US3923969A - Carrier system for a drug with sustained release - Google Patents

Carrier system for a drug with sustained release Download PDF

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US3923969A
US3923969A US36940473A US3923969A US 3923969 A US3923969 A US 3923969A US 36940473 A US36940473 A US 36940473A US 3923969 A US3923969 A US 3923969A
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drug
carrier
pores
pore
release
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Werner Baukal
Heinz-Joachim Kinkel
Erich Robens
Gerhard Walter
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Battelle Institut Ev
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Battelle Institut Ev
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    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
    • A61K9/20Pills, tablets, discs, rods
    • A61K9/2004Excipients; Inactive ingredients
    • A61K9/2009Inorganic compounds

Abstract

A carrier system for a drug which allows the sustained and prolonged release of the drug which is comprised of (i) a porous carrier material which is insoluble or only slightly soluble in the body, which is in compacted form or powder form and which contains cavities which are connected to the outer surface by narrow pore necks, the mean diameters of the cavities in section being over twice as large as the mean internal widths of the necks of the pores, and the internal width of the necks of the pores being preponderantly less than 0.1 Mu m, and (ii) a drug or pharmaceutically active substance is embedded or contained in the cavities.

Description

United States Patent 1 [111 3,923,969

Baukal et al. 1 Dec. 2, 1975 [54] CARRIER SYSTEM FOR A DRUG WITH 3,148,124 9/l964 Gaunt 424/22 SUSTAINED RELEASE [75] Inventors: Werner Baukal, Kronberg, Taunus; P i E i sh K R Heinz-J0a Kinkel, Schwalbach. Attorney, Agent, or FirmChristen & Sabol Taunus; Erich Robens, Friedrichsdorf; Gerhard Walter, Steinbach, all of Germany [57] ABSTRACT [73] Assignee: Battelle-lnstitut e.V., Frankfurt am M i Germany A carrier system for a drug which allows the sustained and prolonged release of the drug which is comprised [22] Wed: June 1973 of (i) a porous carrier material which is insoluble or 2 1 ;3 9 404 only slightly soluble in the body, which is in compacted form or powder form and which contains cavities which are connected to the outer surface by nar- [52] US. Cl. 424/19; 424/22; 424/23; row pore necks the mean diameters of the cavities in 424/357 section being over twice as large as the mean internal [5]] ll'lt. CL A61K 27/12 widths of the necks of the pores, and the internal [58] Fleld of Search 424/19-23, width of the necks of the pores being preponderantly 424/357 less than 0.1 um, and (ii) a drug or pharmaceutically active substance is embedded or contained in the cavi- [56] References Cited ties UNITED STATES PATENTS 2,038,694 4/l936 Wiggins 424/23 1 Claim, N0 Drawings CARRIER SYSTEM FOR A DRUG WITH SUSTAINED RELEASEv BACKGROUND OF THIS INVENTION 1. Field of thislnvention The invention relates to a carrier, depot or bonding system for a drug which allows sustained release of the drug and which can be administered orally, externally or by implantation. The carrier material consists of physiologically innocuous, inorganic or organic materials which are totally or almost non-reabsorbable in the body. For its properties as a carrier of active pharmaceutical substances what is decisive is the special porous structure. It comprises so-called inkwell pores, i.e. it contains cavities connected to the outer surface of the bonding substance by passages (pore necks) which are narrow in relation to their diameters. The drug is embedded in the cavities.

