WO2016004443A2 - Modification de préparations pharmaceutiques pour les rendre mieux appropriées à l'administration transdermique et ultrasonore - Google Patents

Modification de préparations pharmaceutiques pour les rendre mieux appropriées à l'administration transdermique et ultrasonore Download PDF

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Publication number
WO2016004443A2
WO2016004443A2 PCT/US2015/039831 US2015039831W WO2016004443A2 WO 2016004443 A2 WO2016004443 A2 WO 2016004443A2 US 2015039831 W US2015039831 W US 2015039831W WO 2016004443 A2 WO2016004443 A2 WO 2016004443A2
Authority
WO
WIPO (PCT)
Prior art keywords
ultrasonic
substance
sodium phosphate
formulation
dibasic sodium
Prior art date
Application number
PCT/US2015/039831
Other languages
English (en)
Other versions
WO2016004443A3 (fr
Inventor
Bruce K. Redding
Original Assignee
Redding Bruce K
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority to US15/323,636 priority Critical patent/US20170143803A1/en
Application filed by Redding Bruce K filed Critical Redding Bruce K
Priority to EP15815948.3A priority patent/EP3164120A2/fr
Priority to JP2017521048A priority patent/JP2017523237A/ja
Priority to PCT/US2015/039831 priority patent/WO2016004443A2/fr
Priority to CN201580036489.0A priority patent/CN106604723A/zh
Priority to KR1020177003028A priority patent/KR20170041199A/ko
Publication of WO2016004443A2 publication Critical patent/WO2016004443A2/fr
Publication of WO2016004443A3 publication Critical patent/WO2016004443A3/fr

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/22—Hormones
    • A61K38/28—Insulins
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K41/00—Medicinal preparations obtained by treating materials with wave energy or particle radiation ; Therapies using these preparations
    • A61K41/0047—Sonopheresis, i.e. ultrasonically-enhanced transdermal delivery, electroporation of a pharmacologically active agent
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0002—Galenical forms characterised by the drug release technique; Application systems commanded by energy
    • A61K9/0009—Galenical forms characterised by the drug release technique; Application systems commanded by energy involving or responsive to electricity, magnetism or acoustic waves; Galenical aspects of sonophoresis, iontophoresis, electroporation or electroosmosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0014—Skin, i.e. galenical aspects of topical compositions
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/70—Web, sheet or filament bases ; Films; Fibres of the matrix type containing drug
    • A61K9/7023—Transdermal patches and similar drug-containing composite devices, e.g. cataplasms
    • A61K9/703—Transdermal patches and similar drug-containing composite devices, e.g. cataplasms characterised by shape or structure; Details concerning release liner or backing; Refillable patches; User-activated patches
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M37/00—Other apparatus for introducing media into the body; Percutany, i.e. introducing medicines into the body by diffusion through the skin
    • A61M37/0092—Other apparatus for introducing media into the body; Percutany, i.e. introducing medicines into the body by diffusion through the skin using ultrasonic, sonic or infrasonic vibrations, e.g. phonophoresis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M37/00—Other apparatus for introducing media into the body; Percutany, i.e. introducing medicines into the body by diffusion through the skin
    • A61M2037/0007—Other apparatus for introducing media into the body; Percutany, i.e. introducing medicines into the body by diffusion through the skin having means for enhancing the permeation of substances through the epidermis, e.g. using suction or depression, electric or magnetic fields, sound waves or chemical agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M2210/00—Anatomical parts of the body
    • A61M2210/08—Limbs
    • A61M2210/083—Arms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M2210/00—Anatomical parts of the body
    • A61M2210/10—Trunk

