn, increases the concentration of active ingredient in the bloodstream. As a result, the patient gets the increased and proper effect.
25 Example 7 Stlln another exalllple Of LlSlllg the e111bOdllllellt Ot the pTeSellt 111Ve11t1011 illustrated in FIGs. 8-12 comprises using the temperatlue control apparatus 150 for decreasing onset time of an analgesic material from the DDDS 160, 165. By way of example with the use of a commercially available fentanyn patch, such as Duragesic-50", as the DDDS 160, 165, the patient or care giver places the DDDS 160, 165 on the skin 134 of the patient and places the temperature control apparatus 150 over the DDDS 160. Preferably, the temperatlue control apparatus I50 iacnudes a cuff dent alnoLUlt of activated carbon, iron powder, sodium chloride, and water in the temperature regulating 111echa111S111 108 to sustain an exothermic reaction for at least 3 5 4 hours.

The heat fl'0111 the temperature control apparatus 150 increases the temperature at a contact su dace of the skin 134 and the DDDS 160, 165 to temperatures up to about 60°C, preferably a narrow temperatLUe range between about 3 6 ° C and 46 ° C, most preferably between 3 7 ° C and 44 ° C, and maintains this temperature for a period of tinge (i.e., ahp roximately 4 hotus). Dining this dine, the heat increases the speed of fentanyl release from the DDDS 160, 165, the permeation rate across the skin 134, and the speed of blood circulation which carriers the fentanyl into the systemic circulation faster. After the exothermic reaction ceases (approximately 4 hours), the fentallyl absorption and concentration in the I O bloodstream begins to decrease from the elevated levels caused by the heat from the DDDS 160, 165 returns to normal (LUllleated) levels. The patient continues to wear the system for a total of between about 48 and 72 hours. Compared with a DDDS 160, 165 without the use of the temperature control apparatus 150, the fentanyl begins to appear in the bloodstream significantly earlier to yield a shortened onset time and the fentanyl concentrations in the bloodstream in the early hours of application are signiflcalltly higher than that produced by an unheated DDDS
160, 165. The therapeutic serLUn fentanyl concentration varies from person to person. For example some people respond to levels above 0.2 lzglmL. RefelTing to FIG. 6, this 0.2 ng/mL concentration is achieved in about one-third the alnotmt of time for a heated system than for a non-heated system (i.e., aboLlt 70 minutes as compared with about 210 minutes).
After a period of time when the exothermic reaction of temperatlue control apparatus 150 slowly stops generating heat, the fentanyl concentration in the bloodstream starts to gradually approach the normal steady state fentanyl concentrations in the bloodstream which would ultimately be seen with an unheated DDDS 160, 165, given a sufficient amount of time. As a result, the temperattue C011t101 up paratLlS 150 S1g111f1Ca11tly S1101te11S the 011Set t1111e Of DLlrageSlC-~0 ~~ WlthOLlt significantly altering its steady state delivery rates. Thus, the important advantage provided by this approach is that the onset time of a DDDS 160, 165 already in clinical use can be shortened without significantly altering its steady state delivery rates which are not only adequate, belt also familiar to the caregivers and the patients.
Example 8 A further eXa111p1e Of LlSlllg the e111bOdi111el1t Of the preSellt 111Ve11t1011 illustrated in FIGs. 8-12 comprises using the temperature control apparatus 150 for a sustained high absorption rate of an analgesic material front the DDDS 160, 165.
Cancer patient's~tend to develop a tolerance for fentallyl (and other analgesic materials) after extended use. For example, if a patient becomes tolerant to a Duragesic-100° (100 micrograms/hour deliver rate) dermal patch, a care giver may apply both a Duragesic-100° and a Dmagesic-50" (50 micrograms/hom delivery rate) to treat the patient's cancer pain. However, instead of using two Duragesic~' patches, a care giver can use a Duragesic-75° (75 llnCTOgra111S/hOLIT delivery rate) patch in CO11J1iI1Ct1011 Wlth the temperature control apparatus 150, preferably designed to last between about 12 and 24 hours, to increase the fentanyl absorption. The care giver replaces the heating patch, after the designed heating dwing is over, with another heating patch to maintain a desired temperature, and continues to do so until the fentanyl in the Duragesic-7S° patch can no longer supply a therapeutic amount of fentanyl. It is, of coiuse, understood that the temperature control apparatus 150 may be designed to last as long as the expected usage time of the Dmagesic-75° demnal patch.
Heating patches with different heating temperatLUes may be used to achieve different increased levels of fentanyl deliver rates.
Example 9 Yet still another example of using the embodiment of the present invention illustrated in FIGS. 8-12 again comprises using the temperature control apparatus 150 for decreasing onset time of an analgesic material from the DDDS 160, 165. By way of example, a local anaesthetic, such as a eutectic mixture of lidocaine and tetr acaine, can be administer with a DDDS 160, 165 to numb the shin 134 before a painful medical procedure. A faster onset and deeper numbing effect within a short time can be achieved by placing the temperatlue control apparatus 150 over the DDDS
160, 165, wherein the temperature control apparatus 1S0 is capable of providing heating the skin to a narrow range between about 37°C and 41 °C, preferably between 39°C
and 40°C, for at least 30 minutes. The slcin 134 should be nLUnb in 30 minute or less, which is much shorter than that without heating. Depending on the original skin temperature, it is believed that such heating will reduce the onset time by about 60%
of the onset time without heating.
Example 10 StiII another example of using the embodiment of the present invention illustrated in FIGs. 8-12 again comprises using the temperature control apparatus 150 for increasing the solubility of an analgesic from the DDDS 160, 165. By way of example, a formulation may be designed to contain an analgesic which has such low solubility in the formulation that a significant portion is in the form of Lmdissolved particles, and the solubility increases with increasing the temperature of the fOT111Lllat1o11.
A patient places such a DDDS 160, l 6S on his skin. If the amount of the analgesic compound the patient receives from the DDDS 160, 16S is not sufficient, S the patient places the temperatLUe control apparatus 1 SO on or over the DDDS 160, 165. The heat generated in the temperatlue control apparatus 1 SO increases the temperature of the formulation in the DDDS 160, 16S azld maintains the increased temperature for a significant part or substantially the entire length of the DDDS 160, 16S application. The increased temperatlue in the formulation increases the solubility of the analgesic compound in the formulation. Consequently, more allalgeSlC COLIIpOLlIIdS are C115SOlved L11 the fOr111t11at1011 WhlCh gives higher drlvmg Force for the transdermal permeation of the analgesic compoLUld. As a result, more of the analgesic compound enters the patient's body.
Another variation of this example is for the treatment of brealctllrough pain.
1 S If the solubility of the analgesic compound in a formulation in the DDDS
160, 16S is sufficient to treat baseline pain, but not brealallrough pail, a patient can place the temperature control apparatus 1S0 on or over the DDDS 160, 16S when an episode of breakthrough pain occurs. The increased solubility of the analgesic c0mpoluld in the formulation results in the patient obtaining more analgesic compound to treat the breal~through pain. The heating from the temperature control apparatus can be d1SC011t111Lled after the patient determines that the pain is Lulder control.
Although Examples 1-10 discuss the application of specific drugs, it is, of course, understood that the present invention is not limited to any particular drug(s).
It is understood that a considerable variety of drugs classes and specific drugs lnay be 2S used with the present invention. The drug classes can include without limitation androgen, estrogen, non-steroidal anti-inflannnatory agents, anti-hypertensive agents, analgesic agents, anti-depressants, antibiotics, anti-cancer agents, local anesthetics, antiemetics, anti-infectants, contraceptives, anti-diabetic agents, steroids, anti-allergy agents, anti-migraine agents, agents for smoking cessation, and anti-obesity agents.
Specific drugs can include without limitation nicotine, testosterone, estradiol, nitroglycerin, clonidine, dexaznethasone, wintergreen oil, tetracaine, lidocaine, fentanyl, sufentanil, progestrone, msulm, Vitamin A, Vitamin C, Vitamin E, prilocaine, bupivacaine, sumatriptan, and dihydroergotalnine.

