Patent Application
20140350514
This invention relates to administration of substances, such as insulin, into the skin.
Insulin is currently the most effective therapy for treating diabetics. It is typically administered as a bolus and basally. Insulin is administered to patients subcutaneously (SC or SQ), through either pen injectors, hypodermic needles and syringes, or by infusion through a subcutaneously planted catheter connected to a patient-oriented pump. Bolus doses of insulin are administered, for example, at meal times, as the bolus acts rapidly, while when the patient is in a fasting state, a basal dose of insulin, administered once or twice a day, maintains the state of euglycemia in the patient.
Bolus Insulins include rapid-acting analogues with a very short Tmax (time to peak) of typically around one hour and regular insulins with a Tmax of over 2.5 hours, basal insulins have a relatively long Tmax and long half-life (e.g., Sanofi's Glargine (Lantus) is effective for about 20 hours). Combinations of basal and bolus insulins are also in use, such as those disclosed in “Long-Acting Insulin's, Insulin Detemir, Levemir®, Insulin Glargine, Lantus®,” http://www.globalrph.com/long-acting-insulins.htm.
Administration of insulin to the skin has many potential advantages including improved kinetics. Today, insulin is injected to the Subcutaneous (SC) space, using, in most cases, various devices incorporating standard metal needles and usually causing considerable pain and discomfort to the patients. Insulin injection is common, and is typically performed by the patients themselves. However, there are many limitations to this approach.
First, the inter-patient and intra-patient variability of insulin delivered into the SC space is reported to be very high, for example, as disclosed in L. Takiya, et al., “Pharmacist's Guide to Insulin Preparations: A Comprehensive Review,” Pharmacy Times CE (2005), https://secure.pharmacytimes.com/lessons/200510-03.asp. This imposes difficulties on behalf of the clinician and patient with regards to actual dosing, as well as the timing of such (before meal, during or after, with doses reflective of the anticipated calorie intake). Insulin has a narrow therapeutic range compared with other drugs, which necessitates careful dosing management, to prevent both life-risking hypoglycemia, as well as ineffective sub-dosing. Self-injection entails additional challenges, as it may be inaccurate and unreliable, and few, if any, of the available injection devices are user-friendly. Moreover, approximately 15-20% of patients are needle-phobic, making self-injection of insulin additionally challenging.
Additionally, rapid acting analogues such as Novo Nordisk's Novolog® insulin aspart, Eli Lilly's Humalog® insulin lispro, and Sanofi Aventis' Apidra® insulin glulisine, still suffer from a relatively long Tmax (time to peak), which is thought to be much longer than endogenic insulin of a healthy individual. This translates to uncomfortable and hard to manage lifestyles, which require careful planning of injection before meals, identifying and calculating the meal size and timing to prevent hypoglycemia induced by late intake of the food.
While the pharmaceutical industry has worked hard to develop “ultra rapid” analogues mimicking normal insulin secretion (with a half-life of 15 min to 35 min), the development/formulation challenge for researchers is enormous, and has not been successfully met to date. There are various approaches to accelerate the absorption of insulin into the systemic circulation including formulation, local heating, use of local hyaluronidase, etc.
However, none of the aforementioned contemporary solutions has reliably demonstrated clinical results or long term benefits. Intradermal insulin delivery, e.g., the delivery of insulin directly into the skin has shown to accelerate systemic delivery tremendously, and meet the bar of an “ultra short” analogue, with approximately 30-35 min of Tmax, and higher first hour insulin exposure, expressed as area under the curve (AUC) from time zero to one hour, expressed as AUC0-1 hour(h). However the traditional intradermal injection is difficult, unreliable and unlikely to be performed by patients themselves.
Gupta, et al, in “Rapid Pharmacokinetics of Intradermal Insulin Administered. Using Microneedles in Type 1 Diabetes Subjects,” Diabetes Technol. Ther. 2011 April: 13(4); pages 451-456 reported use of 0.9 mm length microneedles of borosilicate glass (single glass cannula) for intradermally perpendicularly injected bolus infusion of lispro insulin followed by the consumption of a standardized meal. The insulin reached peak concentrations in approximately half the time as compared to insulin administration through subcutaneous catheters.