Definitions

  • the present invention relates generally to substance delivery methods, and more particularly to methods suitable for enhancing dermal and transdermal substance delivery.
  • transdermal medicinal compound, or drug, delivery systems employ a medicated patch, which is affixed to the skin of a patient.
  • the patch allows the medicinal compound to be absorbed through the skin layers and into the patient's blood stream.
  • Transdermal drug delivery generally mitigates the pain associated with injections and
  • Transdermal drug delivery also avoids gastrointestinal metabolism of administered drugs, mitigates liver metabolization thereof, and provides a sustained release of the administered drug. Transdermal drug delivery also enhances patient compliance with a drug regimen, because of the relative ease of administration and the sustained release of the drug.
  • Iontophoresis involves the application of an external electric field and topical delivery of an ionized form of drug or unionized drug carried with the water flux associated with ion transport (electro- osmosis). Iontophoresis has been proposed to increase the permeability of skin to drugs. While permeation enhancement with iontophoresis may be effective, control of drug delivery and irreversible skin damage are problems associated with the technique.
  • Ultrasound has also been suggested to enhance permeability of the skin.
  • Ultrasonic signals can be generated by vibrating a piezoelectric crystal or other electromechanical element, such as by passing an alternating current there through.
  • the use of ultrasound to increase the permeability of the skin to drug molecules is sometimes referred to as sonophoresis or phonophoresis.
  • results have been largely disappointing— in that enhancement of skin permeability has been relatively low. This is largely due to the use of sine wave ultrasound to breach the skin cavities and to drive the drug into the skin. Further, it is believed that there is no consensus on the efficacy of ultrasound for increasing drug flux across the skin. While some studies report the success of sonophoresis, others have obtained negative results.
  • a method for improving the ultrasonic transdermal delivery of an drug by modifying the excipient solution to which an active ingredient is intermixed in a drug formulation , whereby the choice of excipient solution is modified to one which will be more conducive to ultrasound and will propagate the drug substance at a higher delivery speed through the skin under ultrasonic excitation
  • FIG. 1 illustrates an absorbent pad incorporating patch suitable for use with ultrasonic signals to deliver a substance transdermally into a patient as disclosed in US Patent no
  • FIG. 2 illustrates a chart indicative of different transdermal delivery rates for different commercially available forms of insulin.
  • Fig. 9 in an array consisting of 4 transducer elements affixed to a stainless steel face plate.
  • Fig. 10 is an alternating ultrasonic transmission.
  • Fig. 11 is the same as Fig. 2 but shows the uniformity of power intensity, ultrasonic frequency and whether Humulin or Humalog was used along with which type of transducer array.
  • Fig. 12 and 13 show the differences in delivery speed for differing types of insulin via a standard ultrasonic excitation.
  • Figure 1 illustrates a transdermal patch 100 suitable for use with ultrasonic signals, wherein the patch employs at least one absorbent pad or layer of absorbent material.
  • Patch 100 is constructed with a backbone or backing material 10 into which a section, or aperture, has been created. In the illustrated embodiment, the aperture accommodates a sonic membrane 11.
  • a peel-away film 12 seals patch 300 until use. Peel-away film 12 may be constructed of any suitable material, including, but not limited to, UV-resistant, anti-static polyethylene film (50 micrometer thickness) available from Crystal-X Corp., of Sharon Hill, Pa.
  • a semi-permeable member 13 may take the form of a membrane or film that comes into functional proximity with the skin of a user.
  • the patch may be adhered to the skin such that membrane 11 is in direct contact with the skin.
  • an absorbent pad 14 In the interior of patch 100 is an absorbent pad 14 that holds a desired substance, e.g., drug or medicinal compound 15.
  • a gasket 16 is placed between backbone 10 and absorbent pad 14.
  • Gasket 16 may be composed of any suitable material, such as, for example, synthetic rubber. Gasket 16 forms a reservoir or well over which absorbent pad 14 is placed.
  • gasket 16 When pressed upon the skin, gasket 16 forms a barrier, which tends to restrict moisture and air from traveling under the patch and interfering with the ultrasonic signal intensity.
  • a sealant compound, ultrasonic gel or other suitable material may be used for or in place of the gasket 16 to provide a sealing action around the borders of patch 100 to provide moisture protection, prevent leakage of substance or the drug from the patch and prevent air from entering under the patch.
  • ultrasound and other forms of external stimuli may be used in addition to or in lieu of ultrasound on delivery devices other than transdermal patches, including but not limited to bandages.
