Drug delivery device

[0002] Th c present invention relates to systems and methods for delivering drugs to a patient. In particular. Lhe present invention relates lo systems and methods for subcutaneous injection of a medicament and using one or more treatment sources to improve effectiveness of the injected drugs.

litickf’roiind of the Invention

[0003] Pen injectors are useful when regular injection by persons without formal medical training occurs. This is increasingly common amongst those having chronic conditions such as diabetes where self-treatment enables such persons effectively manage their condition. Many of the insulin pen injectors arc reusable and usually loaded with an insulin cartridge that may be used for a plurality of injections or for a number of days. Many other diabetic patients use regular syringe(s) and needles for insulin injection.

PCT/IU2O(W/(>51<»49

[0004] Diabetes is a very serious illness affecting millions of people today. Many diabetic patients require injections of insulin to maintain proper levels of glucose in their blood in order to survive. Such injections of insulin require drug injection systems.

[0005] Many medical treatment systems and methods involve drug injection systems that employ subcutaneous injections of therapeutic lluids, drugs, proteins, and other compounds. Such delivery systems and methods, especially for insulin delivery, may use injection pens to inject, insulin to the subcutaneous tissue, or regular syringe. In the conventional insulin injection pens, the pen includes a disposable insulin reservoir and a disposable needle through which insulin is injected into the tissue. The needle is a single use needle, while the insulin reservoir can be used for two to three days. In the conventional insulin injection pens, the injection is done by attaching the insulin injection pen to the skin at the injection site and pressing a button that, first insert the needle using a spring into the subcutaneous tissue and then inject the insulin (0 the subcutaneous tissue,

[0006]In many instances, the patients require insulin injection around the clock to keep proper levels of glucose in their blood. Two major types of insulin can be injected - a longacting insulin that provides the basal insulin rale needed for keeping patient’s blood glucose in the desired range between meals and over night and an insulin bolus injection that provides an amount of insulin for matching a dose of carbohydrates consumed by the patient.

[0007] When patient consumes food, his or her levels of glucose rise. Unfortunately, many conventional subcutaneous injection devices arc incapable of quickly matching and/or preventing the rise of blood glucose. The delay in such matching is also true in case of the “rapid-acting” insulin. Some of the reasons for this delay include a lag in the absorption of insulin from the injection site and the time it lakes for complex insulin molecules to break down into monomers.

[0008] Additionally, since blood glucose levels rise shortly following the meal, the delay in matching insulin to the rising levels causes post prandial hyperglycemic events (i.e., when levels of blood glucose arc above normal) to occur. Occasionally, after certain period of time passes (e.g., 2-3 hours) after the meal, the blood glucose levels drop yet insulin concentrations in the blood rise followed by the peak of the systemic insulin effect and may result in causing hypoglycemic events (i.e., when levels of blood glucose are below normal) to occur. Both hyperglycemic and hypoglycemic events arc highly undesirable. Additionally, since local blood perfusion al the insulin injection region has large variability, depending on the ambient temperature and other parameters, it induces large variations to the delay of the peak of time profile of the insulin action. Those variations in the insulin peak action period further increase the variability in the blood glucose level.

[0009! Thus, it is desirable to provide a system and a method that provides efficient and rapid injection and absorption of the drug to the patient, circulatory system. In particular, it is desirable to provide a system and a method for injection of insulin 10 the patient that improves effectiveness of insulin in lhe blood to maintain normal levels ofblood glucose and prevent or reduce hyperglycemic anil hypoglycemic events.

SUMMARY Ob' ΊΊ 11 INVENTION

10010] The present invention relate to systems, devices and methods for injecting a drug, substances and/or chemicals to a patient that further provides a tissue treatment element for improving the effectiveness of drug delivery upon injection. In some embodiments, the present invention relates to a device for improving performance of drug delivery in the form of injection pens or syringes. In general, lhe present invention’s suggested methods and devices can be used in many drug injection devices, such as injection pcn(s), syringe(s), or jet injcctor(s), or other injection devices. As such, although the present application discusses mainly injection pens, it. is understood by one skilled in the art that such devices can he used with any other injection devices. In some embodiments, the present invention provides for a device lhat further provides an additional treatment to a tissue region where the drug is delivered. In some embodiments, the treatment is utilized to improve drug delivery process by improving the drug’s pharmacokinetic and/or pharmacodynamic profile. The treatment may come in various forms, for example, including analgesic, vasodilator or lhe like. The treatment may be any form of treatment that leads 10 improved vasodilatation of the (issue being injected, including bul. not limited Io, exposing the tissue region to an energy, radiation, heal, mechanical vibrations, suction, massaging, acoustic stimulation, electromagnetic radiation, electric held, magnetic field, elcclrical stimulation, injection of an additional substance(s), or any combination of lhe above to improve the drug’s pharmacokinetic and /or pharmacodynamic profile, Each treatment type may have a separale protocol in order to evoke the necessary reaction such as vasodilatation or the like.

WO 201)8/114223

[0011] In sonic embodiments, lhe present invention provides a needle free drug delivery pen that is coupled to a treatment element. The treatment clement improves lhe pharmacokinetic and/or pharmacodynamic properties 01'the drug that is being delivered to lhe target tissue using a fluid jet. The drug delivery injector lor administering a drug, lor example, insulin, as a jet nozzle configured for firing insulin in a fluid jet in a configuration and with sufficient velocity to penetrate (issue of the patient to a delivery site. A drug containing compartment is associated with the nozzle for containing the drug and feeding the insulin to the delivery nozzle for injection. A firing mechanism includes an energy source is associated with the drug compartment for forcing the drug through the nozzle al a sufficient velocity to penetrate to the target site. In some embodiments, the energy source product ng the fluid jet can be a coil spring, gas spring, or any other spring. Λ trigger or a dosage release button of the drug delivery injector is movable by lhe userand associated with the firing mechanism for activating the energy source that produces the drug fluid jet by forcing of the drug through the nozzle once the release hut Ion is activated.

[0012[ In some embodiments, lhe applied treatment induces vasodilatation through neural stimulation of the tissue oft he drug injection site. The neural stimulation can be induced by thermal stimulation and/or mechanical stimulation and/or chemical stimulation. The human neural response to the thermal stimulation includes several mechanisms such as the Nociceptive Axon Reflex that induce vasodilatation among other effects.

[0013] In some embodiments, the induced neural response, such as the Nociceptive Axon Reflex, also induces widening of the capillary pores and increasing the capillary wall permeability. This effect is also significant for improving the absorption of the drag through the capillary wall.