The present invention pertains to methods and devices for controlling the pharmacokinetics of administered substances, including drug substances, such as insulin, by intradermal injection with microneedles. The invention provides a method for delivering a substance, for example, insulin, to the shallow portion of the dermis in human and other mammalian subjects. This provides enhanced pharmacokinetics and pharmacodynamics, making insulin delivery more rapid and efficient, and accordingly, more effective than the current insulin administration via conventional needles into the SC space.
However, it remains desired for insulin to be injected intradermally (ID). This is due to faster and increased absorption through the increased vascularity and lymphatics of the skin, when compared to absorption in the subcutaneous (SC) space.
Examples of substances that may be delivered in accordance with the present invention include pharmaceutically or biologically active substances including diagnostic agents, drugs, and other substances which provide therapeutic or health benefits such as, for example, nutriceuticals.
Potential diagnostic substances useful with the present invention include macromolecular substances such as, for example, inulin, ACTH (e.g., corticotropin injection), luteinizing hormone-releasing hormone (e.g., Gonadorelin Hydrochloride), growth hormone-releasing hormone (e.g. Sermorelin Acetate), cholecystokinin (Sincalide), parathyroid hormone (PTH) and fragments thereof (e.g. Teriparatide), thyroid releasing hormone and analogs thereof (e.g., protirelin), secretin, other hormones, and the like.
Therapeutic substances that may be used with the present invention include Alpha-1 anti-trypsin, Anti-Angiogenesis agents, Antisense, butorphanol, Calcitonin and analogs, Ceredase, COX-II inhibitors, dermatological agents, dihydroergotamine, Dopamine agonists and antagonists, Enkephalins and other opioid peptides, Epidermal growth factors, Erythropoietin and analogs, Follicle stimulating hormone, G-CSF, Glucagon, GM-CSF, granisetron, Growth hormone and analogs (including growth hormone releasing hormone), Growth hormone antagonists, Hirudin and Hirudin analogs such as Hirulog, IgE suppressors, Insulin, insulinotropin and analogs, Insulin-like growth factors, Interferons, Interleukins, Luteinizing hormone, Luteinizing hormone releasing hormone and analogs, Heparins, Low molecular weight heparins and other natural, modified, or synthetic glycoaminoglycans, M-CSF, metoclopramide, Midazolam, Monoclonal antibodies (mAbs); Pegylated antibodies, Pegylated proteins or any proteins modified with hydrophilic or hydrophobic polymers or additional functional groups, Fusion proteins, Single chain antibody fragments or the same with any combination of attached proteins, macromolecules, or additional functional groups thereof, Small Interfering RNA (siRNA), Narcotic analgesics, nicotine, Non-steroid anti-inflammatory agents, Oligosaccharides, ondansetron, Parathyroid hormone and analogs, Parathyroid hormone antagonists, Prostaglandin antagonists, Prostaglandins, Recombinant soluble receptors, scopolamine, Serotonin agonists and antagonists, Sildenafil, Terbutaline, Thrombolytics, Tissue plasminogen activators, TNF-, and TNF-antagonist, the vaccines, with or without carriers/adjuvants, including prophylactics and therapeutic antigens (including but not limited to subunit protein, peptide and polysaccharide, polysaccharide conjugates, toxoids, genetic based vaccines, live attenuated, reassortant, inactivated, whole cells, viral and bacterial vectors) in connection with, addiction, arthritis, cholera, cocaine addiction, diphtheria, tetanus, HIB, Lyme disease, meningococcus, measles, mumps, rubella, varicella, yellow fever, Respiratory syncytial virus, tick borne Japanese encephalitis, pneumococcus, streptococcus, typhoid, influenza, hepatitis, including hepatitis A, B, C and E, otitis media, rabies, polio, HIV, parainfluenza, rotavirus, Epstein Barr Virus, CMV, chlamydia, non-typeable haemophilus, moraxella catarrhalis, human papilloma virus, tuberculosis including BCG, gonorrhoea, asthma, atheroschlerosis malaria, E-coli, Alzheimer's Disease, H. Pylori, salmonella, diabetes, cancer, herpes simplex, human papilloma and the like other substances including all of the major therapeutics such as agents for the common cold, pain migraines, Anti-addiction, anti-allergy, anti-emetics, anti-obesity, antiosteoporeteic, anti-infectives, analgesics, anesthetics, anorexics, antiarthritics, antiasthmatic agents, anticonvulsants, anti-depressants, antidiabetic agents, antihistamines, anti-inflammatory agents, antimigraine preparations, antimotion sickness preparations, antinauseants, antineoplastics, antiparkinsonism drugs, antipruritics, antipsychotics, antipyretics, anticholinergics, benzodiazepine antagonists, vasodilators, including general, coronary, peripheral and cerebral, bone stimulating agents, central nervous system stimulants, hormones, hypnotics, immunosuppressives, muscle relaxants, parasympatholytics, parasympathomimetrics, prostaglandins, proteins, peptides, polypeptides and other macromolecules, psychostimulants, sedatives, and sexual hypofunction and tranquilizers.