  • An external stimulus such as a source of ultrasonic signals transmits signals 110 into the patch or other delivery device, and at least one pad 14 or at least one layer of absorbent material, often through, but limited to, sonic membrane 11.
  • Substance 15, contained within the at least one pad or at least one layer of absorbent material, is released in response to the impinging ultrasonic signals.
  • the substance is then released from the at least one layer of absorbent material or the at least one absorbent pad and in some embodiments passes through semipermeable membrane 13 and before being deposited on, in or through living tissue, which could be but is not limited to the surface of the patient's skin 3. While a delivery device has been described for use with ultrasound 110, other forms of external stimulus may be used in addition or in lieu of ultrasound.
  • iontophoresis heat therapy, radio waves, magnetic transmission lasers, microwave signals, and/or electric currents applied to the living tissue, which in some embodiments is skin, may be used as the external stimulus.
  • ultrasonic signals may be used together with iontophoresis, or ultrasound may be used as a pre- treatment to the application of iontophoresis.
  • drug should be understood to be used in a non-limiting manner and for purposes of explanation only, as the present invention is suitable for delivering many substances to a patient.
  • pharmaceutical preparation may include, but is not limited to, any substance, solution or suspension including, but not limited to, a medicinal or non-medicinal substance which may be transported through a live surface or live membrane, including, but not limited to, live tissue and other types of live membranes.
  • substances typically include one or more active ingredients and an excipient.
  • Excipient generally refers to a substance used as a diluent or vehicle in a drug for the one or more active ingredients. Excipients are generally inert.
  • transdermally is used herein in a non- limiting manner, and includes intra-dermally (e.g., dermal delivery) and transmucosally as well, for example.
  • a pharmaceutical preparation and substance to be transdermally delivered is preferably in a liquid form.
  • a liquid excipient is used as the carrier for the active substance.
  • a substance to be delivered transdermally may typically consist of an active substance suspended within a liquid carrier or adhesive.
  • active ingredients are generally immersed within an excipient binder fluid, such as saline or an acetate composition, to make them injectable.
  • Insulin for example, is often placed in acetate mixes.
  • Common substance and pharmaceutical liquid carrier excipients include: water, distilled water, distilled water buffered, acetate, saline, phosphate, phosphate buffer with added protein, glycerin, saccharine, grapefruit aroma, methyl p- hydroxybenzoate, propyl p-hydroxybenzoate, sodium acetate, fructose, glucose or sucrose, hydrogenated glucose syrup, mannitol, maltitol, sorbitol, xylitol, gluten, tartrazine, arachis (peanut) oil, sesame oil, beeswax, benzyl alcohol, butylated hydroxyanisole, butylated hydroxytoluene, cetostearyl alcohol (including cetyl and stearyl alcohol (including cet
  • Excipients typically include substituent components.
  • excipients may typically include one or more preservatives, like zinc, and one or more buffers, like dibasic sodium phosphate.
  • certain substances and pharmaceutical preparations contain liquid carrier excipients, and/or excipient ingredients, that inhibit the mobility, and hence deliverability of the active ingredient(s) responsively to insonification.
  • certain substances and pharmaceutical preparations contain liquid carrier excipients, and/or excipient ingredients, that increase the delivery rate of the active ingredient(s) responsively to insonification.
  • Part of the present invention lies in the observation that certain substances and pharmaceutical preparations contain liquid carrier excipients, and/or excipient ingredients, that increase delivery volume per unit of time of the active ingredient(s) responsively to insonification.
  • FIG. 2 it shows a chart 200 indicative of human patient transdermal delivery rates for two commercially available insulin types responsively to insonification.
  • the data of Fig. 2 is indicative of a transdermal delivery of u 100 Humulin ® and Humalog ® to a human patient using a 125 mW, 30kHz ultrasonic signal from a square, four-transducer array.
  • Applicant have discovered that Humulin ® is delivered at a faster rate and at a greater dose transdermally under ultrasonic propagation than Humalog ® . This is due to changes in the chemistry between the two different versions of insulin.
  • Humulin is designed as a slow acting basal insulin
  • Humalog is designed as a fast acting insulin, often prescribed before a meal.
  • Table- 1 illustrates basic ingredients of Humulin ® and Humalog ® .
  • Fig. 2 shows a Comparison of the Delivery Rate of Humulin and Humalog Insulin at Similar Ultrasonic Frequency and Intensity Levels.
  • a comparison of the delivery rate for Humulin and Humalog across the abdominal skin using a standard 4-element transducer array shows a 0.98 -unit/minute-deli very rate for Humulin and a 0.72-unit/minute-delivery rate for Humalog insulin.
  • the difference in delivery flow is due to the difference in interaction between the ultrasound and components within the target drug substance. There is a slight difference in the insulin loading and excipient and preservative package employed between Humulin and Humalog.