Example 11 Yet still another example of LLSlllg the elnbOdllllellt Of the present 111Vellt1o11 111L1Stlated 111 FIGS. 8-12 agalll CO111pT1SeS LLS111g the te111peTatLlTe COlltr0l appaTattlS I50 for maintaining a stable temperature for the DDDS 160, 165. Certain drugs have relatively low therapeutic indices, meaning that the differences between the therapeutic dose and the dose which can cause serious andlor undesired side effects are small. Thus, dermal delivery of such drugs can be dangerous (over-dose) or inelTective (under-dose), especially for individuals whose shin are exposed to highly variable ambient temperatures, such as people worlcillg outdoors in extreme weather conditions. The variations in ambient temperature can cause variations in shin temperatlue which can significantly change the ultimate dermal absorption of the drugs. Covering a DDDS 160, 165 containing a low therapeutic indices drug with the temperature control apparatus 150 can regulate the skin temperature to a narrower range and reduce the variation in dermal drug absorption. Drwgs and classes of drugs that play belleflt fr0111 thlS lllethOd 111ClLlde, bLlt are 1101 hllllted t0, drLlgS SLlCh aS
111COtlne, 111trOglyCer111, C10111d111e, fe11ta11yl, SLlfellta1111, alld 111SL11111; alld classes of drugs such as non-steroidal anti-int~anlnlatory agents, anti-hypertensive agents, analgesic agents, anti-diabetic agents, and anti-migraine agents.
FIGS. 13-19 illustrates another embodiment of a temperature control apparatus 170. FIG. I3 illustrates the temperature control apparatus 170 whicll is S111111ar t0 tile e111bodllllellt of FIG. g, bLLt C0111prISeS a telnperatL.u~e regulating mechanism 108 which is made up of a plurality of chambers 172 separated by non-air permeable v~~alls 174. The temperature regulating mechanism 108 is substantially surrounded by a bottom wall 102, a top wall 104, and side walls 152. Again, the temperature regulating mechanism 108 preferably comprises a composition of activated carbon, iron powder, sodium chloride, water, and, optionally, saw dust, which is disposed in each of the chambers 172. The top wall 104 is preferably also a flexible non-air permeable material having a plurality of holes 114 theretllrough, preferably, a row of holes 114 for each chamber 172. An air permeable lllelllbralle I 16 is disposed between the top wall 104 and the temperatltre regulating 111eCha111S111 108 t0 1'eglllate the a1110L111t Of a1T leaChlllg the te111peratllre TegLllatlllg 111echa111S111 108 through the holes 114. The top wall 104 can have at least one cover covering the plurality of holes 114 for the regulation of the air into the chambers I72.
As illustrated in FIG. 13, three covers are layered on the top wall 104. A
first cover layer 176 is affixed to the top wall 104 and has openings I78 (see FIG. 17) to expose 2 out of 3 holes 114. A second cover layer 182 is affixed to the first cover layer 176 mcl has opening 184 (see FIG. 15) to expose 1 out of 3 holes 114. A tap cover 186, which leas no openings, is affixed to the second cover layer 182. Thus, a patient has a various opinions on what percentage of chambers 172 to expose to ~uubient air. If the heat generated from one third ofthe chambers is required, the top cover I86 is 5 removed, as shown in FIGS. 14 and 15. If the heat generated from two thirds of the chambers is required or if another additional heat is needed after the depletion of the first one-third of the temperature regulating mechanism 108, the top cover 186 and the second cover layer are removed, as shown in FIGS. 16 and 17. If the heat generated fiom all of the chambers is required or if another additional heat is needed 10 after the depletion of the first and second one-third of the temperature regulating mechanism 108, the top cover 186, the second cover layer 182, and the first cover layer 176 are removed, as shown in FIGs. 18 and 19. It is, of course, Lmderstood that more or less cover layers can be used with any number of holes to results in any desired amounts of the temperatlue regulating mechanism 108 being activated.
15 Thus, by way of example a patient can have a number of choices in using the temperature control apparatus 170, such for the suppression of brealctluough pain.
When the breakthrough pain occurs, the patent places the temperature control apparatus 170 over an analgesic material DDDS and can do any of the following:
1) Activate a particular number or percent of chambers 172 by removing 20 the requisite covers depending on how much additional analgesic material is required to treat the brealctluough pain. The covers can be preferably replaced to stop the exothermic reaction when no more additional analgesic material is required.
2) Activate a paTt1ct11aT llLllllber OT percent of chambers 172, exhaust the heat generating capacity of those chambers 172, and then activate other (non-25 activated) chambers 172. This extends the heating duration of the temperature control apparatus 170. The duration ofthe total heating time is detemnined by the typical duration of the particular patient's brealctluough pain.
3) Activate enough chambers 172 to treat one episode of breakthrough pain, and leave the heating patch in place. When the next episode of breaktluough 30 pain occurs, activate unused cha111berS 172.
FIG. 20 illustrates a dermal drug delivery system I90 (hereinafter "DDDS 190") having a rate limiting membrane 192. The structLUe of DDDS 190 is similar to that of FIG. 3. However, the DDDS 190 includes a rate limiting membrane 192 which resides between the drug formulation 128 and the skin 134 of a patient.

Generally, the permeability of the drug in the dlLlg fOT111ll1at1011 128 through the rate limiting member 192 is significantly lower than the permeability of the drug in the drug foT111Lllatloll 128 into the skin of an average patient. Rate limiting membranes 192 are used t0 11111111111Ze the Var1at1011 111 OVeTall peTllleatloll, and to regulate the amolmt of drug delivered to the patient so that overdosing does not occtu~. Another aspect of the present invention is the use of a temperatlue sensitive rate hlllltlllg membrane, such that the drug permeation rate tluough the rate limiting 111elllblalle 111cTeaS2s 51g111f1Calltly with increasing temperature. With such a DDDS
190, the above discussed temperature control mechanisms 100 (FIG. 1 & 2), 150 (FIG. 8), and 170 (FIG. 13) can be used to increase the drug delivery rate across the rate limiting membrane 192 to treat brealctllrough pain, reduce onset time, increase steady state delivery rate, or other advantages discussed above.
The possible temperature control mechalusms are not limited to the exothermic reaction mixture of iron powder, activated carbon, salt, water, and sawdust, as discussed above. FIG. 21 illustrates an electric temperature control mechanism 200 comprising an electric heating element 202 surrounded by a bottom wall 102, a top wall 104, and side walls 152 (similar to FIG. 8). The side walls 152, preferably, extend a distance below the bottom wall 102 to define a cavity 154. It is, of course, understood that the electric heating element 202 does not have to have the side walls 152 forming a cavity 154.
The bottom wall 102 and the side walls i 52 are preferably made of a flexible non-air permeable material, such as non-air permeable closed-cell foam material. A
portion of the bottom of the temperature control apparatus 200 includes an adhesive material 112 on the bottom of the side walls 152 and, preferably, includes a second adhesive material 156 in the bottom of the bottom wall 102, wherein the second adhesive material 156 is preferably less adhesive than the adhesive material 112. The electric heating element 202 preferably comprises a flexible resistor plate that can generate heat when supplied with an electric current tlwough traces 206, 208.
The electric clurent is preferably supplied from a battery 212 attached to a control mechanism 214, and an electronic switch 216. The battery 212, the control mechanism 214, and the electronic switch 216 are preferably attached to the top sluface of the top wall 104. The electric heating element 202 is activated by triggering the electronic switch 216 which begins the flow of electric current from the battery 212 to the electric heating element 202. A temperature sensor 218, such as a thermistor, is preferably attached to the bottom of the bottom wall 102 and sends a signal (corresponding to the temperatlue at the bottom of the bottom wall 102) through electric trace 222 to the control mechanism 214. The control mechanism 214 regulates the flow of current to the electric heating element 202, so that the electric heating element 202 quickly brings the temperature at a contact surface between the bottom wall 102 and a top of a DDDS (not shown) to a pre-determined level and maintains the temperattu~e at that pre-determined level.
The following features may be incorporated into the control mechanism 214: 1) a mechanism that allows a physician or care giver set the length of each heating period for each patient, which allows the physician to limit the heating, and hence the extra drug that the patient can get based on the conditions of the patient; 2) a mechanism that allows the physician or care giver to set the minimum time between the heating periods, and hence how often the patient can get the extra drug through increase heat;
3) a mechanism that allows the physician or care giver to set a pre-determined temperature; and/or 4) a mechanism that allows the physician or care giver to control the heating temperature profile, such as gradually increasing heating temperatlue or decreasing temperatlue over a pre-determined period of time. These features can potentially give simple DDDSs a variety of control options for the physician and/or the patient on the quantity and tlnnng of the delivery of extra drug.
Example 12 An example of using the embodiment of the present invention, such as illustrated in PIG. 21, includes using the temperature control mechanism 200 for decreasing onset time of a local anesthetic comprising approximately 14%
tetracaine/lidocaine eutectic mixture by weight; 8.6% polyvinyl alcohol (PVA) by weight, 0.17% sodilun hydroxide (NaOH) by weigh, and the remainder water (I-hO).
The local anesthetic, in the form of a thin patch, was placed on a volunteer's left forearm and the temperatlue control mechanism 200, set to maintain a 41 °C
temperature, was placed over the local anesthetic. The local anesthetic was also placed on a volunteer's right forearm (at a different time) and left at room temperature (about 24°C). The results are presented in Table D, wherein the effect of the local anesthetic was measure by a pain score when the shin is poked by a blunt object. The pain score is c(efmed as follows:
Score Effect 0 No effect 1 ~ Between no nlunbness and medimn numb 2 Medium numb 3 almost completely nlunb 4 completely lllllllb, but not deep 5 completely numb and deep T1171e (171111LIteS)1a111 SCOI'e wlth 1a111 SCOre VV/0 Tleatlllg Heat111g Thus, it can be seen that heating reduced the onset time of complete and deep numbness by approximately 33%.
~xanlple 13 Another example of using the embodiment of the present invention, such as illustrated in FIG. 21, includes using the temperature control mechanism 200 for a sustained high absorption rate of an analgesic material from the DDDS 160, 165.
Cancer patient's tend to develop a tolerance for fentanyl (and other analgesic materials) after extended use. For example, if a cancer patient becomes tolerant to a DLUagesic-100' ( 100 microgranls/hclur deliver rate) dermal patch, a care giver play apply an electric heating device, such as temperature control mechanism 200, on a DLU'agesic-100' patch and sets the teznperatl.u'e to heat the skin sluface to 38°C to obtain a higher rate of fentanyl delivery from the Duragesic-100° patch for treating the patient's cancer pain. However, if, after a dluation of treatment, the cancer patient becomes tolerant the fentanyl delivery rate at 38 °C, the care giver can adjust the ten117eratLlre C011tr01 1118Cha111S111 200 011 the Of DLlTageSlC-1000 patch t0 heat the skin surface to 40 ° C to obtain all even higher rate of fentanyl delivery fr om the Duragesic-100" patch for treating the patient's cancer pain.
FIG. 22 illustrates another embodiment of a temperatlue control apparatus 240 comprising a substantially flat, flexible bag 242 filled with a supercooled liquid 244, such as a concentrated solution of sodilun acetate. A
bottom portion of the bag 242, preferably, includes an adhesive material 246. The bag 242 is preferably slightly larger than the DDDS 160 such that the adhesive material play contact alld adhere to the skin 1 ~4. The bag 242 ful-ther includes a triggering mechanism 248, such as a metal strip. For example, when a patient wearing a DDDS
containing an appropriate analgesic material feels the ilnlninent onset of brealctllrough pain, the bag 242 is placed over the DDDS 160. The triggering mechanism 248 is activated (such as by bending a metal strip) which triggers crystallization in the supercooled liquid. Tlle heat generated by the crystallization (phase transition) increases the speed of transport of analgesic material into the body alld tile SpeeClS the Telease Of allalgeSlG 111ate1'lal f1'0111 the depot Sltes 111 the skin and the sub-slcin tissues. As a result the patient gets a rapid delivery of extra analgesic material to treat breakthrough pain. Usually, the heat generated by a phase transition can not be sustained over extended time, but may be enough to release adequate amount of analgesic material from the depot sites in the tissues under the skin to treat the breakthrough pain. The advantage of the temperature control apparatus 240 is that it is reusable. After use, the temperatlue control apparatus 240 can be placed in hot water and then cooled to room temperatLU~e to transfer the solidified contents in the bag back to a supercooled liquid 244.
Example 14 All eXalllple Of LLSlllg tile elllbOdllllellt of the present invention illustrated in FIGs. 23-24 comprises using a temperature control apparatus 300 which is capable of heating an d cooling, such that the rate of absorption of a drug formulation in a DDDS
can be increased or decreased, as needed.
For example, as shown in FIG. 23, if the level of the drug in the patient's system requires adjusting, the temperature control apparatus 300 is placed on a DDDS 160. Heating will result in an increase in drug absorption (as previously discussed) and cooling will reduce drug absorption to prevent overdose. FIG.