Substances may be delivered by bolus, metered bolus or infusion, through the microneedle arrays detailed below. Substances may also be delivered by infusion with pumps through the microneedles detailed below.
An embodiment of the invention is directed to a method for delivering a substance to the skin of a human subject. The method comprises: obtaining a substance selected from the group consisting of hormones; and delivering the substance into an intradermal space within the skin of the human subject through a plurality of microneedles, the microneedles of a height of approximately 400 micrometers to approximately 750 micrometers.
Another embodiment of the invention is directed to a substance selected from the group consisting of hormones, for use in the treatment or prevention of hormone deficiency. The substance is delivered into an intradermal space within the skin of the human subject through a plurality of microneedles, the microneedles of a height of approximately 400 micrometers to approximately 650 micrometers.
Attention is now directed to the drawings where like numerals or characters represent like or corresponding components. In the drawings:
The present invention provides for delivery of insulin and other substances, such as drugs and therapeutic agents to human or animal subjects through one or more microneedles, which penetrate the skin to the depth of the intradermal space. Insulin infused as herein described through the microneedles described herein, has been found to exhibit pharmacokinetics better than that for the same substance administered by subcutaneous injection with conventional needles. Additionally, the injection by the disclosed microneedles is painless and non-intimidating for the patient and provides a consistent dose of insulin injected at a consistent delivery depth.
The injection device, also referred to as the delivery device, is used for intradermal delivery of the pharmaceutical composition, drug, agent, or the like. It provides for delivery of the pharmaceutical composition, drug, agent, or the like via one or more microneedles, intradermally (ID).
This structural arrangement and geometry of the microneedle 20, coupled with the microneedle 20 height of approximately 400 micrometers or microns (micrometers and microns are the same and are used interchangeably herein) to 1 mm (1000 micrometers), and, for example, 0.45 mm (45 micrometers) from the substrate surface 22, ensures consistency in delivering the pharmaceutical compositions, drugs, and agents to an intradermal depth of approximately 300 micrometers, close to the epidermal junction. The microneedles 20 are, for example, in accordance with those disclosed in commonly owned U.S. Pat. No. 6,533,949, entitled: Microneedle Structure and Production Method Therefor, the disclosure of which is incorporated by reference herein.
The aforementioned microneedles 20 in the array 21 are arranged on a delivery device (injector) 30, as shown in
The delivery device 30 is formed of an outer member 32, which serves as a removable protective cap (removable prior to injection), which accommodates an inner member 34. The inner member 34 is slideably received and movable in the outer member 32. The inner member 34 supports the substrate surface 22 for the array 21 of microneedles 20 at its distal end 38, as shown in
The delivery device 130, is similar to the delivery device 30 above, in that it is formed of an outer member 132, which serves as a protective cap, for a slideably received inner member 134. The inner member 134 supports the substrate surface 122 for the array 121 of microneedles 120 at its distal end 138, as shown in
Alternative delivery devices include those in accordance with the delivery devices disclosed in commonly owned U.S. Patent Application Publication No. US 2009/0247953 A1 (U.S. patent application Ser. No. 12/096,028), entitled: Microneedle Adaptor for Dosed Drug Delivery Devices, the disclosure of which is incorporated by reference herein.