[0014J In sonic embodiments, the applied treatment may lead to a reduction in the variability of the drug absorption in lhe blood or lymph system and its local and systemic effects. For example, heating the tissue region in lhe vicinity of lhe area of drug delivery Io a preset regulated temperature during and/or after the drug injection and absorption into the blood may cause local blood perfusion at that region to become more reproducible and the drug absorption process more uniform and reproducible as well. Also, by reducing the delay between drug injection into the tissue and absorption into lhe blood system, lhe variability of drug action induced by the delayed profile can be reduced. In some embodiments, the temperature of the region adjacent to the injection region can be regulated for longer periods, but the cost may be lhe energy source volume and weight. Therefore, for minimization of lhe

WO 2(((18/114223

PCT/IB2008/05I049 energy source size, the heating period < >r healing temporal prof ile can he optimized in relation (0 the period 01'the drug injection and absorption into the blood. In some embodiments, in which lhe treatment utilized is, for example, heat, the drug interaction with the treatment substance or type will be taken into consideration and can be avoided. I ׳or example, a drug’s temperature sensitivity will be accounted for so as to avoid protein dcnaturisation. Insulin is a temperature-sensitive protein and to avoid damage to the insulin lhe treatment protocol, heating can be limited to ensure the efficacy of the delivered drug, I׳br example, lhe treatment protocol may control lhe temperature or the location of the treatment delivery site so as to not damage the drug.

[OOlSj In some embodiments, the neural response that, induces vasodilatation is stimulated by applying a mechanical force in the vicinity of the drug infused region, wherein the force includes, but is not limited to, one or more of the following: pressure, massage, vibration, suction and/or any other mechanical stimulation. These tissue treatments or stimulations arc known to stimulate lhe Nociceptive Axon Reflex as well. Among lhe advantages of (he mechanical stimulation is the fact that it docs not damage the drug, whereas for example healing insulin above 37C may cause damage to it. The calibration of the applied mechanical force may be performed by using one of lhe procedures discussed above.

10016[ In some embodiments, an additional fluid substance can be combined with the drug or, alternatively, injected, infused, or topically applied (which may include transdermal delivery of the drug by permealing through (he skin of the paiicnt) lo the drug injection site, such that lhe additional substance induces neural stimulation that leads 10 local vasodilatation and/or increases of the capillary permeability, ־lhe substances can include tolazine, naftidrofuryl, suloctidil, nitroprusside, capsaicin, or any other suitable substance. In some embodiments, an additional substance may induce vasodilatation and improve blood perfusion in lhe drug infused tissue region. I׳’or example, capsaicin stimulates a neural response through the VR1 receptor and produces a similar response to thermal neural stimulation.

[0017ΓΙ he treatment element can be an integral part of the drug delivery injection pen, according lo some embodiments of the present invention. In some embodiments, the treatment clement can he an auxiliary unit that may be interchanged, replaced, or added to an existing drug delivery injection pen. Such a device can be attached lo the drug delivery pen either during or before the drug injection or applied to lhe drug injection site afterward.

[(10181 The treatnicnl element, according to some embodiments, may be any one or more 01' (or a combination of): a healing element, a radiation emitter, a sound transducer, a mcchanical/cleclo-mechanical vibration device, a light emitting device, and an electrode.

[0019] In some embodiments, one or more of properties relating to the treatment clement may be controlled by a processor in order lo achieve a desired response of the tissue region undergoing drug delivery. Such properties include amplitude, phase, frequency, combination of excitation sources, relative ratio and timing between various excitation sources, or any other properties. In some embodiments, the treatment type or sources can be also adjusted according to chemical and/or physical properties of (he drug being delivered. The (issue response lo the treatment clcmcnt/stimulalion enhances the functionality of the injected drug by enhancing the kinetics of molecular transport from the injection site inside the tissue to various compartments surrounding the tissue region and to the blood system.

[0020|In some embodiments, a treatment element or device supplying (issue treatment, or stimulation lo a tissue region can be configured to monitor and control properties of the treatment, source, !¹‘or example, controllable properties of a treatment protocol include amplitude, phase, intensity, frequency, or any other properties. b'urther control can be gained by actively monitoring, such that the information is provided to a controller (“controller” or “processing unit”) that uses the information to reduce the variability of the drug pharmacokinetics. In such embodiments, the device can be configured lo monitor properties of the adjacent tissue, such as local blood perfusion or skin temperature. Based on such monitoring, the information can be provided to the controller that utilizes the information to improve pharmacokinetic or pharmacodynamic profile of the drug us well as its performance and reduce variability of the drug injection process.

[00211 In some embodiments, the present invention’s device includes a sensor or other triggering input mechanism that is configured to prevent deployment of the drug delivery pen unless certain criteria arc fulfilled. Such criteria can include activation of a treatment protocol or clement.

[0022J In some embodiments, tissue treatment can be applied simultaneously with each injection of the drug delivery. In other embodiments, the tissue treatment or stimulation option may be selected manually by the user. In some embodiments, the user may choose to attach the treatment element lo the drug delivery pen. The user can enable or disable mechanically the automatic application of treatment element. The user can activate the

WO 201(8/1 14223

PC'I7IB2(MI8/(I51(M9 treatment device er devices before or after the drug injection to enhance the tissue response to lhe injecled drug. Such activation can be done by pressing a button or a sequence of buttons on the drug delivery pen.

[0023] I ¹'or example, in case of an insulin delivery pen, the pen may have a special button for triggering a “fast bolus” as compared to regular bolus injection provided by the drug delivery injection pen, The fast insulin bolus mode can be configured to slart one of the above treatments parallel to the injection of insulin or short time before or alter the injection of the insulin bolus for a given period of time. This improves or modifies pharmacokinetics or pharmacodynamics of insulin administration, (issue blood perfusion and/or absorption in the blood of a patient and is highly advantageous when applied in con junction with high glycemic index foods. Application of u fast. bolus” may be useful for consumption of high glycemic index foods, where larger rapid glucose excursions occurs, but. also in most, of the cases of using insulin boluses for prandial coverage. In some embodiments, application of a “last, bolus” can be set as the default mode of the drug delivery pen. In some embodiments, the user may apply the tissue treatment or stimulation before the meal 10 further increase the treatment effect.

[0024] In some embodiments, at least one effect of lhe treatments is lo reduce local irritation caused by the infused drug or local inflammation reaction caused by the injection. For example, in case of insulin injection, reducing the period in which the high concentration of insulin remains in the tissue may reduce irritation that may be caused by insulin. It can also reduce unwanted effects of lhe insulin delivery, such as, lipohyperirophy.