illustrates the temperature control apparatus 300 as a thermoelectric module which is be used for both heating or cooling. The: temperature control apparatLlS 300 fL111L'tIOIlS' as a small heat plunp, wherein a low voltage DC power source 304 provides a cLUrent in one direction 306 to a thermoelectric unit 310 which results in heating on a first side 308 (preferably a ceramic substrace) of the temperature control apparatus and cooling on a second side 312 (preferably a finned dissipation structL.ue) of the temperature control apparatus 300. If the current direction is reversed, the first side 308 will cool and the second side will heat.
The ten lperature control apparatus 300 may be control with a closed loop temperature controller 314, as shown in FIG. 24. The temperature controller comprises a positive DC node 316 and a negative DC node 318 supplying circuit to a primary cixcuit 320. The primary circuit 320 delivers all electrical signal 322 through a voltage amplifier 324 and a power amplifier 326 to the thermoelectric Lulit 310.
The primary circuit 320 further includes a temperature sensor 328 receiving a te111peTatLlre Slgllal 330 fr0111 the lher111oeleCtl'1G Lllllt 310, alld fLLTther 111C1LIdeS a te111peTatLlre ad~Llst111e11t 111eCha1115111 332, WhlCh ad JLlStS the eleCtrlCal Slgllal 322.

A variety Of drLlgS alld drLlg ClaSSeS Call be utilized Wlth SLlCh tTeat111ellts. The drugs include, but are not limited to, nicotine, nitxaglycerin, clonidine, dexamethasone, fentanyl, sufentanil, and insulin. The drug classes include, but are not limited to, androgen, non-steroidal alltl-111f1a111111atOry agellt5, anti-hypertensive agents, analgesic agents, anti-depressants, anti-cancer agents, anti-diabetic agents, steroids, anti-migraine agents, anti-asthma agents, and agents for smoking cessation.
It is, of course, understood that the heating devices discussed above could be replaced by an infrared heating device with a feedback mechanism. All of the controls and variations in controls discussed above would apply to such an infrared 10 heating device. The advantage of infrared radiation over simple heat is that the former, with proper wavelengths, penetrates deeper into a patient's skin.
Another aspect of the present invention is to use heat and other physical means, such as ultrasound, microwave, electric clurent, and vibration, to improve absorption of drugs from depot/storage sites. Such depot/storage sites play exist as a 15 result of a drug administered from a dermal patch or a drug directly injected or implanted under the skin surface.
The kind of Iorlnulations that may respond to the physical inducing means discussed above are:
Ultrasoluld: p~uticles containing drug formulation that call break down ill size 20 when treated with ultrasound.
Tvlicrowave: drugs that have limited solubility in surrounding body fluid, but the solubility increases significantly with increasing temperature; and solid formulations whose erosion/degradation speed can be significantly increased by increasing flow/exchange of body fluid 25 surrounding it.
Electricity: drugs that exist in ionized form in the foxlnulations and/or suirolmding body fluid.
Vlbrat1011: drugs that have limited solubility in body fluid; solid formulations whose erosion/degradation speed can be significantly increased by 30 increasing flow/exchange of body fluid surrounding it.
Example 15 One example of enhanced depot site absorption using the embodiment of the present invention illustrated in FIGS. 1 and 2 for administering analgesic material for pain relief consists of a patient or care giver placing the DDDS, such as a fentalryl-35 containing DDDS, on the shin of the patient at a first location. After sufficient depletion of the drug in the DDDS, the DDDS is removed and a second DDDS is placed on the skin of the patient at a second location to continue drug delivery. If an episode of breakthrough pails occurs, t:he ten lperatlue contras apparatus 100 can be applied directly to the patient's skin 134 at the first location (the DDDS is no longer present), aS 5hOW11 111 FIG. 25. The heat frosts the temperature control device 100 increases the speed Of dTLlg release front the depot site 252 in the first skin site and the tissues therelulder to give an increased drug absorption into the systemic circulation 254 to treat the brealctllrough pain.
Exanlole 16 An example of storage site absol'ption using the embodiment of the present invention illustrated in 1?IGs. 1 and 2 consists of a patient or care giver introducing an extended release insulin into his skin by injection or other method such as ultrasound speed hitting (such as products similar to those developed by Powdelject Pharmaceutical, United Kingdom). In the extended release insulin formulation, most of the insulin molecules are in crystalline fOrlll. After injection, insulin is released fTOlll the CTyStal1111e (10111 SIOWIy aS the crystals slowly dISSOIVe 111 the surrolulding body fluid. This provides a baseline insulin release into the systemic circulation.
However, the patient needs additional insulin above the baseline release to suppress sugar from meals. Thus, before each heal the patient places a telnperatlue control apparatus 100, preferably designed to control heat for a pre-determined time (i. e., between about 15 and 60 minutes), onto the shin over the injection site where the injected extended release insulin formulation resides. The heat from the temperature control apparatus 100 increases flow of the blood and another body fluid in the tissues sLU'rounding the eXtended insulin formulation, which increases the dissollitian speed ol~ isle insulin ants carries the insulin into the systemic circulation at higher rate.
The heating duration of the temperature control device I00 is, preferably, designed to last just long enough to release the adequate amount of extra insulin to deal with the sugar from the meal. Thus, the patient receives proper insulin absorption adjustment fiom the extended release formulation, and does not have to make a choice between taking additional insulin shots before meals or suffer the physiological consequences CfLLlSed by 111gh b100d SLlgal' tl'0111 the 111ea1S.
l:,Xa111p1e 1 A110ther eXalllple Of Storage Slte abSUTpt1011 LLS111g the e111bOdllnellt Of the present invention illustrated in FIGs. 1 and 2 consists of a patient or care giver injecting a drug mixed in controlled release pal'ticles under the skill sluface. By way of example, a controlled release formulation of analgesics may comprise an a11a1geSlC, SLlCh a5 Sllfe11ta1111, alfentanil, remifentanil, alld 1110Tp1n112, WhlCh 1S

incorporated into a controlled release drug delivery system (such as AtrigelTM
by Atria Laboratories, Iec., Zion Collies, Colorado, USA) C0111pr1Slllg a biodegradable, biocompatible polymers) [i.e., poly(DL-Iactide), poly(DL-lactide-co-glycolide), poly(DL-lactide-co-s-caprolactoee), polycaprolactone, or a combination thereof] in a biodegradable solvent (i.e., N-methyl-2-pyrrolidone). The controlled release formulation is generally injected into a patient within 3enl, preferably within I cnl, alld 1110St prefelably 0.J C111, frOlll the S1C111 t0 COlltrOl 1115 CallCeT
palll.
It is understood that ally h01110IJOIylllel' or copolymer of lactic and glycolic acid can be utilized. The lactic/glycolic acid polymers are solids, wherein the drug I O and polymers are both dissolved in a biodegradable solvent. After the injection, the biodegradable solvent diffuses out leaving behind the polymers) in the fOr111 Of precipitated, biodegradable particles, which holds lllost of the sufentanil.
As the polymer particles gradually erodes/degrades, the sufeetanil is released into the systemic circulation to treat the cancer pain. The release rate of sufentvlil is determined by how quickly the polymer particles erodes/degrades in the body.
The active drug may also be iecorporated and delivered into the storage site using different methods, such as mixing the drug with tile biodegradable, biocompatible polymers) in a solvent, evaporating the solvent to obtain polymer paltlCleS llllxed Wlth the active drug. The size of the dTllg C011tallllllg pOlylller particles should be, small enough to be incorporated (not dissolved) into a suspension in a liquid (preferably an aqueous liquid). The suspension is injected into the patient's tissue proximate the shin surface. The liquid quickly leaves the depot site, leaving behind a polymer implant containing the active drug. Tlle release of active drug from the polyeler implant can be increased in the mamler described above.
Regardless of the implantation method, the normal release rate of sufeetanil is usually sufficient to treat tile patients baseline cancer pain, but not enough to treat breakthrough pain. When the patient feels a brealahrough pain is coming, he places a temperattue control apparatus 100 over the shin site under which the formulation was injected. The increased blood/body fluid Flow caused by the heat increases the erosioll/degradation speed of the polymer particles and hence the speed of release of sufentanil. When the breakthrough pain is over, the patient stops the heating (such as by removing the heating patch or covering the holes I I4 on the top wall I04 -see FIG. 2) and the polymer particle erosioll/degradation speed gradually returns to normal which returns the sufentanil release rate back to a normal, pre-heated rate.