The substance, pharmaceutical composition, drug, or agent disclosed for use with the microneedles 20, 120 and delivery devices 30, 130 therefor, is for example, insulin, including insulin analogs. One exemplary insulin suitable for use with the microneedles 20, 120 and delivery devices 30, 130 disclosed herein is NovoRapid® insulin (aspart), available from Novo Nordisk A/S of Denmark, a short acting insulin analog.
Examples of substances that may be delivered in accordance with the microneedles 20 and delivery devices 30, 130 of the present invention include pharmaceutically or biologically active substances including diagnostic agents, drugs, and other substances which provide therapeutic or health benefits such as, for example, nutriceuticals.
Potential diagnostic substances useful with the present invention include macromolecular substances such as, for example, inulin, ACTH (e.g., corticotropin injection), luteinizing hormone-releasing hormone (e.g., Gonadorelin Hydrochloride), growth hormone-releasing hormone (e.g. Sermorelin Acetate), cholecystokinin (Sincalide), parathyroid hormone (PTH) and fragments thereof (e.g. Teriparatide Acetate), thyroid releasing hormone and analogs thereof (e.g., protirelin), secretin, other hormones, and the like.
Therapeutic substances that may be used with the present invention include Alpha-1 anti-trypsin, Anti-Angiogenesis agents, Antisense, butorphanol, Calcitonin and analogs, Ceredase, COX-II inhibitors, dermatological agents, dihydroergotamine, Dopamine agonists and antagonists, Enkephalins and other opioid peptides, Epidermal growth factors, Erythropoietin and analogs, Follicle stimulating hormone, G-CSF, Glucagon, GM-CSF, granisetron, Growth hormone and analogs (including growth hormone releasing hormone), Growth hormone antagonists, Hirudin and Hirudin analogs such as Hirulog, IgE suppressors, insulinotropin and analogs, Insulin-like growth factors, Interferons, Interleukins, Luteinizing hormone, Luteinizing hormone releasing hormone and analogs, Heparins, Low molecular weight heparins and other natural, modified, or synthetic glycoaminoglycans, M-CSF, metoclopramide, Midazolam, Monoclonal antibodies (mAbs); Pegylated antibodies, Pegylated proteins or any proteins modified with hydrophilic or hydrophobic polymers or additional functional groups, Fusion proteins, Single chain antibody fragments or the same with any combination of attached proteins, macromolecules, or additional functional groups thereof, Small Interfering RNA (siRNA), Narcotic analgesics, nicotine, Non-steroid anti-inflammatory agents, Oligosaccharides, ondansetron, Parathyroid hormone and analogs, Parathyroid hormone antagonists, Prostaglandin antagonists, Prostaglandins, Recombinant soluble receptors, scopolamine, Serotonin agonists and antagonists, Sildenafil, Terbutaline, Thrombolytics, Tissue plasminogen activators, TNF-, and TNF-antagonist, the vaccines, with or without carriers/adjuvants, including prophylactics and therapeutic antigens (including but not limited to subunit protein, peptide and polysaccharide, polysaccharide conjugates, toxoids, genetic based vaccines, live attenuated, reassortant, inactivated, whole cells, viral and bacterial vectors) in connection with, addiction, arthritis, cholera, cocaine addiction, diphtheria, tetanus, HIB, Lyme disease, meningococcus, measles, mumps, rubella, varicella, yellow fever, Respiratory syncytial virus, tick borne japanese encephalitis, pneumococcus, streptococcus, typhoid, influenza, hepatitis, including hepatitis A, B, C and E, otitis media, rabies, polio, HIV, parainfluenza, rotavirus, Epstein Barr Virus, CMV, chlamydia, non-typeable haemophilus, moraxella catarrhalis, human papilloma virus, tuberculosis including BCG, gonorrhoea, asthma, atheroschlerosis malaria, E-coli, Alzheimer's Disease, H. Pylori, salmonella, diabetes, cancer, herpes simplex, human papilloma and the like other substances including all of the major therapeutics such as agents for the common cold, pain migraines, Anti-addiction, anti-allergy, anti-emetics, anti-obesity, antiosteoporeteic, anti-infectives, analgesics, anesthetics, anorexics, antiarthritics, antiasthmatic agents, anticonvulsants, anti-depressants, antidiabetic agents, antihistamines, anti-inflammatory agents, antimigraine preparations, antimotion sickness preparations, antinauseants, antineoplastics, antiparkinsonism drugs, antipruritics, antipsychotics, antipyretics, anticholinergics, benzodiazepine antagonists, vasodilators, including general, coronary, peripheral and cerebral, bone stimulating agents, central nervous system stimulants, hormones, hypnotics, immunosuppressives, muscle relaxants, parasympatholytics, parasympathomimetrics, prostaglandins, proteins, peptides, polypeptides and other macromolecules, psychostimulants, sedatives, and sexual hypofunction and tranquilizers.