10025] Some embodiments of the present invention also provide methods for improving or modifying a drug’s pharmacokinetic or pharmacodynamic profile in order lo reduce time to peak action in the blood ofthe injecled material by applying a modulation pattern to the infused drug. With this modulation, the injection drug fluid is slightly movcd/pulled in and out ol the !issue during or after lhe drug injection process. In such embodiments, this method may not require an additional device applied to the skin.

[0026] In some embodiments, the drug delivery pen can mechanically attach a small disposable device to the skin cither before, during or after delivery of the drug. The disposable device can apply a treatment or treatments using at least one of the following sources: a heat source (such as a heat, resistor), a suet ion port, for example activated by a pump, a mechanical vibration source, an ultrasound excitation source, an ultrasound

PCT/IB2008/05l049 transducer, a light source, a massaging element, electromagnetic radiation source, electric field source, magnetic held source, additional substance and/or a combination of at least two of sources lo improve drug pharmacokinetics. In sonic embodiments, lhe small disposable device can be attached manually cither before or after injection of the drug.

[0027] In some embodiments, a device lor drug injection includes a disposable injection needle for injecting drug into tissue, a reusable drug delivery pen for inserting (he needle into lhe patient skin or subcutaneous layer and for injection of the drug through the needle into one 01 lhe skin and/or subcutaneous tissue layer, a treatment device for applying a specific treatment or stimulation to the drug injected region in order to improve drug’s pharmacokinetic, pharmacodynamic profile and/or lo increase blood perfusion in that region before, during and/or after Lhe drug injection period 10 improve drug absorption into the blood system. 1 he needle can be injected automatically at the target site using an automatic needle triggering piston or spring. In some embodiments, the needle can he injected al. the target site manually through the action of the user inserting the needle independently.

[0028] In some embodiments, a device fordrug injection includes an injection catheter for insertion into the tissue, a drug injection device for infusing a drug into lhe injection catheter, a treatment device for applying a specific treatment, or stimulation to the drug infused region in order Lo improve, modify and/or stabilize the drug pharmacokinetics, pharmacodynamics, and/or lo reduce variations of the drug absorption into the blood system.

[0029] In some embodiments, a device for drug injection includes at. least one of the following: a display, a button, a memory for boluses, a processing unit, a sensor for skin properties, a sensor lor treatment level, a glucose sensor, a user interface, wireless connection to a PDA or cell phone for having memory and reminders and remote access to support, sites.

[0030] In some embodiments, lhe device fordrtig/insulin injection includes a glucose sensor. The glucose sensor may measure blood glucose level al alternate sites (for example, at sites with reduced blood perfusion, such as arms and legs). The glucose sensor can be provided on the opposite side the injection end.

[0031] In some embodiments, the present invention can be configured for a jet injection. Jet injection involves high pressure injection of material, which obviates the use of needles. This type 01 injection mode is also referred lo as “needle lice” or “needlelcss” injection. In some embodiments, the pen injection device can include a jet injection, in addition lo or in place of,

PC 1/1B2 008/0 51049 !he use of one or more needles. Some examples of conventional needle-1 'rec injection systems include lhe Medi-Jeclor VISION® and some products by Antares. Such systems can he adapted for use with lhe present invention’s jet injection system.

(0032J In some embodiments, the injection device includes a disposable nozzle and a reservoir having an additional substance. The reservoir is located al the nozzle and lhe additional substance is provided in a single use or single dose amount. The reservoir is located within lhe body of the device anil the nozzle features a connector for fluid or other communication with the reservoir.

[0033] In some embodiments, rather than disposing a nozzle along with an additional reservoir, an applicator for an additional substance is provided that is attached to or separate from the device. The nozzle can he disposed along with a gauge for adjusting lhe amount of additional substance to be applied. 1 he applicator may be controlled through a button or other control component. In sonic embodiments, the gauge can be configured as a ring that can he rotated around lhe applicator button or other control device to adjust the amount that lhe button is pressed and/or some function of the oilier control device and/or to adjust the dose of applied additional substance.

[0034] In some embodiments, the drug delivery pen can include an adhesive material, such as a slicker, lor assisting the user to create a skin Ibid for administration of the drug and/or additional substance.

BRlIil׳ DHSCRII’TION 01. Ί Ι11. DRAWINGS 'Πιο invention is herein described, by way of example only, with reference to (he accompanying drawings. With specific reference now to the drawings in detail, it is stressed that lhe particulars shown are by way of example and for purposes of illustrative discussion ol the prclerred embodiments of the present invention only, and arc presented in order to provide what is believed to be the most useful and readily understood description of the principles and conceptual aspects of the invention. In this regard, no attempt is made to show structural details of the invention in more detail than is necessary for a fundamental understanding 01 lhe invention, (he descript ion taken with the drawings making apparent to those skilled in lhe art how the several forms ol’lhc invention may be embodied in practice.

10035] [^,'igiires IA-F illustrate an exemplary drug delivery pen combined with a mechanism lor topical application of an additional substance to the drug injection site, according to some embodiments of the present invention.

[0036] Figures 2A-C illustrates an exemplary drug delivery pen combined with a mechanism for topical application of an additional substance to the drug injection site, according to some embodiments of the present invention.

[0037] 1¹'igures 3A-C illustrates an exemplary drug delivery pen combined with a mechanism for topical application of an additional substance to the drug injection site, according to some embodiments of the present invention.

[0038] Figures 4A-D illustrates an exemplary drug delivery pen combined with a mechanism for topical application of an additional substance to the drug injection site, according to some embodiments of the present invention.

[0039]I ^,'igiires 5A-C illustrates an exemplary drug delivery pen combined with a mechanism lor application of a treatment element on (he drug injection site, according to some embodiments of the present invention.

[0040] Figures 6A-C illustrates an exemplary drug delivery pen combined with a mechanism for application of a treatment, element on the drug injection site, according to some embodiments of the present, invention.

[0041] Figures 7A-C illustrates an exemplary drug delivery pen and cover combined with a mechanism lor application of a treatment clement, on the drug injection site, according to some embodiments of the present invention.

10042] Figures 8A-D illustrates an exemplary drug delivery pen combined with a mechanism lor application of a treatment element on the drug injection site, according to some embodiments of the present invention.

[0043] Figures 9A-C illustrates an exemplary drug delivery pen combined with a mechanism for application of a treatment element on the drug injection site, according to some embodiments of the present invention.

WO 20118/114223

PC'171B2008/051049

[0044] Figures 10Λ-Ι׳' illustrates an exemplary treatment clement, that may be coupled to a drug injection at the drug injection site, according to some embodiments of the present invention.

