CA2146010A1

CA2146010A1 - Ultrasonic transdermal drug delivery system

Info

Publication number: CA2146010A1
Application number: CA002146010A
Authority: CA
Inventors: Lev M. Lipkovker
Original assignee: Individual
Current assignee: Endodermic Medical Technologies Co
Priority date: 1992-10-14
Filing date: 1993-10-13
Publication date: 1994-04-28
Also published as: KR950703383A; US5421816A; WO1994008655A2; JPH08502424A; AU678781B2; US5617851A; WO1994008655A3; EP0684856A1; AU5359194A

Abstract

A transdermal drug delivery system that uses ultrasonic energy to release a stored drug and forcibly move the drug through the skin of an organism into the blood stream of the organism is disclosed. The transdermal drug delivery system includes a housing (81) having a cavity (67) for storing the drug to be de-livered. The cavity is defined by an assembly of ultra-sonic transducers (65) and is separated from the skin by a polymeric membrane (69). The ultrasonic trans-ducer assembly includes a flat, circular ultrasonic transducer (85) that defines the top of a truncated cone and a plurality of transducer segments (87a, 87b, 87c, 87d...) that define the walls of the cone. The resonant frequency of the planar transducer is lower than the resonant frequency of the transducer seg-ments. Located between the transducer assembly and the cavity is a drug-impermeable laminate (77) that also functions as a focusing lens for the transducers.
Control electronics (63) and a power source (61) are also stored in the housing. In operation, the planar, flat, circular transducer generates fixed frequency (5KHz-1MHz range) ultrasonic stimuli impulses for a predetermined period of time (10-20 seconds).
Between the stimuli pulse periods, the transducer segments receive variable frequency ultrasonic pumping pulses. The transducer segments create beams that impinge on the skin at an oblique angle and create a pulsating wave. A skin temperature sensor is in-cluded to prevent the ultrasonic signals from overheating the skin. The system may also include an infrared (IR) or laser transdu-cer for enhancing the operation of the drug delivery system by heating the skin and creating additional ultrasonic waves. Both open loop and closed loop (feedback) versions are provided. The closed loop version includes a sensor for sensing drug delivery effectiveness and using the resulting information to control the rate of drug delivery. The sensor uses ultrasonic energy to remove fluid from the skin for analysis.

Description

WO 94/08655 ~ 1 4 6 0 1 ~ PCI/US93/09798 .. . ..

,, .

ULTR~SONIC TRANSDERMAL DRUG DELIVERY SYSTEM
Technical Area This invention relates to drug delivery systems and, more particularly, to tr~n.sd~rm~l drug delivery systems.
Backglound ofthe Invention A vast majority of pharm~ceuticAl agents (e.g., drugs) in clinical use today aregiven either orally or by injection. While injection provides a fast and direct route to the blood stream, injection often causes pain and anxiety and, occasionally, co~ AI;on. Further, injection does not provide for a conslanl or s..~t~ined 10 delivery of drugs. Finally, when a drug is injected by a syringe, the entire dose is placed in the body and cannot be withdrawn should an adverse reaction occur.
Oral ~.I...;I);~l.~ion ~ub;e t~ the pharm~ceutiç~l agent to hepatic metabolism.
~pAtic metabolism :~Ub~l~..l;Ally degrades the effectiveness of ph~rm~ce~lticAl agents, up to 90 percent in some cases. More specifically, the first organ that receives an 15 ;"le~l;e absorbed drug taken orally is the liver. The liver detoxifies molecules that are foreign to the body. Most drug molecules are considered by the liver to be foreign. As a result, a .~i~nifi~nt quantity of a particular metlicine may never reach the rest of the body due to the liver's deto~i~illg the drug's molecules. The degree of detoxification varies from person to person and may account for adverse reactions in 20 some people and not others by infl~1~ncing the amount of a drug that is left for absorption by the rem~in-l~r of the body. More importantly, the decrease in effectiveness due to hepatic metabolism by the liver leads to increases in the amount of the agent being ~dmini~tered, which leads to undesirable side effects and gastric intolerance. That is, the amount taken by mouth is usually more than the body needs, Wo 94/086~ PCr/US93/09798 6 ~ 2-often res..lting in adverse side effects. Further, because dosage requilcl"e,lLs often vary from individual to individual, it is difficult to tailor individual dosages using the pred~finecl amounts dt;le,l"ined by m~mlf~ctllrers of orally a.l..,;..;~ .cd drugs.
Finally, as with a syringe injection, when a drug is taken by mouth and absorbed, the entire dose is in the body. If an adverse reaction takes place it is difficult to remove the drug to stop the reaction. Nevertheless, oral ~lminictration preselllly is the most plerellcd way of giving pharm~ce ~tic~l agents due to the ease of ~rlminictration and avoidance of the need for invasive vascular access, as required by injections.
The adult skin structure can be broken into three layers. The stratum corneum, which is actually part of the epidermal layer, is the first layer of skin defense against the exterior en~hol""~ L. The stratum COIllculll iS capable of absorbingsuperficial trauma while still . . .~inl s ;- ;- g adequate protection against loss of water and ingress of micro or~ni.cm.c and other substances. The stratum corneum layer is 15-20 cells thick. In many areas of the human body, the stratum corneum layer is very thin, often below several microns. The intercellular space of the stratum corneum is appl,Jx;.~.A~ely 30percent by volume. The intercellular space is filled by lipidcomposition, which is ideally suited to form a transport barrier. The inner layer of the stratum corneum is in contact with granular cells (very moist) and the outer layer is in contact with a dry en~ on",e,ll. Thus a substantial water content gradient exists across the stratum corneum.
The second layer is the epidermal layer, which consists of epidermal cells bound together by tight junctions into a viscoelastic matrix. Between the junctions lie heavily convoluted lipid-filled extracelllli~r spaces Co~ g a host of cellular Iymphocytic factors, el~y~es and other anti-microbial agents. The epidermal layer is the body's prime protective barrier. Its basal cells provide metabolic and additional water barrier functions. The epidermal barrier provides a formidable defense structure even in the absence ofthe stratum collleulll, especially to water-soluble agents that do not possess a lipid extMcell~ r phase. Enzyme activity may be controlled or rendered inactive by employing chemical, enzymic or heat lle~
The innermost layer is the dermal layer. The dermal layer consists of basal germ cells positioned upon a basal ",~",b,~l1e with known permeability of applox;...~lely 40 kilodaltons and below. Unless specific excitation factors arepresent, large molecular weight materials cannot cross the basal r"en~l~ne.
Below the basal membrane are the majority of the capillary loops that 35 collll lise the terminal states of the microcirculation tree (i.e., the blood vessels) of the human O~g~ lllc. The capillary loops are the target of current passive transdermal WO 94/0865~ Pcr/US93/09798 ~3~ ~1~6~10 drug delivery systems (desc,il)ed below). Because a very large number of capillary loops are present, large surface areas are available for the systemic ~xcllAI~ge of fluids.
Pentl~Lillg all three skin layers are l~ulllcrws hair follicles in various growth states--telogen, anagen and c~t~g~n The hair follicle growth stage co,~elales with the 5 depth of the follicle, late-anagen follicles being the deepest and closest to the most heavily developed capillary blood supply. The centerline of the hair follicle ispositioned less than five microns from the encircling capillary blood supply. The stratum CGIIlculll follows the invagination ofthe follicles at the skin level, tel..,;..~l;..g app,u~il"a~ely half-way down the follicles. The sensory nerve nclwolk that surrounds the follicles responds to any physical P"~cit~tiQn on the hair shaft. Thus, a highly sensitive responsive system is present in the hair follicle regions of the skin. Follicle density on skin surfaces varies depending upon location from 100/cm2 to 900/cm2.Other than by syringe, there are two methods by which drugs can be delivered through the skin--passive and active diffusion. Passive diffusion involves placing a concellLlaLion of drug in a reservoir on the surface of the skin and allowing the drug to passively diffuse through the skin into the body. Since there are natural barriers in the skin which keep almost all molecules from entering the body through the skin, only a few molecules from the reservoir of the drug pass through the skin and are absoll,ed first by the blood stream and then by the body.
Due to natural skin barriers, few pharm~ceutic~lc have been succes~fillly diffi.~ed through the skin and into the subdermal microcirculation regions of the human body, i.e., the underlying blood vessels. The most succçc~fi.l drugs to berliffi~sed through the skin are clonidine, nitroglyce~hl, scopolamine, and estradiol.
Because these drugs are effective at very low plasma concentrations, they can beapplied using small passive skin patches. A 10 ng/ml plasma concentration has been allJiLlalily adopted by the industry as a mean figure above which passive transdermal drug delivery is not effective. This concentration level çl;...;..~es the possibility of passive transdermal delivery of such highly succç~fi.l agents as aspirin, which ~e.~uhes a concentration of 150,000 ng/ml to be effective. Currently, ~cet~minophen, cimeti~ine~ and indometh~r.in cannot be delivered by passive transdermal drug delivery systems.
In addition to concentration level, molecular size is an issue with the passive 0 diffusion of drug absorption. The skin's natural barriers limit or prevent absorption of metlis~mPnt~ that are composed of large molecules. Thelt;ro,e, with passive diffusion, if a me~ ine is to be effective in the body, it must work well at very low dosages and be of a molecular size that the skin will allow to enter the body. While çl-Pmic~l ~ 2 1 ~

en'nancers ha~e been investi_ated as solutions to allow for ~reater dosage absorption throu~h the skin by passive diffusion, none have ~-orked w-ell enough to pass the Federal Dru~ Administration (FDA) requirements and/or be successful cornrnercially.
A potentially more viable way for drugs to transcend the skin's barriers is to 5 use an active ener~ source that "pushes" or "pulls" drug molecules through the s~cin and, at the same time controls, the rate of delivery. An energy driven system will allow a greater quantity of the medicine to be delivered in a shorter or variable time frame. Potentially an energy driven system will perrnit larger molecular weight drugs to transcend the barriers of the skin in a short time period.
Two types of active transdermal drug delivery have been proposed. The first, which is called iontophoresis, is a system that uses a direct current of electricity to charge drugs Electrically charged drugs are driven into the skin. To date, there is only one medicine, Lidocaine, used in such a device. Lidocaine is a drug used for local anesthesia. Extensive investigation is presently being conducted by the pharmaceutical industry on the use of iontophoresis for drug delivery. While this method of delivery is slow, it probably will increase the number of medic~ments used for transdermal drug delivery. Furthermore, delivery is better controlled, when compared to passive diffusion.
The other method of active drug delivery uses ultrasound as the energy source. For a variety of reasons, the results of drug delivery by this method have traditionally been inconsistent. Results of previous experiments have been difficult to repeat. More specifically, it has been known for several decades that ultrasoundradiation pressure applied to drug molecules in contact with skin can increase transdermal penetration rate. The mech~nism of action has been unclear with someresearchers citing boundary stirring effect, some citing microchannel production via cavitation and others citing direct radiation pressure onto the dru~, pumping it into the skin.
Some researchers have conducted studies of the interaction of ultrasound and specific drug formulations. Some researchers have applied an ultrasonic field to drug molecules themselves, rather than to the skin and associated structures. Other researchers have shown that ultrasound is effective. in shearin_ polymeric compositions of drugs contained in transdermal patches. The intent of these researchers was to modulate the release rate of a drug from a polymeric matrix.
Finally, some researchers have applied ultrasound to the skin itsel The following U.S. patents describe some of the results of the foregoing research: 4,657,543;
4,767,402; 4,780,212; 4,787,888; 4,821,740; 4,948,587; 4,953,565; and 5,007,438.

