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WO2001076553A2 - Procede et dispositif d'administration transdermique renforcee de medicament - Google Patents

Procede et dispositif d'administration transdermique renforcee de medicament Download PDF

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Publication number
WO2001076553A2
WO2001076553A2 PCT/US2001/011120 US0111120W WO0176553A2 WO 2001076553 A2 WO2001076553 A2 WO 2001076553A2 US 0111120 W US0111120 W US 0111120W WO 0176553 A2 WO0176553 A2 WO 0176553A2
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WIPO (PCT)
Prior art keywords
biological membrane
permeability
polysaccharide
drug
identified area
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PCT/US2001/011120
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English (en)
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WO2001076553A3 (fr
Inventor
Samir S. Mitragotri
Tuan A. Elstrom
Scott C. Kellogg
Joseph Kost
Linda Custer
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Sontra Medical, Inc.
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Application filed by Sontra Medical, Inc. filed Critical Sontra Medical, Inc.
Priority to AU2001251349A priority Critical patent/AU2001251349A1/en
Publication of WO2001076553A2 publication Critical patent/WO2001076553A2/fr
Publication of WO2001076553A3 publication Critical patent/WO2001076553A3/fr

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    • 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
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
    • 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

Definitions

  • the present invention relates to transdermal drug delivery, and, more particularly, to a method and device for transdermal drug delivery of proteins and peptides.
  • TDD Transdermal drug delivery
  • injections and oral delivery offer several advantages over traditional delivery methods including injections and oral delivery.
  • TDD avoids gastrointestinal drug metabolism, reduces first-pass effects, and provides sustained release of drugs for up to seven days, as reported by Elias, in Percutaneous Absorption: Mechanisms-Methodology-Drug Delivery,
  • the skin is a complex structure. There are at least four distinct layers of tissue: the nonviable epidermis (stratum corneum, "SC"), the viable epidermis, the viable dermis, and the subcutaneous connective tissue. Located within these layers are the skin's circulatory system, the arterial plexus, and appendages, including hair follicles, sebaceous glands, and sweat glands. The circulatory system lies in the dermis and tissues below the dermis. The capillaries do not actually enter the epidermal tissue but come within 150 to 200 microns of the outer surface of the skin. The highly-ordered structure of the lipid bilayers confers an impermeable character to the SC (Flynn, G.
  • U.S. Pat. No. 5,323,769 to Bommannan discloses ultrasound enhanced delivery of molecules into and through the skin, in combination with chemical permeation enhancers.
  • the ultrasound is applied at frequencies above 10 MHz.
  • the ultrasound must be applied "relatively simultaneously" with the molecules being delivered, within at least six minutes, preferably within two minutes.
  • a method for transdermal delivery of proteins and peptides is disclosed. This method may also be used to deliver proteins and peptides across other biological membranes including, but not limited to, cell membranes, oral mucosa, nasal mucosa and pulmonary alveoli.
  • the present invention uses the ability of polysaccharides to permeate biological membranes and stabilize as well as carry proteins/peptides across the membranes.
  • the formulation can be prepared by, for example, combining the protein with polysaccharides in multiple ways including but not limited to: i) co- solvation of the drug and polysaccharide in a solvent, ii) tethering of the drug to the polysaccharide, and iii) microparticles containing the drug and the polysaccharide.
  • polysaccharides include dextran, heparin, and hyaluronic acid.
  • a method for the enhanced delivery of at least one drug across a biological membrane includes the steps of (1) identifying an area of biological membrane; (2) contacting at least one high-permeability polysaccharide with the identified area of biological membrane; (3) contacting at least one drug with the identified area of biological membrane; and (4) transporting the at least one drug into or through the identified area of biological membrane. Steps (2) and (3) may occur in any order, or may occur substantially simultaneously.
  • the biological membrane may include tissue, mucous membranes, cornified tissues, oral mucosa, skin, nasal membrane, pulmonary capillary wall, cell membrane, organs, tissues, buccal, nails, and the gastro-intestinal tract.
  • the polysaccharide may have a permeability of at least 1 x 10 "5 cm hr.
  • Preferred polysaccharides include hyaluronic acid, heparin, dextran, chondroitin sulfate, and salts thereof.
  • ultrasound may be applied to the biological membrane to enhance the permeability of the biological membrane.
  • the ultrasound may be applied before, during, or after the high-permeability polysaccharide is contacted with the biological membrane.