[0045] Figures 11 Λ-l i arc block diagrams of exemplary drug delivery devices, according to some embodiments of the present invention.

[0046] Figures 12A-C illustrate an exemplary drug delivery pen combined with a mechanism for application of a treatment element on the drug injection site, according to some embodiments of the present invention.

[0047] Figure 13 is a flow chart illustrating an exemplary method for controlling temperature of healing that is provided by a treatment clement in order to prevent degradation of a temperature sensitive drug.

DETAILED DESCRIPTION OF’THE INVENTION

[0048| I 'he present invention relates to a drug delivery pen or other drug injection devices for the injection of a drug al a drug injection site, where lhe drug in injection device applies a treatment that can improve injected drug’s pharmacokinetic and/or pharmacodynamic properties. The following description will refer to a drug injection pen for illustrative, nonlimiting purposes, however, as can be understood by one skilled in lhe art, the present invention is applicable to any other drug injection devices.

[0049] Figures 1 Λ-C are schematic diagrams of an exemplary drug delivery pen 100 having a treatment element coupled to the delivery pen, according to some embodiments of the present invention. Figures 1 A and 1 B depict an exemplary drug delivery pen 100 having a pen shaft 110, an injection piston release tri gger/bu tion 1 12 (for actuating a piston pump, for example, within lhe housing of the deli very pen), a treatment release tri gger/bu !.ton 108 (for actuating a pump lor delivering the treatment), a needle opening and a housing 102, treatment delivery openings 104, and a drug dosage selector 106. Figure IA is a perspective view of the drug delivery pen 100. Figure IB is a side view of the pen 100.

[0050] The drug delivery pen, for the delivery of insulin, may function as do stale of the art drug delivery pens by injecting lhe selected and determined drug dosage 106 and using injection piston release button 1 12 to release the piston (not shown) that presses and/or otherwise places pressure on the drug reservoir syringe or vial, for causing injection of the required dosage of drug (not shown) into the targeted area and through needle housing 102. In some embodiments, a fluid jet of (he delivered drug can be utilized instead of a syringe to delivery the drug Ihrough housing 102 lo lhe targeted delivery site. The drug delivery pen can provide an additional treatment, element, such as, an anesthetic, a drug for inducing treatment, a drug for improving effectiveness of lhe primary drug being injected. 'The primary drug can be insulin.

10051] The treatment can be delivered over lhe target tissue using the treatment, delivery openings 104, wherein a fluid treatment substance can be applied or sprayed onto the tissue, figure 1C is a cross-sectional view of the ding delivery pen 100 showing the treatment element 130 and components thereof. Treatment clement 130 includes treatment compartment 120, a plurality of valves 122, a pump 126 and a treatment release button 128. In some embodiments, the treatment compartment 120 stores a formulation of a liquid, ointment, solution, aerosol, foam, solid, gel foam, pressurized liquid, gas, spray, pain reliever drug, analgesic, vasodilatation drug, septic, alcohol, or the like for treatment of the skin tissue area. In some embodiments, treatment may be applied prior to or following deployment of the needle.

L0052J Treatment substance stored in compartment 12() can be pumped to lhe treatment release openings 104 using schematic pump 126 that is activated by pressing treatment release button 128. The treatment release bulton 128 releases valves 122 (0 deliver treatment liquid from the compartment 120 through the tube 124 that, leads to openings 104. The treatment applied loan area can lead to improved pharmacokinetic and/or pharmacodynamic properties of lhe primary drug being delivered by way of injection. The pathway by which the pharmacodynamic and/or pharmacokinetic properties of the drug arc improved may be dependent on the treatment substance or element utilized.

[0053] figure I D is a partial exploded view of a drug delivery pen 140 having a manual injection portion 141, according lo some embodiments of lhe present invention. Pen 140 includes a pen body !50, a dosage release button 142, a treatment release button 148, a drug dosage selector 146, and an injection coupling portion 144. Injection coupling portion 144 is a conneclion mode to securely affix injection portion 141 to lhe pen portion 140. 'lhe coupling of the injection portion 141 lo lhe pen portion 140 may be accomplished by al least one or more connecting pieces, such as, male/leniale connectors, threaded connectors, snap conneclor(s), turn key connectors, hook connectors or any other suitable connectors.

[0054] Manual injection portion 141 includes a treatmenl substance reservoir 152, a Ircatmcnl delivery opening 154 and a needle 158. The manual injection portion 141 can be disposable after a single use. 1 lowever, the injection portion 141 can be reusable and can be used a number of times or repeatedly over a period of time. Prior to drug delivery (he drug delivery pen body 150 is securely coupled to manual injection portion 141 allowing a user to use lhe drug delivery pen 140 by selecting a drug dosage using dosage selector 146. Treatment, release button 148 triggers lhe release of lhe treatmenl substance from the treatment reservoir 152 through delivery openings 154, The liming of treatmenl release can be performed prior lo, during or following drug delivery, or in a combination thereof. Drug delivery can be accomplished by setting lhe dosage amount using dosage selector 146, manually inserting needle 158 into the large! site, releasing treatment substance through delivery openings 154 and finally delivering the drug with dosage release button 142.

[0055] Figure IE depicts an additional optional embodiment of the manual drug delivery pen of I^,igure 1D. Manual drug delivery pen includes a drug delivery pen housing 160 and manual injection portion 161. Pen housing 160 includes a pen body 170, a dosage release button 162, a drug dosage selector 166, a treatment release button 168, a treatment dosage selector 178, a treatment substance lube 176, and an injection coupling portion 164. The injection coupling portion 164 can be configured to securely affix injection portion 161 1.0 the pen body portion 160. Coupling of the injection portion 161 to pen portion 160 can be accomplished by al least one or more connecting pieces, such as, a male lo female conncclor(s), threaded connectors, snap conncclor(s), turn key conncctor(s), hook connectors or any other connection devices.

[0056] Manual injection portion 161 is disposable for single use, however, injection portion 161 may be used a number of times, or repeatedly over a continuous period of lime. Prior 10 drug delivery the drug delivery pen body 170 is securely coupled to manual injection portion 161 allowing a user to use drug delivery pen 160 by selecting a drug dosage using drug dosage seleclor 166. Treatmenl dosage selector 178 determines the dosage of lhe treatment substance 10 be released with treatment release button 168. Pressing treatment release button 168 triggers the release of the t reatment substance from the treatment reservoir (not shown) through at least one or more treatment delivery lube 176 that ends in treatment delivery openings 174. Timing of treatmenl dosage selection ami release may he performed prior 10, during or following drug delivery, or in a combination thereof. Drug delivery is accomplished by selling the dosage amount using dosage selector 166, manually inserting

WO 2(1(18/1 14223

I'CT/1132(48/(151049 needle 158 into lhe target site, releasing treatment substance through delivery openings 174 as described above and finally delivering lhe drug with dosage release button 162.