  • Dibasic sodium phosphate has a specific gravity of 1.67 (higher than that of water, which is the bulk medium in the insulin variant, Humalog ® ⁇ It is surmised this is the influencing factor that slows the delivery rate of Humalog ® responsively to ultrasound.
  • ultrasound transduction through denser mediums is slower than through leaner or less dense materials. Ultrasound is reflected by dense materials and delivery power is impeded. It is surmised that the presence of high specific gravity dibasic sodium phosphate in Humalog ® results in the impedance of ultrasound - thereby slowing transdermal delivery thereof.
  • a quantity of insulin, a standard 100 units, as measured by a standard insulin syringe is loaded onto the absorbent pad.
  • An ultrasound source (6.5) is placed onto the top portion of the flask (6.2) and may be either:
  • a stacked array of 4 transducer elements is affixed to a stainless steel face plate as seen in Fig. 9, with another layer of transducers placed atop the original layer.
  • Ultrasound drives insulin from the absorbent pad, and through the sample of human skin, and into the collection flask (6.4) where it collects (6.6).
  • a sampling port (6.5) on the size of the cell (6.1) is used to draw samples of the collected drug (6.6) for analysis.
  • experiment 1 a single element transducer as show in fig. 7 was used to deliver insulin, 100 units of wither Humulin or 100 units of Humalog into the Franz cell.
  • the single transducer element is a piezoelectric transducer crystal (7.1) designed to convert electrical energy into mechanical force, which was coated by an epoxy resin (7.3) and electrically connected to an ultrasonic generator circuit.
  • the ultrasonic frequency was 23-30 KHz, at 125 mW/sq. cm intensity. Duration of ultrasonic excitation was 1 minute, but the experiment was conducted 10 times and an average delivery determined to be 14.7 units/hour for Humulin and 10.8 units/hour for Humalog.
  • a transducer system corresponding to the design shown in Fig. 9 was employed.
  • four piezoelectric crystals (9.2) are glued to a stainless steel face plate (9.3) using a conductive epoxy (9.4) and electrically connected so that all the crystals activate in tandem electrically through power sent through a cable (9.1).
  • the ultrasonic frequency was 23- 30 KHz, at 125 mW/sq. cm intensity for each transducer.
  • a transducer system corresponding to the design shown in Fig. 8 was employed.
  • nine piezoelectric crystals (8.1) are fixed within a polymer potting panel (8.3) and electrically connected so that all the crystals activate in tandem electrically through power sent through a cable (8.4).
  • the Array of transducers (8.2) is connected to an ultrasonic generator circuit.
  • the ultrasonic frequency was 23-30 KHz, at 125 mW/sq. cm intensity for each transducer.
  • FIG. 12 and 13 contain a table of those observations.
  • a waist mounted ultrasonic delivery system where a modified transdermal patch (4.3) is loaded with a target drug, in this instance insulin, and mounted onto the abdomen of a patient (4.4)
  • a controller device (4.1) delivers electrical signals to the transducer coupler (4.2) which forces insulin from the patch into the skin of the patient, effecting ultrasonic insulin delivery.
  • an arm mounted ultrasonic delivery system is shown, where a modified transdermal patch (5.3) is loaded with a target drug, in this instance insulin, and mounted onto the arm of a patient (5.6)
  • a controller device (5.1) is fitted on, or near or over the patch (5.3) and held in place by an arm band (5.4).
  • the control unit (5.1) delivers electrical signals to the transducer coupler connected to the patch (5.3), which forces insulin from the patch into the skin of the patient, effecting ultrasonic insulin delivery.
  • insonification changes the delivery equation in relation to the excipient formulation used in the drug carrier.
  • dibasic sodium phosphate is a source for sodium ions in Humalog ® .
  • Sodium ions are positively charged.
  • the presence of excess positive charges may lead to interactions with oppositely charged materials in a substance containing patch— and adsorb or absorb therein or thereto via weak electrostatic attraction. This may obstruct the path of substance, e.g., insulin, molecules through the solution from the patch to the skin, and there-through.
  • excess positive charges may interact with the substance, e.g., insulin, molecules, themselves, which then adsorb or absorb onto patch materials, or even the biotransformable layers of the skin, thereby slowing their delivery into viable skin or blood circulation.
  • ultrasonically induced transdermal delivery of an insulin and dibasic sodium phosphate containing substance from a patch may be hastened by reducing the amount of dibasic sodium phosphate therein.
  • ultrasonically induced transdermal delivery of other substances such as other pharmaceutical preparations including other active ingredients, can be similarly improved by reducing the amount of dibasic sodium phosphate therein or altering the ingredient composition of the excipient solution with less metals, and less preservative.
  • ultrasonically induced transdermal delivery of substances, such as insulin containing drugs can be improved by reducing the amount of excipient ingredients having a specific gravity greater than that of water.