  • a driving force such as an osmotic pressure gradient, a concentration gradient, iontophoresis, electroporation, magnetic fields, ultrasound, and mechanical pressure, may be applied to alter the movement of the drug through or into the biological membrane.
  • a method for the enhanced transport of a drug into or through a biological membrane is disclosed. The method includes the steps of (1) preparing a complex of the drug with a high-permeability polysaccharide; and (2) transporting the complex into or through the biological membrane.
  • the high-permeability polysaccharide may include hyaluronic acid, heparin, dextran, and chondroitin sulfate, and salts thereof.
  • the complex may be delivered by injection, inhalation, oral ingestion, or by contact with the biological membrane.
  • the complex may be in the form of a gel, a spray, a liquid, a powder, microdroplets, an ointment, and a cream.
  • a device for enhanced drug delivery includes at least one high- permeability polysaccharide and at least one drug.
  • the device may also include a contact layer that contacts a biological membrane and a medium layer containing the at least one high-permeability polysaccharide and the at least one drug.
  • the device may be a wearable patch.
  • the device may also include a source of permeabilizing force, and source of a driving force.
  • the high-permeability polysaccharide may have a permeability of at least lxlO "5 cm/hr, and includes hyaluronic acid, heparin, dextran, and chondroitin sulfate, and salts thereof.
  • the drug and the high-permeability polysaccharide may be complexed.
  • a technical advantage of the present invention is that a method for delivering drugs through, into, or across biological membranes involving the use of complexes of proteins/peptides with polysaccharides is disclosed.
  • Another technical advantage of the present invention is that a method for delivering drugs across a biological membrane, including oral mucosa, nasal membrane, pulmonary capillary wall, or cell membrane is provided.
  • Another technical advantage of the present invention is that a time for a drug to cross a biological membrane is reduced. Another technical advantage is that the high-permeability polysaccharides are very biocompatible. Another technical advantage of the present invention is that a complex of proteins/peptides with polysaccharide is achieved by tethering of the drug to the polysaccharide through electrostatic interactions, covalent interactions, hydrogen bonding, hydrophobic interactions, van der Waals forces, or other interactions. Yet another technical advantage of the present invention is that the complex of the microparticle with polysaccharide is achieved by attaching polysaccharide on the surface of the microparticle. Another technical advantage of the present invention is that the drug may be entrapped in a polysaccharide and the release of the drug may be sustained.
  • Still another technical advantage of the present invention is that the complex of polysaccharide with the protein/peptide can be made into various formulations, including a solution for transdermal drug delivery or injections, dry powder for inhalation, gels, sprays, microdroplets, a suspension of microparticles for oral delivery, and patches.
  • Another technical advantage of the present invention is that additional permeabilization methods, such as the use of ultrasound, may be used to increase the permeability of a biological membrane.
  • a technical advantage of the present invention is that additional driving forces may be applied in order to assist in the drug delivery through or into the biological membrane.
  • Fig. 1 is a flowchart of a method for transdermal drug delivery using polysaccharides according to one embodiment of the present invention
  • Fig. 3 is a graph depicting the enhanced transdermal delivery of
  • Fig. 4 is a plot of skin permeability versus donor hyaluronic acid concentration according to one embodiment of the present invention.
  • Fig. 5 is a plot of skin permeability versus donor dextran concentration according to one embodiment of the present invention. DETAILED DESCRIPTION OF THE INVENTION
  • Therapeutic ultrasound is typically between 20 kHz and 5 MHz.
  • Near ultrasound is typically about 10 kHz to about 20 kHz. It should be understood that in addition to ultrasound, near ultrasound can be used in embodiments of the present invention.
  • Sonic is defined as the application of ultrasound to the biological membrane resulting in enhanced transdermal transport of molecules.
  • “Low frequency sonophoresis or ultrasound” is defined as sonophoresis or ultrasound at a frequency that is less than 2.5 MHz, more typically less than 1 MHz, more preferably in the range of 20 to 100 kHz.
  • "Biological membrane” is defined as tissue, mucous membranes, cornified tissues, oral mucosa, skin, nasal membrane, pulmonary capillary wall, cell membrane, organs, tissues, buccal, the gastro-intestinal tract, and nails, as well as other biological surfaces.
  • Drug is defined as a therapeutic, prophylactic, or diagnostic molecule or agent, and can be in a form dissolved or suspended in a liquid, a solid, or encapsulated and/or distributed in or within micro- or nano-particles, emulsions, liposomes or lipid vesicles.
  • Drug delivery is defined as the delivery of a drug into blood, lymph, interstitial fluid, a cell, tissue, or skin.
  • Transdermal transport is defined as movement of analyte into or through the biological membrane or delivery of drug into or through a biological membrane.