~ 214601~

Also see Patent Cooperation Treaty (PCT) application ~o. 91/1277~ and German Patent ~i-o. 27 56 460. ~rost, if not all, of the foregoing patents show a lack or no control of application direction, little or no control of frequenc- and power le~els, no control of duty cycle and ignorance of a host of other controlling factors.
Various criteria for drug delivery enhancer design have been established. They are: (i) the enhancer should elicit no pharmacological response; (ii) the enhancer should be specific in its action; (iii) the enhancer should act immediately with a predictable duration and its action should be reversible; (iv) the enhancer should be chemically and physically stable, and be compatible with all of the components of the drug formulation; (v) the enhancer should be odorless, colorless, and tasteless; and (vi) the enhancer should be nontoxic, nonallergenic, and a nonirritant. These criteria can be conveniently applied with slight modification to all transdermal drug delivery enh~ncPment approaches, both chemical and nonchernical. No single drug delivery enh~ncement approach available today meets all of the foregoing criteria. Or anic enhancers produce a characteristic foul taste in the mouth shortly after skin application. Several alcohol or solvent-based enhancers cause severe skin irritation and can lead to an e~7~m~tous reaction. Device-based enhancers such as iontophoretic titrators come closer to satisfying all of the criteria, but fall short in broad spectrum general applicability, specificity of action, reversibility of action and nonirritabilit,v.
As will be better understood from the following discussion, the present invention is directed to providing an active transdermal drug delivery system that enhances the diffusion of large molecular wei~ht substances (e.g., large molecular weight drugs) between an external device-based reservoir and the subdermal microcirculation tree of an organism, such as the hurnan body. This result is achieved by using ultrasonic energy to excite the skin system of the organism in a way that allows multifrequency, multidirectional subsurface waves to diffuse large molecular weight substances through the skin in an efficient and controllable manner.
Summary of the Invention In accordance with this invention, an ultrasonic transdermal drug delivery system is provided. ~lore specifically, a transdermal drug delivery system formed in accordance with this invention in~ es ultrasonic transducers that create ultrasonic waves. The ultrasonic waves release a stored pharrn~ce~ltical a ent (e.g., a drug) and forcibly move the agent through the skin of an organism, such as the human body,into the blood vessels underlying the tr~n~ucers. The transdermal drug delivery system incl~ldes a housing having a reservoir for storing the drug to be released. The A~tEN~D S~IET

WO 94/0865~ PCr/US93/09798 -6- 21~6Dll~

reservoir is separated from the skin by an ultrasonically controllable polymeric."G-"I"~ne. ~It~ l;vc;ly, the ultrasonically controllable polyrneric me",b,~1e can store the drug to be released. An adhesive ~tt~f.hçs the delivery system to the skin.
The cavity is defined by an assembly of ultrasonic tran.qd~lcPrs. The ultrasonictr~nqdllcPr assembly incllldes a stimuli tr~nqducPr for creating an ultrasonic stimuli wave in the skin of an o,~;alfi~,n and at least one pumping (drug delivery) tr~nqd~lcer for moving the drug through the polymeric ~c~b~ne and the skin into the blood vessels of the or~ani~",. Control electronics, pi~re,~bly stored in the housing, control the operation ofthe stimuli tr~n.qd-lcer and the at least one pumping tr~nqducP~r.
In accordance with other aspects of this invention, the tr~nqd~lc~r assembly hasthe shape of a trl.nc~ted cone.
In acco~-lal-ce with further aspects of this invention, the stimuli tr~n.qdllcçr is located in the top of the cone and the at least one pumping tr~nqd~lcer is located in the wall of the cone.
In acco~dal-ce with additional aspects of this invention, the top of the cone isdefined by the stimuli tr~nqd~lcçr~ which has a flat, circular shape, and the walls of the cone are defined by a plurality of tr~n.qdllcçr se~ ; each of which forms a pumping tr~nqd~lcer. Preferably, the resol1a,l~ frequency of the flat, circular tranqdllcer is less than the reson~nt frequency of the tr~nqdllcP,r segmP.ntq In acco,d~-ce with yet other aspects of this invention, located between the tr~nqdllcPrs and the reservoir is a drug-impermeable l~min~te that also functions as a focusing lens for the tr~n~d~lcers.
In accoidance with still other aspects of this invention, the control electronics apply ultrasonic stimuli pulses to the skin by energizing the stimuli tr~nqducçr at a first frequency, preferably Iying in the 5 KHz-1MHz range for a predetelll~ined period of time (10-20 seconds). Between the stimuli pulse periods, the control electronicsapply variable frequency ultrasonic pumping pulses to the skin by ene,~ i,-g thel,ulllph~g tr~n.qdllcPr se~,nel"s. Preferably, the frequency of the variable frequency ultrasonic ~,u"",i"g pulses lie in the 50MHz-300MHz range.
In accordance with yet further aspects of this invention, a skin temperature sensor is positioned in the housing to sense the te"~pe,~ re of the skin leceiving the drug. The temperature h~"a~ion is used by the control electronics to prevent theultrasonic waves from overheating the skin.
In acco~-lance with still further aspects of this invention, the drug delivery system also inchldP,s one or more additional stimuli tr~n.qdllcers, such as infrared (~) or laser emitters, in the housing. The additional stimuli tr~nqdllcP.rs emit stimuli pulses WO 94/0865~ 2 1 4 6 0 1 o Pcr/US93/09798 at selccled intervals during the variable frequency ultrasonic pumping portion of the operational cycle. The additional stimuli pulses enh~nce the operation of the drug delivery system by heating the skin and/or creating additional ultrasonic waves in the shn.
In acco~dance with yet still further aspects of this invention, the variable frequency, ultrasonic ~JU~ J;llg pulses are applied to opposed tr~ncd~lc~r seg...~
In accordance with yet still other aspects of this invention, the variable frequency, ultrasonic ~ulllp;l~ pulses are applied to alternate pairs of tr~ncd~lc~r seg...~ in a rotational manner.
In acco-dance with yet still additional aspects of this invention, the drug delivery system incl~ldes a sensor for sensing drug delivery effectiveness and using the res~llt~nt i,~""alion to control the rate of drug delivery.
In acco~dance with still yet other aspects of this invention, the sensor, which may function as a stand-alone device, in~ ldes a cavity, an ultrasonic tr~ncd~lcçr, a focusing lens, and a substance sensing tr~ncdllcer located in the cavity, plus energizing electronics for the ultrasonic tr~ncdllcer and a test data processor for evalu~ting the output of the substance sensing tr~ncdllcer. The cavity is juxtaposed against the skin and the ultrasonic tr~ncdllcer and focusing lens are sized evenly and ene-gi~ed to cause body fluid to be drawn into the cavity.
In ~.. ~ly, the invention provides a new and improved transdermal drug delivery system. The transdermal drug delivery system is an active system that uses ultrasonic waves to çnh~nce drug delivery. Relatively low frequency ultrasonic pulses excite or stimlll~te the nervous system of an Ol~;~S"I, such as the human body, similarly to the way the nervous system is excited by skin trauma, such as heat or a 25 blow to the shn. As is well understood by those shlled in the medical arts, skin trauma stimlll~tion causes both the dermal-epidermal junction (i.e., the basal) ",e",b,~ne and the capillary endothelial joints to open so that fluids can be moved to the area of the trauma. The invention takes advantage of these opellings to pumpdrugs from a reservoir through the shn into the capillary loops which form the ends 30 of the microcirculation tree of the organism. Pumping is accomplished by applying variable frequency ultrasonic ~uu~ Jing pulses to the skin by ene-~i,ing the pumping tr~n~ducer se~ e b~lweell stim~ tion pulses. Because the tr~n~d~lcer seg~ s that receive the variable frequency ultrasonic ~wll~;llg pulses form the walls of a trllnc~ted cone, the ultrasonic waves produced by the tr~n.~dllcers impinge on the 35 underlying skin at an oblique angle. The ultrasonic waves create a pumping action that first creates large openings on the surface of the skin for the initial receipt of wo 94/086s2i ~6 ~ ~ PCI/US93/09798 drugs in a first layer of skin cells. The received drugs are pumped through the skin as the wave alternately moves the skin cells away from and then toward one another in an inward direction. The drug is also forced through the aperture surrounding the hair follicles and through the sweat glands of the 01,~3alU~ln.
In ecs~nc~, ultrasound is used by this invention to open ~.h~nn~ in the skin surface and then literally pushes a merliç~m~nt which has been dissolved in a fluid through the r.h~nn~ls between the cells in the second layer of skin, the epidermis. The ultrasound also opens the cells in the deepest layer of the skin, the dermis. The dermis is a layer of cells one cell thick which controls the immllnology of the skin and produces cells which migrate to the top surface of the skin to renew the stratumcorneum. Ordinarily, this layer is closed to permeation except for certain stiml~l~tions~ such as trauma, local infection or ~hçmic~l irritation, for example through an insect bite. The ultrasound opens the basal layer of the dermis. In addition to the skin, the ultrasound pumps medicants through the çh~nn~l~
sullo~ ding hair follicles and sweat gland pores. Large quantities of many drugs(in~l~lrling those with large molecules) can be ~lmini~tlo.red through the skin using the present invention.
Clusters or loops of blood vessel capillaries located directly beneath the skin basal layer and surround the hair follicles and sweat gland por,es receive the 20 a~h;~ eled medicant. Once the merlic~nt enters the capillaries, it is absorbed into the systemic or blood circulation of the body and delivered to where it is needed.
In some embodiments of the invention, additional stimlllation is provided by IR or laser emiKers during the pumping portion of the cycle. Excess heating of the skin is prevented by terrnin~ting stim~ tion of skin when heating eYceed~ a predetermined level. Further, feedb~c~ control of drug delivery is provided in some embodiments of the invention. A novel sensor determines the m~gnitl~de of a substance conlained in the plasma and inlel~LiLial fluid of the body that relates to the effort of the drug being delivered. The sensor inc.l~ldes an ultrasonic tran~dllcPr and a focusing lens constructed and oriented in a way that withdraws fluid into a cavity that houses a substance sensing tran~d~lcer. The sensor can be used as a stand-alone device separate and apart from a drug delivery system.
Brief Description of the Drawings The foregoing aspects and many of the ~ttend~nt advantages of this invention will become more readily appleciaLed as the same becoll-es better understood by rere.c;~ce to the following detailed description, when taken in conjunction with the acco.llpallyillg drawings, wherein:

W O 94/0865~ PC~r/US93/09798 ~ 9 21~6~10 FIGU R E 1 is a three-dimensional view of a section of the skin of the human body;
FIGU RE 2 is a seqllçnce of diagrams illustrating the growth cycle of a hair follicle;
FIG U RE 3 is a series of diagrams illustrating the typical angle of insertion of hair follicles in di~renl regions of the human body;
FIGllR E 4 is a flow diagram illustrating the various paths a drug can take through the skin into the cells of the human body;
FIGllRE 5 is a block diagram of an ultrasonic transdermal drug delivery 10 system formed in accordance with the invention;
FIGIJRE 6is a cross-sectional, pictorial view ofthe structural ~l~ngelllenl of transdermal drug delivery system illustrated in FIG U RE 3;
FIG U RE 7 is a pictorial view of the ultrasonic trancd~lcer assembly portion ofthe transdermal drug delivery system illustrated in FIG U RE 6;
FIG U RE 8 is a plan view of the tr~n.cduc~r 5eg~"~1 portion of the ultrasonic tr~n.cd~lc~r assembly illustrated in FIG URE 5;
FIG U RE,9 is a block diagram of the electronic control portion of the ultrasonic transdermal drug delivery system illustrated in FIGU RES 5 and 6;
FIG U RE 10 is a timing diagram illustrating the drug delivery cycle of the ultrasonic transdermal drug delivery system illustrated in FIGU RES 5 and 6;
FIGU RE 11 is a cross-sectional view of the ultrasonic tr~nc~ cer assembly illustrated in FIG U RE 7 and the drug reservoir enclosed by the assembly;
FIG U RE 12is a plan view showing the Illovelllenl of waves across the surface of the skin produced by the ultrasonic tr~ncd-lcer assembly illustrated in FIG U RE 11;
FIG U RE 13 is a pictorial cell diagram illustrating the effect of applying an ultrasonic tr~nedllcpr signal perpendicularly to the skin;
FIG U RE 14 is a pictorial cell diagram illustrating the effect of applying an ultrasonic tr~ncduc~r signal to the skin at an oblique angle;
FIG U RE 15 is a cross-sectional, pictorial view of the structural arr~ng~mPnt of an alternative embodiment of an ultrasonic transdermal drug delivery system formed in accordallce with the invention;
FIG U RE 16 is a block diagram of the electronic control portion of the ultrasonic transdermal drug delivery system illustrated in FIG U RE 15;
FIG U R E 17 is a timing diagram illustrating the drug delivery cycle of the ultrasonic transdermal drug delivery system illustrated in FIG U R E 15;

