HK1074590A - Enhanced systemic absorption of intradermally delivered substance - Google Patents

Description

Promoting systemic absorption of intradermally transported substances

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation-in-part application of U.S. patent application No.09/897801, filed on 6/29/2001.

Technical Field

The present invention relates to methods and devices for intradermal administration of substances.

Background

The importance of effective and safe use of pharmaceutical substances, such as diagnostic agents and drugs, has long been recognized. Although it is an important consideration for all pharmaceutical substances, the need to obtain efficient and repeated absorption has recently been of great interest in view of the problem arising in the biotechnology industry to obtain macromolecules such as proteins with appropriate bioavailability (Cleland et al, curr. Opin. Biotechnol.12: 212-219, 2001). The use of conventional needles has long provided a means for delivering pharmaceutical substances to humans and animals by transdermal administration. Considerable effort has been expended in achieving repeatable and effective transport through the skin, while improving ease of injection and reducing patient apprehension and/or pain associated with conventional needles. In addition, some delivery systems completely eliminate the needle and rely on chemical agents or external driving forces such as ionic influx or electroporation or thermal perforation or acoustophoresis (sonophoresis) to break through the outermost stratum corneum layer of the skin and transport the substance across the skin surface. However, this delivery system is unable to repeatedly breach the skin barrier or to deliver the drug substance to a given subcutaneous depth, and the results are variable clinical outcomes. Thus, it is believed that a mechanical break through of the stratum corneum, such as with a needle, provides the most reproducible method of administering drugs through the skin surface, and provides controllability and reliability in the use of the administered substance.

Studies on the subcutaneous delivery of substances have almost completely involved transdermal administration, i.e. the transport of the substance through the skin to the subcutaneous site. Transdermal administration includes subcutaneous, intramuscular, and intravenous routes of administration, with Intramuscular (IM) and Subcutaneous (SC) injections being the most common.

Anatomically, the outer surface of the body is composed of two major layers of tissue, the outer epidermis and the inner dermis, which together make up the Skin (for a review see Physiology, Biochemistry, and molecular Biology of the Skin, second edition, ed., l.a. gold, eds., Oxford university Press, New York, 1991). The epidermis is subdivided into 5 layers with a total thickness of 75 to 150 μm. Subcutaneous is the dermis, which includes 2 layers, the outermost portion being called papillary dermis and the deeper layer being called reticular dermis. The papillary dermis contains a large number of microcirculation blood and lymphatic plexuses. In contrast, the reticular dermis is relatively acellular and non-vascular and consists of thick, colloidal and elastic connective tissue. Epidermis and hypodermis are subcutaneous tissues, also known as subcutaneous, which are composed of connective tissue and adipose tissue. The muscle tissue is under the subcutaneous tissue.

As described above, subcutaneous tissue and muscle tissue are often used as administration sites for medicinal substances. However, the dermis is rarely used as a target site for the administration of substances, which may be due, at least in part, to the difficulty in accurately placing the needle within the dermis. Furthermore, even if, particularly for the dermis, a papillary dermis is known in which highly concentrated vascularity is present, it has not hitherto been recognized that one can take advantage of the high concentration of vascularity to obtain improved absorption characteristics of the administered substance compared to subcutaneous administration. This is because small drug molecules are generally absorbed into the subcutaneous tissue quickly after administration, which is easier and pre-located than the dermis. On the other hand, large milk proteins are not normally well absorbed through the capillary epithelium, regardless of the degree of their vascularity, and thus, even for large molecules, one would not expect to obtain a more significant absorption advantage over subcutaneous administration by more difficult to achieve intradermal administration.

The method of subcutaneous administration and access to the intradermal air space has been routinely used in the Mantoux tuberculin test. In this method, a purified protein derivative is injected into the skin surface at the shallow bend (shallow angle) using a 27 or 30 gauge needle (Flynn et al, Chest 106: 1463-5, 1994). However, the uncertainty of the injection site may lead to some false negative test results. In addition, a local injection was used in this test to elicit a response at the injection site, and the Mantoux approach has not resulted in the use of a substance administered by an intradermal injection system.

Some researchers have reported systemic administration by so-called "intradermal" injection. In one of the reports, comparative studies of subcutaneous and so-called "intradermal" injections were performed (Autret et al, Therapie 46: 5-8, 1991). The drug substance tested was calcitonin, a protein with a molecular weight of about 3600. Although it is stated that calcium drugs are injected intradermally, the injection uses a 4mm needle and is advanced at a 60 degree angle. This will result in an injection depth of about 3.5mm and into the lower part of the reticular dermis or into the subcutaneous tissue, rather than into the papillary dermis, which is heavily vascularised. Indeed, if the group is injected into the lower part of the reticular dermis rather than into the subcutaneous tissue, it is expected that the calcium substance will either be slowly absorbed in the less vascular reticular dermis or will diffuse into the subcutaneous region, making it function as if it were administered and absorbed subcutaneously. Such substantially and functionally subcutaneous administration may explain the reported lack of differences in concentration and area under the curve at the time of reaching maximum plasma concentrations between subcutaneous and so-called intradermal administration at each test point.

Similarly, Breslole et al used ceftazidime sodium, which was characterized by "intradermal" injection with a 4mm needle (Breslole et al, J.Pharm.Sci.82: 1175-1178, 1993). This will result in injection to a depth of 4mm subcutaneously, resulting in a practical or functional subcutaneous injection, although good subcutaneous absorption would be expected in this example, due to the fact that ceftazidime sodium is hydrophilic and of a smaller molecular weight.

Another group reports so-called intradermal drug delivery devices (us patent 5007501). As stated, the injection is slow and the injection site is in some area under the epidermis, i.e. at the interface between the epidermis and the dermis or in the dermis or subcutaneous tissue. However, this document does not provide any teaching suggesting intradermal administration, nor does it suggest any possible pharmacokinetic advantage such selective administration may bring.

Thus, there is a continuing need for effective and safe methods and devices for administering pharmaceutical substances.

Summary of The Invention

The present disclosure relates toAnd a novel parenteral method of administration based on direct targeting to the dermal space, whereby the method greatly alters the Pharmacokinetic (PK) and Pharmacodynamic (PD) parameters of the substances used. Direct Intradermal (ID) administration refers hereinafter to means of accessing the dermis, for example, micro-needle based injection and infusion systems (or other means capable of precisely targeting the intradermal space), and the pharmacokinetics of many substances, including drugs and diagnostic substances, particularly proteins and peptide hormones, are altered compared to the traditional parenteral routes of administration for subcutaneous and intravenous delivery. These findings are not only relevant to injection means based on microdevices, but also to other methods of transport into the ID space, such as needle-free or non-needle-firing injections of fluids or powders, Mantoux-type ID injections, improved iontophoresis by microdevices, and improved direct accumulation of fluids, solids or other forms of administration in the skin. Disclosed are methods of increasing the absorption rate of a parenterally administered drug that must enter IV. A significant advantage of this transfer method is that it provides a shorter T_max(time to maximum blood concentration of drug). Potentially necessary advantages include a higher maximum concentration (C) for a given unit dosage form_max) Higher bioavailability, faster absorption rate, faster onset of drug or biological effects, and reduced drug storage effects. According to the present invention, improved pharmacokinetics means an increased bioavailability, lag time (T) for a given amount of compound used, as compared to other parenteral modes of subcutaneous, intramuscular or drug delivery, which are not IV_lag) Reduction of (1), T_maxReduced, faster absorption, faster onset and/or C_maxAnd (4) increasing.

Bioavailability refers to the total amount of a given dose that reaches the blood. Typically measured by the area under the curve of a concentration versus time plot. "lag time" refers to the delay between the time a compound is administered and the time blood or plasma levels are detected. T is_maxDenotes the time at which the maximum blood concentration of the compound is obtained, and C_maxIs the maximum blood concentration obtained for a given dose and method of administration. The start-up time is T_lag、T_maxAnd C_maxFunction of (2)All of these parameters affect the time to reach the blood (or target tissue) concentration required to achieve a biological effect. T is_maxAnd C_maxCan be determined by visual inspection of the graphical results and often provides sufficient information to compare the two methods of administration of the compounds. However, more accurate determinations (as described below) can be made by using kinetic model analysis and/or other methods known to those skilled in the art.