  • Transdermal patch is an externally-applied device for delivery or extraction of molecules into or through the biological membrane.
  • “Driving force” means a chemical or physical force that alters movement of a drug into or through a biological membrane.
  • Polysaccharides are polymers of sugar residues that have a high molecular weight (“MW"). Some polysaccharides, however, have a unique ability to cross biological membranes, such as skin, at a relatively high rate. This property of polysaccharides is especially significant because the monomers that comprise the polysaccharides permeate biological membranes at a relatively slow rate. For example, monomeric or dimeric sugar molecules, such as glucose, mannitol, and sucrose permeate skin with a permeability rate of about lxlO "5 cm/hr. It is well- known that hydrophilic molecules permeate biological membranes at a slow rate.
  • hyaluronic acid having a MW of about 300,000, permeates the skin with a permeability rate of about 2xl0 "3 cm/hr from a solution containing 25 mg/ml hyaluronic acid. This permeability rate is 200 times higher than that of the monomer it is made from.
  • Dextran a polysaccharide having a MW of 70,000, permeates skin with a permeability rate of 4x10 "4 cm/hr from a solution containing 400 mg/ml dextran, a value about 40 times greater than its monomer.
  • heparin having a MW of between 5,000-20,000, was found to permeate with a permeability rate of 2x10 "4 from a solution containing 300 mg/ml heparin, a value that is about 20 times higher than its monomer.
  • hyaluronic acid permeates biological membrane with a permeability rate of about 2xl0 "3 cm/hr. With this permeability, about 30 mg of hyaluronic acid can be delivered per day from a source, such as a patch, having an 25 cm area, and containing hyaluronic acid at a concentration of 25 mg/ml.
  • a "high-permeability polysaccharide” is a polysaccharide having a passive permeability of greater than about lxlO "5 cm/hr, preferably greater than about lxlO "4 cm/hr, and most preferably greater than about lxlO "3 cm/hr.
  • Examples of high-permeability polysaccharides that are useful according to the present invention include heparin, dextran, hyaluronic acid, chondroitin sulfate, and salts thereof.
  • One of ordinary skill in the art can readily determine the passive permeability of other high-permeability polysaccharides candidates and make additional solutions based on the foregoing criteria.
  • a flowchart depicting a method for transdermal drug delivery is provided.
  • an area of biological membrane into or through a drug is to be administered is identified.
  • the identified area is located at a site selected based on convenience to the patient as well as maximum drug penetration, as well as need.
  • the arm, thigh, and stomach represent areas of relatively thin biological membrane and high surface area, while the hands and feet are uneven and callused.
  • a high-permeability polysaccharide such as hyaluronic acid, is contacted with the identified area of biological membrane in order to increase the permeability of the biological membrane.
  • the area of biological membrane that is to have its permeability enhanced preferably has a size approximately equal to the size of the application device.
  • a transdermal patch such as the Fentanyl ® , available from ALZA Corporation, Mountain View, CA
  • the polysaccharide, or other enhancing forces are preferably administered to a surface area of 40 cm 2 .
  • Other size patches, including both smaller and larger patches, are within the contemplation of the present invention. Additional enhancing forces can be applied to increase the permeability, or assist in the permeabilization, of the biological membrane.
  • ultrasound may be applied to the identified area to increase its permeability.
  • Techniques for increasing the permeability of a biological membrane are disclosed in U.S. Patent Nos. 6,041,253 and 6,190,315, the disclosures of which is hereby incorporated by reference in their entireties.
  • Ultrasound is preferably administered at frequencies of less than or equal to about 2.5 MHz, preferably at a frequency that is less than one MHz, more typically in the range of 20 to 100 kHz. In one embodiment, ultrasound is applied at a frequency of 50 kHz.
  • Exposures are typically for between 20 seconds and 10 minutes, continuously, but may be shorter and/or pulsed, for example, 100 to 500 msec pulses every second for a time sufficient to permeabilize the biological membrane.
  • the ultrasound intensity should be at a level that preferably does not raise the biological membrane temperature more than about one to two degrees Centigrade or cause permanent damage to the biological membrane, under the conditions and with the particular device to be used. This typically will be less than 20 W/cm 2 , preferably less than 10 W/cm 2 .
  • the intensity and time of application are inversely proportional, so that higher intensities should be applied for shorter periods of time, in order to avoid biological membrane damage. It should be understood that although the normal lower range of ultrasound is 20 kHz, one could achieve comparable results by varying the frequency to less than 20 kHz, that is, into the sound region down to about one kHz. The time needed is dependent upon the frequency and intensity of the ultrasound and the biological membrane condition. At 20 kHz, for example, at an intensity of 10 W/cm 2 , and a duty cycle of 50%, biological membrane on a human forearm is sufficiently permeabilized in about five minutes.