W O 94/086~5 PC~r/US93/09798 214fi~l. -10- --FIGU RE 18 is a block diagram of another alternative embodiment of an ultrasonic transdermal drug delivery system formed in accordance with the invention;
FIG U RE 19 is a cross-sectional, pictorial view of the structural a, ofthe embodiment ofthe invention illustrated in FIGllRE 18;
SFIG U RE 20 is a block diagram of the electronic control portion of the ultrasonic transdermal drug delivery system illustrated in FIGU RES 18 and 19;
FIG U RE 21 is a timing diagram illusLl~ling the drug delivery cycle of the embodiment ofthe invention illustrated in FIG U RES 18 and 19;
FIG U RE 22 is a partially pictorial, partially block diagram of a substance 10concentration sensor formed in accoldance with this invention;
FIG U RE 23 is a partially pictorial, partially sçhem~tic diagram of a substancesensing tr~n~d~lc~r suitable for use in the substance conce"L,~Lion sensor illustrated in FIGIJRUE 23.
FIG U RE 24 is a pictorial diagram of an alternative substance sensing 15tran~dllcer suitable for use in the substance concentration sensor illustrated in FIGIJRUE 22.
FIG U RE 25 is a cross-sectional, pictorial view of the structural arr~ng~m~nt of a further alternative embodiment of an ultrasonic tr~n~d--c~r drug delivery system formed in accordance with the invention; .-20FIG U RE 26 is a block diagram of the electronic control portion of the ultrasonic transdermal drug delivery system illustrated in FIG~ R E 25;
FIG U RE 27 is a timing diagram illustrating the drug delivery cycle of the embodiment of the invention illustrated in FIGVRE 25;
FIGU R E 28 is a pictorial, exploded view illustrating a replaceable drug 25canister portion of the embo~im~nts of the invention shown separated from the housing;
FIG U RE 29 is a master flow diagram illusLl~ling the operation of th microprocessor of the embodiment of the invention illustrated in FIG U R E 26;
FIG U R E 30 is a flow diagram of the initi~li7~tit)n and det~rmine drug 30concentration portions of the master flow diagram illustrated in FIGURE 29.
FIG U RE 31 is a flow diagram of the determine initial skin temperature and apply stimuli pulse portions of the master flow diagram illustrated in FIGU RE 30; and FIG U RE 32 is a flow diagram of the delivery drug portion of the master flow diagram illustrated in FIG U RE 29.

WO 94/0865~ PCr/US93/09798 -11- 2146~1~

Detailed Description of the Plerelled Embo~ e As will be better understood from the following description, the present invention provides an act*e tr~nederm~l drug delivery system that uses ultrasonic energy to both excite the skin in a manner that "fools" the nervous system of anS organism and pump a pharm~ce ~tical agent (e.g., a drug) from a reservoir through the skin to the capillary loops just below the skin surface. Prior to describing theplesel,lly p~ lled embo-lim~nte of the invention, in order for the invention to be more easily understood, a brief description of the skin is set forth.
As shown in FIGURE 1, the skin incl~ldes two primary layers--the epidermis31 and the dermis33. Located beneath the dermis33 is sub.;ulalleous tissue 35 followed by deep fascia 37 and, then, muscle 39. F.xtçntling through the epidermis31 and the dermis33 are hair follicles41. As shown in FIGURE2, depending on their age, hair follicles te".linate in a dermis layer 33 or in the epidermis or subcutaneous tissue near the dermis layer. As shown in FIGURE 3, the angle of15 hair follicles varies b~lween 30 and 60 depending upon the location of a follicle.
Sweat pores43 (FIGURE 1) extend through the dermis and epidermis layers 31 and 33, te, ...;~ g at sweat glands 45 located in the subc~lt~neolle tissue35. F.~t~n~ling through the muscle39, the fascia37 and the subc~lt~neous tissue 35 are b,~nches 47a, 47b, 47c . . . and 49a, 49b, and 49c . . . of the venous and 20 arterial ~y~lc~ s of the o-gan;sThe veins and artery b.~nches terminate at capillary loops 51, which comprise the terminal stages of the microcirculation tree of theorganism. Capillary loops are located at the dermal-epidermal interface, the bulbous regions of the hair follicles, ~dj~c~nt the sweat glands 45, and in a variety of other areas.
The present invention is directed to providing an active transdermal drug delivery system that uses ultrasonic energy to ~nh~nce both the movement of drugs and the type of drugs deliverable from a drug rese,~/oi, positioned on the surface of the skin to the capillary loops 51 as well as directly to body cells. As shown in FIGURE 4, various paths exist for drugs to move from the surface of the skin of an 30 or~,allis- such as the human body to the cells of the ol~ ani~lll. One path is through the hair follicles and sweat glands to the capillary loops. Another path to the capillary loops is through the extr~cçll~ r fluid that surrounds body cells. A third path is through the cells, namely, through inter- and intra-cellular çh~nn~le of cell integral ploteins. Drugs entering the capillary loops travel to body cells through the blood circulatory and body capillary systems. In addition, extracç~ r fluid intra- andinter-cellular c.h~nn~le create direct paths to body cells.

WO 94/086~5 ~ 6 ~ 1~ PCI`/US93/09798 Except in cases of localized therapeutic L~ ...P ,I the p,i",a,y path for transdermally a.lmini~t~red drugs is through the follicles and glands. The next most si nific~nt path is the extr~ce~ r fluid path. The slowest or least effective path is Ihrougl~ the cells' inter- and intra-cellular çh~nnPI~ In cases of localized therapeutic 5 ~e~ the plilllaly path is the extr~cçl~ r path followed by the follicle and gland path and, then, the inter- and intra-cellular ç~nnPI~
As will be better understood from the following description, the invention provides an active transdermal drug delivery system that uses ultrasonic waves to first stim.ll~te the skin in a manner that opens (i) the dermal-epidermal junction or basal 10 "~t;"~l"ane and (ii) the capillary endothelial cell joints and, then, pumps a stored drug through the skin into the capillary loops. Stim~ tion is accomplished by applying relatively low frequency (SKHz-lMHz) ultrasonic stim~ tion pulses through the skin for a predt;le"l,illed period of time (10-20 seconds). Thereafter, higher, variable frequency (SOMHz-300MHz) pulses are applied obliquely to the skin. The obliquely 15 applied pulses create a pumping action that pumps drugs through the openings created by the stimuli pulses. Some embodimP.nts of the invention also use ultrasonic waves to wiLLdlavv body fluids into a cha..lbt;l to test for substance (drug) concellLr~ion. The results of the test are used to control drug delivery. Further, the subs~ ce concentration sensor can be used as a stand-alone device.
20FIGURE 5 is a block diagram illustrating a first embodiment of the invention.
The embodiment of the invention illustrated in FIGURE S incl~ldes: a power supply 61; electronic control circuit 63; an ultrasonic tr~n~ducPr assembly 65; a drug ;se,vuh 67; a polymeric ,llelllblane 69; and a te".pe.~L,lre sensor 71. The polymeric lllenll)lane is a polymeric membrane whose porosity is controllable by ultrasonic 25 waves, i.e., the polymeric leb.ane is an ultrasound controllable polymeric ..~ll.l~l~e.
Also illustrated in FIGURE5 is a section of skin73 conl~ g a single arteriole 74, and a single venule 75 joined by a plurality of capillary loops 76. The illusLlaLed ~angel"ent is to be taken as illu~LlaLi~e of the capillary loops and other 30 blood vessels illustrated in FIGURE 1 and described above, and not as limiting As shown, the telupelaLule sensor 71 and polymeric me",l~lane 69 are juxtaposed against the surface of the skin 73. The drug reservoir 67 is located on the opposite side of the polymeric membrane 69. The tr~n~d~1c~r assembly is located atop the reservoir, or more co" ~clly as shown in FIGURE 6 and described below, around 3 5 the reservoir. The power supply, under the control of the electronic control, supplies WO 94/08655 PCr/US93/09798 -l3 2~f~6010 power to the ultrasonic tritn.edl.cP.r assembly. The electronic control is more fully shown in FIGURE 9 and described below. =
FIGURE-6 is a section~l, pictorial view of the structured a"~ Pnt of the embodiment of the invention illustrated in FIGURE 5 and described above.
5 FIGURE 6 illustrates that the drug reservoir 67 has the shape of a tn.ncated cone and that the polymeric ~c...b.ane 69 is located along the large side of the trl-ncated cone.
The tri~neducPr assembly 65, which is illustrated in FIGURES 7 and 8 and described below, defines the wall and smaller side of the trunc~ted cone. Located bclwcen the tr~n.cducPr assembly 65 and the reservoir 67 is a drug-impermeable l~min~te 77. The 10 drug-impermeable l~min~tP~, in addition to being i~pc~ eable to the drug contained in the reservoir 67, also functions as a focusing lens for the tr~neducers that form the tr~neducP,r assembly 65. In this regard, p~crcl~bly the drug-impermeable lilmin~te is a Fresnel lens.
The temperature sensor 71 is positioned at the edge of the polymeric 15 me."b,ane. Surrounding the polymeric membrane 69 and the tclllpclal~lre sensor 71 is an adhesive film seal79. The power supply61, the electronic control63, the tr~neducer assembly 65 and the re."~ components are all mounted in a hat-shaped housing 81. The adhesive seal 79 and the mc...b.ane 69 enclose the open end of the hat-shaped housing 61. If desired, enC~psul~tion material 83 can be used to support 20 and Pnc~pslll~te the power supply61 and the electronic control circuit63, andprovide support for the tr~neducPr assembly 65. As illustrated in FIGURE 29 and described below, preferably, the drug-h~pc~...eable l~ Ale 77 and the polymeric ~..c...b.ane 69 form a sealed canister that is removably mounted in the hat-shaped housing 81.
As illustrated in FIGURES 7 and 8, the tr~neducP~r assembly 65 in~ des a fiat, circular tr~n.educPr 85 that defines the small side of the tr~.n~ted cone formed by the tr~ned~lcP,r assembly 65. A plurality of equally sized and equally spaced tri neducPr seP...~ ; 87a, 87b, 87c, 87d, . . . define the walls of the trl.nc~ted cone. Plcrclably, the number of equally sized and equally spaced tr;neducPr SC~ iS an even 30 number. While, as shown in FIGURE 8, which is a plan view of the tr~ned~lcPr seg....~ , the illustrated embodiment of the tran.educer assembly includes twelve (12) seg,.,e~ , this number should be taken as illustrative, and not limiting Preferably, the esol-;...l frequency ofthe flat, circular tr~neducer is lower than the lesonanl frequency ofthe tr~nedllcer segmPnte For example, the ~csonan~ frequency ofthe flat, circular 35 tr~neducer may be 1MHz while the reson~ frequency of the tr~neducer segmPnte 87a, 87b, 87c, 87d . . . may be 50MHz.