The microneedles 20, 120 are, for example, inserted into the skin obliquely, for an intradermal delivery. For an approximately 450-600 micron microneedle 20, 120 (extending from the substrate surface 22), the “Depth of Insertion,” the deepest point of the microneedle going into the skin, is approximately 300-500 microns. The insulin is, for example, administered as a bolus, and distributed internally, typically covering a depth of less than 1000 microns, so as to be delivered intradermally (less than 1500 microns). This administration depth of insertion or depth of injection (the “Depth of Injection” defined as the deepest point in which substance enters the skin upon injection before it is distributed) or the microneedles 20 remains intradermal, regardless of skin thickness affects such as site, body mass index (BMI) race and age. See, Laurent A, Mistretta F, Bottigioli D, Dahel K, Goujon C, Nicolas J F, Hennino A, Laurent P E, “Echographic measurement of skin thickness in adults by high frequency ultrasound to assess the appropriate microneedle length for intradermal delivery of vaccines,” Vaccine, 25(34):6423-30 (Aug. 21, 2007).
The applicants of this application conducted a study of Insulin Delivery using the microneedles 20, 120 and delivery devices 30, 130, also known as the MicronJet® delivery devices, disclosed herein with NovoRapid® insulin, in a Phase I study of healthy subjects and patients with Type II Diabetes Mellitus (DM or diabetes). The study compared insulin delivery of NovoRapid® insulin by the microneedles 20 and delivery devices 30 in intradermal administration, compared to identical doses of NovoRapid® insulin administered subcutaneously (SC) by conventional needles and syringes (collectively “needles”), for the same subject a week apart. The results for MicronJet® injection and conventional needle SC injection are provided in the graph of
While insulin is detailed herein, the devices and methods disclosed herein may be used for other pharmaceutical compositions, drugs and the like, including those as detailed herein.
As shown in the
Further inter patient variability in Tmax is lower in MJ as compared with SC, as shown by the ratio between the dispersion and the central tendency measure (interquartile range IQR/median 28.6% compared to 68.6% in all DM subjects, and 28.6% as compared to 77.8% in fasting DM subjects. This may have a potential benefit of a more practical post prandial glucose response.
One reason for this may be that the consistent delivery depth of the microneedles 20, 120 compared with SC insulin delivery using standard needles, possibly in conjunction with the more preserved capillary network in the dermis, which is more consistent in size (and hence more consistent in delivery/diffusion across its vessel barrier) than the SC blood vessels which are typically of larger diameter range, and barrier (vessel wall) range, as well as having varying distance from the injection bolus.
Additionally, the levels of insulin of the late phase after administration are lower using intradermal delivery (ID). Accordingly, the propensity of hypoglycemia effected by high insulin levels at this phase of several hours post-meal, is potentially lower than SC insulin administration, making injection by the microneedles 20, 120 and delivery devices 30, 130 disclosed herein (the route/method/device) potentially safer than standard SC needle delivery.
Moreover, the aforementioned microneedle 20, 120 delivery of insulin results in a patients' ability to absorb insulin faster (shorter time to ½Cmax). This absorption from microneedles 20, 120 delivery (via delivery devices 30, 130) as disclosed herein, resembles normal pancreatic function to a greater degree than a SC needle injection pharmacokinetic (PK) profile. The ID insulin administration, as disclosed herein using the disclosed microneedles 20, 120 and delivery devices 30, 130, may result in long term biological benefits of lower average glucose levels, which may contribute to better blood glucose and end organ preservation.