  • Permeabilizing ultrasound can be applied for a predetermined amount of time or can be applied only until sufficient permeabilization is attained. Since biological membrane conditions can change over time, based on aging, diet, stress, and other factors, it may be preferable to measure permeability as ultrasound is applied to ensure sufficient ultrasound is applied and to minimize the risk of biological membrane damage. Several methods can be used to determine when sufficient permeabilization has been reached.
  • PCT International Patent Application No. PCT/US99/30067 entitled “Method and Apparatus for Enhancement of Transdermal Transport," the disclosure of which is incorporated by reference in its entirety discloses methods and devices for determining the permeabilization of skin.
  • One way to measure permeabilization is to measure relative biological membrane conductivity at the permeabilization site versus a reference point. These measurements are performed by applying a small AC or DC electric potential across two electrically isolated electrodes in contact with biological membrane. The electric current flowing through these electrodes is measured using an ammeter and the biological membrane resistance is measured using the values of the potential and the current.
  • Another way to determine when sufficient permeabilization has been reached is to measure absolute conductivity.
  • the degree of permeability can also be monitored using a sensor that determines the concentration of the drug being delivered or analyte being extracted. As the permeability decreases, the drug concentration will decrease, and vice versa.
  • the biological membrane is preferably permeable for at least 30 minutes, preferably at least an hour, or two hours. Under some conditions, the biological membrane may remain permeable for up to twenty-four hours. It may be desirable to repermeabilize the biological membrane under the same, or different conditions.
  • a drug may be contacted with the identified area of biological membrane.
  • an application device such as a patch, may be used to contact the drug to the biological membrane.
  • Drugs to be administered include a variety of bioactive agents, including proteins and peptides. Specific examples include insulin, erythropoietin, and interferon. Other materials include nucleic acid molecules, such as antisense, and genes encoding therapeutic proteins, synthetic organic and inorganic molecules including anti-inflammatories, antivirals, antifungals, antibiotics and local anesthetics, saccharides, polysaccharides (e.g., heparin), growth hormone, vaccines, and Leutinizing Hormone Releasing Hormone.
  • the drug will typically be administered in an appropriate pharmaceutically acceptable carrier having an absorption coefficient similar to water, such as an aqueous gel, ointment, lotion, or suspension.
  • transdermal patch can be used as a carrier. It may be desirable to include protease inhibitors with protein and peptide drugs to minimize protease activity. Molecules for biological membrane treatment such as retinoids, dyes, and vitamin D, may also be delivered.
  • the drug may be in the form of, or encapsulated within, a delivery device such as a liposome, lipid vesicle, emulsion or polymeric nanoparticles, microparticle, microcapsule, or microspheres (referred to collectively as microparticles unless otherwise stated).
  • a delivery device such as a liposome, lipid vesicle, emulsion or polymeric nanoparticles, microparticle, microcapsule, or microspheres (referred to collectively as microparticles unless otherwise stated).
  • a delivery device such as a liposome, lipid vesicle, emulsion or polymeric nanoparticles, microparticle, microcapsule, or microspheres (referred to collectively as microparticles unless otherwise stated).
  • These can be formed of polymers such as polyhydroxy acids, polyorthoesters, polyanhydrides, and polyphosphazenes, or natural polymers such as collagen, polyamino acids, albumin and other proteins, al
  • the drug may be a complexed with a polysaccharide. This will be discussed in greater detail, below.
  • a transdermal transport enhancer may be applied to enhance the transdermal transport of the drug.
  • Transdermal transport enhancers that can be applied before, during or after the permeabilizing include chemical enhancers and/or driving forces, physical driving forces, and cavitation producing forces.
  • Chemical enhancers include lipid bilayer disrupting agents and solubility enhancers. Chemical enhancers have been found to increase drug transport by different mechanisms. Chemicals that enhance permeability through lipids are known and commercially available. For example, ethanol has been found to increase the solubility of drugs up to 10,000-fold and yield a 140-fold flux increase of estradiol through the biological membrane, while unsaturated fatty acids have been shown to increase the fluidity of lipid bilayers. Examples of fatty acids that disrupt lipid bilayer include linoleic acid, capric acid, lauric acid, and neodecanoic acid, which can be in a solvent.