WO 94/08655 PCr/US93/09798 ~6~ 14- --FIGURE 9 is a functional block diagram of the elcc~ ~ic control 63. The block diagram inr.l~ldes: a clock 60, a pulse modulator 62, a manual titration ndillctm~nt control 64, a pulse generator 66 and an ultrasonic tr~nsdllc~r mllltip'~Yer 68. FIGURE 9 also inr,h~des the telnl)elal~lre sensor 71 and the 5 tr~n~dl~cer array 65. The clock 60 generates clock pulses at a rate at or above the highest frequency of the ~uulll~Jing pulses to be applied to the tr~n~ducer se~ 87a, 87b, 87c, 87d .... The pulse modulator 62 divides the clock pulses to a suitablelevel and produces control pulses that control the operation of the pulse gen~ or 66 so that pulses of suitable amplitude, length (duty cycle) and frequency are applied to 10 the multiplexer as the multiplexer couples the output ofthe pulse generator to the flat, circular tr~n~duc~rs 85 and the tran~dllc~r segm~.nt.e 87a, 87b, 87d . . . of the tr~n~dllc~r assembly in the sequence illustrated in FIGURE 10 and described below.
:For ease of illustration and because circuits for opel~hlg multiplexers are well known, the control system for the multiplexer is not shown in FIGURE 9.
The manual titration adj~lctm~.nt control is coupled to the pulse modulator and controls the enablement of the pulse modulator in a way that controls the amount of drug delivered from the reservoir to the organism in the manner described below.That is, the manual titration adjllstment control controls the ability of the pulse modulator to start a drug delivery cycle and cause the pulse generator to send a20 sequence of delivery control pulses to the multiplexer and, thus, to the tr~n.~duc~rs of the tr~n~ducer assembly 85.
The lelllpel~ule sensor is connecte-l to the pulse generator and prevents the pulse generator from applying a sequence of delivery pulses to the tran.~duc~r assembly if the temperature of the skin rises above a predetermined level. Thus, the 25 telll,oel~u,e sensor functions as a safety device.
FIGURE 10 is a timing diagram illustrating a drug delivery cycle or, more speçific~lly, the sequence of application of ultrasonic pulses to the flat, circular tran.~dllcer 85 and to the tr~nsduc~r segm~nt.c 87a, 87b, 87c, 87d .... As shown in FIGURE 10, first, ultrasonic stimuli pulses produced by the pulse genel~lor 66 are 30 applied to the flat, circular tran~ducer 85 by the multiplexer 68. Prerel ~bly, the stimuli pulse frequency lies in the 5KHz-1MHz range. The ultrasonic stimuli pulses are applied to the flat, circular tran~d~lcer 85 for a predeLelllllned period of time (O--tl) adequate to open the dermal-epidermal junction ll,e-ubl~l1e and the capillary endothelial cell joints. The predetermined period of time is dependent upon the power 35 co..~ d in the stimuli pulses and the time the dermal-epidermal junction melllblane and the capillary endothelial cell joints are to be opened, i.e., how long it takes for the WO 94/086~ PCr/US93/09798 ~ -15- 214601~

skin to return to normal. For example, the application of 1MHz pulses co~ ;ng about 0.2 watts for about 20 seconds will result in the dermal-epidermal junction and the endothelial cell joints lÇ.~IAill;llg open for about five min~tes The application of lM~ pulses co~ g 0.3 watts of power for 20 seconds will result in the dermal-5 epidermal junction melllbl~ne and the capillary endothelial cell joints ~ i"g openfor applo~illlalely 20 mimltec Applying the same frequency and power stim..l~tion pulses for a significantly longer period of time does not significantly extend the opening time. Conversely, increasing the power to 3 watts (which is unacceptablyhigh) at the same frequency (lMHz) for 20 seconds increases the openi,lg period to 10 over 30 min-lte~c.
Between ultrasonic stimuli pulse periods (i.e., during time t1--t2), higher, variable frequency ultrasonic pulllping pulses are applied to the ultrasonic tr~ncducçr sep..~ ; 87a, 87b, 87c, 87d .... The variable frequency, ultrasonic pulses, which are produced by the pulse generator 66, are applied to pairs of opposing tr~ncd~1c~r 15 seg...e~ in a rotating manner by the mulliplc~er 68. More specifically, a sequence of variable frequencies is first applied to one pair of opposed tr~ncd~lc~r seg...~ C; The pre~lled initial pumping pulse frequency is the l~sonalll frequency of the seg...~lc--SOMHz, for example. After the resonant frequency is applied for a period oftime, pulses at the second and then the third hall"onic (lOOMHz and 150MHz) are 20 sequçnti~lly applied for a predetermined period of time. If desired, pulse trains at the fourth, fifth and sixth harmonics can be seqllçnti~lly applied theleaner. After a harmonic sequence has been applied to one pair of opposed tr~ncd--cçr segm~nte, the cycle is repeated with the next ~djacçnt pair of opposed tr~ncd~lcer seg...~-ls in one direction or the other, i.e., clockwise or counterclockwise. That is, first a train of 25 pulses at the resonant or fi.~ ...e~-lal frequency is applied to the next pair of opposed tranccl~lcer seg...~.ls followed by trains of pulses at the first hallllonic, second harrnonic, etc. Pulses are contin..o..cly applied in this rotating manner until the transdermal drug delivery cycle ends. A r~sonalll or filn~1~m~nt~l frequency of around 50ME~ is important because the wave length of a 50MHz signal is appro~ ely 30 twice the ~ nce between body cells. As a result, the pumping energy moves thecells receiving the energy approX;...~i~ly one cell flict~nce. As will be betterunderstood from the following discussion, it is the pumping motion of the body cells that, in part, moves the drug stored in the restlvoil through various skin palhway~
into the bloodstream. After t2, the cycle is repe~ted, unless inhibited by the 35 tellll)elalule sensor.

W O 94/0865~ PC~r/US93/09798 2 ~ 4 6 ~ l a -16-FIGURES 11-13 illustrate further the operation of the invention. As noted above, initially, ultrasonic stimuli pulses are applied to the flat, circular ultrasonic tran~d~lcer 85 for a predeterrnined period of time. Since the flat, circular ultrasonic tr~ned~lcçr85 lies parallel to the skin, the stimuli pulses travel along axisa and 5 impinge on the skin pt;~ .licul~rly hitting first at point A. As noted above, the stimuli pulses open the dermal-epidermal junction l..e...b.~1e and the capillaryendothelial cell joints. After the stimuli pulses have been applied for an adequate period of time, the higher, variable frequency ultrasonic pulses are applied to pairs of opposed tr~n.cd~lc~r seg...~n~ in a rotating manner, as described above. Because the 10 tr~n.educçr segmt?nte are angled with respect to the surface of the skin, ultrasonic waves produced by the pairs of tr~n~d~lG~r segm~ntS 87a through 87g impinge on the skin at an oblique angle, depicted by lines b and c in FIGURE 11. Impingement isc~l.Leled at points B and C, le~e.,~ ely. The higher, variable frequency ultrasonic pulses create opposing moving waves in the skin. Ultrasonic waves i,llpil.ging at 15 point B create skin waves bl, b2, b3, b4 . . . that move toward point C and ultrasonic waves impinging at point C create skin waves c1, c2, c3, c4 . . . that move toward point B. The res~llting waves cause a pumping action that moves the drug located in the reservoir 67 first through the polymeric nwlllbl~i-e 69 and then through the skin into the blood vessels. The angle of inclin~tion of the tr~n~d~lcer se)~ in 20 coml)illalion with the focal length of the Fresnel lens formed by the drug-illlpt;llneable l~min~te 77 positioned in front of the tr~n~ducer seg..l~ can be ~dj-leted to achieve a desired depth of penetration. The greater the oblique angle formed by axes b and c with respect to the underlying skin, the deeper the penetration of the ultrasonic waves.
FIGURES 13 and 14 illustrate the pumping action that occurs when ultrasonic waves are applied to the skin both vertically and at an oblique angle as illustrated in FIGURE 11 and described above. More specifically, FIGURE 13 illustrates a plurality of skin cells 91 and the type of skin wave that is created when a suitable frequency ultrasonic pulse is applied perpen-liclll~rly to the skin. As can be seen, the cells all remain generally equally spaced as the wave moves through the skin.
FIGURE 14 illustrates what occurs when a suitable frequency ultrasonic wave il.lpil1ges on the skin at an angle. When this occurs, the space in between the cells 91 varies as the wave passes through the skin. Initially, the spacing be~ween some of the cells at the skin surface becomes larger than normal and belweel~ others becomescloser than normal. The larger than normal openings receive the drug to be delivered to the bloodstream. As the wave moves, the spacing between lower skin cells becomes greater while the spacing between higher skin cells becomes closer. This WO 94/086~ PCr/US93/09798 -17- 2I~8010 increase and decrease in spacing creates a "pulllping" action that moves a drug positioned on the surface of the skin through the skin to the underlying cells and blood vessels. The ~wllp;llg action occurs not only to the skin cells. A sim--ilar ~u...l.;..P action occurs along the walls of the hair follicle ch~nnt?lc and the sweat 5 glands which, as noted above, creates additional passageways into the blood vessels.
Because the space between the cells is increased and decreased, drug molecules larger than in the past can be moved through the skin into the blood vessels. Because the fimrl~...~..l~l pumping frequency is chosen to equal one-half the spacing beLween skin cells, the system is highly Pfficient That is, the gleate~L cellular movement for the 10 energy applied occurs because one-half of the wavelength of the applied ultrasonic energy equals the spacing between the cells being moved. Both higher and lower frequencies are less efficient. F.fficiçncy of movement through the çh~nn~.lc around hair follicles is high because of the angular orientation (FIGURES 2 and 3) of hair follicles.
As best understood, the ultrasonic stimuli pulses create the same effect as skintrauma, i.e., a blow to the skin or the application of heat to the skin. In the case of an injury, the trauma causes the basal ~ ,b,~le and the capillary system to open and fluids to flow to the injured area of the skin. The ultrasonic pulses create the same type of opening. The present invention takes advantage of the "gates" that are opened 20 to pump drugs through the skin into the blood stream of the ol~Sal~isl.l. Because of the nervous system (and/or local tissue reaction) the skin rapidly learns that no trauma has occurred and, thus, closes the "gates" a~er 15-20 minlltes (or more), depending upon the m~nihlde of the applied energy, as shown in FIGURE 10, ultrasonic stimuli pulses must be reapplied. As noted above, the ple~lled frequency of the ultrasonic 25 stimuli pulses lie in the 5KHz-lM~ range.
FIGURES 15 and 16 illustrate an alternative embodiment of the invention.
Since the embodiment of the invention illustrated in FIGURES 15 and 16 is generally similar to the embodiment of the invention illustrated in FIGURES 5-9, similar e1emrntc, which are identified by the same reference numerals, are not further 30 described except with respect to their interaction with additional ~lem~.nts The p~i"laly di~rence between the embodiment of the invention illustrated in FIGURES 5-9 and the embodiment of the invention illu~ ted in FIGURES 15 and 16 is the addition of one or more infrared (IR) or laser e~ le,~ 101. As shown in FIGVRE 15, the IR or laser emitters 101 are col-l-ecled to the control electronics. As 35 shown in FIGURE 16, the control electronics is modified to include an additional pulse generator 102 and, if more than one IR or laser emitter 101 is in~l~lde~, a WO 94/0865;~ PCI/US93/09798 ~ - -18-'~
multiplexerlO4. Like the pulse generator66 connected to the planar, circular ultrasonic tr~n~d~c~or 85 and the tr~n~dllcer seg...~ 87a, 87b, 87c, 87d . . . of the tr~n~dllcer assembly 65, the adtlition~l pulse generator 102 is controlled by the pulse modulator 62. The output of the additional pulse gene,alor 102 is co~ euled via the additional multiplexer 104 to the IR or làser emitters 101. As before, the control electronics for the multiplexer 104 are not illustrated because mulLiplc,~e. control electronics are well known. Rather, the mulLiple,~el timing is shown in FIGURE 17 and described below.
The tel~-pt;~alule sensor 71 is also connected to the additional pulse generator 102 to limit the application of energy to the IR or laser e-- ill~-~ 101. This limiting connection is i-,-po-l~--l because in this version of the invention the majority ofthe heat generated in the skin is created by the IR or laser e---ill~.~, rather than by the ultrasonic tr~n.cdllcers.
As shown in F~GURE 17, the IR or laser emitters 101 emit pulses at regular intervals during the period of time that variable frequency, ultrasonic pumping pulses are being applied to the skin by the tran.~d-lcPr seg...~ 87a, 87b, 87c, 87d . . . in the manner helt;lo~.e described. The IR or laser emitter pulses improve the operation of the invention. As best understood, the IR or laser emitter pulses improve the operation of the invention by increasing blood flow similar to the way e~xercise creates blood flow This causes the drug being delivered to di~ipate faster through the body.
The IR or laser emitter pulses also generate heat in the skin as well as create a shock wave similar to the shock wave created by a blow to the skin. It has been found that some IR frequencies are better than others. The best frequencies fall in the following ranges: 500-800 nm (nanometers); 1500-1700 nm; 2100-2300 nm; 3600-4100 nm;
and 10,000-10,900 nm.
FIGURE 15 also illustrates that the reservoir 67 and the ultrasound controllable polymeric ...e.-.l"~. e 69 can be co~--l)i"ed into a single unit 68. The single unit 68 is also an ultrasound controllable polyrneric membrane that holds the pharm~ce~ltic~l to be delivered, as well as controls the release of the pharm~ce~ltic~l 30 A single-layer polymer or a multiple-layer polymer with di~- ~--l ultrasound controlled characteri~tics can be used. In the latter case, one of the polymers forms the reservoir and the other prevents the l~se,voil from releasing or oozing in the absence of ultrasound of a suitable frequency.
FIGURES 18-20 illustrate another alternative embodiment of the invention.
35 The alternative embodiment of the invention illustrated in FIGURES 18-20 is similar to the embodiment of the invention illustrated in FIGURES 5-9. As a result, as with ~ -19~ 6 1~ 1 Q