Exaln ule 18 The effects of heating on the release of a drug incorporated in a bioconlpatible, biodegradable polymer matrix were examined. All a11e5thetlC
(i.e., lidocaine) was incorporated into the polymer matrix (i. e. , lactide/glycolide polymer) to form an anesthetic dlug/polynler eonlposition. The anesthetic dlLlg/polymer C0111pOS1t1011 play be LlSed f01 111JeCtlllg/plalltlllg Lllldel the slcin of a patient, wherein the drug is gradually released into the body as the polymer matrix slowly erodes in the body.
The anesthetic drug/polymer composition was made by dissolving one tenth of one gram of lactide/glycolide polymer (Medisorb Grade 8515DL, Medisorb Technologies International, L.P., Cincillllati, Ohio, USA) and 0.1 gram of lidocaine base 111 2 g1a111S Ol- aCetOlle t0 (01111 a SOhltlOll. ApplOxllllately 5 111L
Of Water (pII
adjusted to above 8) was slowly added into the solution while the solution was stirred by a rapidly rotating Teflon coated magnetic bar. A Medisorb-lidocaine mixture precipitated OLIt as a textured material attached on the magnetic bar and as fine particles suspended in the solution. Approximately 0.5 mL of the solution containing the fine particles were injected into a 0.2 micrometer PTFE filter (Nalgene, 25 nnn).
Normal saline was infused tlllough the filter via a 3MTM 3000 Modular Infusion PLlnlp at a rate of 2n11/hr for approximately 7 days. This was to wash away the lidocaine that was not incorporated in to the Medisorb matrix and particles smaller than 0.2 micrometer, while lidocaine-polymer particles bigger than 0.2 micrometer were trapped in the filter. The particles slowly degraded due to hydrolysis and thLLS
gradually releases lidocaine to the saline passing through the filter.
A blunt needle was tightly attached to the exit end of the filter, and a thin plastic tube was attached to the blunt needle. Filtered solution from the distal end of the thin plastic tube was collected according tile following steps:
Step 1: Filter at room temperatzue (about 24°C) and collect the filtered solution into a glass vial for approximately 1 bolo.
Step 2: Immerse the filter into a 36°C (approximate) water bath, wait 3 0 approximately 1 hour, and collect the filtered solution from the thlll tube for approximately 1 hole.
Step 3 : Increase the temperature of the water bath to about 44 °
C, wait approximately 1 hour, and collect the filtered solution for approximately 1 hozu.

Step 4: Talce the filter out of the water bath and leave at room temperature (about 24 ° C) for approximately 0.5 horns, collect tile filter solution far approximately 1 hour.
Step 5: Repeat Step 4 after approximately 2 hours.
Saline was infused through the filter at the 2 mL/hour rate for the entire experiment. The solution coming out of the thin plastic tub during non-collecting time were discarded. Concentrations of lidocaine in above collected solutions were determined by an HPLC (High Performance Liquid Chromatography) method.
Lidocaine release rates from the polymer matrix at different temperatures were calculated from lldoCa111e Co11Ce11tr at1o11S 111 the collected samples.
The release rates are shown in Table E, as follows:
TABLE E
Step Temperature Lidocaine Release Rate (mcg/holu) 1 24C 0.36 2 36C 0.61 3 44C 1.59 4 24C 0.47 5 24C 0.38 As the results demonstrate, the lidocaine release rate increased when temperature at the filter (and hence the temperature of the lidocaine-polymer particles) was increased, and decreased when the temperature was decreased.
Although the filter temperature in Steps 4 and 5 were the same, the lidocaine release rate in Step 5 was lower than that in Step 4, and approaches that in Step 1.
Although the total quantities of Medisorb and lidocaine in the filter were not measLUed, the relative differences in the lidocaine release rates at different temperatures demonstrate that lidocaine release rate fr0111 Medisorb polymer increases with temperature. The finding that lidocaine release rate in Step 5 was lower than that in Step 4 suggest that the release rate decreases gradually after the temperature is lowered.
Since the degradation (hydrolysis) of Medisorb polymer is believed to control the release rates, these results suggest that Medisorb polymer degradation rate increases with increasing temperature. This suggests that the release rate of any drug incorporated in the Medisorb matrix (or other similar materials) and injected into the body can be increased by increasing temperature. In addition to increasing hydrolysis rate of the lvledisorb-lidocaine particles, heat is also expected to increase fine flow of body ('laid surrounding tile particles in the storage site in actual application, which should cause an additional increase in the drug absorption rate.
5 Another experiment was conducted on the Medisorb (same type as discussed above). A first sample of the Medisorb (transparent beads) weighing 0.1024 grams was placed in a first glass vial with 9.9024 grams of 0.9% sodium chloride injection solution. The first glass vial was sealed with parafllm and placed in all oven which maintained a temperature of about 43 °C. A second sample of the Medisorb 10 weighing 0.1028 grams was placed in a second glass vial with 9.9167 grams of 0.9%
sodium chloride injection solution. The second glass vial was sealed with parafilm and placed in a room with a temperature of about 23 °C.
After 29 days, few visible change had occLlrred to the Medisorb held at room temperatlue (second sample). However, tile Medisorb held at about 43 °C
changed 15 fro111 a transparent lllaterlal to a nlillcy-white color with smoothed edges. The Medisorb beads also appeared smaller than the original sire. This simple experiment demonstrates that the degradation rate of the Medisorb polymer increases with increasing temperature.
Example 19 20 Still another example of storage site absorption using the embodiment of the present invention illustrated in FIGs. 1 and 2 consists of a patient or care giver implanting a solid piece (t. e., plate, rod, or the like) made of a biocompatible, blogradable materlal(s), SLlch aS listed 111 Exa111p1e 16, L111der 1112 S1C111 SLITfaCe. By Way Of eXa111p1e, 1115111111 Call be 111COlpOrated into such a material. The insulin-containing 25 solid piece is implanted into a diabetic patient in a pOSltloll Wlth111 ~
C111, preferably within 1 cm, and most preferably within 0.3 cm, from the slcin. The insulin release rate from the solid piece is designed to be sufficient to provide the baseline insulin need for extended period of time (e.g., a few months). Before each meal, the patient places the temperature control apparatus 100, preferably with a pre-determined 30 heating duration, on to the slcin site under which the solid piece resides.
The heat from the temperature control apparatus 100 increases the flow of blood or other body fluid surromlding the solid piece, thus increases the erosioll/degradation of the solid piece and delivers extra insulin to the systemic circulation to suppress the sugar from the meal. After the pre-determined duration of temperatlue control apparatus 100 is 35 over or after the patient discontinues the heating fro111 the temperatlue control apparatus 100, the erosion/degradation rate of the solid piece gradually returns to normal, as does the insulin release rate.
Furthermore, such a system can be used with testosterone in a solid piece which implanted in the patient's skin. Preferably, the temperature control apparatus 100 is designed to last substantially longer (i.e., approximately 6-10 hours).
The patent applies the temperature control apparatus I00 on the skin site under which the solid piece resides to obtain increased testosterone levels in the blood ill the period fiom morning to evening when testosterone is most needed.
Although only a small number of drugs have been disclosed in Examples 13-I O I 8, any drug used in a treatment that fits the following description may potentially benefit from the methods: 1) the treatment requires that the drug have a baseline deliver rate over long treatment duration (such as longer than a day, preferably over a week), and 2) the treatment requires the drug to have increased delivery rates for a period or periods of time dLUing the long treatment duration. A variety of drugs and drug classes can be utilized with such treatments. The drugs include, but are not limited to, nicotine, testosterone, estradiol, nitroglycerin, clonidine, dexamethasone, tetracaine, lidocaine, fentanyl, sufentanil, progestrone, 1115111111, prilocaine, bupivacaine, sumatriptan, and dihydroergotamine. The drug classes include, but are not limited to, androgen, estrogen, non-steroidal alltl-111f1a11ll11atOry agents, anti-hypertensive agents, analgesic agents, anti-depressants, antibiotics, anti-cancer agents, local anesthetics, antien mtics, anti-infectants, contraceptives, anti-diabetic agents, steroids, anti-allergy agents, anti-migraine agents, agents for smoking cessation, anti-astlnna agents, alld anti-obesity agents.
Example 20 Still yet another example of storage site absorption using the embodiment of the present invention illustrated in FIGS. 1 and 2 consists of a patient or care giver imbedding a drug into the depot site. By way of example, a care giver can embed an alltl-1111gra111e drug, SLlCh a5 a l~OWder fOrlll Of dlhydr0elgota111111e, SLI111atr1pta11, OT
ergOta111111e, by h1tt111g tile drLlg lllt0 a depot Slte lulder the S1Q11 at hlgh Speed (SLlCh a5 by a device manufactured by Powderject Pharmaceutical, United Kingdom) when a patient feels an episode of migraine headache is imminent. With the Powderjet device, the drug powder is accelerated to a speed higher than the speed of sotmd and hit into the skin. A temperature control apparatus 100, preferably lasting approximately 1 hour, is innnediately applied on the sl'in over tile location of the embedded drug. The heat from the temperature control apparatus 100 increases the speed of the body fluid flow surrounding the anti-migraine drug and carries the anti-migraine drug into the systemic circulation faster. As a result, therapeutical blood concentrations of the anti-migraine drug is reached earlier and in time to treat the lnigr aine headache.
This technique may also be used to deliver a preventative baseline release rate of a drug, SLICK aS a11t1-Illlgra111e drug or Nitroglycerine. A heating patch is then applied to release extra drug when a medical episode begins.
It is, of course, understood that the heating devices discussed above could be replaced by an ilrfrared heating device or a microwave heating device with a feedback mechanism. All tile controls and variations in controls discussed above would apply to such devices.
Example 21 Ultrasound call be used to increase release rate of injected controlled release drug formulations, particularly, when the controlled release formulations are in the form of relatively large particles (i.e., 25 ~~m or larger). The controlled release formulation is injected into the patient's tissues within 3 cm, preferably within 1 cm, and most preferably 0.3 cm from the skin. The erosion/degradatioN rate of the particles deterNlines the rate of release of the drug, and the steady state release rate of the drug is designed to deliver a therapeutical level of drug to the patient.
ror analgesic drugs, the steady state release rate is usually slightly below that needed to treat an average person's post-operative pain. I~ or a particular patient in whom the steady state release rate is not sufficient (because of his pharmacolcinetics and/or level of pain), an ultrasound is directed into formulation and breala the particles into smaller ones (this requires that tile particles are capable of being broken by LlltTaSOLIIld).
This increases the surface area of the formulation exposed to the surrounding body fluid, and hence increases the release rate for the rest Of the adlllllllstrat1011.
ThlS lllethOd allOWS the ad1111111StTat1011 Of a lOW release rate fOr111Ll1at1011 WhICh 1S
safe, and then increasing the release rate for patients who need higher delivery rates.
The intensity, frequencies, and dLUation of ultrasound can be chosen to increase the release rate to proper levels. Exemplary ultrasound treatment and devices can be found in U.S. Patent 4,948,587 issued August 14, 1998 to ILOSt et al., hereby incorporate herein by reference.
Example 22 The generation of an electric potential on a portion of a patient's body can be used to increase release rate of injected controlled release dTLIg fOr111L11at1011S, lJa1'tICLllarly, Whell the controlled release formulations exist 1111011IZed f01111 Ill the Formulations and/or surrounding (body fluid. For example, when a controlled release insulin is injected into a diabetic patient's skin, the normal release rate of insulin from this formulation is controlled by the dissolution rate of the particles in which insulin resides wherein the normal release rate provides an adequate baseline insulin level in the patient. As shown in FIG. 26, the patient places a first electrode 262 on the S1C111 134 OVer the lll~ection site of tile COlltrOlled release IllSLl1111 fOT111LI1at10n 264.
A second electrode 266 is placed an a skin 134 in a position near the injection site of the controlled release insulin formulation 264 (i. e., at least a few centimeters away).
Before each meal when the patient needs to increase his blood insulin level to suppress sugar from the heal, the patient connects the first electrode 262 alld the second electrode 266 with wires 268 and 270, respectively, to an electric current generating device 272. The electric current generating device 272 introduces all electrical potential between the first electrode 262 and the second electrode 266.
Preferably, with the use of insulin, the electrical amperage should be in the range of between about 0.2 and 4 mA. Because at the physiological pH, insulin molecules carry net negative electric charges, the first electrode 262 should have a negative charge which pushes the negatively charged insulin away fiom the body fluid surrolulding the formulation and llltO the SySte1111C CIrCLllat1011 254. This malces the insulin release faster. Preferably, the intensity and duration of the cLLrrent can be altered with the electric cul-rent generating device 272 to deliver tile requisite therapeutic amount of extra insulin.
Exaln ule 23 The generation of a vibration over the inj ection site of controlled release drug formulations can be used to increase release rate of the formulations, pal.-ticularly, when the controlled release formulations have limited solubility in body fluid or with solid formulations whose erosioll/degradation speed can be significantly increased by increasing flow/exchange of body fluid surrounding the solid formulation. For example, when a controlled release insulin is injected into a diabetic patient's shin, the normal release rate of insulin fr0111 this formulation is controlled by the erosioll/degradation or dissolution rate of the particles ill Which insulin resides wherein the normal release rate provides an adequate baseline insulin level in the patient. As shown in FIG. 27, before each heal, the patient places a vibration generating device 282 on the slcin 134 over the injection site of the controlled release 111SLi1111 fOl'IllLIlatl011 264. The vibration generating device 282, preferably, delivers vibration of between about 20 and 400 Hz. The vibration agitates the body fluid (not ShOWII) SLIrrOL111dII1g the controlled release insulin 264 alld increases its circulation.