Purpose—The purpose of this study was to evaluate the safety, pharmacokinetics and pharmacodynamics profile of Insulin injected by MicronJet® (MJ) delivery device, i.e., delivery device 30 detailed above, as compared to SC injection, in healthy volunteers and diabetes mellitus Type II subjects.
Study Design—An Open Label Study in Healthy Volunteers and Diabetes Mellitus Type II Subjects to Determine the Safety, Pharmacokinetics and Pharmacodynamics Profile of Insulin Injected by the MicronJet™ Device, specifically, delivery device 30 detailed above and shown in
Objectives—The pharmacokinetics (PK) and pharmacodynamics (PD) of insulin Novorapid® (Novo Nordisk) injected via the MicronJet device intradermally, at an injection depth of approximately 300 microns intradermally, into the skin as the needles are 450-600 microns and inserted obliquely. The insulin was administered as a bolus of drug, which was distributed internally, typically covering a depth of 100-1000 microns.—This mode of injection was compared to conventional needles injected into the SC space.
Patient Population—The study population incorporated 2 primary types of subjects: 1) Healthy volunteers aged 18-40 years; and 2) Type 2 diabetic volunteers aged 30-70 years
Study Groups—Four Study Groups were evaluated:
Procedure—Blood samples for glucose and insulin were collected at 5 minutes, baseline (0), and 10, 20, 30, 40, 50, 60, 70, 80, 90, 100, 110, 120, 150, 180, 210, 240, 270, 300, 330 and 360 minutes post-dose.
17 diabetic and 6 healthy subjects were enrolled; 20 subjects successfully completed the study and were included in the per-protocol (PP) analysis.
The following observations were noted.
MJ has statistically significant median shorter Tmax than SC in all groups, 35 minutes as compared to 88 minutes in all diabetes patients, with p<0.001, and 35 minutes, as compared to 90 minutes in fasting diabetic patients, with p<0.001 and 30 minutes, as compared to 60 minutes in healthy subjects, with p=0.042). Shorter Tmax may have a positive effect on post-prandial glucose and may allow insulin injection post-meal and not before as currently used. MJ has statistically significant shorter time to ½Cmax than SC (14 minutes as compared to 26 minutes in all diabetes mellitus (DM), with p-0.008 subjects and 13.5 minutes as compared to 25 minutes in diabetes mellitus (DM) fasting subjects, with p=0.02). This shorter time to ½Cmax suggests an earlier glucose response.
MJ has statistically significant increased initial coverage (AUC0-1.5 h) (p=0.033) and reduced late exposure (AUC4-6 h) (p=0.009)—potential better glucose control and reduction in the risk of late hypoglycemic events.
The inter-patient variability in Tmax is lower in MJ when compared to SC (27% as compared to 67% in all DM, and 27% compared to 78% in fasting diabetic patients) potentially more predictable PK profile may allow better prediction of glucose effect as well as less hypoglycemic/hyperglycemic events.
Cmax was higher following MJ injection than SC in the diabetic patients (not statistically significant). This suggests a possible benefit of improved insulin coverage, with early rise and earlier decline which are more similar to endogenic insulin in healthy subjects.
Insulin AUC was similar in both injections, suggesting appropriate overall bioavailability, which is differentiated from most passive or active transdermal delivery systems for insulin; as well as from alternatives routes of administration like the inhaled, intranasal, oral delivery technologies.
Although the invention has been described in conjunction with specific embodiments thereof, it is evident that many alternatives, modifications and variations will be apparent to those skilled in the art. Accordingly, it is intended to embrace all such alternatives, modifications and variations that fall within the spirit and broad scope of the appended claims.
All publications, patents and patent applications mentioned in this specification are herein incorporated in their entirety by reference into the specification, to the same extent as if each individual publication, patent or patent application was specifically and individually indicated to be incorporated herein by reference. In addition, citation or identification of any reference in this application shall not be construed as an admission that such reference is available as prior art to the present invention.