The direct targeting of the dermal space taught by the present invention provides a more rapid onset of action for pharmaceutical and diagnostic substances. The present inventors have discovered that these substances can be rapidly absorbed and systemically distributed by controlled ID administration selectively into dermal blood vessels and lymphatic capillaries, and thus, these substances can advantageously act more rapidly than SC administration. This is of particular interest for drugs that require a rapid onset, such as insulin for lowering blood glucose, analgesics for blocking cancer pain, or anti-migraine drugs, or emergency drugs such as epinephrine and anti-snake poison. The natural hormones are also rapidly burst released in a pulsatile manner, followed by rapid clearance. Examples include insulin released in response to biological stimuli such as hyperglycemia. Another example is female reproductive hormones, which are released in a pulsatile manner over a period of time. Human growth hormone is also released in a pulsatile manner during sleep in normal patients. This advantage provides better efficacy to synthetic drug compounds by simulating natural body rhythms. Also, it may better facilitate some general therapeutic approaches, such as controlling blood glucose through insulin transport. Many of the current attempts to make "closed loop" insulin pumps have been hampered by insulin administration and waiting for a delay period in which biological action is immediate. This presents difficulties in determining whether sufficient insulin has been administered to avoid the risk of drug overdose and hypoglycemia. The more rapid PK/PD of ID delivery eliminates most of these problems.

As mentioned above, mammalian skin comprises two layers, specifically, the epidermis and the dermis. The epidermis consists of 5 layers, including stratum corneum, stratum lucidum, stratum granulosum, stratum spinosum and stratum germinatum, while the dermis consists of two layers, the upper papillary epidermis and the deep reticular epidermis. The thickness of the dermis and epidermis varies from individual to individual, but varies from one body part to another within the same body. For example, it has been reported that the thickness of the epidermis is about 40 to about 90 μm, while the thickness of the dermis is less than 1mm deep in some areas of the body just below the epidermis to 2 to about 4mm in other areas of the body, depending on the specific study report (Hwang et al, Ann Plastic Surg 46: 327-.

As used herein, "intradermal" is used to refer to the administration of a substance into the dermis in a manner such that the substance readily reaches the vascularized papillary dermis and is rapidly absorbed into the capillaries and/or lymphatic vessels so as to be systemically bioavailable. This allows the substance to be placed in the upper region of the dermis, i.e., the papillary dermis or the upper portion of the reticular dermis with less blood vessels, allowing the substance to readily diffuse into the papillary dermis. It is believed that placing the substance primarily at a depth of at least about 0.5mm to a depth of no more than about 2.5mm, more preferably no more than about 2.0mm, and most preferably no more than about 1.7mm, will result in rapid absorption of the macromolecule and/or hydrophobic substance. Placing the substance primarily deeper into the reticular dermis and/or into the lower portion of the reticular dermis is believed to result in slow absorption of the substance in the less vascular reticular dermis or in the subcutaneous region, neither of which is subject to absorption of large molecules and/or hydrophobic substances. The controlled transport of substances in this dermal space in the reticular dermis under the papillary dermis (but above the dermal and subcutaneous tissue interface is sufficient) should allow for the efficient migration (outward) of the substance to areas (in the papillary dermis) where there is no distribution of blood and lymphatic capillaries so that it can be absorbed through these capillaries into the systemic circulation without being "sequestered" through other skin tissues.

Another advantage of the present invention is that a more rapid systemic distribution and onset of the drug or diagnostic agent is obtained. This is also relevant for the hormones secreted in a pulsatile manner in many bodies. Many side effects are associated with sustained circulating levels of the substances used. A very relevant example is the continuous production of hormones, which do have an opposite effect (causing infertility) when present in the blood for a prolonged period. Likewise, it is suspected that the persistence and elevation of insulin levels down-regulate the insulin receptor in terms of quantity and sensitivity.

Another advantage of the present invention is that it achieves a higher bioavailability of the drug or diagnostic agent. This effect is most convincing for ID administration of high molecular weight substances, in particular proteins, peptides and polysaccharides. The most immediate advantage is that ID administration with improved bioavailability allows the use of less active agent while achieving equivalent biological effects. This brings direct economic benefits to the pharmaceutical manufacturer and perhaps the consumer, particularly with respect to expensive protein therapeutics and diagnostics. Also, higher bioavailability may allow for lower total doses to be administered and lower patient side effects associated with higher doses.

Another advantage of the present invention is that a higher maximum concentration is obtained for the drug or diagnostic substance. The inventors have found that the substance administered ID is absorbed more rapidly, with a bolus injection resulting in a higher initial concentration. This is most advantageous for substances whose effect is related to the maximum concentration. Faster onset results in higher C with less material_maxThe value is obtained. Thus, the dosage can be reduced, which provides an economic benefit as well as a physiological benefit, since the body removes only a small amount of the drugs and diagnostic agents from the blood.

Another advantage of the present invention is that there is no change in the systemic clearance rate or intrinsic clearance mechanism of the drug or diagnostic agent. All studies carried out by the applicant have now shown that the tested substances maintain the same systemic clearance rate as the route of administration by IV or SC. This is advantageous from a regulatory point of view, since there is no need to re-study degradation and clearance pathways before filing the application to the FDA. This is also advantageous from a pharmacokinetic point of view, as it gives predictability to the dosing regimen. Some substances may be cleared more quickly from the body if their clearance mechanism is concentration dependent. Higher C due to ID transport_maxAlthough the inherent mechanism remains unchangedAs a result, but the clearance may increase.

Another advantage of the present invention is that there is no change in the pharmacodynamic or biological mechanism. As mentioned above, administration by the methods given by the applicant still exerts its effect by the same biological pathway that is inherent to other transport methods. Any pharmacodynamic changes are only related to the different ways in which a drug or diagnostic agent appears, disappears, and the concentration of the drug or diagnostic agent in the biological system.

With the method of the present invention, the pharmaceutical compound can be administered by bolus injection, or by infusion. As used herein, the term "bolus" is used to refer to a drug being delivered in less than 10 minutes. "infusion" is used to refer to the transport of a substance over a period of greater than 10 minutes. It is understood that bolus administration or delivery may be performed at a controlled rate, e.g., using a pump, or without a specific rate-controlling means, e.g., a user injecting themselves.

Another advantage of the present invention is the removal of the physical or kinetic barrier to the passage of the drug and its capture in the skin tissue prior to systemic absorption. Eliminating such barriers has led to extremely widespread use of multiple drug types. Many subcutaneously administered drugs exert this depot effect, i.e. the drug is slowly released from the SC space where it is trapped, a rate-determining step prior to systemic absorption, due to affinity for adipose tissue or slow diffusion through the tissue. This depot effect leads to a lower C compared to ID_maxAnd a longer T_maxAnd may lead to a high variability of absorption between individuals. This effect is also relevant compared to transdermal delivery methods, including active patch technology with or without penetration enhancers, iontophoretic technology, acoustophoresis, or stratum corneum ablation or disruption methods. Transdermal patch technology relies on the distribution of drugs across the highly impermeable stratum corneum and epidermal barriers. Few drugs, in addition to highly lipophilic compounds, can breach this barrier, and even after breaching, often exhibit prolonged migration kinetics due to tissue saturation and entrapment of the drug. Active transdermal handThe segments, while generally faster than active transfer means, are still limited by the type of compound that can be moved by charge repulsion and other electronic or electrostatic means, or actively transported through transient pores by cavitation of the tissue during application of the acoustic wave. The stratum corneum and epidermis still provide an effective means for inhibiting this transport. Removal of the stratum corneum by heat or laser ablation, abrasion methods, or other means, still lacks the motivation to accelerate drug penetration or absorption. Direct ID administration by mechanical means overcomes the kinetic barrier properties of the skin and is not limited by the pharmaceutical or physicochemical properties of the drug or its formulation excipients.

Another advantage of the present invention is a highly controllable dosing regimen. Applicants have determined that ID infusion studies demonstrate highly controllable and predictable dosing characteristics due to the rapid onset and compensatory kinetics of drugs or diagnostic agents delivered via this route. This provides nearly absolute control over the required dosing regimen when the ID delivery is combined with fluid control means or other control systems to regulate the metering of drugs or diagnostic agents into the body. One advantage of this is the primary goal of most drug or diagnostic agent delivery methods. The ID bolus substance administration as described above, gives very similar kinetics to IV injection and is highly desirable for the following drugs: pain relief compounds, meal-time insulin, emergency medications, erectile dysfunction compounds, or other compounds requiring rapid onset of action. Combinations of substances which act individually or synergistically are also included. Extending the ID dosing time by infusion can effectively mimic SC absorption parameters, but is more predictive. This property is particularly beneficial for substances such as growth hormones or analgesics. Longer infusion, typically at lower infusion rates, can result in sustained low baseline levels of drug, which are required for anticoagulants, baseline insulin, and chronic pain management. These kinetic properties can be combined in a manner that results in the display of virtually any kinetic property that is desired. One example is the pulsatile transport of progestagens (LHRH) which causes pregnancy, which requires intermittent peaks to be generated every 90 minutes, with complete clearance between peaks. Other examples are a rapid peak onset of migraine-alleviating drugs followed by lower levels to prevent pain.