AS a Teslllt, 1110Te 1115111111 1S released fr0111 the controlled release 1115111111 fOT111LlIatlOll 264 to the systemic circulation 254 shortly before the heal to suppress the sugar from the meal. Preferably, the intensity allCl duration of the vibration can be altered with the vibration generating device 252 to deliver the requisite therapeutic amount of extra insulin.
Although only a few drugs have been disclosed in Examples 19-22, any drug used in a treat111el1t that fits the following description may potentially benefit from the physical methods fOT 111dL1Clllg increased release: 1) the treatment requires that the drug have a baseline deliver rate over Iong treatment duration (such as longer than a day, preferably over a week), 2) the treatment requires the drug to have increased delivery rates for a period or periods of tinge during the long treatment duration, and 3) the formulations respond to the one or more of the physical methods fOr 111dL1Clllg increased release. A variety of drugs and drug classes can be utilized Wlth SLICK treat111ellts. The drugs include, belt are not limited t0, 111COt111e, testosterone, estradiol, nitroglycerin, clonidine, dexamethasone, tetracaine, lidocaine, felltallyl, Sllfe11ta1111, pTOgeSt1011e, 1115L11111, pr110Ca111e, bLlplVc'1Ca111e, S11111atTlptall, and dlhydr0elgota111111e. The dlLlg ClaSSeS 111C1L1Cle, bLlt al'e 1101111111ted t0, allChOgell, eStrOgell, 11011-Ste1'Oldal allll-111~~a111111at01'y agelltS, a11t1-hyperte11S1Ve agents, allalgeSlC
agelltS, a11t1-depreSSalltS, a11t11.~10t1CS, alltl-CaIlCe1 agelltS, local alleSt11et1CS, a11t1e1netICS, anti-infectants, contraceptives, anti-diabetic agents, steroids, anti-allergy agents, anti-migraine agents, and agents fog SI1101C111g cessation.
Example 24 Another example of the present invention comprises using a telnperatlue control apparatus 300, similar to that shown in FIG. 23, which is capable of heating and cooling, such that the rate of absorption of injected controlled release drug formLllation can be increased or decreased, as needed.
For example, when a controlled release drug formulation is injected into a patlellt'S S1C1I1, the I10PI11a1 release rate of the drug from thlS
fO1I11111at1011 IS COlltrOlled by the erosioll/degradation rate of the particles in which the drug resides wherein the normal release rate provides all adeqllate baseline drug level in the patient.
As shown in FIG. 2~, if the level of the drug in the patient's system requires adjusting, the temperature control apparatus 300 is placed of the skin 134 over the injection site of the controlled release drug formulation 302. Heating will result in an increase in drug absorption (as previously discussed) and cooling will reduce drug absorption to prevent overdose. FIG. 23 illustrates the temperatlue control apparatus 300 as a theTI120eleCtrlC IllOdllle VVhICh 1S be used for both heating or cooling. The temperatLZre control apparatus 300 functions as a small heat pomp, wherein a low voltage DC
power source 304 provides a current in one direction 306 to a thermoelectric unit 310 WhlCh TeSLIItS 111 heating on a first side 308 (preferably a ceramic substrace) of the temperature control apparatus 300 and cooling on a second side 312 (preferably a 5 finned dissipation structure) of the temperature control apparatus 300. If the current direction is reversed, the first side 308 will cool and the second side will heat. The temperature control apparatus 300 may be control with a closed loop temperature controller, as show previously in FIG. 24.
A variety of drugs and drug classes can be utilized with such treatments. The 10 dl'LlgS 1I1C1Llde, bLlt aI'e 1101 112111ted t0, IllCOtlIle, Illtl'OglyCe11I1, ClOllldllle, dexamethasone, fentanyl, sufentallil, and I11SLL1111. The drug classes include, but are not limited to, androgen, non-steroidal anti-inflalnlnatory agents, anti-hypel'tensive agents, analgesic agents, anti-depressants, anti-cancer agents, anti-diabetic agents, steroids, anti-migraine agents, and agents for smoking cessation.
15 Example 25 Another example of the present invention comprises using the temperate re control apparatus 300, as shown in FIG. 23, or any device which is capable of cooling tile Slilll 111 COIl~tLllCtloll Wlth a111nJeCtable liquid drug delivery formulation containing thermal gel.
20 The main difference between a thermal gel and a regular gel is that a thermal gel is a liquid in room temperature (i.e., about 20-25 °C) and is a gel at body temperatlu'e (t. e., about 37 °C), whereas, with regLllar gel, the viscosity of the gel generally lowers with increasing temperature. ThLls, while the thel'lnal gel is at room temperature (i.e., in liquid form), a drLtg formulation is mixed into the thermal gel.
25 The thermal gel/drug mixture play then be easily drawn into a syringe and injected to the patient. Once in the patient's body, the thermal gel/drug lnixtlue quickly solidifies into a gel. Tlle gel then dissolves over time releasing the drug formulation into the patient systemic circulation.
Using a cooling device, such as the temperature control apparatus shown ill 30 FIG. 23, the thermal gel/drug mixture which has solidified under the shin can be cooled to revert the gel back into a liquid. In a liquid state, the drug formulation diffilsion rate and release rate increase, thereby increasing the drug formulation present in the patient's systemic circulation when needed.
An example of a thermal gel is Smart HydrogelTM developed by Gel 35 Science/GelMed and consists of an entangled network of two randomly grafted polymers. One polymer is poly(acrylic acid) which is bioadllesive and pII-responsive. The other polymer is a tribloclc copolymer containing polypropylene oxide) (''PPO") and polyethylene oxide) ("PEO") segments in the sequence PEO-PPO-PEO.
An example of using the present invention with a thermal gel is the delivery of additional insulin to a diabetic patient prior to the intake of food. The thermal gel containing the insulin caL be injected subcutaneously in order to form a gel to release a continuous baseline dosage of insulin. At a meal when insulin is needed to absorb extra sugar in tile CITCLllat1o11, the patient can apply the cooling device on the slcin adjacent the injection site and cool the injection site to a temperature below the gelling temperature of the thermal gel/insulin mixture. The gel will, of course, become a llqLlld and increase the insulin level in the patient's body to compensated for the ingested meal. This process can be repeated many times Lentil the injected thermal gel/insulin mixture is gone. The advantage of this drug delivery system is that the diabetic patient can control insulin delivery during the course of a few days, even a few weeks, with only one inj ection.
Example 26 As shown in FIG. 29, an insulating material can be incorporated with the controlled temperate re apparatus to assist in not only minimizing the temperature Varlat1011, bLtt alSO 111CTeaSlllg the te111peratLlTe Of the DDDS alld the Sk111 Ltllder It (by decreasing heat loss), each of which tend to increase dermal drug absorption.
FIG. 29 illustrates a configuration similar to that illustrated in FIG. 4 wherein the temperature control apparatus 100 of FIG. 2 is attached to the DDDS 120 of FIG.
3. The DDDS 120 attached to a portion of the skin 134 of a patient. An insulating sleeve 350 abuts the skin 134 and encases a substantial portion of the temperatLU-e control apparatus 100 and the DDDS 120.
FIG. 30 illustrates another insulating sleeve 360 made of aal insulating material, such as closed-cell foam tape, with adhesive edges 362 attached to a patient's skin 134, slightly larger than and covering a DDDS 364. FIG. 31 illustrates the insulating sleeve 360 covering a heating apparatus 366 and the DDDS 364 attached to a patient's shin 134. FIG. 32 illustrates the insulating sleeve covering all area over the skin 134 where an injected/implanted/
controlled/extended release drug formulation 368 has been located.
Example 27 Another application of the present invention involves the use of a heating deVICe, SLICK aS dISCLlSSed above, IIl CO11JLI11CtI011 Wlth a typlCal llqLIId drLtg lIlJeCt1011.
FOT 50111e ClrLlgS, 111CTeaSed speed Of abSOrpt1011 lllt0 the systemic circulation after they are injected into the body lnay provide treatment to the patients. For instance, to be effective, the anti-migraine drug, dihydroergotamine, must reach an effective concentration level in the blood stream within a certain amount of time from the onset of the migraine attack or the drug will be ineffective. Currently, a drug's absorption into the patient's systemic circulation cannot be altered after it is injected.
Thus, the controlled heating aspect of the present invention can be used to increase the absorption speed of subcutaneously and intramuscularly injected drugs.
For example, after a drug is injected sllbcutaneously or intramuscularly, a heating patch, such as described in the above examples, may be placed on the skin under which the injected drug resides. The heating increases the circulation of body fluid surrounding the injected drug, increases the permeability of blood vessel walls in the surroL~nding tissue, and, thus, resLilts in increased speed of absorption of the drug 11110 the systemic circulation.
Such a method would be usefitl for drugs which are injected into a part of the body that can be heated by a heating means on or outside the skin and whose effect can be improved by increased absorption speed into the systemic circulation or deeper tissues. Stlch drugs may include; anti-migraine agents, anti-hypertensive agents, analgesics, antiemetics, cardiovascular agents. Specific drugs may include clihydroergotamine, ergotamine, sumatriptan, rizatriptan, zolmitriptan, and other selective 5-hydroxytryptamine receptor subtype agonists, morphine and other narcotic agents, atropine, nitroglycerin, fentanyl, sufentanil, alfentanil, and meperidine.
Since increased absorption speed into the systemic circulation usually can cause higher peak concentrations in the blood, this teclmology may also be used to increase peak blood concentrations of drugs that are injected subcutaneously and intramuscularly.
Some drugs need to be inj ectecl intravenously because systemic absorption for subcutaneous and intramuscular injections tape too long to talce effect.
However, intravenous injection is more difficult to perform and involves more rislcs.
With the use of the present invention, the absorption speed of some drugs may be increased ell0llgh 50 that 5t1bCL1ta11eOL1S Or 111tra1nL1SCL11aT 111JeCt1011 Call provide sufficient speed of absorption. Therefore, this technology may also be used for replacing intravenous injections with sL~bcutaneous or intralnuscular injections for some drugs.
As a specific example, a patient may inj ect himself with sumatriptan or 3S dlhydrOeTgOtalllllle SLIbCLltalleotlSly after he feels a migraine attack.
He then removes a heating patch containing a heat generating medium comprising iron powder, activated carbon, water, SOdlLllll ChlOTlde, and sawdust (similar to Example 1) out of its air-tight container and places it over the injection site. The heating patch quickly 111CTea5e5 tile te111pelatLlTe OI the SIClll Llllder the heat111g patch IIltO
a llarrOW range Of 39-43 ° C and maintains it there for at Ieast I S minutes. The circulation speed of the body fluid slurolulding the injected drug and the permeability of the blood vessels in the sLlrrolulding tissues are both increased by the heating. As a result, the drug enters the systemic circulation and reaches the acting site more rapidly, and the patient receives more rapid and/or better control of the migraine attack.
In another example, a nurse can inject morphine into a patient's muscle tissue to treat severe pain. The nurse then places a heating patch, as describe above, over the injection site. The speed of morphine absorption into the SyStenlIC
CITCLlIatI011 IS
increased as previously discussed. As a result, the patient receives more rapid and/or better pan control.
Example 28 Another application of the present invention involves the use of a heating device, such as discussed above, to mimic circadian patterns. For example, testosterone or its derivatives, such as testosterone enanthate and testosterone cypionate, call be injected intramuscularly into men to substitute or replace diminished or absent natural testicular hormone. Testosterone enanthate and testosterone cypionate are preferred over testosterone, as they have longer dlu~ation of action than testosterone. However, it is understood that testosterone or its derivative, such a testosterone ester, play be incorporated into a controlled release polymer matrix, such as homopolymer or copolymer of lactic and glycolic acid, preferably poly(DL-lactide), poly(DL-lactide-co-glycolicle), and poly(DL-lactide-co-(-caprolactone)), to increase the duration of action. Following intramuscular injection, testosterone enanthate is absorbed gradually from the lipid tissue phase at the injection site to provide a duration of action of up to 2-4 weeks. However, natural blood testosterone concentrations in healthy man are higher in a day and lower in the night. So blood testosterone concentrations obtained from injected testosterone derivatives do not mimicking the natural circadian pattern.
By way «( example, a patient can inject testosterone enallthate either subcutalleously or intramuscularly (if intramuscularly, the injection should be relatively close to the slcin sLUface). The patient then places a heating patch on the injection site every morning (1111tH all the injected testosterone enanthate is depleted).
The heating patch quickly increases the temperature of the injection site to a narrow range, and 111a111ta111S It theTefOre a desirable dluation of tinge (i.e., abOLlt 8 hours).