the FIGURES 15 and 16 embodiment ofthe invention, similar reference numerals areused with similar components and previously described components are not furtherdes~ilil,ed. The plilllaly difference between the embodiment of the invention illustrated in FIGURES 5-9 and the embodiment of the invention illustrated in FIGI~RES 18-20 is the addition of a substance concentration sensor 111 dç.~i~ned to d~ e drug effectiveness. As illustrated in FIGURE 18, the drug effectiveness sensor supplies a drug effectiveness signal to the electronic control 63.
.As illustrated in FIGURE 19, the subsLance concentration sensor 111 is positioned acljacent to the periphery of the polymeric membrane 69. Alternatively, the 10 drug effectiveness sensor could be located remotely from the drug delivery system. In any event, the substance concentration sensor 111 withdraws fluid (serum) from the skin, plerelably using the ultrasonic tr~n.educer meçl~ ... illustrated in FIGURE 22 and described below. The removed fluid is analyzed to determine the effectiveness of the drug delivery system. The result of the analysis is used by the cle~,llolliccontrol 63 to control the operation of the tr~n.~duc~r assembly65 and, thus, thedelivery of the drug stored in the reservoir 67 to the blood vessel 75.
As shown in FIGURE 20, in addition to the inclusion of a substance concentration sensor 111, the electronic control 63 is modified. Rather than inrluriinp a simple clocWpulse generating meçh~ni~m, the electronic control system includes a microprocessor 116 controlled by a control program 118 stored in a suitable memory, such as a read-only memory (ROM). The microprocessor controls the pulse modulator 62, which in turn controls the rate and nature of pulses produced by the pulse generator 66 that are applied to the tr~n.cclucçrs of the tr~n.ed~lcçr assembly 65 via the multiplexer 68. The microprocessor also controls the operation of a second pulse generator 112, which applies drive pulses to a tran~ducer that forms part of the ~ub~ ce concentration sensor 111. The output of a substance sensing tr~n.cd~lc~rthat also forms part of the hereinafter described (FIGURE 22) substance conc.o.ntr~tit~n sensor 111 is applied to the microprocessor 116 via a sensing signal amplifier 114. A drug concentration analysis program 119 controls the operation of the microprocessor 116 during the substance concentration dete~ alion portion ofthe overall cycle of operation.
In operation, as will be better understood from the following description of thesubstance concentration sensor illustrated in FIGURE22, the second pulse generator 112 produces pulses that cause an ultrasonic tr~n~duc~r in~luded in the ~ul)sL~ce concentration sensorlll to cause fluid to flow into a cavity in the substance concentration sensor 111. A suitable substance sensing tr~n~ducer, which WO 94/086~ PCr/US93/09798 may take the form of a diffusion cell, a piezoelectric sensor, a pyroelectric sensor, or an ISFET sensor that forms part of the substance concentration sensor 111, d~Lel-l--l,es the concentration of a predetermined substance in the fluid. The results of the detelllli-laLion, after being amplified by the sensing signal amplifier 114, are analyzed by the microprocessor 116 in accoldallce with drug analysis program 119.
The results of the analysis are used to control the delivery character of drugs via the pulse modulator 62, the pulse generator 66, the multiplexer 68 and the tr~neducer assembly 65 in the manner heretofore descl;l)ed. The output of the lelllpe~ re sensor 71 is utilized by the microprocessor 116 to limit the rate of drug delivery in the event skin temperature exceeds a predetermined level.
FIGURE 21 is a timing diagram of the drug delivery cycle of the embodiment of the invention illustrated in FIGI~RES 18-20. As shown in FIGVRE 21, at the be~ g of each drug delivery cycle (0--tl), the substance concentration sensor 111 is activated and the microprocessor analyzes substance concentration in accoldance with the drug concentration analysis program 119. Thereafter, in the manner heretofore described, ultrasonic stimuli pulses are produced by the flat, circular, ultrasonic tr~ned~lcer 85 (t1--t2). As noted above, the stimuli pulses eim~ te "skin trauma" that causes the basal me.,.b.~ne and capillary endothelial cell joints to open.
Then, variable frequency, ultrasonic pumping pulses are produced by opposed pairs of tr~neducer segmente 87a, 87b, 87c, 87d . . . in a rotating manner (t2--t3). The variable frequency, ultrasonic pumping pulses produced by the tr~n~d~lc~r se~
cause the drug to move from the reservoir 67 through the polymeric me,l.b.~lle 69 and the skin 73 into the systemic circulation system. Thereafter, the cycle is repeated.
FIGURE22 illustrates a stand-alone substance concentration sensor 120 formed in accordance with the invention. While illustrated as a stand-alone device, the concentration sensor shown in FIGURE 22 is suitable for use in the embodiment of the invention illustrated in FIGI~RES 18-20. In addition to the substance concentration sensor 120, FIGI~RE 22 in~llld~e a pulse generator 121 and a data processor 122. The substance concentration sensor 120 is shown positioned on a section of skin 124.
The substance concentration sensor 120 illustrated in FIGURE 22 incl~des an extraction tr~nedus~r 126 and a substance sensing traneduc~r 133. The extractiontr~nsducer incl~ldes a container 123; a planar piezoelectric (ultrasonic) tr~neducet 124;
a focusing lens 125; and a backing layer 127. The container is preferably hat shaped and in~udes, at the bottom, a flange 129 that is ~tt~çhed to the skin 124 of an WO 94/086~ PCI /US93/09798 ~ -21- 2~01~

organism by an adhesive film seal 131. When implem~nted in a drug delivery system of the type shown in FIGURES 18-20, the co"lainel can be çl;, . .;l ".l ed, if desired.
The focusing lens 125 has a plano concave shape oriented such that the concave side faces the skin 124 of the or~alfi~n~. Thus, the focusing lens 125 defines a cavity 135. Located in the cavity 135 is the ~ubslance sensing tr~ncducer 133.Positioned above the foc.lcing lens is the ultrasonic trancduc~r 124. Positioned above the ultrasonic trancducçr 124 is the bac~ing layer 127. The pulse generator 121 is conl-çcled to and drives the ultrasonic trancducer. The data processor is connçcted to the substance sensing tr~ncdw~.r 133.
In operation, the ultrasonic tr~ncducer pulses are focused by the focusing lens 125 into the organism and tr~..m~fi7e the skin underlying the cavity 135. The trauma causes the dermal-epidermal junction me-.~b-~ne and the capillary endothelial joints to open and allow fluid 136 to be drawn into the cavity 135. The fluid 136 is sensed by the ~ubsLance sensing tr~ncducer 133, causing the output of the tr~n.cduc~r to change. The output çh~es are analyzed by the data processor 122.
A substance conce"~ ion sensor of the type illustrated in FIGURE22 pre~ably has a skin sample extractor area of about 3.5cm2. Preferably, the sensor is ~tt~Chpd to the arm of a person so as not to interfere with arm articul~tion. The stratum co, .,~u", layer of the epidermis does not have to be striped.
The ~ hn,llll extraction depth created by the negative radiation pLes~u.e produced by the substance sensing tr~ncd.~c~r depçnrlc on a variety of factors. The th~ nçss of all layers bt;Lween the tr~ncd~cer and the ~ub~;ulaneous layer and the ratio of all layer thicl~nesses are i"")o~ la,~ factors. The location of the lens focal plane with respect to the lens face is another factor related to maximum extraction depth, as is the frequency of the ultrasonic wave. The p.esel,Lly prerel,~d frequency range is 3MHz-50MHz. The ratio of the speed of sound in sequent~ y coupled layers and theacoustic i."pedal-ce of the layers are other important factors. The rate of dilation of the capillary system and intr~cçll~ r micro circulation tree are other factors. In general, ultrasonic wave propagation will start from the layer having higher density and flow into the media laving a lower density. Based on this knowledge, the extraction tr~ncducçr 126 should be constructed so that the focal point of the focal lens is positioned at a higher density skin layer level rather than a lower density skin layer level.
FIGURE 23 is a partially pictorial, partially scllcn~aLic diagram of a sul~sl~cesensing tr~ncducer circuit wLel~;in the tr~n.cduc~r el~m~nt is an ISFET (ion sensitive field effect transistor) sensor 140. One source of such sensors is Sentron, Inc., WO 94/0865~Ç PCr/US93/09798 ~6~ 22-Federal Way, W~h;~ ol1. In general, shown in FIGURE 23, an ISFET sensor 140 incl~lrlçs a base 141 formed of p-type silicon, and source and drain regions 143a and 143b formed of n-type silicon çmhedded in the base. Overlying the base and the source and drain regions is an in~ ting layer of silicon oxide (Si 2) 144. Overlying 5 the silicon oxide layer is a layer of silicon nitride (Si3 N4) 145. A ch~mic~lly sensitive layer 146, surrounded by a protective coating, overlies the silicon nitride layer 147.
Aligned with the chçmic~lly sensitive layer is a reference electrode 148.
The reference electrode creates a conduction gate when the ISFET sensor 140 is suitably biased. The source region 143a and base 141 are held at the same electrical 10 potential and the drain is biased positive 149a with respect to the base. When the gate (,t;rerence) electrode is biased positive 149b with respect to the base, base electrons are attracted to the reference (gate) electrode 148. When this occurs, a thin c-~n~lcting channel rich in elec~luns forms between the source and drain regions 143a and 143b. Current increases as the reference (gate) electrode 148 is made more 15 positive. Thus, the gate potential reg~ tes current flow b~;lween the source and the drain regions.
The ese~nti~l feature of the ISFET sensor 140 is the chçmic~lly sensitive layer 146, which is typically 1mm2 in size. Silicon nitride is sensitive to H+ ions, making the ISFET sensor able to measure the pH of solutions. A hydrolyzing 20 enzyme, such as polyacrylamide co.\~ .;..g penicillin~e, placed atop the silicon nitride layer makes thè ISFET sensor able to sense the presence of penicillin insolution. Thus, applopl;ale çh~mic~l~ allow an ISFET sensor to be used to measure the concentration of particular antibodies in a solution and, thus, allows a s~ nce concenllalion sensor formed in accordance with this invention to determine drug 25 effectiveness. An ISFET sensor is capable of measuring the concellLl~Lion of a particular ~ l,s~ ce in a volume of fluid as small as 5 microliters. Obviously, a res~onse delay, which will depend on the drug being ~dmini~tered, must be taken into consideration.
FIGURE 24 illustrates an alternate substance sensing tr~n~ducer. More 30 specifically, FIGURE 24 illustrates a substance sensing tr~nsd-~cer comprising a thin film of polyvinylidene fluoride (PVDF) 151 having a conductive layer 153a, 153b on either side. The conductive layers are connected to a data processor 155. Thin films of PVDF can be made piezoelectric or pyroelectric. A pyroelectric result occurs when a thin film of PVDF l~min~ted on both sides with a suitable conductor is heated 35 while a strong electric field is applied across the conductors and the film is stress oriented by stretc.hing The field is kept in place as the film is cooled. Coating one -23- 2146~