Another advantage of the present invention is the reduction of degradation of pharmaceutical and diagnostic agents and/or unwanted immunogenic activity. Transdermal methods use chemical penetration enhancers or iontophoresis, or acoustophoresis or electroporation or thermal perforation techniques, which require the passage of the drug through a viable epidermal layer, which is highly metabolized and inactive. Metabolic conversion of substances in the epidermis or sequestration by immunoglobulins reduces the amount of drug that can be absorbed. ID administration circumvents this problem by placing the drug directly in the dermis and thus completely through the epidermis.

These and other advantages of the present invention are achieved by direct targeted absorption into the papillary dermis, and by controlled transport of drugs, diagnostic agents, and other substances into the dermal space. The inventors have found that by specifically targeting the intradermal space and controlling the rate and manner of transport, the pharmacokinetics exhibited by a particular drug can be unexpectedly improved and, in many cases, can vary with the clinical benefit obtained. Such pharmacokinetics cannot be readily obtained or controlled by parenteral routes of administration other than IV.

The invention improves the clinical utility of ID delivery of drugs, diagnostic reagents and other substances to humans or animals. The method uses a means of accessing the dermis (e.g., a small gauge needle, particularly a micro needle) to directly target the intradermal space and deliver the substance to the intradermal space in a bolus injection or in trans through an infusion. It has been found that placing a device into the dermis provides effective delivery and pharmacokinetic control of the active agent. The device into the dermis is designed to induce leakage of the substance from the skin and to improve absorption in the intradermal space. The pharmacokinetics of technical drugs delivered according to the method of the invention have been found to be very different from the pharmacokinetics of conventional SC delivery of drugs, indicating that ID administration according to the method of the invention will provide improved clinical results. Delivery devices that place the dermal-access device at the appropriate depth in the intradermal space and control the amount and rate of fluid delivery provide assurance that the substance is accurately delivered to the desired site without leakage.

The present invention discloses a method for increasing the absorption rate of a parenterally administered drug without the need for IV administration. This transport provides a shorter T_max. Potential corollary advantages include higher peak concentrations (C) for a given unit dose_max) Higher bioavailability, faster onset of pharmacodynamic or biological effects, and reduced drug depot effects.

It has also been found that the pharmacokinetics of hormone drugs delivered according to the methods of the invention can, if desired, produce clinical results similar to conventional SC delivery of drugs, by controlling the appropriate depth of entry into the dermal device in the intradermal space.

The pharmacokinetic properties of an individual compound will vary with the chemical nature of the compound. For example, larger compounds with molecular weights of at least 1000 daltons, as well as larger compounds of at least 2000 daltons, at least 4000 daltons, at least 10000 daltons, and larger and/or lipophilic compounds, are expected to show the most significant changes compared to traditional parenteral administration methods such as intramuscular, subcutaneous and intradermal injection, and overall, ID transport will show similar kinetics as the other methods.

Description of the drawings

Figure 1 shows the time course of plasma insulin levels for the intradermal to subcutaneous bolus administration of fast acting insulin.

Figure 2 shows the time course of blood glucose levels for intradermal to subcutaneous bolus administration of fast acting insulin.

Figure 3 shows a comparison of rapid action versus bolus ID administration of conventional insulin.

Figure 4 shows the effect of different intradermal injection depths of bolus injections of fast acting insulin on the time course of insulin levels.

Figure 5 shows a time course comparison of insulin levels for subcutaneous and intradermal bolus injections of long acting insulin.

Figures 6 and 7 show a comparison of pharmacokinetic and pharmacodynamic results for granulocyte colony stimulating factor delivered intradermally, subcutaneously, intravenously with single needle or three-point needle rows.

Figures 8, 9 and 10 show a comparison of low molecular weight heparin delivered by bolus injection, short infusion, long infusion intradermally versus subcutaneously.

Figure 11 shows the time course of plasma genotropin levels given by single needle intradermal, needle row intradermal and bolus subcutaneous administration.

Detailed Description

The present invention provides methods of treatment by delivering a drug or other substance to a human or animal by direct targeting to the intradermal space, where the drug or substance is administered into the intradermal space through one or more of the devices into the dermal device. It has been found that the substances infused in accordance with the method of the present invention exhibit superior pharmacokinetics and are clinically more desirable than the same substances administered by SC injection.

The dermal-access device for ID delivery of the present invention is not critical, so long as the gas penetrates the skin of the subject to the desired target depth in the intradermal space without penetrating the dermis. In most cases, the device will penetrate the skin to a depth of about 0.5-2 mm. The dermal-access device may include all types of conventional injection needles, cannulas or microneedles, which may be used alone or in a multiple needle array. The dermal-access device may include a needle-less device, including a firing syringe. The term needle(s) is used herein to include all needle-like results. The term "needleless" is used herein to include structures less than about 30 gauge, typically about 31-50 gauge, when the structure itself is cylindrical. The term needle includes non-cylindrical structures and thus may have comparable diameters and includes conical, rectangular, octagonal, wedge-shaped, and other geometric shapes. The dermal-access device also includes a launching fluid injector, a powder jet transporter, a piezoelectric, electromotive, electromagnetic transporter, a pneumatic transporter that penetrates directly through the skin to provide access for transport or to transport substances directly to a targeted site of the intradermal space. Providing varying targeting depths for the substance transported by the dermal-access device allows the pharmacokinetic and pharmacodynamic (PK/PD) behavior of the drug or substance to be tailored to the desired clinical application most suited to the particular patient's condition. The targeted depth of substance transport into the dermal device may be manually controlled by the operator or may be indicated by the attainment of a desired depth with or without the aid of an indicator device. Preferably, however, the device has structure to control the depth of penetration into the intradermal space. Most commonly this is done by means of a widened region or sleeve connected to the push rod of the dermal-access device, which may be a scaffold or platform connected to the needle. As a dermal-access device, the length of the microneedle is easily variable during the manufacturing process, and is typically less than 2mm in length. The micro-needle is very sharp and of extremely small gauge, further reducing pain and other sensations during injection or infusion. They may be used in the form of a single lumen microneedle, or multiple lumen microneedles may be assembled or fabricated in a linear or two-dimensional array to increase the transport rate for a given amount of material to be transported over a given period of time. The micro-needle may be mounted in a variety of devices such as holders or carriers that may also be used to limit the depth of penetration. The dermal-access device of the present invention may also be equipped with a reservoir for loading the substance prior to delivery, or other means for delivering the drug or other substance in accordance with a pump or pressure. Alternatively, the means for supporting the dermal-access device may be externally connected to such additional components.

IV-like pharmacokinetics is accomplished by administering drugs into the dermis to impinge capillary and lymphatic microvasculature. It is understood that infusion capillaries or capillary beds refer to the vascular or lymphatic vascular pathways within the dermis region.

Without being bound to any theoretical mechanism of action, we believe that the rapid absorption observed when administered into the dermis results from an enrichment of the blood vessels or lymphatic plexus in the dermis. However, the presence of the intradermal vascular and lymphatic plexuses alone is not expected to produce increased macromolecular absorption. This is because capillary endothelium is generally low permeable or impermeable to macromolecules such as proteins, polysaccharides, nucleic acid polymers, substances linked to polymers such as pegylated (pegylated) proteins, and the like. These macromolecules have a molecular weight of at least 1000 daltons, or greater: at least 2000 daltons, at least 4000 daltons, at least 10000 daltons, and even higher. Furthermore, the slow discharge into the blood vessels from interstitial lymph does not allow one to expect a rapid increase in plasma concentration when the drug substance enters the dermis.

One possible explanation for the unexpected increase in absorption reported herein is that upon injection of the substances, they readily reach the papillary dermis, thus leading to an increase in blood flow and capillary permeability. For example, it is known that insertion of a needle to a depth of 3mm produces an increase in blood flow, which has been hypothesized to be independent of painful stimuli, but due to histamine release by the tissue (Arildsson et al, microvascularRes.59: 122-. This is consistent with the observed transient increase in blood flow and capillary permeability as a result of acute inflammatory reactions caused by Skin damage (see Physiology, Biochemistry, and Molecular Biology of the Skin, second edition, L.A. Goldsmith eds., Oxford Univ.Press, New York, 1991, p.1060; Wilhem Rev.Can.biol.30: 153-. At the same time, injection into the dermis layer would be expected to increase the void pressure. Increasing the void pressure value from about-7 to about +2mmHg (beyond the "normal range") is known to dilate vessels and increase lymphatic flow (Skobe et al, J.Invwstig.Dermatol.Symp.Pro.5: 14-19, 2000). Thus, it is believed that the increased void pressure caused by injection into the dermis layer causes increased lymphatic flow and increased absorption of the substance injected into the dermis.