  • Suitable solvents include water; diols, such as propylene glycol and glycerol; mono-alcohols, such as ethanol, propanol, and higher alcohols; DMSO; dimethylformamide; N,N-dimethylacetamide; 2- pyrrolidone; N-(2-hydroxyethyl) pyrrolidone, N-methylpyrrolidone, 1- dodecylazacycloheptan-2-one and other n-substituted-alkyl-azacycloalkyl-2-ones and other n-substituted-alkyl-azacycloalkyl-2-ones (azones).
  • diols such as propylene glycol and glycerol
  • mono-alcohols such as ethanol, propanol, and higher alcohols
  • DMSO dimethylformamide
  • 2- pyrrolidone N-(2-hydroxyethyl) pyr
  • DMSO dimethylsulfoxide
  • aqueous solutions of DMSO such as those described in U.S. Pat. No. 3,551,554 to Herschler; U.S. Pat. No. 3,711,602 to Herschler; and U.S. Pat. No. 3,711,606 to Herschler, and the azones (n-substituted- alkyl-azacycloalkyl-2-ones) such as noted in U.S. Pat. No. 4,557,943 to Coope.
  • DMSO dimethylsulfoxide
  • aqueous solutions of DMSO such as those described in U.S. Pat. No. 3,551,554 to Herschler; U.S. Pat. No. 3,711,602 to Herschler; and U.S. Pat. No. 3,711,606 to Herschler
  • azones n-substituted- alkyl-azacycloalkyl-2-ones
  • Surfactants can act as solubility enhancers for some drugs as well as permeability enhancers by fluidizing the lipid bilayer.
  • a preferred surfactant is sodium lauryl sulfate (SLS) present in an amount of about 0.25 to 5%, preferably about 1%.
  • SLS sodium lauryl sulfate
  • Other useful surfactants include fatty acids, fatty alcohols, esters of fatty acids, alkyl sulfonates, sodium salts of sulfonic acid, alkyl sulfonic acid, TweenTM, SpamTM, and pluronicsTM, typically in a concentration in the range of 0.25 to 5% weight/volume.
  • Driving forces include osmotic pressure gradient, concentration gradient, iontophoresis, electroporation, magnetic fields, additional ultrasound, and mechanical pressure. Driving forces may be applied after permeabilization to enhance transport of the drug into or through the biological membrane.
  • the driving force can be applied continuously over a period of time or at intervals during the period of permeabilization.
  • Application of electric current enhances transdermal transport by different mechanisms.
  • application of an electric field provides an additional driving force for the transport of charged molecules across the biological membrane
  • Iontophoresis and second, ionic motion due to application of electric fields can induce convective flows across the biological membrane, referred to as elecfrosmosis. This mechanism is believed to play a dominant role in transdermal transport of neutral molecules during iontophoresis. Iontophoresis involves the application of an electrical current, preferably DC, or AC, at a current density of greater than zero up to about 1 niA/cm 2 . Typically, a constant voltage is applied since resistance changes over time, usually in the range of between greater than zero and four volts.
  • the iontophoresis may be provided in a range of from about 10 ⁇ A to about 1000 ⁇ A. Preferably, the iontophoresis is provided at 100 ⁇ A.
  • Additional ultrasound can be applied at higher, lower, or the same frequency as the initial permeabilizing ultrasound. In other cases, it may be preferable to use lower frequency, "maintenance" doses of ultrasound to keep the biological membrane permeabilized.
  • Greater transdermal transport can be achieved by inducing cavitation either inside or outside of the biological membrane. Cavitation is the growth and oscillations of air bubbles present in fluids and air pockets present in the keratinocytes of the SC. Application of low-frequency ultrasound appears to induce cavitation inside as well as outside the biological membrane and disorganize the SC lipid bilayers thereby enhancing transdermal transport, hi addition, oscillations of cavitation bubbles can result in significant water penetration into the disordered lipid regions and can cause the formation of aqueous channels through the intercellular lipids of the SC. This allows transport of permeants across the disordered lipid domains, then across keratinocytes and the entire SC.
  • This transport pathway can result in an enhanced transdermal transport as compared to passive transport because the diffusion coefficients of permeants through water, which is likely to primarily occupy the channels generated by ultrasound, are up to 1000-fold higher than those through the ordered lipid bilayers, and the transport path length of these aqueous channels can be much shorter (by a factor of up to 25) than that through the tortuous intercellular lipids in the case of passive transport.
  • Cavitation can be enhanced by providing nuclei in the form of gas bubbles, crevices, or particulate.
  • cavitation enhancers include flourocarbons, particulate matter (for example, microspheres, silica, titanium dioxide particles, polymer particles), gases (for example, argon, air), and stabilized air bubbles.
  • Occurrence of cavitation on the biological membrane surface can also be enhanced by coating the biological membrane surface with a wetting agent in the entire area of application of ultrasound except for a spot. Cavitation can preferentially occur at the spot due to the difference in wetting properties of the biological membrane and the coating.
  • the coating may be made from a polymer such as poly(methyl methacrylate) or it may be a membrane made from poly(vinyl difluoride), for example.