[0057] Figures 2A-C illustrate an exemplary drug delivery pen according lo lhe present invention which is similar lo the embodiments depicted in Figures 1A-C. In Figures 2A-C embodiments, the treatment opening is on the opposite side of the needle housing. Figures 2Λ and 2B depict a drug delivery pen 200 including a pen shaft 210, an injection release button 208, a treatment release button 212, a needle opening and a housing 202, a treatment delivery opening 204 and a drug dosage selector 206. Figure 2A is a perspective view of the drug delivery pen 200. Figure 2B is a side view 01' pen 200.

[0058] 1 ^,he drug delivery, such as insulin delivery, functions in a similar fashion as some conventional pens, such as NovoPcn, Flexl’en, Sanofi Aventis pens or the like, by setting the determined drug dosage 206 and pressing an upper button (not shown in Figures 2A-C) that pushes the syringe piston (not shown in Figures 2A-C) at lhe required distance lo inject the dosage that was set, such that injection release button 208 is not required. For other pens, such as the Autopen 24, after setting the determined drug dosage 206, the drug is injected by releasing lhe injection release button 208 which releases (he piston (not shown in Figures 2ΛC) that pushes lhe syringe piston to (he required distance lo inject, lhe desired dosage as set. by dial 206. In some pens, for drug delivery, lhe drug is accomplished by selling lhe determined drug dosage 206 and pressing lhe needle release bulton 208, to release the needle (not shown in Figures 2 A-C) into the targeted area and through needle housing 202, thereby injecting the required drug dosage through that needle. I lowever, the drug delivery pen according lo the present invention provides an additional treatment element, such as, in Lhe form of another drug, lo induce a treatment for improving (he primary drug being injected. The above injection pen’s configuration and mechanism as well as other injection devices, such as syringes or jet injectors, can be configured (0 be used wilh devices and methods for applying additional (realment lo lhe vicinity of the drug injection site, as described by the present and related applications. In some embodiments, the primary drug can be insulin.

[0059]The treatment is delivered over the target tissue using the pen’s treatment delivery openings 204, wherein a fluid treatment substance is applied onto the tissue. Figure 2C is a cross-sectional view of drug delivery pen 200 showing lhe treatment clement 230 and components thereof. Treatment elcmcnl 230 includes a treatment compartment 220, a plurality of valves 222, a pump 226, a treatment, luhe 224 and a ircalmenl release bulton 228. '111c treatment compartment 220 stores a formulation, a fluid, such as a liquid, ointment,

WO 20(18/114223 solution, aerosol, pressurized liquid, gas, spray, pain relieve drug, analgesic, vasodilatation drug, septic, alcohol, or the like for treating the skin tissue area. The treatment may be applied prior to or following deployment of the needle, in a two step process one end of the pen lor substance treatment delivery using opening 204 and (he opposite end for (he injection using housing 202.

[006(»] A treatment substance stored in the compartment 220 can be pumped to the treatment release openings 204 using schematic pump 226 that is activated by pressing the treatment release button 228. The treatment release button 228 releases valves 222 to deliver treatment liquid from the compartment. 220 through the tube 224 that leads to the openings 204. In some embodiments, the treatment applied to an area may lead to improved pharmacokinetic and/or pharmacodynamic properties of the primary drug being delivered by way of an injection. The pathway by which the pharmacodynamic and/or pharmacokinetic properties of lhe drug are improved may be dependent on the treatment substance or clement utilized,

[0061] Figures 3A-C illustrate an exemplary pen-type drug delivery device similar to that described in connection with Figures I Λ-F and 2A-C, however, in this case, the treatment substance is applied by way of a roller-applicator ball 304 onto the tissue being treated.

Figures 3Λ and3B illustrate similar views of drug delivery pen 300. The drug delivery function of pen 300 is similar to the functions of pens shown in Figures IA-F and 2A-C. The drug dosage can he controlled and determined using a dosage dial 306 that is delivered via the needle housing 302 lhal encloses a needle (not shown in Figures 3A-C), which is triggered using an injection release button 312. A treatment substance may be applied to the injected area cither prior to or following injection.

[0062] Figure 3C depicts treatment element 330 including treatment substance container 320 and substance application ball 304. The treatment compartment 320 stores a lluid, such as, a liquid, ointment, solution, aerosol, pressurized liquid, gas, spray, pain relieve drug, analgesic, vasodilatation drug, septic, alcohol, or the like for treating the skin tissue area. Treatment may be applied with a bull 304 prior to or following deployment of the needle, in al least a two-step process one end of the pen for substance Ircalmcnt delivery using ball 304 the opposite end for lhe injection using housing 302.

[00631 Figures 4A-C illustrate another exemplary drug delivery pen 400, according to some embodiments of lhe present invention. Treatment substance 430 used to improve the pharmacokinetic and/or pharmacodynamic properties of the drug being delivered, such as

WO 201)8/114223 insulin, may come in the form of a solid, gel, gel form, thixotropic solution or the like, '[^,he substance 430 may he applied to a treatment area cither prior to or following drug delivery using a needle delivered through needle housing 402. The treatment substance 430 can be a solid, stick, ointment, solution, pain relieving drug, analgesic, vasodilatation drug, septic, alcohol, or the like to treat the skin or tissue area. Substance treatment 430 can he rubbed, rolled over the treated area or applied in any other ,suitable way.

[0064] The drug delivery pen 400 may be manufactured separately from the individual treatment substance 430; alternative, the drug delivery pen 40() may be manufactured along with treatment substance 430 being coupled thereto, !^,'igurc 41) depicts the treatment substance 430 that can be configured to fit over the pen shaft. 410 using a slicker, a threading, an adhesive layer, a clip, or any other coupling tools. The pen shaft 410 can be pushed through the lumen of treatment substance 430. The treatment substance 430 can be configured to fit circumferentially around lhe pen shaft 410. In some embodiments, a single use or a reusable treatment substance 430 can be used with other drug injection devices, such as a syringe.

10065]I ^,’igurc 5Λ illustrates an exemplary drug delivery injectable pen having a needle housing that can accept secondary devices for substance treatment deployment or use, according to some embodiments of the present invention. Drug delivery pen 500 includes shaft. 510 that is configured to contain a volume of lhe injectable drug (such as insulin) for delivery. Λ dosage dial 506 sets the dosage to be injected with a needle that is injected via an injection release button 520 through lhe needle and the needle housing 502.