"improved pharmacokinetics" refers to an improvement in pharmacokinetic properties obtained, for example, by standard pharmacokinetics such as the time to peak plasma concentration (T)_max) Amplitude of peak plasma concentration (C)_max) And the time (T) to yield the minimum detectable blood or plasma concentration_lag) To detect. Improved absorption characteristics means that absorption is improved or greater by detection of such pharmacokinetic parameters. Detection of pharmacokinetic parameters and determination of minimum effective concentrations can be routinely performed in the art. The values obtained are indeed improved compared to the standard route of administration, such as subcutaneous or intramuscular administration of cells. In these comparisons, it is preferred, although not necessary, to use the same dosage levels, i.e., the same amount and concentration of drug and the same carrier, and the same rate of administration in amounts and volumes per unit time, for administration into the dermal layer and for administration to a reference site, e.g., subcutaneously. Thus, for example, intradermal administration of a given drug at a concentration such as 100 μ g/ml and at a rate of 100 μ L per minute over a period of 5 minutes is preferably compared to subcutaneous administration of the same drug at the same concentration of 100 μ g/ml and at a rate of 100 μ L per minute over a period of 5 minutes.

It is believed that the improved absorption characteristics are particularly evident for substances that are poorly absorbed when injected subcutaneously, such as macromolecules and/or lipophilic substances. Generally, subcutaneous administration of macromolecules is poorly absorbed, probably due not only to their inappropriate size relative to the capillary pore size, but also to their slow rate of diffusion through the interstices due to their size. It is understood that macromolecules may have discrete functional domains with hydrophobic and/or hydrophilic properties. In contrast, small molecules that are hydrophilic when administered subcutaneously generally absorb well, and it may be found that the absorption characteristics upon injection into the dermis are not improved as compared to absorption after subcutaneous administration. Hydrophobic substances are understood herein to mean low molecular weight substances, for example substances having a molecular weight of less than 1000 daltons, which have low water solubility or even are substantially insoluble.

The PK and PD advantages described above are best achieved by precise direct targeting of the dermal capillary bed. This can be accomplished, for example, by a micro-needle system having an outer diameter of less than about 250 microns and an exposed length of less than 2 mm. Such systems may be constructed in known ways from various materials including steel, silicon, ceramics, other metals, plastics, polymers, sugars, biological and/or biodegradable substances, and/or combinations thereof.

It has been found that certain features of the intradermal administration method provide clinically useful PK/PD and dose accuracy. For example, it has been found that placing the needle outlet into the skin restrictively affects the PK/PD parameters. The outlet of a conventional or standard gauge needle with a bevel angle has a large exposed height (referred to as the vertical height). Although the needle tip may be placed at a desired depth in the intradermal space, the greater exposed height of the needle outlet causes the transported substance to be deposited at a shallower depth from the skin surface. As a result, the substance tends to flow out of the skin due to the backpressure of the skin itself, and due to the pressure of the accumulated fluid injected or infused. That is, outlets from needles with greater exposed heights in greater depths will still effectively seal, while outlets with the same exposed height will not effectively seal when placed at a shallower depth in the dermis. Typically, the exposed height of the needle outlet is from about 0 to about 1 mm. The needle outlet, which is exposed to a height of 0mm, has no bevel angle, and is at the needle tip. In this case, the depth of the outlet is the same as the depth of penetration of the needle. The needle outlet formed by the bevel angle or by the needle side opening has a measurable exposed height. It is understood that a single needle may have more than one opening or outlet suitable for transporting substances into the dermal space.

It has also been found that by controlling the pressure of the injection or infusion, high back pressures generated by the ID administration set can be avoided. By applying a constant pressure at the liquid interface, a more constant transport rate can be achieved, which can optimize absorption and achieve improved pharmacokinetics. The transport rate and volume may also be controlled to prevent the formation of blisters at the site of transport and to prevent backpressure created by the withdrawal of the device into the dermis from the skin. The appropriate transport rates and volumes to achieve these effects for the selected materials can be determined experimentally using only ordinary skill in the art. The space between the multiple needles allows for a wider fluid distribution and an elevated transport velocity or a larger fluid volume. Furthermore, it has been found that ID infusion or injection often gives higher initial plasma levels of the drug compared to conventional SC administration, especially for drugs that are prone to degradation or clearance in vivo, or for compounds that have affinity for SC adipose tissue, or for macromolecules that diffuse slowly through the SC matrix. In many cases, this may allow only a small dose of the substance to be used by the ID route.

Methods of administration useful in practicing the invention include bolus injection and infusion delivery of drugs and other substances to human or animal subjects. Bolus doses are single doses delivered in a single volume unit in a relatively short period of time, typically less than about 10 minutes. Infusion administration includes administration in fluid form at a selected rate, which may be constant or variable, over a relatively long period of time, typically greater than about 10 minutes. To transport the substance, the entry dermal device is placed adjacent the subject's skin, directly targeted into the dermal space, and the substance(s) are transported or administered to the intradermal space where they may act locally or be absorbed and distributed systemically by the blood stream. The dermal-access device may be coupled to a reservoir loaded with the substance(s) to be transported. The form of the substance(s) to be delivered or administered includes solutions in pharmaceutically acceptable diluents or solvents, emulsions, suspensions, gels, microparticles, such as suspended or dispersed micron-or nano-sized particles, and in situ-forming carriers thereof. The transport from the depot to the intradermal space may be passive, exerting no external pressure or other driving force on the substance(s) being transported, and/or active, exerting pressure or other driving force. Preferred means of generating pressure include pumps, syringes, elastomeric membranes, pneumatic, piezoelectric, electric, electromagnetic pumps, or belleville springs or washers or combinations thereof. The rate of transport of the substance can be varied, if desired, by controlled variation of the pressurizing means. As a result, the substance enters the intradermal space and is absorbed in an amount and at a rate sufficient to produce a clinically effective result.

As used herein, the term "clinically effective result" refers to a clinically useful biological response, including responses useful for diagnosis and therapy, resulting from the administration of a substance or substances. For example, diagnostic tests or prevention or treatment of a disease or condition are clinically effective results. Such clinically effective results include diagnostic results such as measurement of glomerular filtration pressure after inulin injection, diagnosis of adrenal cortex function in children after ATCH injection, causing contraction of gallbladder and draining bile after cholecystokinin injection, etc.; and the results of treatment, such as proper control of blood glucose levels clinically upon insulin injection, proper treatment of hormone deficiency clinically after hormone injection, such as parathyroid hormone or growth hormone, proper treatment of toxicity clinically after antitoxin injection, and the like.

Substances that may be intradermally delivered according to the present invention include drugs and biologically active substances, including diagnostic agents, drugs, and other substances that provide therapeutic and health benefits such as nutraceuticals. Diagnostic substances useful in the present invention include macromolecular substances such as inulin, ACTH (e.g., corticotropin injection), luteinizing hormone releasing hormone (e.g., gonadorelin hydrochloride), growth hormone releasing hormone (e.g., sertraline acetate), cholecystokinin (sincalide), parathyroid hormone and fragments thereof (e.g., teriparatide acetate), thyroid releasing hormone and analogs thereof (e.g., protorelin), secretin, and the like.