  • the drug to be transported transdermally may be complexed with a polysaccharide, such as hyaluronic acid, and may be delivered with the polysaccharide transdermally.
  • complexation can be performed by attaching drugs to the carboxyl groups of hyaluronic acid.
  • peptide drugs can be tethered to hyaluronic acid by forming a linkage between the carboxyl group of hyaluronic acid and the amino group of the peptide. Once the drug crosses the biological membrane, this linkage can be broken by natural enzymes to release the peptide.
  • Complexation can alternatively be performed through electrostatic interactions, covalent interactions, hydrogen bonding, hydrophobic interactions, van der Waals forces, or other interactions between the polysaccharide and the peptide.
  • the negative charges on the polysaccharide can be used to form a non-covalent complex with the peptide or protein.
  • polysaccharides can be used for oral drug delivery. Oral drug delivery is limited by poor stability of proteins in the gastrointestinal tract and poor transport of the proteins across oral mucosa. Complexation of proteins with polysaccharides can alleviate these limitations by increasing the stability of the proteins as well as increasing their transport across the oral mucosa.
  • complexes of polysaccharide with the protein/peptide can be made into a dry powder for inhalation.
  • a solution containing complexes of polysaccharide with the protein/peptide can be injected, hi other embodiments, the complexes may be present in gels, microdroplets, creams, sprays, etc.
  • Other techniques for administering the complexes of polysaccharide with the protein/peptide are within the contemplation of the present invention.
  • complexes of polysaccharides with DNA can be used for gene therapy.
  • High-permeability of polysaccharides across membranes can enhance DNA uptake by cells.
  • Hyaluronic acid receptors can contribute to the enhanced uptake of hyaluronic acid-DNA complex as well.
  • Hyaluronic acid can also be attached to the particles loaded with the drug.
  • the high permeability of hyaluronic acid across membranes can enhance trans-membrane transport of particles.
  • the hyaluronic acid-modified particles may be taken orally, or may be injected to deliver drugs.
  • Polysaccharides can also be used to increase bioavailability of injectable or pulmonarily delivered drugs. The enhancement of bioavailability originates from the enhanced transdermal permeability
  • Biological membrane 250 is contacted with patch 200.
  • Patch 200 may include several layers, such as contact layer 202, medium layer 204, and membrane 206.
  • Contact layer 202 contacts biological membrane 250.
  • Medium layer 204 includes at least one high-permeability polysaccharide and a drug, including complexes of polysaccharides and drugs, as discussed above.
  • Medium layer 204 may be a hydrogel, a liquid, or other suitable medium.
  • Membrane 206 may be a semi-permeable membrane.
  • a source of additional permeabilization (not shown) and a source of a driving force (not shown) may be provided for patch 200.
  • This may include, inter alia, ultrasonic transducers, electrodes, etc. as desired.
  • Contact layer 202 may include a transdermal adhesive (not shown) for remaining in contact with biological membrane 250. Other methods for contacting biological membrane 250 may be provided as required.
  • Table I summarizes the measured permeabilities of several sugar molecules including, mannitol (MW 180), inulin (MW 5,000), heparin (MW about 10,000), dextran (MW 70,000), and hyaluronic acid (MW 300,000) across pig skin measured in vitro.
  • glucose permeates the biological membrane at a low rate, about 10 "5 cm/hr.
  • the permeability of some high molecular weight polysaccharides including heparin, dextran and hyaluronic acid is exceptionally high.
  • inulin another polysaccharide having a molecular weight of about 5000 Da, does not permeate the biological membrane at a high rate. Thus, only some of the examined polysaccharides exhibit exceptionally high biological membrane permeability.
  • This example demonstrates the use of hyaluronic acid to enhance transdermal drug delivery.
  • Passive biological membrane permeability to LHRH is relatively low (about lxlO "4 cm/hr).
  • hyaluronic acid 15 mg/ml
  • biological membrane permeability to LHRH is increased by a factor of about 10 during the first 24 hours.
  • the enhanced permeability of LHRH due to hyaluronic acid can be used for transdermal drug delivery.
  • Fig. 4 shows the variation in the biological membrane permeability to hyaluronic acid across pig biological membrane from a solution containing hyaluronic acid at a concentration in the range of about zero to 25 mg/ml.
  • the rate of hyaluronic acid permeation increases nearly exponentially with its concentration in the donor solution.
  • Fig. 5 shows a similar plot in the case of dextran.
  • the biological membrane permeability increases with increasing dextran concentration up to a concentration of 200 mg/ml after which decreases with further increase in the concentration. Exceptionally high biological membrane permeability of polysaccharides is also observed in human biological membrane.
  • Table 2 summarizes permeability of human biological membrane to various mono- and polysaccharides under similar donor concentrations. Table 2
  • polysaccharides are large in size and very hydrophilic.