  • ultrasonically induced transdermal delivery of substances, such as insulin containing drugs can be improved by predominantly using excipient ingredients having a specific gravity less than 1.67.
  • substances can be identified as good candidates for ultrasonic transdermal delivery or re-formulation for transdermal delivery using similar criteria. For example, a list of substances and corresponding compositions may be made or acquired. Those substances having excipient ingredients with specific gravities under 1.67 and/or omitting dibasic sodium phosphate and/or having excipient components with specific gravities around that of water may be selected as good candidates for ultrasonically induced transdermal delivery. Similarly, those substances having excipient ingredients with specific gravities around 1.67 or higher, and/or including dibasic sodium phosphate may be selected as less attractive candidates for reformulation for ultrasonically induced transdermal delivery.
  • the good candidates are predicted to generally have a higher ultrasonically induced transdermal delivery rate of the active ingredient(s) thereof higher than less attractive candidates have the same active ingredient(s).
  • Humulin® may be classified in a first class as being a good candidate, while Humalog® may be classified in a second class as being a less attractive candidate for rapid transdermal delivery from a patch responsively to ultrasound insonification.
  • Part of the present invention also lies in the observation that certain substances and pharmaceutical preparations containing liquid carrier excipients, and/or excipient ingredients that include sodium, such as but not limited to saline, increase the delivery rate of the active ingredient(s) responsively to insonification and enable the delivery of larger compounds responsively to insonification.
  • certain substances and pharmaceutical preparations containing liquid carrier excipients, and/or excipient ingredients that include dibasic sodium phosphate increase the delivery volume per unit of time of the active ingredient(s) responsively to insonification and enable the delivery of larger compounds responsively to insonification.
  • An embodiment of the invention is a method for improving the transdermal delivery rate of an active ingredient in a substance made in accordance with a dibasic sodium phosphate containing formulation responsively to insonification thereof, comprising:_reducing the amount of dibasic sodium phosphate in the formulation to provide a reduced dibasic sodium phosphate formulation; and, making a substance in accordance with the reduced dibasic sodium phosphate formulation.
  • the substance further comprises insulin.
  • the insonifying comprises ultrasonic insonification.
  • the reducing the amount of dibasic sodium phosphate comprises replacing the dibasic sodium phosphate with a component having a specific gravity less than 1.67.
  • the reducing comprises replacing said dibasic sodium phosphate with a component having a specific gravity approximately that of water.
  • An embodiment of the invention is a method for classifying the predicted suitability of a substance for ultrasonically induced transdermal delivery into a patient comprising :_a) determining if the substance contains dibasic sodium phosphate; and, b) if it does, classifying the substance in a second class; and c) if it does not, classifying the substance in a first class, and d) wherein, the first class is associated with substances having a relatively high predicted transdermal delivery rate, and the second class is associated with substances having a relatively low predicted transdermal delivery rate.
  • a list of substances are provided, wherein the above-referenced determining and classifying occurs for each of the substances on list.
  • An embodiment of the invent ion is a method for improving the transdermal delivery of an active ingredient in a substance by varying the excipient solution or carrier accompanying said active ingredient, to enable a greater speed of transdermal delivery when used with an ultrasonic drug delivery system.
  • An embodiment of the invention is an ultrasonic delivery system for delivering a drug, which employs a transdermal patch containing at least one absorbent pad, and which is connected to either a single or array of transducers, and controlled by a wearable control device, wherein ultrasound is delivered through the drug laden patch and delivers the dose to the patient.
  • the system is mounted on the arm of the patient.
  • the system is mounted on the waist of the patient.
  • the ultrasonic transmission may be a standard sinusoidal waveform version of ultrasonic transmission.
  • the ultrasonic transmission may be a combination of ultrasonic waveforms.
  • An embodiment of the invention is an ultrasonic delivery system for delivering a drug, which employs a transdermal patch containing at least one absorbent pad, and which is connected to either a single or array of transducers, and controlled by a wearable control device, wherein ultrasound is delivered through the drug laden patch and delivers the dose to the patient, wherein a alternating ultrasonic waveform transmission is employed to avoid cavitation or over heating the drug or the patients skin.