[0066] In some embodiments, the drug delivery pen 500 includes a glucose sensor 501 for measuring blood glucose with a finger slick. Glucose sensor 501 can be configured to be on the lop of the drug delivery pen 500. The pen 500 can be used to release a needle that, is used to draw a drop of blood that may be placed over a finger stick (not shown in Figures 5A-C) and is placed over the glucose sensor 501 for reading lhe glucose levels in the drawn blood sample. Additionally, Lhe drop of blood can be applied to a finger stick like glucose sensor inserted into a glucotncler type slit, for example on the top of pen 500 (not shown in Figures 5A-C).

[0067] !^,’igurc 5B depicts a treatment clement apparatus 530 that may be coupled to lhe drug delivery pen 500, as shown in !׳'igurc 5C, to form drug delivery apparatus 540. The drug

WO 20(18/114223

1’CT/IU2(IO«/(I511)49 delivery apparatus 540 including the treatment element apparatus 530 and drug delivery pen

510 may he single unit.

[0068] Thc Irealment element apparatus 530 includes :1 female connector 524 that can he securely coupled lo Lhe needle housing 502, which has a corresponding male conneclor shape. The coupling can he undertaken hy threading, fitting, pin lock assembly, adhesives or any other coupling methods. The drug delivery pen 530 includes ircatnienl substance dispenser 520 that contains a roll 520 adhered to a plurality of treatment element 526. The treatment element 526 can be securely placed over lhe end of needle housing 502. The treatment, element 526 can be implemented in the form of a pad (e.g., releasing an additional substance), a heating pad, a PCB healing element, an optical treatment, element, an electromagnetic radiation irealment element, an electrical current treatment element, an acoustical treatment, element, a massaging (reatmenl element or an element related (o any of lhe Irealment. methods discussed above. The treatment element 526 can deliver treatment to a target tissue prior lo injection, following injection, or at the time of injection to improve lhe pharmacodynamic and/or pharmacokinetic properties of an injectable drug. Treatment element 526 can also include a power source to provide the desired irealment power. Treatment element can include a control element, such as an electrical circuit, to control (lie treatment profile. Treatment, element, can be disposable, e.g., single use treatment element, whereby after the treatment profile ends, the user can dispose of the treatment element 526. Trcalmcnl. element can be reusable, whereby ai'lcr the Irealment prolile ends, the user can recharge it, exchange the power source, or exchange only a portion of (he Irealmenl element 526 that is disposable and (hen reload it into a new or lhe same (reatmenl substance dispenser 520 or a substance dispenser 630 shown in I'igure 6Λ or any other configuration, as disclosed in the present application.

[0069] P'igures 6A-C illustrate exemplary irealmenl element dispensers that may be coupled lo a drug delivery pen 500, as illustrated in I'igure 5Λ. !’igutc 6Λ illustralcs a irealment dispenser 630 that is an optional alternative lo dispenser 530 of I'igure 5B. Treatment dispenser 630 includes stackable treatment elements 626 that may be coupled to the pen drug delivery device. I'igure 6B illustrates how a drug delivery חסון is coupled to the treatment element dispenser 630. Once the treatment element, dispenser 630 is decoupled from (he deliver}׳ pen apparatus 650, the needle end of the apparatus is coupled with a irealmenl element 626. The treatment element 626 is alignable with the needle of drug delivery pen 650. This alignment provides for a drug delivery and ircatnienl apparatus 650 lo induce

WO 20(18/1 14223

I’CT/1B2(1O8/()51()49 application of treatment using element 626 prior to, following, or al lhe same lime as undertaking ding delivery with the drug delivery pen 600 in a one step process.

10070]In some embodiments, the drug delivery using the pen 60() and evoking treatment, using clement 626 may he undertaken in a two-step process, where treatment clement 626 is coupled to a non-needle end of lhe drug delivery pen 600. This allows drug delivery and treatment to be performed individually. 1¹’or example, one can trigger the drug delivery with the injection release button 612 and later evoke treatment using clement 626. The reverse is also true where treatment may precede drug delivery.

[0071] In some embodiments, the treatment element, such as treatment element 526 (shown in I^,'igtircs 5A-C) or element 626, is coupled to a single use needle that is secured to the pen before each dose injection (as shown in Figures 11) and 11(), such (hat. when the needle is inserted into Lhe body, Lhe treatment element is attached to and/or otherwise adheres to or around the injection site, automatically, without the need of additional operations by the user.

[0072] I ׳’or any oflhc embodiments shown herein, the treatment element may include an energy source, which can provide heat, radiation, mechanical vibrations, suction, magnetic energy, ultrasound, light irradiation, KI־’irradiation, microwave irradiation, electrical stimulation, or any other form of energy or combinations of those energy sources, For example, the treatment element, may include a healer to heal, the injection site; or a source of optical energy for the energy source, such as a light source, including but not limited to LEDs or laser diodes for example, with one or more other optical elements; or a micro-wave generator or emitter configured to irradiate the injected region with micro-wave radiation; or a radio frequency electromagnetic radiation generator or emitter configured Io irradiate (he injected region with radio frequency electromagnetic radiation; ora vibration device configured to vibrate the injected region; or a vacuum device for applying suction to the injected region; or an electric Held generator or emitter configured to apply an electric field to lhe injected region; or a magnetic field generator or emitter configured to apply magnetic field to the injected region; or an acoustic signal generator or emitter configured to apply acoustic stimulation to the injected region.

10073] I ׳igures 7A-C illustrates an exemplary drug delivery pen 70(1 similar (0 the pens shown in FIGS. 5A-C and 6A-C, that is coupled to a treatment element dispenser73(1 as shown in Figure 7B to create drug delivery and treatment, apparatus 750. The apparatus 750 includes a treatment clement, dispenser 730 al. lhe non needle end of drug delivery pen 700.

IS

PC171B2008/051049 ^,!’he apparatus 750 provides the drug delivery pen with an ability to deliver drug(s) in a chosen dosage while providing lhe treatment clement that may improve the pharmacokinetic and/or pharmacodynamic property 01' the delivered drug. In some embodiments, the user can store his/her treatment elemenl(s) in a special case, or in the case 01' the drug injection device. Before or after lhe drug injcclicin, the user inserts lhe treatment clement, as discussed above, into lhe treatment clement dispenser 730 and applies it to the injection sile. In some embodiments, the treatment element can have a similar shape as the treatment element dispenser 730 and can be coupled direct ly to the drug delivery pen 700 without using the trealmcnl clement dispenser as an adaptor.