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  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne un procédé et un dispositif d'administration transdermique renforcée de médicament. Dans un mode de réalisation, le procédé comporte les étapes consistant à : (1) identifier une zone de membrane biologique ; (2) mettre en contact au moins un polysaccharide à perméabilité élevée avec la zone identifiée de membrane biologique ; (3) mettre en contact au moins un médicament avec la zone identifiée de membrane biologique ; et (4) transporter le ou les médicaments dans ou à travers la zone identifiée de membrane biologique. Dans un autre mode de réalisation, le procédé de transport renforcé de médicament dans ou à travers une membrane biologique comporte les étapes consistant à : (1) préparer un complexe renfermant le médicament et un polysaccharide à perméabilité élevée ; et (2) transporter le complexe dans ou à travers la membrane biologique. Selon une autre forme de réalisation, l'invention concerne un dispositif d'administration renforcée de médicament, qui comprend au moins un polysaccharide à perméabilité élevée et au moins un médicament. Le dispositif peut aussi comprendre une couche de contact qui est en contact avec la membrane biologique, et une couche intermédiaire contenant le(s) polysaccharide(s) à perméabilité élevée et le(s) médicament(s).
PCT/US2001/011120 2000-04-06 2001-04-06 Procede et dispositif d'administration transdermique renforcee de medicament WO2001076553A2 (fr)