side of the sandwich with a suitable enzyme 157 and placing the sandwich in a solution co~ .;. g the ~ubslance being tested for causes a voltage to be generated by the heat of the reaction b~lween the enzyrne and substance. The m~gnitude of thevoltage is related to the concentration of the substance. For example, peroxide concenL,alion can be tested for using the organic catalyst c~t~ e as the enzyme.FIGURES 25 and26 illustrate a further alternative embodiment of the invention that is similar to the embodiment of the invention illustrated in FIGURES 18-20. Since the embodiment of the invention illustrated in FIGURES 25 and26 is generally similar to the embodiments of the invention illustrated in FIGURES 18-20, the same reference numerals are utilized to identify similar elem~nts The main difference between the embodiment of the invention illustrated in FIGURES 25 and 26 and the embodiment of the invention illustrated in FIGURES 18-20 is the inclusion of an IR (infrared) or laser emitter 101 similar to the D~ or laser emitter incl~lded in the embodiment of the invention illustrated in FIGURES 15 and 16. Rather than being connected to the pulse sensor 102 that applies pulses to the IR or laser emitter 101 via the multiplexer 104 as in the embodiment of the invention illustrated in FIGURES 18-20, the temperature sensor 71 in the embodiment of the invention illustrated in FIGURE 26 is connected to the microprocessor 116.
As shown in FIGURE 27 and more fully described below with respect to FIGURES 29-32, as in the FIGURES 15 and 16 embodiment of the invention, the IR
or laser emitters are controlled to produce IR or laser pulses during the period of time the variable frequency, ultrasonic pumping pulses are applied to the tran~ducer se~ s 87a, 87b, 87c FIGURE 28 illustrates a det~ch~hle canister assembly. While suitable for use in any of the embo-lim~nt~ of the invention, the canister assembly is more usable in more eA~ellsi~re embotlimçnt~ of the invention, such as those shown in FIGURES 18-20 and 25 and 26. The canister assembly insludes the hat-shaped housing 81 incl~lded in all of the illustrated embo~im~nt~ of the invention.
Perm~n~?ntly housed in the housing are the ultrasonic tran.~ducer assembly 65, and the various electronic subsystems heretofore described. In addition to the housing, the canister assembly includes a canister 161. The canister is formed by the elements that surround the reservoir 67 in which the drug to be delivered is located. Specifically, the canister is formed by the drug-hll,~)e~-lleable l~minate,77 that also functions as a focusing lens and the polymeric lllembl~lle 69. Suitably located on the exterior of the cal~sler is a m~chine (optically, magnetically, electrically or chemically) readable W O 94/0865~ PC~r/US93/09798 ~6Q~ -24- ~

code 163, such as a bar code 163. The m~hine readable code is read by a code reader (not shown).embedded in the housing81. The m~chine readable code j~çntifies the drug housed in the canister 161 and may include instructions regarding the dosage to be a.l...;l- cl~led, acceptable skin te.,.p~;lal~lre, etc.
FIGU R E 29 is a master flow diagram illustrating the operation of the microprocessor of the embodiment of the invention. That is, FIGI~R E 29 is a master flow diagram illustrating how the control program controls the operation of the microprocessor of the embodiment of the invention illustrated in FIG U RE 26. As will be better understood from the following description, the program can be readily modified to control the microprocessor of the embodiment of the invention illustrated in FIG U RE 20 by ~ g unnecess~ry steps, namely, the steps related to the control of the IR or laser emitters 101.
First, the microprocessor is initi~li7e-1 As will be better understood from the following description of the initi~li7~tion ~,ub~uul;ne illustrated in FIGUl~E 30, during initi~li7~tion, a test is made to determine if the proper drug canister is present. If the proper drug cani:iLel is not present, the program ends. After the initi~li7~tionsubroutine, the substance concentration sensor is enabled and the substance to be tested for is detected and analyzed. After the determined drug conce~ Lion subroutine, which is also illustrated in FIGURE 30 and described below, is completed, the initial skin tw--p~ lre of the organism is dete.ll ined. After the initial skin tenlpel~L~lre has been determined, or this subroutine is by-passed if the initial skin temperature was previously determined, a stimuli pulse is applied to the skin. After the time period t1-t2 has elapsed, the drug is delivered. After the drug delivery cycle is ended, i.e., at tg, the sequence of operation is repeated.
As illustrated in FIGURE 30, the first step of the initi~ tion subroutine is to do a conventional system diagnostic check of the microprocessor. ~ccllming the check is s~ticf~ctQrily passed, a test is made to determine if a canister co,.l;.;.~il-g the proper drug is present. As noted above, if the proper drug canister is not present, the control program ends. If the proper drug canister is present, the system logic is initi~li7ed Tniti~1i7~tion may be based on the code contained on the drug canister.
The.ealler, the program cycles to the determine substance concentration subroutine.
The first step in the determine substance concel.Ll~Lion subroutine is to enablethe substance sensing ultrasonic pulse generator 112. As previously diccllecetl~ during the period of time the substance sensing pulse gene-~Lor 112 is enabled, fluids are withdrawn from the human body into the cavity 135 of the extraction tr~nC~ cer 126.
After the substance sensing ultrasonic pulse generator has been enabled, a test is made W094/0865~ 2~,560ln PCI/US93/09798 to determine if the to-tl time has elapsed. If the time has not Pl~pse~l the test is rtpeaLed. After the to-tl time has elapsed, the substance sensing ultrasonic pulse generator 112 is disabled. Th~;lealler, the drug analysis program is enabled and the subs~ ce concentration data generated by the substance sensing tr~ncducer 133 is5 analyzed. The results of the analysis are stored. Next, the absolute value and the change in substance conce"ll~Lion are determined and the results of the dete,l"ina~ion stored. Thele~lel, the program cycles to the detçrmine initial skin te",?e~ re subroutine illustrated in FIGI~RE 31 and described next.
The first step in the det~rmine initial skin telllpela~lre sublou~ine is a test to 10 determine if the initial skin temperature has been stored. If the initial skin te~pe~u~e has not been stored, the initial skin temperature is determined and stored. Thereafter, or if the initial skin te~ el~ul~ was previously stored, the program cycles to the apply stimuli pulse sul)ruuline~ which is also illustrated in FIGURE 31.
The first step in the apply stimuli pulse subroutine is to enable the stimuli 15 ultrasonic pulse generator 66 (via the pulse modulator 62) to cause stimuli pulses to be generated for application to the flat, circular (stimuli) tr~n.cducer85 by the m~ ;pl~ ,er 68. Thereafter, a test is made to determine if the tl-t2 time period has el~rsed If the t1-t2 time period has not elapsed, the test is repeated. After the t1-t2 time period has Pl~rse~l, the stimuli ultrasonic pulse generator 66 is disabled. That is, 20 the pulse modulator stops the pulse gene~or66 from genel~li"g stimuli pulses.Thereafter, the program cycles to the deliver drug subroutine illustrated in FIGURE 32 and described next.
The first step in the deliver drug subroutine is to enable the drug delivery ultrasonic pulse generator 66 via the pulse modulator 62. More specifie~lly, the pulse 25 mod~ tor controls the pulse generator 66 so that variable frequency drug delivery pumping pulses are applied to the tr~ncducer segmentc 87a, 87b, 87c, 87d . . . in the manner heretofore described. Next a test is made to d~Le",lil1e if the t2-tg time period has el~.rsed If the t2-tg time period has elapsed, the drug delivery ultrasonic pulse generator 66 is again disabled and the program cycles to the initi~li7ed subroutine 30 illustrated in FIGURE 30 and described above. If the t2-tg time period has not e1~psed a test is made to determine if it is time to generate another IR pulse. If it is not time to generate another IR pulse, the program cycles to the t2-tg time period elapsed test.
If it is time to ~el1e,~e another IR pulse, the skin te~pe~lure is del~l,,uned 35 and stored. Next, the change in skin te"")e,~ re from the previously recorded value is determined. Then a test is made to d~Lel",il,e if the skin temperature change has - ~46010 reached a predetermined limit. If the limit has been reached, the program cycles to the t2-t9 time period elapse test. As a result, no IR pulse is generated. ~o IR pulse is generated because the skin temperature has reached a predetermined change limit.Rather than a change limit, an absolute temperature test can be performed or both 5 tests can be performed.
If the sl~in temperature has not reached a predetermined limit, the IR emitter pulse generator 102 is enabled. Next a test is made to determine if the IR pulse time has elapsed. If the ~R pulse time has not elapsed, this test is repeated. A~er the IR
pulse time has elapsed, the IR emitter pulse generator 102 is disabled and the program 10 cycles to the t2-tg time period elapsed test.
As ~ill be readily appreciated from the foregoing description, the invention provides an ultrasonic transdermal drug delivery system. The system is noninvasive since it does not require that a needle or other mechanical device invade the shin in order to deliver drugs. Rather, transdermal drug delivery systems formed in 15 accordance with this invention use ultrasonic energy to release a stored pharmaceutical agent (e.g., a drug) and forcibly move the agent through the skin of an organism, such as the human body, into the blood vessels underlying the ultrasonic transducers that produce the ultrasonic energy. The invention can be embodied in a variety of forms. In one form, drugs are delivered in accordance with a predetermined 20 setting. Alternative embo.li",æ~; of the invention include a me~h~ni.~m for determining the concentration of a particular substance in fluid withdrawn from the body, in the same or a diL~I~.Lt region of the organism from where the pharmaceutical agent is being delivered. The withdrawn fluid is analyzed and the results used to control the deLivery of the pharrn~sel-tic~l agent. The substance concentration sensor 25 that removes fluid from the body and analyzes the fluid can also be provided as a stand-alone unit, i.e., a test unit independent of a drug delivery system. As with the drug delivery system, the substance concentration sensor is noninvasive, i.e., it does not use a needle or other mech~nical device to withdraw fluid from the organism for analysis. Rather, the substance concentration sensor uses ultrasonic energy to forcibly 30 remove fluid from the organism for analysis.

A~ ~D SI~EET
.

Claims

The embodiments of the invention in which an exclusive property or privilege is claimed are defined as follows:

1. An ultrasonic transdermal dmg delivery system comprising a housing(81), an ultrasonic transducer assembly(65) mounted in said housing, an electronic control means (63), a membrane (69) whose porosity is controllable byultrasonic waves, and attachment means (79) for attaching said transdermal drug delivery system to an organism having a skin characterized by:
(a) said ultrasonic transducer assembly(65) including a stimuli transducer (85) and at least one drug delivery transducer (87a, 87b, 87c, 87d,...), said stimuli and said at least one drug delivery transducer oriented so as to at least partially define a reservoir (67) having an open side for storing a pharmaceutical to be delivered;
(b) said membrane being positioned to close the open side of said reservoir;
(c) said attachment means being positioned to attach said transdermal drug delivery system such that said membrane faces said skin and separates said reservoir from said skin; and (d) said electronic control means (63) being coupled to said stimuli transducer (85) and said at least one drug delivery transducer (87a, 87b, 87c, 87d,...) for causing said stimuli transducer to emit ultrasonic stimuli pulses for a predetermined period of time and, subsequent to said predetermined period of time, causing said at least one drug delivery transducer to emit variable frequency ultrasonic pumping pulses that cause the pharmaceutical stored in said reservoir to be forcibly moved through said membrane to said skin and into said skin.

2. The ultrasonic transdermal drug delivery system claimed in Claim 1 wherein said at least one drug delivery transducer(87a7 87b, 87c, 87d,...) is oriented such that said variable frequency ultrasonic pumping pulses intersect said membrane at an oblique angle.