They heating causes increased release of testosterone enanthate and/or increased rate of conversion frOlll testosterone enanthate to testosterone, and, thLlS, higher blood testosterone concentrations. The "used-up" hatch I5 TelllOVed befOl'e a IleW
heating patch is placed on the salve. Using this intermittent heat application tecllllique, blood teStOSteTOlle CO11Ce11trat1011S are lOW 111 the night and high in the day, thus 11111111C1Clllg the LlatLlral ClrCadlall pattern.
Rapid Delivery One embodiment of clurelit invention is related to using controlled heat to transdermally deliver pharmaceuticals in a lulique way. In transdermal drug delivery, I O a fOrllllllat1011 COllta111111g a drug is applied to the shin and the drug permeates across the skin to reach the systemic circulation or regional tissues. Typically, a portion of the drug that permeates across the slcin's main barrier, stratlun corneum, stays in the S1C111 alld/Or SLIb-S1C111 tissues. This drug storage and/or storage site in the skin is referred to as "depot or depot site" hereafter. If the transdermal permeation of the 15 drug continues, a steady state depot can be established. After the transdermal permeation of the drug stops, the drug ill the depot will gradually migrate into the systemic circulation. The inventors have recently determined that when the depot is heated, at least a pol-tion of the drug in the depot can be released (dlunped) into the SyStel111C Clrclllatl011 Very rapidly. The depot play eXISt 111 the shin and Or SLLbS1C111 20 tissues. For pluposes of this application, the depot is generally considered to eXist under the surface of the shin.
In the clu-rent invention, a t~ransdermal delivery system is applied to the user's skin to deliver a pharmaceutical agent (drug) through transdermal permeation.
Some of the drug reaches the systemic circulation while a portion of the drug is stored in 25 the depot. When there is a need to rapidly increase the drug's concentration in the systemic circulation, a heating solace is applied to the shin area colder which the depot eXists. The heating then rapidly releases a portion of the drug in the depot into the systemic circulation. The mechanism of this rapid release may involve heat-induced increased blood circulation, blood vessel dialation and/or increased drug 30 solubility. The rapid rate at which drugs are released from the depot and absorbed into the systemic circulation due to heating the skin is surprising.
The method of the present rapidly "dumping" a drug front a depot created by transdermal drug delivery allows transdermal drug delivery to be used to (1) promptly treat an acute symptom or illness; and (2) rapidly increase drug 35 concentration in the systemic circulation on demand.