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Abstract

L'invention concerne un procédé pour améliorer la délivrance transdermique ultrasonore d'un médicament par modification de la solution d'excipient avec laquelle un ingrédient actif est mélangé dans une formulation de médicament, le choix de solution d'excipient étant modifié en faveur d'un excipient qui sera mieux conducteur des ultrasons et propagera la substance médicamenteuse à une vitesse d'administration plus élevée à travers la peau sous excitation ultrasonore. Un exemple d'un tel changement d'excipient comprend la conversion d'une formulation contenant du phosphate de sodium dibasique standard en une formulation en utilisant beaucoup moins de sodium ou moins de compositions de conservation. L'invention concerne une formulation à teneur réduite en phosphate de sodium dibasique. Pour répondre à son insonification, elle comprend : la réduction de la quantité de phosphate de sodium dibasique dans la formulation pour obtenir une formulation à teneur réduite en phosphate de sodium dibasique ; et, la préparation d'une substance conformément à la formulation à teneur réduite en phosphate de sodium dibasique.
PCT/US2015/039831 2014-07-03 2015-07-09 Modification de préparations pharmaceutiques pour les rendre mieux appropriées à l'administration transdermique et ultrasonore WO2016004443A2 (fr)

Priority Applications (6)

Application Number Priority Date Filing Date Title
US15/323,636 US20170143803A1 (en) 2014-07-03 2015-07-06 Modification of pharmaceutical preparations to make them more conducive to ultrasonic transdermal delivery
EP15815948.3A EP3164120A2 (fr) 2014-07-09 2015-07-09 Modification de préparations pharmaceutiques pour les rendre mieux appropriées à l'administration transdermique et ultrasonore
JP2017521048A JP2017523237A (ja) 2014-07-09 2015-07-09 超音波による経皮デリバリーにより資する（ｃｏｎｄｕｃｉｖｅ）ようにさせる、医薬製剤の変更
PCT/US2015/039831 WO2016004443A2 (fr) 2014-07-03 2015-07-09 Modification de préparations pharmaceutiques pour les rendre mieux appropriées à l'administration transdermique et ultrasonore
CN201580036489.0A CN106604723A (zh) 2014-07-09 2015-07-09 更易于超声经皮传递的药物制剂的改良
KR1020177003028A KR20170041199A (ko) 2014-07-03 2015-07-09 초음파 경피 전달을 더 증진시키기 위한 약학적 조제물들의 변형

Applications Claiming Priority (21)

Application Number Priority Date Filing Date Title
US61/998,623 2014-07-03
US61/998,624 2014-07-03
US61/998,622 2014-07-03
US61/998,683 2014-07-07
US201461998790P 2014-07-09 2014-07-09
US201461998788P 2014-07-09 2014-07-09
US61/998,788 2014-07-09
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