[0074] Figures 8A-D illustrate an exemplary treatment apparatus, similar to the one shown in FIGS. IA-3C, according some embodiments of lhe present invention. Figure 8Λ depicts a drug delivery pen 800 used to deliver an injectable drug. Figures 8B anil 8C are views of the treatment element 830 that can be coupled to the drug delivery pen 80(), thus, forming a drug delivery and treatment apparatus, as shown in Figure 8Λ. The trealmcnl clement 830 can be coupled to the pen 800 via the opening 840 that receives the needle end of the drug delivery pen 800. Treatment clement 830 includes a treatment substance compartment 820 that, can be utilized to store treatment, fluid. The treatment compartment 820 stores a fluid, such as gel, foam, liquid, ointment, solution, aerosol, pressurized liquid, gas. spray, pain relieve drug, analgesic, vasodilatation drug, septic, alcohol, or the like for treating the skin tissue area. Treatment can be applied prior 10 or following deployment of lhe needle.

[0075] Treatment liquid stored in the compartment 820 can he delivered to the target tissue through the opening 804 using pump 826 that is activated by pressing the treatment release button 828. 'lhe treatment release button 828 releases valves 822 to deliver treatment liquid front the compartment 820 through the lube 824 that leads to the opening 804. In sonic embodiments, the amount of irealnicnt liquid can he preset for a user. In some embodiments, a special dial or other means, (not shown in Figures 8Λ-Ι), but illustrated in F'igurc 1E), may he used to set. the amount of applied trealmcnl substance. The treatinenl applied to an area can lead to improved pharmacokinetic and/or pharmacodynamic properties of the primary drug being delivered by way of injection (e.g., insulin). The pathway by which the pharmacodynamic and/or pharmacokinetic properties of lhe drug are improved is optional and may be dependent on the treatment substance or element utilized.

[0076] Figures 9A-C illustrate the drug delivery pen 900 having the treatment element provide pressure-related treatment, such as suction, massage, or lhe like, according to some embodiments 01' the present invention, figure 9 A depicts a drug delivery pen and treatment apparatus 950 including a drug delivery pen 900 and a treatment element attachment 930 (hat can be mechanically coupled. The apparatus 950 can be provided as an assembled or unitary drug delivery device. The apparatus 950 can be coupled lo lhe treatment element 940 that is made from a pliable material (hat can withstand pressure. Such material can be rubber, latex, or any other suitable material configured lo create suction over a given treatment area similar to a plunger. The apparatus 950 is placed over the treatment element 940 and is compressed lo create further pressure, as shown in figures 9B and 9C, or suction when the pen is lifted. Such suction will bring about vasodilatation in the treated tissue and is configured to improve pharmacodynamics and/or pharmacokinetics of the delivered drug. Drug delivery deployment can be undertaken in the compressed form of (he treatment element 940, as shown in figure 9C.

[0077] figures 10A-D illustrate a variety of pressure based treatment elements, according to some embodiments of the present invention. Figure Ι0Λ is a cross-sectional view of the treatment element shown in figure 10B. l he treatment clcmenl can be used during drug delivery and includes a lumen 1000 allowing the needle to penetrate through, figure !0(3 is a cross-sectional view of (he treatment element shown in figure 10D. The treatment element of figure 10D can be utilized cither prior to or following drug delivery in order to create suction over the tissue area, 'lite treatment elements of figures Ι0Α-Ι) can be used to create suction or vacuum in lhe vicinity of the drug injection site and to induce local vasodilatation.

[0078] figures lOf. and I Of illustrate an exemplary trcalmcnl clement configured as a durable adhesive tape (hat is uscil to effectively pinch a fold of skin while maintaining its shape. The trcalmcnl element shown in figure 101 (includes two sticky ends 1050 that are bridged by a malleable section 1052. Each one of the ends 1050 is placed over a patch of skin where an inject ion for example with a syringe or a drug delivery pen is to be undertaken. Once in place, the ends 1050 arc pushed toward each other by the malleable section 1052 to form a bell type shape. Seclion 1052 can be manufactured from a strong malleable material that can hold its shape, while being repeatedly formed and deformed, figure I Of depicts the treatment element of figure I Of in a folded form. Section 1052 can be moulded and reshaped forming a treatment clement for example lo bring about vasodilatation.

[0079] 1 ¹'igure 11A is a block diagram of an exemplary drug delivery apparatus 1100 having a treatment element 1 102 incorporated into a drug delivery pen 1104, wherein lhe treatment element is integrated into lhe drug delivery pen, according lo some embodiments of the

PC171B2008/051049 present, invention. Figure I 111 is a block diagram of an exemplary drug delivery apparatus 11 10 having a treatment clement 1112 and a ding delivery device I 114 that are removably coupled lo each other, according lo some embodiments of the present invention. The drug delivery device 1 114 or treatment element I 1 12 can function independently of one another and can be securely coupled lo each other lo form a single drug delivery and treatment apparatus I I 10, similar lo the embodiment of Figures 4A-6C. Drug delivery device I I 14 can be implemented as a syringe, drug delivery pen, drug delivery jet injector or the like.

(00801 Figure 1 IC is a block diagram of an exemplary drug delivery and treatment apparatus that further includes a sensor 1126, such as a glucose stick sensor, for measuring blood glucose. The drug delivery apparatus 1 120 communicates with an external processing unit I 130. The processing unit can be a PDA, a cellular phone, a computer, a laptop or any other device. The unit I 130 includes a controller I 132 and a display 1134. The controller 1132 controls analysis of data received from the drug delivery apparatus I 120 to determine treatment, or dosage form or the like related lo the functioning of drug delivery pen 1124, and treatment clement I 122. The processing unit I 130 provides the user with data regarding historical and current use of the drug delivery apparatus 1120.

10081] Figure 11D is a block diagram of an exemplary drug delivery device similar Lo the device shown in Figure IIC, where the drug delivery apparatus I 140 has an integrated sensor I 146, a processing unit. 1 150 and a display I 148, according to some embodiments of the present invention. This allows the user lo fully control, visualize all activity related Lo the drug delivery pen I 144 or the treatment clement I 142.