Therapeutic substances that may be used in the present invention include alpha-1 antitrypsin, antiangiogenic agents, anti-sensitogenic agents (antinesens), butorphan, calcitonin and analogs thereof, ceredase, COX-II inhibitors, dermatological agents, dihydroergotamine, dopamine agonists and antagonists, enkephalins and other opioid peptides, epidermal growth factor, erythropoietin and analogs thereof, follicle stimulating hormone, G-CSF, glucagon, GM-CSF, granisetron, growth hormones and analogs thereof (including growth hormone releasing hormone), growth hormone antagonists, hirudin and hirudin analogs such as hirulog, IgE inhibitors, insulin, insulinotropin and analogs thereof, insulin-like growth factor, interferon, interleukin, lutein, luteinizing hormone releasing hormone and analogs thereof, heparin, low molecular weight heparins, and other natural substances, Modified and synthetic glycosaminoglycans, M-CSF, metoclopramide, midazolam, monoclonal antibodies, pegylated proteins and any other protein modified with hydrophilic or hydrophobic polymers or other functional groups, fusion proteins, single chain antibody fragments or any combination thereof with a linker protein, macromolecular substances or other functional groups thereof, sedative analgesics, nicotine, non-steroidal anti-inflammatory drugs, oligosaccharides, ondansetron, parathyroid hormone and its analogs, parathyroid hormone antagonists, prostaglandin antagonists, prostaglandins, recombinant soluble receptors, scopolamine, 5-hydroxytryptamine agonists and antagonists, sildenafil, terbutaline, thrombolytic agents, tissue plasminogen activators, TNF-and TNF-agonists, vaccines (with and without carriers/adjuvants), including prophylactic or therapeutic antigens (including but not limited to subunit proteins, peptides and polysaccharides, polysaccharide conjugates, toxoids, gene vaccines, live attenuated, reassortant, inactivated whole cell, viral and bacterial vectors) associated with addiction, arthritis, cholera, cocaine addiction, diphtheria, tetanus, HIB, Lyme disease, meningococcus, measles, mumps, chickenpox, yellow fever, respiratory syncytial virus, tick-borne Japanese encephalitis, pneumococci, streptococcus, typhoid, influenza, hepatitis (including A, B, C and D types), otitis media, rabies, polio, HIV, parainfluenza, rotavirus, Epstein-Barr virus, chlamydia, atypical pertussis, moraxella mucositis, human papilloma pyridine, tuberculosis including BCG, gonorrhea, eradication, atherosclerosis, malaria, E-coli, bacterial strains, strains, Alzheimer's disease, H.Pylori, Salmonella, diabetes, cancer, herpes simplex, human papilloma; other substances include all primary therapeutic agents such as common cold drugs, anti-addiction drugs, anti-allergic agents, antiemetics, antiobesity drugs, anti-osteoporosis agents, anti-infective agents, analgesics, anesthetics, appetite suppressants, antiarthritics, antihistamines, anticonvulsants, antidepressants, antidiabetics, antihistamines, anti-inflammatory agents, antimigraine agents, antimuscarinics, antineoplastics, anti-Parkinsonism agents, antipruritics, antipsychotics, antipyretics, anticholinergics, benzodiazepine antagonists, vasodilators (including general, coronary, peripheral and cerebral vessels), bone stimulants, central nervous system stimulants, hormones, hypnotics, immunosuppressive agents, muscle relaxants, sympatholytic agents, parasympathetic mimetics, prostaglandins, proteins, peptides, polypeptides and other macromolecules, peptides, and other macromolecules, Nerve stimulators, sedatives and hypoactive drug resistance and tranquilizers.

Pharmacokinetic analysis of insulin infusion data was as follows. The insulin concentration-time data from each individual animal was analyzed by stepwise non-linear minimum regression. First, an empirical bi-exponential equation was developed that fits the insulin concentration-time data for the negative control group. This analysis assumes a first order release of micro-residual insulin and regains the parameters of the first order rate constant of release, residual insulin concentration at the site of release, delay time of release, and first order rate constant of insulin clearance from the circulatory system. The analysis of the phase-regained production is not important per se, but merely accounts for the endogenous circulating insulin fraction.

The second step of the analysis involves deriving a well-defined compartmental model that fits the insulin concentration-time data during or after subcutaneous or intradermal infusion. The scheme on which the mathematical model depends is shown in FIG. 1[ PK/PD model diagram]The upper part of (a). Insulin infusion is carried out for 240 minutes from t-0; a delay time (t)_lag，2) Thereafter, the absorption by the infusion site is regulated by a first order process, which is controlled by the absorption rate constant Ka. The insulin absorbed into the systemic circulation is distributed as an apparent volume V, doped with the unknown fraction of bioavailability F, and removed according to a first order rate constant K. Proper procedure for t_lag,2Ka, V/F and K; constant (C) associated with endogenous insulin distribution_R、t_lag,1、K_R) Which is obtained from the first step of analysis and is considered to be a constant.

Estimates of the parameters are reported as mean ± SD. Significance of differences in specific parameters between two different models of insulin administration (subcutaneous versus intradermal infusion) was assessed using paired student t-test.

Pharmacodynamic analysis of insulin infusion data was calculated as follows. Plasma concentrations of blood glucose are used as a surrogate for the pharmacological effect of insulin. The change in the reaction variable R (blood glucose concentration) versus time t is set as:

wherein k is_inIs a zero-order infusion of glucose, k_outIs the first order rate constant that regulates glucose elimination, and E is the effect of insulin according to the sigmoidal Hill relationship as follows:

wherein E_maxIs insulin pair K_outMaximum stimulation of, EC₅₀Is K_outC is the insulin concentration and r is the Hill coefficient of the relationship. The initial model used plasma concentrations of insulin as a modulator of the pharmacological response. However, this method does not capture the delay in the glycemic response that occurs to elevated plasma insulin concentrations. Therefore, finally a compartment-of-action model was adopted, in which insulin action is regulated by a putative compartment of action (peripheral to the systemic pharmacokinetic compartment).

The pharmacodynamic analysis is carried out in two steps. The first step of the assay, from the blood glucose concentration in the negative control groupThe degree-time data determines an initial estimate (k) related to the glucose profile_outAnd volume of glucose distribution, V_Glucose). Then, a fully integrated pharmacokinetic-efficacy model was simultaneously developed that simultaneously fits the glucose concentration-time data obtained from each animal in the negative control and each insulin delivery groups (i.e., two sets of efficacy parameters were obtained for each animal-one set was simultaneously analyzed for subcutaneous insulin infusion/negative control data and the other set was simultaneously analyzed for intradermal insulin infusion/negative control data). In all pharmacodynamic analyses, the parameters controlling insulin distribution obtained in the pharmacokinetic analysis of the insulin concentration-time data for each animal were kept constant.

All other pharmacokinetic analyses were calculated in a non-compartmental method using similar software programs and techniques known in the art.

Having generally described the invention, the following specific but non-limiting examples, and with reference to the accompanying figures, give different examples of methods of performing dermal, direct targeted drug delivery, and give examples of intradermally administered drugs that provide improved PK and PD effects.

A representative example of an access dermal microdevice includes a single needle (micro group, inc., Medway, MA) made of 34 gauge steel material and ground with an 800 grit emery wheel to a single 28 ° bevel angle. The needle was cleaned by continuous sonication in acetone and distilled water and checked for flow with distilled water. The micro-needle was protected with UV treated epoxy in a small gauge catheter (Maersk Medical). The needle length was set with a mechanical dial, using the cannula of the catheter as a depth-limiting control and determined with an optical microscope. For testing, needles of different lengths were used, and the exposed needle lengths were adjusted to 0.5, 0.8, 1, 2 and 3mm with an indexing disc. The connection to the fluid metering device (pump or indicator) is through a complete Luer at the inlet of the conduit. During injection, the needle penetrates perpendicularly to the skin surface, and for rapid bolus delivery, the site is held by gentle manual pressure, and for longer infusions, the site is held with medical tape. The function of the device and the fluid flow rate were checked immediately before and after the injection. This Luer Lok single needle cannula design is hereinafter referred to as SS1 — 34.

Another arrayed micro device into the dermis is made of a 1 "diameter disc, machined from acrylic polymer, with a low volume fluid path that is shunted by individual needles of a central inlet. The Hamilton microinjector was connected through a low volume tubing set and the transfer rate was controlled by the injector pump. The needles were arranged in a disc with a diameter of 15 mm. Three needles and six needle arrays were constructed with a distance of 12 and 7mm between needles. All arrays were designed as single bevel, 1mm long 34G stainless steel micro needles. The three needle 12mm pitch catheter design is hereinafter referred to as SS3_34B, and the six needle 7mm pitch catheter design is hereinafter referred to as SS6_ 34A.

Another arrayed micro device into the dermis is made of an 11mm diameter disc, machined from acrylic polymer, with a low volume fluid path that is shunted by individual needles of a central inlet. The Hamilton microinjector was connected through a low volume tubing set and the transfer rate was controlled by the injector pump. The needles were arranged in a circular disc of about 5mm diameter. Three needles were arranged about 4mm apart and connected to the catheter as described above. These designs are hereinafter referred to as SS3S _34_1, SS3C _34_2, and SS3S _34_3, with needle lengths of 1mm, 2mm, and 3mm, respectively.

Another ID infusion device incorporating dermis was constructed with a stainless steel 30 gauge needle bent at a 90 angle near the needle tip to provide a 1-2mm length penetration through the skin. When the needle is inserted, the outlet (tip) of the needle is at a depth of 1.7-2.0mm of the skin, and the total exposed height of the needle outlet is 1.0-1.2 mm. This design is referred to hereinafter as SSB1_ 30.