3. The ultrasonic transdermal drug delivery system claimed in Claim 2 wherein the frequency of said ultrasonic stimuli pulses lie in the 5KHz-1MHz range.

4. The ultrasonic transderrnal drug delivery system claimed in Claim 3 wherein the frequency of said variable frequency ultrasonic pumping pulses lies in the 50MHz-300MHz range.

5. The ultrasonic transdermal drug delivery system claimed in Claim 4 wherein said variable frequency ultrasonic pumping pulses are harmonics of one another.

6. The ultrasonic transdermal drug delivery system claimed in Claim 5 wherein said variable frequency ultrasonic pumping pulses have a fundamental frequency that lies at the lower end of said 50MHz-300MHz range.

7. The ultrasonic transdermal drug delivery system claimed in Claim 2 wherein the frequency of said variable frequency ultrasonic pumping pulses lies in the 50MHz-300MHz range.

8. The ultrasonic transdermal drug delivery system claimed in Claim 7 wherein said variable frequency ultrasonic pumping pulses are harmonics of one another.

9. The ultrasonic transdermal drug delivery system claimed in Claim 8 wherein said variable frequency ultrasonic pumping pulses have a fundamental frequency that lies at the lower end of said 50MHz-300MHz range.

10. The ultrasonic transdermal drug delivery system claimed in Claim 2 wherein said reservoir (67) includes walls that define a truncated geometric shape and said ultrasonic drug delivery system includes a plurality of drug delivery transducer segments (87a, 87b, 87c, 87d,...), said plurality of drug delivery transducer segments forming at least a part of the walls of said reservoir.

11. The ultrasonic transdermal drug delivery system claimed in Claim 10 wherein said truncated geometric shape is a truncated cone, and wherein said stimuli transducer (85) defines the small end of said truncated cone and said membrane (69) closes tke larger end of said truncated cone.

12. The ultrasonic transdermal drug delivery system claimed in Claim 11 wherein the frequency of said ultrasonic stimuli pulses lies in the 5KHz-1MHz range.

13. The ultrasonic transdermal drug delivery system claimed in Claim 12 wherein the frequency of said variable frequency ultrasonic pumping pulses lies in the 50MHz-300MHz range.

14. The ultrasonic transdermal drug delivery system claimed in Claim 13 wherein said variable frequency ultrasonic pumping pulses are harmonics of one another.

15. The ultrasonic transdermal drug delivery system claimed in Claim 14 wherein variable frequency ultrasonic pumping pulses have a fundamental frequency that lies at the lower end of said 50MHz - 300MHz range.

16. The ultrasonic transdermal drug delivery system claimed in Claim 11 wherein the frequency of said variable frequency ultrasonic pumping pulses lies in the 50MHz-300MHz range.

17. The ultrasonic transdermal drug delivery system claimed in Claim 16 wherein said variable frequency ultrasonic pumping pulses are harmonics of one another.

18. The ultrasonic transdermal drug delivery system claimed in Claim 17 wherein said variable frequency ultrasonic pumping pulses have a fundamental frequency that lies at the lower end of said 50MHz-300MHz range.

19. The ultrasonic transdermal drug delivery system claimed in Claim 11 including a drug-impermeable laminate (77) located between said reservoir (67) and said stimuli transducer (85) and said plurality of drug delivery transducer segments (87a, 87b, 87c, 87d,...).

20. The transdermal drug delivery system claimed in Claim 19 wherein said drug-impermeable laminate (77) also functions as a focusing lens for said stimuli transducer and said plurality of drug delivery transducer segments.

21. The ultrasonic transdermal drug delivery system claimed in Claim 20 wherein the frequency of said ultrasonic stimuli pulses lies in the 5KHz-1MHz range.

22. The ultrasonic transderrnal drug delivery system claimed in Claim 21 wherein the frequency of said variable frequency ultrasonic pumping pulses lies in the 50MHz-300MHz range.

23. The ultrasonic transdermal drug delivery system claimed in Claim 22 wherein said variable frequency ultrasonic pumping pulses are harmonics of one another.

24. The ultrasonic transdermal drug delivery system claimed in Claim 23 wherein said variable frequency ultrasonic pumping pulses have a fundamental frequency that lies at the lower end of said 50MHz-300MHz range.

25. The ultrasonic transdermal drug delivery system claimed in Claim 20 wherein the frequency of said variable frequency ultrasonic pumping pulses lies in the 50MHz-300MHz range.

26. The ultrasonic transdermal drug delivery system claimed in Claim 25 wherein said variable frequency ultrasonic pumping pulses are harmonics of one another.

27. The ultrasonic transdermal drug delivery system claimed in Claim 26 wherein said variable frequency ultrasonic pumping pulses have a fundamental frequency that lies at the lower end of said 50MHz-300MHz range.

28. The ultrasonic transdermal drug delivery system claimed in Claim 20 wherein the number of said plurality of drug delivery transducer segments (87a, 87b, 87c, 87d,...) is an even number, and wherein pairs of drug delivery transducer segments are positioned on opposite sides of said truncated cone.

29. The ultrasonic transdermal drug delivery system claimed in Claim 28 wherein said pairs of opposed drug delivery transducer segments (87a, 87b, 87c, 87d,...) positioned on opposite sides of said truncated cone are simultaneously energized to ernit variable frequency ultrasonic pumping pulses.

30. The ultrasonic transdermal drug delivery system claimed in Claim 29 wherein the frequency of said ultrasonic stimuli pulses lies in the 5KHz-1MHz range.

31. The ultrasonic transdermal drug delivery system claimed in Claim 30 wherein the frequency of said variable frequency ultrasonic pumping pulses lies in the 50MHz-300MHz range.

32. The ultrasonic transdermal drug delivery system claimed in Claim 31 wherein said variable frequency ultrasonic pumping pulses are harmonics of one another.

33. The ultrasonic transdermal drug delivery system claimed in Claim 32 wherein said variable frequency ultrasonic pumping pulses have a fundamental frequency that lies at the lower end of said 50MHz-300MHz range.

34. The ultrasonic transdermal drug delivery system claimed in Claim 29 wherein the frequency of said variable frequency ultrasonic pumping pulses lies in the 50MHz-300MHz range.

35. The ultrasonic transdermal drug delivery system claimed in Claim 34 wherein said variable frequency ultrasonic pumping pulses are harmonics of one another.

36. The ultrasonic transdermal drug delivery system claimed in Claim 35 wherein said variable frequency ultrasonic pumping pulses have a fundamental frequency that lies at the lower end of said 50MHz-300MHz range.

37. The ultrasonic transdermal drug delivery system claimed in Claim 29 wherein sequential pairs of opposed drug delivery transducer segments (87a, 87b,87c, 87d,...) are simultaneously energized to emit variable frequency ultrasonicpumping pulses rotating about the central axis of said truncated cone.

38. The ultrasonic transdermal drug delivery system claimed in Claim 37 wherein the frequency of said ultrasonic stimuli pulses lies in the 5KHz-1MHz range.

39. The ultrasonic transdermal drug delivery system claimed in Claim 38 wherein the frequency of said variable frequency ultrasonic pumping pulses lies in the 50MHz-300MHz range.

40. The ultrasonic transdermal drug delivery system claimed in Claim 39 wherein said variable frequency ultrasonic pumping pulses are harmonics of one another.

41. The ultrasonic transdermal drug delivery system claimed in Claim 40 wherein said variable frequency ultrasonic pumping pulses have a fundamental frequency that lies at the lower end of said 50MHz-300MHz range.

42. The ultrasonic transdermal drug delivery system claimed in Claim 37 wherein the frequency of said variable frequency ultrasonic pumping pulses lies in the 50MHz-300MHz range.

43. The ultrasonic transdermal drug delivery system claimed in Claim 42 wherein said variable frequency ultrasonic pumping pulses are harmonics of one another.

44. The ultrasonic transdermal drug delivery system claimed in Claim 43 wherein said variable frequency ultrasonic pumping pulses have a fundamental frequency that lies at the lower end of said 50MHz-300MHz range.

45. The ultrasonic transdermal drug delivery system claimed in Claim 2, 11, 20, 29 or 37 including an energy emitter (101) mounted in said housing adjacent said transducer assembly, said energy emitter connected to said electronic control means, said electronic control means controlling said energy emitter such that said energy emitter produces further stimuli pulses at predetermined intervals during the period of time said variable frequency ultrasonic pumping pulses are being produced by said drug delivery transducer segments.

46. The ultrasonic transdermal drug delivery system claimed in Claim 45 wherein said energy e nitter (101) is an infrared (IR) emitter.

47. An ultrasonic transdermal drug delivery system as claimed in Claim 45 wherein said energy emitter (101) is a laser emitter.

48. The ultrasonic transdermal drug delivery system claimed in Claim 45 including temperature sensing means, said temperature sensing means including a temperature sensing device (71) positioned in said housing for sensing the temperature of the skin of said organism when said transdermal drug delivery system is attached by said attachment means to an organism having a skin, said temperature sensing device connected to said electronic means for preventing said electronicmeans from causing said stimuli transducer to emit ultrasonic stimuli pulses if the temperature sensed by said temperature sensing means exceeds a predetermined parameter.

49. The ultrasonic transdermal drug delivery system as claimed in Claim 48 wherein said electronic control means is inhibited from energizing said energy emitter if the temperature sensed by said temperature sensing means exceeds a predetermined parameter.

50. The ultrasonic transdermal drug delivery system claimed in Claim 20, 29 or 37 wherein said drug delivery reservoir is part of a canister (161) that also includes said membrane and said drug-impermeable laminate.

51. The ultrasonic transdermal drug delivery system as claimed in Claim 2, 11, 20, 92 or 37 including a substance concentration sensor(111) for withdrawingfluid from said organism and analyzing said fluid to determine the concentration of a particular component of said fluid, and wherein said electronic means controls the delivery of drugs based on said concentration determination.

52. The ultrasonic transdermal drug delivery system claimed in Claim 51 wherein said substance concentration sensor includes:
(a) an ultrasonic sensor transducer (124) for generating ultrasonic sensing pulses when energized;
(b) energizing means (121) for energizing said ultrasonic sensor transducer;
(c) focusing means (125), including a cavity adjacent the skin of said organism when said transdermal drug delivery system is attached by said attachment means to an organism having a skin, for focusing the ultrasonic sensing pulses generated by said ultrasonic sensor transducer into said organism, said ultrasonic sensing pulses focused by said focusing means causing fluid to be withdrawn from said organism through said skin into said cavity;
(d) a substance sensing transducer (133) mounted in said cavity for sensing a substance in said fiuid; and (e) analysis means (122) coupled to said substance sensing transducer for determining the concentration of said substance sensed by said substance sensing transducer.

53. The ultrasonic transdermal drug delivery system claimed in Claim 52 wherein said ultrasonic sensor transducer (124) is planar and lies in a plane parallel to the surface of the skin of said organism.

54. The ultrasonic transdermal drug delivery system claimed in Claim 53 wherein said focusing means (125) is a plano-concave lens positioned such that the concave side of said lens faces the skin of said organism and said ultrasonic sensor transducer is located on the plano side of said plano-concave lens.

55. The ultrasonic transdermal drug delivery system claimed in Claim 54 wherein said substance sensing transducer (133) is an ISFET.

56. The ultrasonic transdermal drug delivery system claimed in Claim 54 wherein said substance sensing transducer (133) is a sandwich formed of a polyvinylidene fluoride film located between two layers of conductive material.

57. The ultrasonic transdermal drug delivery system claimed in Claim 52 wherein said focusing means (125) is a plano-concave lens positioned such that the concave side of said lens faces the skin of said organism and said transducer is located on the plano side of said plano-concave lens.

58. The ultrasonic transdermal drug delivery system claimed in Claim 57 wherein the frequency of said ultrasonic stimuli pulses lies in the 5KHz-1MHz range.

59. The ultrasonic transdermal drug delivery system claimed in Claim 58 wherein the frequency of said variable frequency ultrasonic pumping pulses lies in the 50MHz-300MHz range.