10082] Figures 12A-C schematically illustrate exemplary treatment clement dispensers that may be coupled lo a ding injection device 1200 (as shown in Figure 12C), according to some embodiments of the present invention. Figure Ι2Λ illustrates a treatment element 1210 with a power source 1211. In some embodiments, the treatment element 1210 includes a power source and a control clement to control a treat menl profile, For instance, in case of heal ing, treatment clement 1210 can include a heater to heal the tissue around the injection site to a temperature that improves drug’s pharmacokinetics and pharmacodynamics. In case of temperature sensitive drugs, such as insulin, treatment element 1210 can include a heater to heat the (issue around the injection site lo a temperature that improves drug’s pharmacokinetics and pharmacodynamics, without healing the drug above a limiting temperature that may degrade it, such as 37^״C in the case of some types of insulin. Treatment

WO 20(18/114223

PCT/1B2008/05I049 element 1210 may include also an adhesive layer on its bottom side covered with a laminate

1212.

[0083]In some embodiments the user has a case with one or lew treatment elements 1211). When the user wants (0 use treatment element over drug inject ion site, the user takes adaptor 1220, which can be stored in the same case or a different one, and allaches one (realincnl clemcnl 1210 to adaptor 1220, as shown in Figure 12B. Treatment clement 1210can be attached to adaptor 1220 with a weak mechanical locking, such as a plastic clip, or weak adhesive or other ways known in the art. '['hen laminate 1212 can be removed. Afterwards, adaptor 1220 is assembled or threaded over drug delivery pen or syringe 1230, as shown al Figure 120. In some embodiments needle cap 1231, can be removed from the needle. Then, the needle is inserted into injection site (issue, the drug injection device is operated and the drug is injected through needle into the tissue. During that time, or slightly before or after adaptor 1230, is pushed down to the tissue and treatment clement 1210 is attached to the tissue around drug injection site.

[0084] In some embodiments, the attachment of trealmcnt element 1210 to the tissue is configured to activate it automatically and the treatment starts according to a predetermined treatment profile. This function can be performed, for example, by a small switch which is pressed when treatment clement 1210 is attached to the tissue. In some embodiments, the treatment element 1210 can be activated manually. In some embodiments, treatment, clement can he controlled and/or programmed for a specific treatment clement through a remote control or a connection to its case. Afterwards, the injection device 123(.) and the adaptor 1220 arc lifted off, cither together or separately, and the treatment, clement 1210 is left attached to the tissue and applies trealmcnt to the vicinity of the drug injection site. The user can remove treatment element after treatment ends or later on. In some embodiments, the treatment element includes an indicator for the user that indicates the beginning of the treatment and the end of the treatment. In some embodiments, the treatment clement 1210 may be disposable.

[0085] In some embodiments, the treatment element’s 121() power source 1211 may be rechargeable, so that after the treatment ends and the user removes it from the skin, it can he put back to the case and/or placed in a charging cradle for recharging which may be disposed in said case. In some embodiments, the treatment clement. 1210 may have a disposable portion and a reusable portion. In some embodiments, the drug injection device and al least one treatment clement are disposed in the same case prior to injection. This provides additional comfort lor (he user and allows lhe user lo use both of them together or one after the other.

10086] Figure 13 is a flow chart depicting a method for controlling lhe temperature of heating provided by a treatment elements that heal the injection site tissue vicinity in order 10 prevent degradation of a temperature sensitive drug. As shown in step 13()(), a drug is provided for injection to the patient, where the drug is sensitive lo degradation above a limiting temperature. In step 1301, a treatment element is provided that features a controllable heating through a controllable beating clement. In step 1302, the treatment element is placed in thermal contact with the tissue to be heated, such that heat from the treatment element is transferred to lhe tissue 10 be heated.

]0087] In step 1303, a maximum temperature provided by the treatment element is controlled, such (hat lhe temperature experienced by lhe drug (that is, in the environment of the drug) docs not exceed (he limiting temperature sustainable by the drug before degradation occurs.

In some embodiments, he maximum temperature can be calibrated for each drug and/or class of drugs. For example, for some types of insulin, the limiting temperature is about 37 C.

[00881 In some embodiments, such control can be provided through a microprocessor or other processor for controlling the temperature output by a heating element. A sensor can be provided in order to measure the temperature at and/or near the tissue being heated, in order to determine the temperature experienced by the tlrug.

[00891 The treatment clement includes one or more materials capable of generating an exothermic reaction, in which lhe amount of such materials and/or ratio can be calculated in order for the temperature of the reaction not lo exceed the maximum temperature set for the treatment element based on the desired limiting temperature oflhc drug. The exothermic reaction can be a heat-genct'aling oxidation reaction, for example, with a mixture of iron powder, activated carbon, salt and waler. As can be understood by one skilled in the art, other such mixtures of materials can be used.

[0090] In sonic embodiments, lhe treatment element and the drug delivery pen arc not disposed in (he same housing. However, in such cases lhe user may forget lo apply the treatment to lhe injection site in some cases, thereby changing the pharmacokinetics, which is undesirable. Therefore, to prevent that the drug delivery pen can include a mechanism for reminding the user to apply the required treatment, before, during or after injecting the drug into lhe tissue, In some embodiments, the drug delivery pen includes a mechanism (hat identifies whether the treatment was applied or not. and permits drug injection only when the tissue treatment was applied. In some embodiments, (he drug deli very pen includes, in addition to the drug injection mechanism, a sensor that indicates whether the treatment was applied or was not applied anti a processing unit that enables injection of the drug only when the tissue treatment was applied. Such sensor can be an optical sensor that measures optical properties of the local tissue, or Laser Doppler Flowmeter (“LI)I׳) that can measure local blood perfusion and identify that the vasodilatation inducing local treatment was applied and that the treatment level was adequate.

[0091] Example embodiments oflhe methods and components of the present invention have been described herein. As noted elsewhere, these example embodiments have been described for illustrative purposes only, and arc not limiting. Other embodiments are possible and are covered by the invention, For example, at the present application many of the suggested methods and devices can be used for many oflhe drug injection devices, such as injection pens or syringes or jet injector and other known in the art injection devices, so although the examples arc mainly given for injection pens they arc applied l.o the other injection devices as well. Such embodiments will be apparent to persons skilled in the relevant art(s) based on the teachings contained herein. Thus, the breadth and scope oflhe present invention should not be limited by any oflhe above-described exemplary embodiments, but should be defined only in accordance with the following claims and their equivalents.

[0092] Any and all references to patents, patent applications, articles and other published and ηυη-published documents made in the present disclosure arc herein incorporated by reference in their entirety.

[0093] It is to be understood that while the invention has been described in conjunction with the detailed description thereof, the foregoing description is intended to illustrate and not limit lhe scope of the invention, which is defined by the scope of the appended claims. Other aspects, advantages and modifications are within the scope of the following claims.