Example I

Slow infusion ID insulin delivery was demonstrated for a hollow, silicon-containing, single lumen miniature needle (2 mm total length, 200X 100 μm OD, corresponding to approximately 33 gauge) for pigs with the outlet 1.0 μm (exposed height) from the tip of the needle100 μm) prepared by known methods (us patent 5928207) and fitted with a microporous catheter (disttronic). The distal end of the microneedle was placed into a plastic catheter and bonded with epoxy to form a cannula of limited depth. The needle outlet was placed about 1mm outside the epoxy sheath, thus limiting the penetration depth of the needle outlet into the skin to about 1mm, which corresponds to the depth of the intradermal space in pigs. The catheter was connected to a MiniMed 507 insulin pump to control fluid transport. The distal end of the microneedle was placed into a plastic catheter and bonded with epoxy to form a cannula of limited depth. The needle outlet was placed about 1mm outside the epoxy sheath, thus limiting the penetration depth of the needle outlet into the skin to about 1mm, which corresponds to the depth of the intradermal space in pigs. The clarity of the fluid flow path was confirmed by visual inspection and no clogging was observed when pressurized with a standard 1cc syringe. The catheter was connected to an external insulin infusion pump at the outlet of the catheter by a complete Luer connection. The pump is filled with Humalog^TM(Lispro) insulin (Eli Lilly, Indianapolis, IN) was infused into the catheter and microneedle according to the manufacturer's instructions. Sandostatin by IV infusion of anesthetized pigs^(Sandoz, East Hanover, HJ) solution was administered to inhibit basal pancreatic function and insulin secretion. After appropriate induction period and baseline sampling, the micro needle filled with the drug solution was inserted vertically into the skin surface of the animal's flank until the sleeve stopped. Insulin infusion was performed at a rate of 2U/hour and maintained for 4 hours. Blood samples were collected periodically and analyzed for serum insulin concentration and blood glucose values. The pre-infusion baseline insulin level served as the background for the test detection level. After the infusion was started, an increase in serum insulin levels was indicated, which corresponded to the prescribed infusion rate. The blood glucose levels showed a corresponding decrease relative to the negative control group (NC) without insulin infusion, which was improved over the conventional SC infusion. In this experiment, the microneedle was shown to properly pass the skin barrier and transport the drug in vivo at a pharmaceutically proportional rate. ID infusion of insulin was shown to be a pharmaceutically acceptable route of administration, and also to show a pharmacodynamic response to blood glucose lowering. Calculation of PK parameters for ID infusionsIslanding absorbs more rapidly than SC administration. ID space absorption starts almost immediately: delay time before absorption (t) of ID and SC_lag) 0.88 and 13.6 minutes, respectively. The absorption rate at the administration site was also increased by about 3-fold, and the k of ID and Sc_a0.0666 and 0.0225min respectively^-1. The bioavailability of insulin delivered by ID administration was increased by about 1.3 fold over SC administration.

Example II

The rapid bolus delivery of Lilly Lispro rapid acting insulin was performed using the ID and SC bolus administration. The ID micro-injector was designed SS3 — 34 for entry into the dermal row. Diabetic Yucatan piglets were given 10 international units (U) of insulin, corresponding to a volume of 100. mu.L. Test animals have been made diabetic by chemical ablation of islet cells of the pancreas and are no longer able to secrete insulin. The test animals were injected with insulin by inserting them laterally through the micro needle array and through a standard 30G × 1/2 inch needle into the SC tissue space. Circulating insulin levels were measured using a commercially available chemiluminescence assay kit (Immulite, Los Angeles, Calif.) and blood glucose levels were measured using blood glucose test strips. The ID injection was done by hand pressing with a micro-syringe for analysis, with an injection time of about 60 seconds. In contrast, SC administration takes only 2-3 seconds. Referring to fig. 1, serum insulin levels after bolus administration show faster absorption and distribution of injected insulin when by the ID route. Time to peak concentration (T) for ID and SC administration_max) Shorter and the resulting peak concentration (C)_max) And higher. In addition, figure 2 also shows the pharmacodynamic biological response of insulin administration, as measured by a decrease in Blood Glucose (BG), with BG showing a faster and greater change after ID administration as more insulin is provided earlier.

Example III

Lilly Lispro is considered as a fast acting insulin, with a slight change in protein structure compared to natural human insulin. Hoechst regular insulin maintains the native human insulin protein structure (similar in active structure), but absorbs more slowly than Lispro when administered by the traditional SC route of administration. These two types of insulin were bolus injected by the ID route to determine if there was an identifiable difference in their absorption upon administration by this route. Two types of insulin, 5U, were administered into the ID space with the access dermal microdevice design SS3 — 34. The insulin concentration versus time data are shown in figure 3. The PK profile of regular and fast acting insulin is essentially the same when administered by the ID route, and both types of insulin show faster absorption than the traditional SC route using Lispro. This indicates that the absorption mechanism of ID administration is less affected by minor biochemical changes of the administered substance and that ID transport provides a favorable PK absorption profile for conventional insulin, which is superior to SC administration of fast acting insulin.

Example IV

Rapid bolus delivery of Lilly Lispro rapid acting insulin through micro needle rows of varying needle length indicated that precise deposition of drug into the dermal space was necessary to obtain PK superiority and differentiation over SC. Thus, 5U of Lilly Lispro rapid acting insulin was administered with the entry dermal design SS3 — 34. Other microdevices of the same needle array configuration were prepared to lengthen the exposed needle length of the microdevice array, including needle lengths of 2 and 3 mm. The average total dermal thickness of Yucatan piglets is 1.5-2.5 mm. Thus, insulin is expected to deposit into the dermis, approximately at the dermal/SC interface, and below the dermis and within the SC, with needle lengths of 1mm, 2mm and 3mm, respectively. Bolus insulin administration is described in example II. The mean insulin concentration versus time curve is shown in figure 4. The data clearly show that as the length of the microneedle increases, the resulting PK profile begins to more closely resemble SC dosing. This data demonstrates the advantages of direct targeting to the dermal space, including rapid absorption and distribution and high initial concentration. Since the data is an average of several examples, the PK profiles obtained with longer microneedles at 2mm and 3mm did not show an increase in inter-individual variability. This data indicates that since skin thickness may vary from individual to individual, even within an individual, shorter needle lengths that accurately target the dermal space are repeatable in their PK profile, since they deposit the drug more consistently within the same tissue space. This data indicates that the longer microneedle, which deposits or administers the substance at a deeper location in the dermal space, or partially or fully into the SC space, reduces or eliminates the PK advantage compared to a shallower, direct targeted drug delivery to highly vascular enriched dermal regions.

Example V

Rapid bolus delivery of Lantus long-acting insulin was performed via the ID pathway. Lantus is an insulin solution that forms microparticles at the site of administration upon injection. These microparticles are slowly solvated in vivo to provide (per manufacturer's literature) more stable low levels of circulating insulin compared to other conventional long acting insulins such as crystalline zinc precipitates (e.g., Lente, NPH). Lantus insulin (10U dose, 100 μ L) was administered to diabetic Yucatan piglets using the dermal-entry design SS3-34 and standard SC protocol, as described above. Referring to fig. 5, similar PK profiles were obtained when administered by the ID route compared to SC. Minor differences include a slightly higher "burst" occurring immediately after ID insulin delivery. This indicates that even for very high molecular weight compounds or small particles, absorption can be obtained by ID administration. More importantly, this supports the fact that the in vivo bioremediation mechanism is not appreciably altered by the route of administration or by the mode of use of the pharmaceutical substance. This is extremely important for pharmaceutical compounds with long circulating half-lives (examples are large soluble receptor compounds or other antibodies in cancer therapy, or chemically modified types such as pegylated drugs).

Example VI

Rapid bolus ID delivery of human Granulocyte Colony Stimulating Factor (GCSF) (Neupogen) to Yucatan piglets was performed by entering the dermal microdevice design SS3-34B (array) or SS1_34 (single needle). The transport rate was controlled by a Harvard syringe pump and administered within 1-2.5 minutes. Figure 6 shows PK effectiveness of GCSF in plasma, detected by ELISA immunoassay specific for GCSF. Administration via IV and SC transport served as controls. Referring to FIG. 6, the rapid bolus ID transport display for GCSFFaster uptake associated with ID transport is shown. C_maxObtained at about 30-90 minutes, whereas SC were obtained at 120 minutes. Bioavailability increased dramatically by about a factor of 2, as evidenced by the higher area under the curve (AUC). Circulating levels of GCSF can be detected over extended periods of time, indicating that ID transport does not alter the intrinsic biological clearance mechanism or rate of the drug. These data also indicate that the device design has minimal effect on the rapid absorption of the drug from the ID space. The data in figure 7 also shows the extent and time course of increased numbers of leukocytes as a result of GCSF administration compared to the negative control group (not receiving GCSF). White Blood Cell (WBC) counts were determined by standard blood cell count clinical veterinary methods. ID transport showed the same clinically significant biological consequences. While all modes of delivery give about the same PD results, the data indicate that ID delivery can achieve the same physiological results with half the dose compared to SC due to the increase in bioavailability with about 2 doses.