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AU2001251349A AU2001251349A1 (en) 2000-04-06 2001-04-06 Method and device for enhanced transdermal drug delivery

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US19504100P 2000-04-06 2000-04-06
US60/195,041 2000-04-06

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WO2001076553A3 WO2001076553A3 (fr) 2002-01-24

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Cited By (5)

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WO2004060473A3 (fr) * 2002-12-26 2004-11-25 Alza Corp Dispositif d'administration de principe actif comprenant des elements composites
WO2015188223A1 (fr) * 2014-06-11 2015-12-17 International Scientific Pty Ltd Dispositif et méthode pour traiter ou prévenir la dégénérescence articulaire
KR20200110256A (ko) * 2019-03-14 2020-09-23 주식회사 에스엔비아 활동성이 향상된 손톱 및 발톱 성장 촉진용 마이크로니들 밴드
WO2020185053A3 (fr) * 2019-03-14 2020-12-10 주식회사 에스엔비아 Bande de micro-aiguilles présentant une activité améliorée pour favoriser la croissance des ongles des doigts et des orteils
WO2021144080A1 (fr) * 2020-01-15 2021-07-22 Beiersdorf Ag Procédé d'incorporation de substances actives dans la peau

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CN110025770A (zh) * 2019-04-20 2019-07-19 长春生物制品研究所有限责任公司 一种稳定的重组人干扰素软膏及其生产方法

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AU657681B2 (en) * 1990-03-30 1995-03-23 Alza Corporation Device and method for iontophoretic drug delivery
WO1993015722A1 (fr) * 1992-02-07 1993-08-19 Syntex (Usa) Inc. Liberation controlee de produits pharmaceutiques a partir de microparticules poreuses preformees
AU1958295A (en) * 1994-04-13 1995-11-10 Novartis Ag Temporally controlled drug delivery systems
AU5623298A (en) * 1996-12-31 1998-07-31 Altea Technologies, Inc. Microporation of tissue for delivery of bioactive agents
US6173202B1 (en) * 1998-03-06 2001-01-09 Spectrx, Inc. Method and apparatus for enhancing flux rates of a fluid in a microporated biological tissue
EP1060741B1 (fr) * 1999-06-14 2003-09-03 Baxter International Inc. Microsphères à libération prolongée

Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2004060473A3 (fr) * 2002-12-26 2004-11-25 Alza Corp Dispositif d'administration de principe actif comprenant des elements composites
WO2015188223A1 (fr) * 2014-06-11 2015-12-17 International Scientific Pty Ltd Dispositif et méthode pour traiter ou prévenir la dégénérescence articulaire
CN106456663A (zh) * 2014-06-11 2017-02-22 国际科学私人有限公司 治疗或预防关节退化的装置和方法
AU2015274237B2 (en) * 2014-06-11 2019-11-14 International Scientific Pty Ltd Device and method to treat or prevent joint degeneration
KR20200110256A (ko) * 2019-03-14 2020-09-23 주식회사 에스엔비아 활동성이 향상된 손톱 및 발톱 성장 촉진용 마이크로니들 밴드
WO2020185053A3 (fr) * 2019-03-14 2020-12-10 주식회사 에스엔비아 Bande de micro-aiguilles présentant une activité améliorée pour favoriser la croissance des ongles des doigts et des orteils
KR102404662B1 (ko) * 2019-03-14 2022-06-02 주식회사 에스엔비아 활동성이 향상된 손톱 및 발톱 성장 촉진용 마이크로니들 밴드
WO2021144080A1 (fr) * 2020-01-15 2021-07-22 Beiersdorf Ag Procédé d'incorporation de substances actives dans la peau

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WO2001076553A3 (fr) 2002-01-24

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