hl One elllbOd1111e11t of the present invention, a transdermal delivery system is applied to the user's slcin. The concentration of the drug in the user's blood starts to steadily rise after an initial period of time, referred to as the lag time.
The drug concentration in the user's blood reaches a steady state after another period of time.
5 The period of time between fine start of transdermal delivery and the steady state is referred to herein as the time to steady state or steady state time. When there is a need to rapidly increase the drug concentration in the blood, a heating source capable of heating the skin to a predetermined temperature range for a predetermined duration is applied proximate to the skin area under which the depot exist. A
pol-tion 10 of the drug in the depot is released and the drug concentration in the blood then increases rapidly. After the heating source is removed or terminated, the blood drug concentration starts to decrease gradually to normal.
Although the user may be able to adjust or terminate the heating, it is more desirable to design and use a heating source that can generate heat to a pre-15 determined temperature and for a pre-determined duration. This will minimize the overdose potential. For example, if a patent forgets to remove a heating source from a transdermal fentanyl patch after obtaining an adequate bolus fentanyl dose and the heating source continues to beat, the patient may eventually be overdosed with fentanyl. On the other hand, if the heating source is designed to only last for a period 20 of tune that has been tested to be safe (i.e., 10 minutes), the patient will not be overdosed regardless if he/she remembers to remove the heating source. In a typical application, the pre-determined heating duration only needs to be long enough to release a therapeutic amount of the drug from the depot. Typically, this heating time is not more than about fifteen minutes to thirty minutes, unless there is a need to keep 25 the elevated drug concentrations in the blood for an extended time. It is possible that the heating time can be very shol-t, even seconds long, as the heat induced increase in blood circulatian and blood vessel dilation can be nearly instanteous. The heating temperature also needs to be well designed and precisely controlled. If the heating temperatlue is too low, the release of the drug fiom the depot may be insufficient. If 30 the heating temperatlue is too high, shin damage and/or drug overdose may occlu.
Therefore, in the current invention, both heating temperature and heating duration are preferably well controlled.
In order to release the dlltg from the depot, a significant amount of drag has to be delivered into the depot tluough the skin lust. In one embodiment, after the 35 transdermal drug delivery system is applied to the user's skin, a pre-determined minimlun time is allowed to elapse without heating. This period of time is generally referred t0 a5 the depot aCC11111L11at1011 t1111e. The length of t1111e Of this initial depot accumulation depends on many factors such as potency and other properties of the drLlg and tile nature of the therapy. The depot aceunlulation time preferably is determined clinically or experimentally for each drug. It is estimated that a minin 1um of 10-20 minutes of Lulheated transdermal delivery is needed for any drug to establish a large enough depot from which a therapeutically significant bOlLIS dose can be released. It is likely that most drugs require at least 30-60 nlinutes depot aCCL1111L11at1011 t1111e 111 Order t0 belted SLleh a depot Whel1 heat 1S 110t LlSed to increase absorption. It is usually not necessary to establish a steady state concentration before using heat to "dump" tile drug fiom the depot. The un-heated depot delivery time only needs to be as long as it takes to build a significant depot so that a therapeutic amount of the drug call be released from the depot.
After the drug is released from the depot by controlled heat, the depot is depleted or partially depleted. If the trallsdermal drug delivery continues, the depot will be felled again. Therefore, another depot accumulation time may leave to elapse before a thela17et1t1C alllollllt Of the drLlg Cai1 be released front the Sa111e depot Slte again by C011t1'Olled lleatlllg. ThlS SllbSeqllellt depot a.CClll11Ll1at1011 tune lnay b2 difFerent Ii'om the initial depot acclunulation time. It will not only depend on all the factors that affect the initial depot accumulation time, but will also depend on how much drug remains after a portion of the drug was depleted by the prior heat-induced bolus release. It is conceivable that if the prior controlled heat- induced release only depleted a small portion of the drug in the depot, the subsequent depot accumulation time may be quite short. The depot depletion-refill process can be repeated numerous times as long as enough time is given before each controlled heat-induced drug release an d transdermal drug delivery continues. Since the initial and the subsequent depot accumulation times are of similar natlue, they are both referred to as depot accumulation time hereafter.
The depot site may be heated during the depot accumulation tulle, as long as the heating temperatlue is significantly lower than the heating temperature used to release the drug from the depot. This low level heating will reduce the amount of the drLlg to be released ii'om the depot, duo to reduced temperature difference.
ZIowever, tine low temperature heating may provide the benefit of reducing the time to steady state, and therefore should be considered.
Two classes of drug may be delivered beneficially with this method. The first class of drugs are those that can be delivered transdennally, and for which a rapid increase in blood concentration upon demand is beneficial for the user. The second class of drugs are those that can be delivered transdermally, for which a relatively CollStallt level of tile drug in the blood is beneficial, and for which a rapid increase in blood concentration (in addition to the drug level already present in tile blood) upon denmuzd is beneficial. Use of the present invention allows the first class drugs, v~~lziclz are often delivered by injection, to be delivered non-invasively. This n Method is particularly advantageous for the second class of drugs.
The second class of drugs referred to above includes, but is not limited to the following drugs:
Analgesics: providing a constant desired drug level in the blood helps I O alleviate baseline pain and, a rapid release of the drug from the depot into the systemic circulation upon demand may takes care of breaktluough pain or other suddenly increased but short lasting pain.
Anti-mental disorder drugs: providing a constant desired drug level in blood prevents some or most episodes of a mental disorder (e.g. panic attack) from 15 happening, and a rapid release of the drug from the depot into the systemic circulation may help prevent or reduces the severity of some attacks that are not preventable using the baseline drug levels.
Migraine drugs: providing a constant desired drug level in blood prevents some or most episodes of migraine attacks from happening, and a rapid increase of 20 the drug from the depot into the systemic circulation may help prevent or reduce the severity of some sudden and severe attaclcs that are not preventable by the baseline drug levels.
Anti-inflammatory drugs: providing a constant desired drug level in blood minimizes a user's pain or eliminates the pain most of the time, and a rapid release of 25 the drug from the depot into the systemic circulation may help prevent or reduces the severity of a more severe, acute pain. These drugs include, but are not limited to, steroids and nonsteroidal anti-inflannnatory agents.
Cardiac dI'LIgS: providing a constant desired drug level in blood helps prevent or reduce heart disorders, and a rapid release of drug from the depot into the 30 systemic circulation may help prevent or reduce the severity of sudden and severe heart disorders that are not preventable by the baseline drug levels.
Hypertension drugs; providing a constant desired drug level in blood keeps the blood pressure at relatively constant levels most of the time, and a rapid release of the drug from the depot into the systemic circulation may suppresses sudden and 35 serious blood pressLUe increases that are not preventable by the baseline drug levels.

The rapid release of the drugs mentioned above front the depot into the SySte1111C Cll'Clllatloll by applylilg heat play be aCCOlllp115hed by either the p11yS1C1a11 OT
the patient when he/she senses a clinical need.
example 1 The following human test results demonstrate that a drug in a slcill/sub-skin depot can be rapidly released into the systemic circulation.
hl Oile arlll Of the StLldy, a 25 mcg/llr Dluagesic° trallsdermal fentanyl patch was applied to the shin of tile subjects at time 0 (t=0). At t = 24 hours, after a significant depot of fentanyl was formed in the slcill/sub-skin tissues, a heating patch capable of heating the shin to about 40-43 C for about GO minutes was placed on top of the Duragesic~ patch. Both the heating patch and the Duragesic"'' patch were removed at t = 30 hours. Mean serum fentanyl concentrations of the ten subjects at pre-determined time points were measured by radioinlmunoassay, and are shown in Table 1.
Table 1 IIolus Mean 0 O.OOG