Example VII

Peptide drug substance (peptide drug entity): ID administration test was carried out with human parathyroid hormone 1-34 (PTH). PTH was infused for 4 hours followed by 2 hours of clearance. The SC space of the skin is inserted laterally through a standard 31 gauge needle using the "squeeze" technique. ID infusion was performed by the dermal-access device design SSB1 — 30 (stainless steel 30 gauge needle bent at 90 ° at the needle tip for a length of 1-2mm to penetrate the skin). The needle outlet (tip) is 1.7-2.0mm deep in the skin when the needle is inserted. The 0.64mg/mL PTH solution was infused at a rate of 75. mu.L/hr. Sulfuric acid was controlled by a Harvad syringe pump. Body weight corrected plasma PTH levels are shown in figure XX. The body weight corrected transport profile showed a larger area under the curve (AUC), indicating higher bioavailability, higher peaks at early sampling time points (e.g., 15 and 30 minutes), indicating a faster onset of ID transport, and a rapid decline after infusion cessation (also indicating rapid absorption, no depot effect).

Example VIII

See fig. 8, which shows the difference byResults in dermal microdevice representative weight corrected plasma profiles after rapid bolus transport of Fragmin (fragment protein), a low molecular weight heparin fragment (LMWH), to Yucatan piglets. In each case, the fragment protein (100. mu.l of 25000IU/mL preparation) was delivered at a dose of 2500IU (International units). Standard SC delivery was performed by lateral insertion into the SC tissue space using a standard 30G needle by extrusion techniques. The administration was performed with an entry dermal micro device design SS1 — 34 connected to a catheter with a needle length of 0.5 or 1.0 mm. During drug delivery, the entire exposed length of the microneedle is inserted perpendicularly into the skin surface to a depth limit and secured by mechanical means during drug instillation. The micro needle rapid thick injection is carried out by manually pressing a glass micro syringe in 1-2.5 minutes. The calculated pharmacokinetic results given in Table 1 show C resulting from microdevice transport_maxIncrease and T_maxIs reduced.

TABLE 1 calculated LMWH PK data

Condition	SC		1.00m micro needle		0.5mm micro needle
								Mean value of	SD	Mean value of	SD	Mean value of	SD
tmax(h)	3.0	3.6	1.0	0.3	0.8	0.3
							Cmax(IU/mL)	6.0	0.3	1.1	0.1	1.5	0.3

The resulting properties of the two microneedle devices were substantially equivalent, indicating that the transport properties were substantially independent of the device structure as long as the device was properly entering and transporting the drug into the dermal tissue compartment. Equivalent changes in pharmacokinetic absorption can be produced with other dermal-entry microdevice systems, including arrays consisting of 3 and 6 rows of microneedle tips of the same size and penetration depth.

Example IX

Referring to fig. 9, comparative plasma properties for a bolus dose of Fragmin are shown for the following dosing conditions: 1) SC 100 μ L injection volume; 2500IU total dose, 2) ID 100 uL injection volume; 2500IU total dose; 1.0mm needle length (SS1 — 34); and 3) ID 100 uL injection volume; 2500IU total dose; 0.5mm needle length (SS 1-34). The weight of these animals was matched at the time of administration, ranging from 8.8 to 12.3 kg. All plasma profiles were corrected to an average animal weight of 15.0kg by multiplying the raw data by the animal's weight at the time of administration and dividing by 15. However, individual plasma curves were not calibrated for dose variation. PK production was calculated based on raw data and corrected for dose level and animal body weight. This data shows that ID administration has a reduced onset time for drug bioavailability and distribution compared to SC.

TABLE 2a test series for bolus injection

Condition	Pathway(s)	Injection quantity of mu L	Concentration IU/mL	Delivery dose IU	Needle length mm	n
							1	SC	100	25000	2500	30G	5
2	SC	200	12500	2500	30G	3
							3	ID	100	25000	2500	1.0	6
4	ID	100	25000	2500	0.5	3
							5	ID	100	10000	1000	1.0	4
6	ID	80	12500	1000	0.8	2
							7	ID	40	25000	1000	1.0	3

TABLE 2b calculated PK data

Conditions are as follows:	1		3		4		5		6		7
														mean value of	SD	Mean value of	SD	Mean value of	SD	Mean value of	SD	Mean value of	SD	Mean value of	SD
Dosage (IU/kg)	253.8	23.9	240.0	22.6	229.7	24.0	80.7	4.5	81.1	-	71.4	4.7
													tmax(h)	3.0	3.6	1.0	0.3	0.8	0.3	1.6	0.8	0.8	-	0.7	0.3
Cmax(IU/mL)	0.6	0.3	1.1	0.1	1.5	0.3	0.4	0.1	0.7	-	0.6	0.0
													t1/2z(h)	9.3	4.9	2.9	0.5	6.5	5.5	7.1	2.2	3.9	-	3.4	0.4
CL/F(mL/h*kg)	31.4	11.3	37.6	3.4	27.2	8.9	21.0	6.0	23.2	-	24.8	8.3
													AUC/dose	0.018	-	0.023	-	0.033	-	0.043	-	0.041	-	0.038

Example X

See fig. 9, which shows representative post-recalibration plasma profiles of short infusion transport in Yucatan piglets for Fragmin LMWH. LMWH was infused at a total dose of 2500IU (12500IU/mL concentration) in a volume of 200. mu.L over 0.5-2.0 hours. The infusion rate by volume measurement was 100-400. mu.L/hour. The entry dermal array microdevice is designated SS3 — 34, which is connected to a syringe pump that controls fluid transport. Each microneedle in this array had an extension length of 1mm for insertion. An equal amount (100. mu.L, 25000IU/ml) of LMWH was bolus injected through a similar microneedle array ID in less than 2 minutes, andstandard SC bolus dosing was used as a control. The resulting plasma profiles show highly controlled drug delivery profiles obtained with microdevice intradermal delivery systems. The data shows that the infusion control mode can adjust pharmacokinetics by infusion speed. When the infusion rate by volume decreases, C_maxAnd T_maxRespectively lowered and raised. Within experimental error, T of Fragmin_maxIs routinely obtained when infusion is stopped. This short infusion administration shows the ability to deliver a larger standard total fluid volume than the standard ID administration (the Mantoux technique is now about 100 to 150 μ L/dose).

Example XI

Referring to fig. 10, a representative post-recalibration plasma profile of the Fragmin LMWH slow infusion transport in Yucatan piglets is shown. A total of 2000IU (25000IU/mL concentration) was delivered in a volume of 80. mu.L over 5 hours. The infusion rate was 16. mu.L/hr by volume. The infusion set was a commercially available insulin pump connected to an ID micro device design SS1 — 34, or to a commercially available insulin infusion tube. The resulting plasma profile again indicates a more rapid onset of LMWH input through the microdevice. At 5 hours, the ID transporter showed a lack of depot effect after removal of the catheter, as evidenced by a detectable immediate decrease in plasma activity. In contrast, plasma levels of the SC-infused LMWH did not peak until 7 hours, after 2 hours of infusion had ceased. Neither infusion method reached steady state during the experiment, but this was predicted by the PK model. This test readily shows that at low infusion rates and degrees of control, the PK advantage of controlled ID delivery is obtained, which is known in the dose profile. This particular profile is optimal for drugs that require a low continuous circulating basal level without peak concentrations such as LMWH, insulin, etc.

Example XII

See table 3, which shows body weight corrected serum levels of hGH after rapid bolus delivery of Genotropin recombinant human growth hormone by intradermal delivery microdevice and standard subcutaneous injection methods at 3.6 IU. The injection volume was 100. mu.L, and the drug concentration is 36 IU/mL. The percutaneous drainage type microdevice is designed to SS1_34 and SS3_34, and the exposed length of the needle is 1 mm. The injection rate of the micro-device with single needle and three needles arranged was controlled at 45. mu.L/min by a syringe pump, and the so-called bolus infusion time was 2.22 minutes. SC transport was already performed at a flow rate of 1.0 mL/min for 10 seconds through a 27G insulin catheter. The pharmacokinetic differences obtained are evident, with the ID transport giving a sharp decrease in t_maxAnd higher C_max. Statistically, the biological half-lives and bioavailability of the ID and SC pathways are comparable. Administration into the dermal microdevice structure using a single needle and needle arrangement for intradermal administration resulted in comparable pharmacokinetic behavior.