60 The ultrasonic transdermal drug delivery system claimed in Claim 59 whelein said variable frequency ultrasonic pumping pulses are harmonics of one another.

61. The ultrasonic transdermal drug delivery system claimed in Claim 60 wherein said variable frequency ultrasonic pumping pulses have a fundamental frequency that lies at the lower end of said 50MHz-300MHz range.

62. The ultrasonic transdermal drug delivery system claimed in Claim 61 wherein the frequency of said ultrasonic sensing pulses lies in the 3MHz-50MHz range.

63. The ultrasonic transdermal drug delivery system claimed in Claim 57 wherein the frequency of said variable frequency ultrasonic pumping pulses lies in the 50MHz-300MHz range.

64. The ultrasonic transdermal drug delivery system claimed in Claim 63 wherein said variable frequency ultrasonic pumping pulses are harmonics of one another.

65. The ultrasonic transdermal drug delivery system claimed in Claim 64 wherein said variable frequency ultrasonic pumping pulses have a fundamental frequency that lies at the lower end of said 50MHz-300MHz range.

66. The ultrasonic transdermal drug delivery system claimed in Claim 65 wherein the frequency of said ultrasonic sensing pulses lies in the 3MHz-50MHz range.

67. A noninvasive apparatus for withdrawing fluid from an organism and determining the concentration of a substance in the fluid, said noninvasive apparatus comprising:
(a) a container (123);
(b) attachment means (131) for attachino said container to the skin of an organism;
(c) an ultrasonic transducer (124) positioned in said container for generating ultrasonic energy when energized;
(d) energizing means (121) for energizing said ultrasonic transducer;
(e) focusing means (125), including a cavity adjacent the skin of an organism when said container is attached to the skin of an organism, for focusing the ultrasonic energy generated by said ultrasonic transducer into said organism, said ultrasonic energy focused by said focusing means causing fluid to be withdrawn from said organism through said skin into said cavity;
(f) a substance sensing transducer (133) mounted in said cavity for sensing a substance in said fluid; and (g) analysis means (122) coupled to said substance sensing transducer for determining the concentration of said substance sensed by said substance sensing transducer.

68. The noninvasive apparatus claimed in Claim 67 wherein the frequency of said ultrasonic energy lies in the 3MHz-50MHz range.

69. The noninvasive apparatus claimed in Claim 67 wherein said ultrasonic transducer (124) is planar and lies in a plane parallel to the surface of the skin of said organism when said container is attached to the skin of an organism.

70. The noninvasive apparatus claimed in Claim 69 wherein the frequency of said ultrasonic energy lies in the 3MHz-50MHz range.

71. The noninvasive apparatus claimed in Claim 69 wherein said focusing means (125) is a plano-concave lens positioned such that the concave side of said lens faces said skin of an organism when said container is attached to the skin of anorganism and said ultrasonic transducer is located on the plano side of said plano-concave lens.

72. The noninvasive apparatus claimed in Claim 71 wherein the frequency of said ultrasonic energy lies in the 3MHz-50HIz range.

73. The noninvasive apparatus claimed in Claim 67, 69 or 71 wherein said substance sensing transducer (133) is an ISFET.

74. The noninvasive apparatus claimed in Claim 73 wherein the frequency of said ultrasonic energy lies in the 3MHz-50MHz range.

75. The noninvasive apparatus claimed in Claim 67, 69 or 71 wherein said substance sensing transducer (133) is a sandwich formed of a polyvinylidene fluoride film located between two layers of conductive material.

76. The noninvasive apparatus claimed in Claim 74 wherein the frequency of said ultrasonic energy lies in the 3MHz-50MHz range.

77. A transdermal drug delivery method comprising the steps of:
(a) placing a reservoir containing a pharmaceutical on the skin of an organism having a skin;
(b) applying ultrasonic stimuli pulses to said skin in the region where said reservoir is placed for a first predetermined period of time;
(c) applying variable frequency ultrasonic drug delivery pulses to said skin in said region where said reservoir is placed for a second predetermined period of time subsequent to said first predetermined period of time; and (d) sequentially repeating the steps of applying ultrasonic stimuli pulses followed by the step of applying variable frequency ultrasonic drug delivery pulses to the skin of said organism.

78. The method claimed in Claim 77 wherein said ultrasonic stimuli pulses are applied perpendicular to said skin.

79. The method claimed in Claim 78 wherein said variable frequency ultrasonic drug delivery pulses are applied to said skin at an oblique angle.

80. The method claimed in Claim 79 wherein a pair of variable frequency ultrasonic drug delivery pulses are simultaneously applied to said skin at oblique angles from opposed directions.

81. The method claimed in Claim 80 wherein said pair of obliquely applied variable frequency ultrasonic drug delivery pulses are applied in a rotating manner about a common center.

82. The method claimed in Claim 77, 78, 79, 80 or 81 wherein said ultrasonic stimuli pulses have a frequency falling in the frequency range of 5KHz-1MHz.

83. The method claimed in Claim 82 wherein said variable frequency ultrasonic drug delivery pulses fall in the frequency range of 50MHz-300MHz.

84. The method claimed in Claim 83 wherein said variable frequency ultrasonic drug delivery pulses are harmonics.

85. The method claimed in Claim 84 wherein said variable frequency ultrasonic drug delivery pulses have a fundamental frequency that lies at the lower end of said 50MHz-300MHz range.

86. The method claimed in Claim 77, 78, 79, 80 or 81 wherein the frequency of said variable frequency ultrasonic drug delivery pulses falls in the frequency range of 50MHz-300MHz.

87. The method claimed in Claim 86 wherein said variable frequency ultrasonic drug delivery pulses are harmonics.

88. The method claimed in Claim 87 wherein said variable frequency ultrasonic drug delivery pulses have a fundamental frequency that lies at the lower end of said 50MHz-300MHz range.

89. The method claimed in Claim 77, 78, 79, 80 or 81, including the additional step of applying further stimuli pulses to the skin of said organism during the period of time said variable frequency ultrasonic druo delivery pulses are applied to said organism.

90. The method claimed in Claim 89 wherein said ultrasonic stimuli pulses have a frequency falling in the range of 5KHz-1MHz.

91. The method claimed in Claim 90 wherein the frequency of said variable frequency ultrasonic drug delivery pulses falls in the frequency range of 50MHz-300MHz.

92. The method claimed in Claim 91 wherein said. variable frequency ultrasonic drug delivery pulses are harmonics.

93.. The method claimed in Claim 92 wherein said variable frequency ultrasonic drug delivery pulses have a fundamental frequency that lies at the lower end of said 50MHz-300MHz range.

94. The method claimed in Claim 93 wherein said further stimuli pulses are infared energy pulses.

95. The method claimed in Claim 93 wherein said further stimuli pulses are laser pulses.

96. The method claimed in Claim 89 wherein the frequency of said variable frequency ultrasonic drug delivery pulses falls in the frequency range of 50MHz-300MHz.

97. The method claimed in Claim 96 wherein said variable frequency ultrasonic drug delivery pulses are harmonics.

98. The method claimed in Claim 97 wherein said variable frequency ultrasonic drug delivery pulses have a fundamental frequency that lies at the lower end of said 50MHz-300MHz range.

99. The method claimed in Claim 98 wherein said further stimuli pulses are infrared energy pulses.

100. The method claimed in Claim 98 wherein said further stimuli pulses are laser pulses.

101. The method claimed in Claim 89 including the steps of detecting the temperature of the skin of said organism and terminating the application of saidfurther stimuli pulses when the temperature of the skin of said organism exceeds a predetermined parameter.

102. The method claimed in Claim 77, 78, 79, 80 or 81 including the steps of withdrawing fluid from said organism and using the results of said determination to control the application of said ultrasonic stimuli pulses and said ultrasonic drug delivery pulses to said organism.

103. The method claimed in Claim 102 wherein said step of withdrawing fluid from said organism is performed in a noninvasive manner.

104. The method claimed in Claim 103 wherein said ultrasonic stimuli pulses have a frequency falling in the frequency range of 5KHz-1MHz.

105. The method claimed in Claim 104 wherein the frequency of said variable frequency ultrasonic drug delivery pulses fall in the frequency range of 50MHz-300MHz.

106. The method claimed in Claim 105 wherein said variable frequency ultrasonic drug delivery pulses are harmonics.

107. The method claimed in Claim 106 wherein said variable frequency ultrasonic drug delivery pulses have a fundamental frequency that lies at the lower end of said 50MHz-300MHz range.

108. The method claimed in Claim 107 including the additional step of applying further stimuli pulses to the skin of said organism during the period of time said variable frequency ultrasonic drug delivery pulses are applied to said organism.

109. The method claimed in Claim 108 wherein said further stimuli pulses are infrared energy pulses.

110. The method claimed in Claim 108 wherein said further stimuli pulses are laser pulses.

111. The method claimed in Claim 104 wherein the frequency of said variable frequency ultrasonic drug delivery pulses falls in the frequency range of 50MHz-300MHz.

112. The method claimed in Claim 111 wherein said variable frequency ultrasonic drug delivery pulses are harmonics.

113. The method claimed in Claim 112 wherein said variable frequency ultrasonic drug delivery pulses have a fundamental frequency that lies at the lower end of said 50MHz-300MHz range.

114. The method claimed in Claim 113 including the additional step of applying further stimuli pulses to the skin of said organism during the period of time said variable frequency ultrasonic drug delivery pulses are applied to said organism.

115. The method claimed in Claim 114 wherein said further stimuli pulses are infrared energy pulses.

116. The method claimed in Claim 114 wherein said further stimuli pulses are laser pulses.

117. The method claimed in Claim 103 wherein said substep of withdrawing fluid from said organism comprises the substeps of creating a cavity above the skin of said organism and applying ultrasonic sensing pulses to the skin of said organism beneath said cavity.

118. The method claimed in Claim 117 wherein said ultrasonic stimuli pulses have a frequency falling in the range of 5KHz-1MHz.

119. The method claimed in Claim 118 wherein the frequency of said variable frequency ultrasonic drug delivery pulses falls in the frequency range of 50MHz-300MHz.

120. The method claimed in Claim 119 wherein said variable frequency ultrasonic drug delivery pulses are harmonics.

121. The method claimed in Claim 120 wherein said variable frequency ultrasonic drug deliver, pulses have a fundamental frequency that lies at the lower end of said 50MHz-300MHz range.

122. The method claimed in Claim 121 includino the additional step of applying further stimuli pulses to the skin of said organism during the period of time said variable frequency ultrasonic drug delivery pulses are applied to said organism.

123. The method claimed in Claim 122 wherein said further stimuli pulses are infrared energy pulses.

124. The method claimed in Claim 122 wherein said further stimuli pulses are laser pulses.

125. The method claimed in Claim 117 wherein the frequency of said variable frequency ultrasonic drug delivery pulses falls in the frequency range of 50MHz-300MHz.

126. The method claimed in Claim 125 wherein said variable frequency ultrasonic drug delivery pulses are harmonics.

127. The method claimed in Claim 126 wherein said variable frequency ultrasonic drug delivery pulses have a fundamental frequency that lies at the lower end of said 50MHz-300MHz range.

128. The method claimed in Claim 127 including the additional step of applying further stimuli pulses to the skin of said organism during the period of time said variable frequency ultrasonic drug delivery pulses are applied to said organism.

129. The method claimed in Claim 128 wherein said further stimuli pulses are infrared energy pulses.

130. The method claimed in Claim 128 wherein said further stimuli pulses are laser pulses.

131. A noninvasive method of withdrawing a fluid from an organism and determining the concentration of a substance in the fluid, said noninvasive method comprising the steps of:
(a) creating a cavity juxtaposed against the skin of said organism;

(b) applying a focused beam of ultrasonic energy to the skin of said organism in the region of said cavity to cause fluid to be withdrawn into said cavity;
and (c) analyzing fluid withdrawn into said cavity.

132. The method claimed in Claim 131 wherein the frequency of said focused beam of ultrasonic energy lies in the range of 3MHz-50MHz.