1 0.008 2 O.03S

3 0.130 4 0.239 5 0.347 G 0.485 7 0.520 2S . 8 0.539 9 0.544 IO O.G58 11 0.598 12 0.707 3O 13 0.660 14 0.662 15 0.75 1 G 0.746 17 O.G90 35 18 0.747 19 0.819 20 0.769 21 0.775 22 0.808 ? 3 0.874 24 0.855 24.08 1.378 24.17 1.423 24.25 1.331 24.33 1.412 24.50 1.374 24.67 1.407 24.83 1.334 25 1.253 25.5 1.125 26 1.114 27 0.876 28 0.744 29 0.759 30 0.798 31 0.582 32 0.573 33 0.454 34 0.432 35 0.389 36 0.425 In another arm of the study, a 25 megll-lr Duragesic'~' transdermal fentanyl patch was applied to the slein of the sLibjects at time 0 (t=0). A heating patch capable of heating the skin to about 40-42 C for about 240 minutes was placed on top of the DLUagesic'~ patch also at t = 0. At t = 8 hours, the heating patch was removed, but the Duragesic~" patch remained. At t = 12 hours, a heating patch capable of heating the shin to the temperature range of about 40-42 C for about 15 minutes was placed on top of the Dluagesic"" patch. The heating patch's heating area covered only about 50 percent of the drug delivery area of the Duragesic'~ patch. This heating patch was removed at t = 14 hours while the Duragesic'''-' patch remained. Another identical frFteen minute heating patch was placed on the Duragesic patch at t = 16 hours, and covered the half of the Dwageic"" patch area that was not covered by the heating patch applied at t = 12 hours. Both the heating and Dtuagesic~' patches were removed at t = 20 hollrS. Meal serum feltalyt concentrations of the five subjects at predetel'111111ed tlllle pO111tS Were 111eaSL1reC1 by a Tad10111ll11L111oaSSay, alld are ShOWIl 111 Table 2. The fotlr-hoLll heating patch used at the begllllllg of the Dnragesic" patch 5 application was for the purpose of shortening the time to reach therapeutic serum feltanyl concentrations.
Table 2 Title (hour) Avera a 0 0.0196 10 1 0.0640 2 0.3473 3 0.4402 4 0.4199 5 0.3915 15 G 0.4603 7 0.4219 8 0.3797 9 0.3727 10 0.3889 20 11 0.4196 12 0.4933 12.083 O.G493 12.17 O.G322 12.25 0.6524 25 12.33 O.G738 12.5 O.G577 12.67 O.G121 12.83 0.5894 13 0.5777 30 13.5 0.5466 14 0.5588 15 0.4796 1 G 0.4844 16.083 0.5837 35 16.17 O.G019 16.25 O.G515 16.33 O.G415 16.5 0.6139 16.67 0.5648 16.83 0.5435 S I 7 0.5281 I7.5 0.5919 18 0.5280 19 0.5424 20 0.5241 2 I 0.4328 22 0.4344 23 0.3969 24 0.3880 The heating patches used in both arms of the study generated heat by the 1 S oxidation of iron powder. The heating patches had a closed chamber defined by an air-impermeable bottom, air impermeable sidewall and all air-impermeable cover.
The edges of the bottom and cover were joined to the air impermeable sidewall and form a closed chamber within which a heat-generating medilun resided. The cover had predetermined number of holes with predetermined size to allow oxygen in ambient air into the heat-generating medium at pre-determined rates. The heating patches were stored in air-tight pouches. When the heating patches were removed from the pouches, oxygen in ambient air flowed into the heat-generating medium via the holes on the cover to start an exothermic reaction (oxidation reaction of iron powder). The number and size of the holes on the cover determined the rate at which oxygen entered tile heat generating medilun, and hence the heating temperature. The heat gelleTat111g 111ed111111 C0111pOS1t1011 had the following approximate weight portions:
Activated carbon: 15.63% (i.e. IIDC grade, Norit Americas, Inc.) Fine iron powder: 50.04% (i.e. - 325 mesh) Wood powder:9.38% (i.e. <20 mesh) Sodium chloride: 6.25%
Water: 18.7%
The one-hour heating patch used in the first arm of the study had a heating area of about 40 C111~, and contained about 8.6 g of the heat generating medilun. The 15 minute heating patch used in the second arm of the study had a heating area of about 4.7 cnl'-, and contained about 0.62 g of the heat generating medium. The covers of the one-hour and the fifteen-minute heating patches had 36 and 9 holes (diameter = 1/16"), respectively. Those holes were covered by a lnicroporous membrane (CoTran 9711, 3M). The four-hour heating patch had a heating area of abOLlt 40C111~ alld WdS SL1n11aT t0 that Of the Olle-10111 lleatlllg lJatCh, eXCept that It had 12.3 g Of the heat-gelleratlllg 111ed1L1111. The Olle 110L11 alld fOLIr 110LIr heatlllg patCheS
covered more than the l Ocm2 drug delivery area of the Duragesic~ 25mg/h patch.
In the first arm, tile mean serum fentanyl concentrations increased over 60 percent within five minutes following the heating at t = 24 hours, and remained close to that level for about one-and-a-half hours before starting to decrease gradually, as the heating patch stopped generating heat and the skin temperature began to decrease gradually at about t = 25 hours. In the second arm, the mean serum fentallyl COIICelltrat1011S 111CreaSed 20-30 perCellt Wlthlll flVe lnlIlLLteS fOllOWlIlg tile heatlllg at t = 12 horns and at t = 16 hours, and remained close to that level for about one-half hour before starting to decrease gradually, as the heating patch stopped heating at about t = 12.3 hOLIrS alld at t = 16.3 lIOLUS, respectively, and the skill temperatLUe started to decrease.
These results suggest the following: (1) heating the skin after applying the transdermal fentanyl patch for certain period or tinge can rapidly release the drug in tile depot into the systenlic circulation; (2) a longer heating duration can maintain the elevated serum fentanyl levels for longer time; and (3) heating a fraction of the fentanyl transdermal patch (and hence a fraction of the depot) releases a fraction of the depot. In this case, heating approximately 50 percent of the depot (second arln) resulted in an increase in serlun fentanyl concentrations that was approximately one-half of that obtained by heating 100 percent of the depot (first arm).
It should be noted that in the second arm of the study, applying heat at the beginning of the Duragesic'~" patch application did not cause a rapid increase in serum fentanyl levels for some time. But applying heat after some time of un-heated transdermal application of the DLUagesic"' patch caused very rapid increase in serLUn fentanyl levels, as observed in both arms of the study. This supports the theory that the rapid increase was caused by release of the drug from depot, which tales solve time to build. It should also be pointed out that t = 5 minutes was the first data point at which drug rerun l concentrations were measured after heating was applied.
It is conceivable that the serum fentallyl concentrations could have increased significantly before the 5 minute point.
In both arms of the study, the speeds of increase in serum fentanyl concentrations when the heat was applied after the establishment of the depot were so Tapld that they app101Ch the speed produced by 111traVellOLlS 111JeCt1011, alld 111L1Ch faster than any other delivery methods, mcludmg oral 111L1COSal absorption, 111tra111Ll5Clllal 111~eCt1011, SLIbCL1ta11e0L15 111JeCtlOll, alld Oral ad1111111Strat1011.
These f111d111gS are S1g111f1Callt. Transdermal drug delivery has never been used to deliver any drug for any treatment therapy that requires rapid onset of drug S effect, and has never been used in situations that reduire a rapid increase in blood drug levels on demand. The present invention makes it possible to use transdernlal drug delivery ill these and other advantageous ways.
Many heating methods may be used to produce the controlled heat for releasing the drug from the depot, including, but not limited to, electrical heating, heat produced by phase transition, other exothermic chemical reactions, and heat produced by infrared radiation.
The present invention lay be embodied in other specific forms without departing from its spirit or essential characteristics. The described embodiments are to be considered in all respects only as illustrative and not restrictive. The scope of 1 S the invention is, therefore, indicated by the appended claims, rather than by the foregoing description. All changes which come within the meaning and range of equivalency of the claims are to be embraced within their scope.
What is claimed is:

JS

Claims (31)

1. A method of delivering a drug into a user's systemic circulation, comprising:
establishing a drug depot in tissues under the user's skin surface by applying a transdermal drug delivery system on a user's skin;
allowing said transdermal drug delivery system to be applied on said skin area without heating for at least a predetermined depot accumulation time so that a drug depot is formed in tissues under the surface of said skin area; and placing a heating source proximate to said skin area when there is a need to increase said drug's concentrations in the user's systemic circulation.

2. The method of claim 1, wherein said drug is capable of providing a clinical benefit to a user if said drug's concentrations in said user's systemic circulation can be rapidly increased when a clinical need arises.

3. The method of claim 1, wherein said drug is capable of providing certain clinical benefit to a user when said drug's concentrations in said user's systemic circulation are maintained at pre-determined levels for all extended period of time, and is capable of providing added clinical benefit to said user if its concentrations in said user's systemic circulation can be rapidly increased on demand.

4. The method of claim 1, wherein said drug is an analgesic.

5. The method of claim 1, wherein said drug is fentanyl.

6. The method of claim 1, wherein said drug is sufentanil.

7. The method of claim 1, wherein said drug is a narcotic agent.

8. The method of claim 1, wherein said drug is an anti-migraine agent.

9. The method of claim 1, wherein said drug is nicotine.

10. The method of claim 1, wherein said drug is an anti-hypertension agent.

11. The method of claim 1, wherein said drug is an agent for the treatment of mental disorders.

12. The method of claim 1, wherein said drug is an agent for treating panic disorder.

13. The method of claim 1, wherein said drug is antiemetic agent.

14. The method of claim 1, wherein said drug is a hormone.

15. The method of claim 1, wherein said drug is agent for treating cardiac disorder.

16. The method of claim 1, wherein said pre-determined depot accumulation time is about 30 minutes.

17. The method of claim 1, wherein said pre-determined depot accumulation time is at least about one minute.

18. The method of claim 1, wherein said pre-determined depot accumulation time is longer than at least 60 minutes

19. The method of claim 1, wherein said pre-determined depot accumulation time is about 60 minutes.

20. The method of claim 1, wherein said heating source is capable of heating for a predetermined duration.

21. The method of claim 1, wherein said heating source is capable of heating for a predetermined duration between about 5 seconds and 60 minutes.

22. The method of claim 1, wherein said heating source is capable of heating for a predetermined duration between about 10 seconds to 30 minutes.

23. The method of claim 1, wherein said heating source is capable of heating said skin area to a predetermined temperature range for longer than 60 minutes.

24. The method of claim 1, wherein said heating source is capable of heating said skin area to a predetermined temperature range for a predetermined duration of between about 5 seconds to 60 minutes.

25. The method of claim 24, wherein said predetermined temperature range is between about 37-45 C.

26. The method of claim 24, wherein said predetermined temperature range is between about 39-43 C.

27. A method to provide baseline concentrations of an analgesic in a human being's systemic circulation and to rapidly deliver a bolus dose of said analgesic into said systemic circulation when said human being is suffering from an increased level of pain, comprising:
applying a transdermal analgesic delivery system onto a skin area of a human being to establish baseline concentrations of said analgesic in said human being's blood;
allowing said transdermal analgesic delivery system to be applied without locating for a time sufficient to allow the formation of an analgesic depot in tissues under the surface of said skin area of said human being; and placing a heating source proximate to said skin area when said human being suffers from increased level of pain.

28. A method of delivering a drug into the systemic circulation of a human being, comprising:
establishing a drug depot in tissues under the surface of a skin area by applying a transdermal drug delivery system on the skin area of a human being and heating said shin area to a first pre-determined temperature range;
allowing said transdermal drug delivery system to be applied while heating said skin area to said first temperature range for at least a predetermined minimum time period; and heating said skin area to a second temperature range, which is higher than said first temperature range, for a second pre-determined period of time.

29. A method to provide baseline concentrations of fentanyl in a human being's systemic circulation and to rapidly deliver a bolus dose of fentanyl into said systemic circulation when said human being is suffering from an increased level of pain, comprising:
applying a transdermal fentanyl delivery system onto a shin area of a human being to establish baseline concentrations of fentanyl in said human being's blood;
allowing said transdermal fentanyl delivery system to be applied without heating for a time sufficient to allow the formation of a fentanyl depot in tissues under the surface of said shin area of the said human being;
and placing a heating source proximate to said skin area when said human being suffers from increased level of pain.

30. A method to provide baseline concentrations of sufentanil in a human being's systemic circulation and to rapidly deliver a bolus dose of sufentanil into said systemic circulation when said human being is suffering from an increased level of pain, comprising:
applying a transdermal sufentanil delivery system onto a skin area of a human being to establish baseline concentrations of sufentanil in said human being's blood allowing said transdermal sufentanil delivery system to be applied without heating for a time sufficient to allow the formation of a sufentanil depot in tissues under the surface of said skin area of the said human being; and placing a heating source proximate to said skin area when said human being suffers from increased level of pain.

31. An apparatus for heating skin of a humor to release a depot of a drug located beneath the skin, the apparatus comprising:
a drug depot formed in tissues under at least a portion of a skin surface;
a transdermal drug delivery system coupled to the shin surface; and a heating source coupled to the skin surface.