Table 3: calculated PK parameters for Genotropin dosing

PK parameters	SC	ID single needle	ID 6-needle row
				Dose(IU/kg)	0.161±0.01	0.164±0.01	0.160±0.02
Cmax(mIU/L)	158.5±31.0	612.6±187.1	582.1±391.0
				tmax(h)	2.75±0.46	0.47±0.25	0.63±0.23
t1/2z(h)	1.19±0.49	2.02±0.48	1.71±0.43
				AUCINF(pred)(mIU×h/L)	920.2±251.7	850.0±170.0	847.4±332.3
F(％)	114.6	104.0	101.7

Example XIII

Referring to the data in table 4, a rapid bolus delivery of Almotriptan, a low molecular weight, highly water soluble anti-migraine compound, was performed by intradermal microdevice and standard subcutaneous methods, showing statistically equivalent PK profiles. The following table shows the calculated PK parameters determined by measuring serum levels after injection of 3.0mg of almotriptan. The injection volume for both SC and ID was 100. mu.L, and the drug concentration was 30 mg/mL. Dosing was performed with the microdevice design SS3_34 and SS6_34 in approximately 2-2.5 minutes. almotriptan is an hourly hydrophilic compound whose SC injection did not show a significant depot effect. Thus, no difference in pharmacokinetic absorption was observed between ID and SC dosing. The drug can be readily distributed in the tissue space and rapidly absorbed by both routes. However, ID administration still has advantages in terms of reducing patient perception and enabling easy and rapid access to the appropriate injection site.

Table 4: mean (. + -. Standard deviation) PK parameters of almotriptan after SC and ID dosing

Parameter(s)	SC	ID (Single needle)	ID (needle row)
				AUC0-∞(ngh/mL)	55.9(6.04)	53.3(15.7)	54.6(14.0)
Clearance rate (L/hr)	55.1(5.87)	60.1(15.3)	58.7(12.7)
				Cmax(ng/mL)	61.0(19.4)	63.6(26.1)	77.2(54.2)
tmax(h)	0.13(0.05)	0.14(0.08)	0.16(0.08)
				□z(h-1)	0.36(0.04)	0.36(0.08)	0.31(0.08)
t1/2(h)	1.95(0.23)	2.03(0.46)	2.39(0.64)

The above examples and results show that the delivery method of the present invention using multiple point-by-point ID delivery and single needle ID delivery results in faster absorption, higher C than SC injection_max. With a needle length of about 0.5 to about 1.7mm, ID absorption and distribution is not significantly affected by device geometry, needle number and needle spacing. No concentration limitation of bioabsorption was found, whereas PK profiles were primarily indicated by concentration-based transport rates. The major limitations of ID administration are the total volume and infusion rate by volume, which limit the leak-free instillation of exogenous material into the dense tissue compartment. Since drug uptake by the ID space appears to be insensitive to device design and infusion rate by volume, a large number of formulation/device combinations can be used to overcome these limitations and provide the desired therapeutic properties. For example, volume-limiting dosing regimens may be circumvented by using more concentrated formulations and increasing the total number of infusion sites. In addition, effective PK control is achieved by controlling the infusion and administration rate of the substance.

In summary, ID delivery by the methods described herein with a microneedle device into the dermis provides an easily accessible and reproducible route of parenteral delivery with high bioavailability and the ability to modulate plasma properties by modulating the infusion parameters of the device, since absorption is not rate limiting as known from the bioabsorption parameters.

In the above examples, the methods practiced by the present invention demonstrate the ability to transport drugs in vivo at greatly improved, pharmaceutically relevant rates. The data of the present invention show improved pharmaceutical results for ID administration, and other drugs for use in humans are contemplated in accordance with the present invention.

Claims (54)

1. A method of administering a substance to a mammal, the method comprising injecting the substance into the dermis of the mammal, wherein improved systemic absorption occurs relative to subcutaneous injection of the substance, and wherein the substance is growth hormone, low molecular weight heparin, or a dopamine receptor agonist.

2. The method of claim 1, wherein the substance is human growth hormone.

3. The method of claim 1, wherein the substance is low molecular weight heparin.

4. The method of claim 1, wherein the substance is a dopamine receptor agonist.

5. The method of claim 1, wherein the substance is in the form of nanoparticles.

6. The method of claim 1, wherein the injection is through at least one hollow needle, or by electroporation, or by thermal poration.

7. The method of claim 6, wherein the injection is through at least one hollow needle.

8. The method of claim 7, wherein the at least one hollow needle comprises an array of micro needles.

9. The method of claim 1, wherein the substance is administered by bolus injection.

10. The method of claim 9, wherein the substance is administered by repeated bolus injections.

11. A method of administering a substance to a mammal, the method comprising selectively injecting the substance into the dermis of the mammal to obtain systemic absorption of the substance from the dermis, wherein the substance is growth hormone, low molecular weight heparin or a dopamine receptor agonist.

12. The method of claim 11, wherein the selective injection of the substance into the dermis is performed by injection through at least one hollow needle, or by electroporation, or by thermal poration.

13. The method of claim 12, wherein selectively injecting the substance into the dermis is through at least one hollow needle having a length and an outlet adapted to deliver the substance into the dermis to obtain systemic absorption of the substance from the dermis.

14. The method of claim 11, wherein the substance is human growth hormone.

15. The method of claim 11, wherein the substance is low molecular weight heparin.

16. The method of claim 11, wherein the substance is a dopamine receptor agonist.

17. The method of claim 11, wherein the substance is in the form of nanoparticles.

18. The method of claim 13, wherein the at least one hollow needle comprises an array of micro-needles.

19. The method of claim 11, wherein the substance is selectively injected into the dermis to achieve improved systemic absorption compared to absorption produced when the substance is administered subcutaneously.

20. The method of claim 11, wherein the substance is administered by bolus injection.

21. The method of claim 21, wherein the substance is administered by repeated bolus injections.

22. A method of administering a substance to a mammal, the method comprising selectively injecting the substance into the dermis of the mammal, wherein systemic absorption of the substance from the dermis is produced, and wherein the substance is growth hormone, low molecular weight heparin, or a dopamine receptor agonist.

23. The method of claim 22, wherein the selective injection of the substance into the dermis is performed by injection through at least one hollow needle, or by electroporation, or by thermal poration.

24. The method of claim 23, wherein selectively injecting the substance into the dermis is through at least one hollow needle having a length and an outlet suitable for delivering the substance into the dermis.

25. The method of claim 22, wherein the substance is human growth hormone.

26. The method of claim 22, wherein the substance is low molecular weight heparin.

27. The method of claim 22, wherein the substance is a dopamine receptor agonist.

28. The method of claim 22, wherein the substance is in the form of nanoparticles.

29. The method of claim 22, wherein the at least one hollow needle comprises an array of micro needles.

30. The method of claim 22, wherein the substance is selectively injected into the dermis to achieve improved systemic absorption compared to absorption produced when the substance is administered subcutaneously.

31. The method of claim 22, wherein the substance is administered by bolus injection.

32. The method of claim 31, wherein the substance is administered by repeated bolus injections.

33. A device for administering a composition comprising growth hormone, low molecular weight heparin or a dopamine agonist to a mammal, said device being constructed so as to selectively deliver said composition into the dermis to achieve systemic absorption of said composition, wherein said device is an electroporation or thermal electroporation system.

34. A device for administering a composition comprising growth hormone, low molecular weight heparin or a dopamine agonist to a mammal, said device being constructed to selectively deliver said composition into the dermis wherein systemic absorption of said composition is achieved, wherein said device is an electroporation or thermal electroporation injection system.

35. A method of administering a substance to a mammal, the method comprising selectively transporting the substance into the dermis to achieve improved systemic absorption compared to that produced upon bolus subcutaneous administration of the substance, wherein the substance is growth hormone, low molecular weight heparin or a dopamine receptor agonist.

36. The method of claim 35, wherein the substance is human growth hormone.

37. The method of claim 35, wherein the substance is low molecular weight heparin.

38. The method of claim 35, wherein the substance is a dopamine receptor agonist.

39. The method of claim 35, wherein the substance is in the form of nanoparticles.

40. The method of claim 35, wherein the substance is administered by hollow needle, by electroporation, or by hot-puncture injection.

41. The method of claim 35, wherein the transporting is through at least one hollow needle.

42. The method of claim 35, wherein the at least one hollow needle comprises an array of micro needles.

43. The method of claim 35, wherein the substance is administered by bolus injection.

44. The method of claim 35, wherein the substance is administered by repeated bolus injections.

45. A method of administering a substance to a mammal, said method comprising selectively transporting said substance into the dermis to achieve improved systemic absorption compared to that produced when said substance is given subcutaneously as a bolus injection at the same dose, wherein said substance is growth hormone, low molecular weight heparin or a dopamine receptor agonist.

46. The method of claim 45, wherein the substance is human growth hormone.

47. The method of claim 45, wherein the substance is low molecular weight heparin.

48. The method of claim 45, wherein the substance is a dopamine receptor agonist.

49. The method of claim 45, wherein the substance is in the form of nanoparticles.

50. The method of claim 45, wherein the substance is administered by hollow needle, by electroporation, or by hot-puncture injection.

51. The method of claim 45, wherein the transporting is through at least one hollow needle.

52. The method of claim 45, wherein said at least one hollow needle comprises an array of micro-needles.

53. The method of claim 45, wherein the substance is administered by bolus injection.

54. The method of claim 45, wherein the substance is administered by repeated bolus injections.