2. Prior Art Sustained release preparations make it possible for the dosage of a drug to be accurately controlled over a long period of time and for a plurality of active substances to be released on a set time schedule. A number of methods of obtaining sustained release are already known. For example, the drug may be enclosed in a capsule which will dissolve in the body after a certain amount of time or which allows the drug to diffuse through its porous wall. In the case of microincapsulation, the drug is enclosed in a large number of very small membrane capsules. Tablets may be coated with lacquers to achieve delayed release. The drug may be suspended in water, oil or buffer solutions. The drug may be etherified or esterified to put it in a form in which it is difficult to reabsorb. If the drug is applied as a crystal suspension or a crystal implant, its release will be delayed because its surfaces will be small relative to the amorphous substance. Absorption of the drug in carrier materials which can swell, such as gelatin, cellulose or certain plastics also delay release. If the drug is bonded by adsorption to large surfaces, release will be slow due to the low speed of desorption, as, e.g., in the case of the adsorbate innoculate or vaccine, a result of admixture with aluminium hydroxide. If a powdered drug is compressed together with powdered plastics, a porous tablet will form in which the plastic material will partly cover the surface of the powdered drug and will delay its release (see British Pat. No. 808,014, German Pat. No. 1,201,950 and U.S. Pat. No. 3,279,996).

BROAD DESCRIPTION OF THIS INVENTION The problem solved by this invention was the developement of a carrier, bonding or depot system for sustained release preparations which has the following advantages as compared with known carrier means: 1 it is adapted to incorporate various solid or liquid drugs, independent of their chemical nature, solubility and mechanical or thermal stability, and (2) the rate at which the drug is released from the carrier substance into the body remains constant over a selectable period of time independently of the amount of stored drug or varies in accordance with a schedule or program.

According to this invention, these requirements are fulfilled when the drug, medicament or pharmaceutically active substance is incorporated in a porous car rier substance which is insoluble or only slightly soluble in the body (human and/or animal) and when the pores of the carrier substance each have an inkwell shape. In

the literature (see, e.g., G.J. Gregg and K.S.W. Sing, Adsorption, Surface Area and Porosity: London, Academic Press (1967), page ff), inkwell pores are pores which, in the simplest case, comprise a cavity which opens towards the outside through a narrow neck. With these pores two essential parameters can be chosen independently of one another: (i) the volume of the cavity and (ii) the dimensions (internal width and length) of the neck of the pore. If the volume of the neck is small relative to the volume of the cavity, the amount which can be stored in the pores will depend virtually only on the volume of the cavity, while the timing of the release or temporal course of delivery into a surrounding medium will be affected predominately by the dimensions of the pore neck. The pore systems having inkwell pores which are used in this invention are composed ofa plurality of pores of different shapes and sizes, and the cavities are frequently interconnected and open to the outer surface of the porous substance through a plurality of necks. Pore systems of such very complex construction can be described, in their adsorption behavior action, as an inkwell shape, if the diameters of the cavities are on the average more than twice as large as the associated pore necks. This invention involves or uses only those inkwell pores in which the necks are within the microand mesopore range, i.e., having internal widths or diameters of less than 0.1 u, m down to the diameter of only a few atoms diameters (see, e.g., D.l-I. Everett and RH. Ottewill, (eds), Surface Area Determination London, Butterworths (1970) page 63).

For the sustained release preparation according to this invention, a porous carrier material which is insoluble or dnly slightly soluble in the body is used. The dimensions of the pores in such a material is virtually invariable during the period or time of application, so the rate at which the stored drug is discharged (rate of delivery) remains constant so long as the concentration in the cavities does not drop.

After the application or taking of a sustained release preparation comprised of an insoluble carrier substance having inkwell pores and a drug incorporated therein, body fluid first enters the pores and dissolves the drug or mixes with it. The drug then diffuses outwardly via the pore necks filled with body fluid while more body fluid diffuses inwardly. The drug initially has saturation concentration in the cavities and almost zero concentration outside (in the body). With regard to the timing of the release of drug when the starting processes are over, one should distinguish between the following two cases:

1. The active substance is soluble only to a limited extent in the body fluid and forms a separate phase. In this case the concentration of active substance in the solution in the cavity, and with it the rate of release or delivery, will remain constant until the separate phase has disappeared. It will then decrease.

2. The active substance can be mixed with the body fluid in any ratio. The concentration of active substance and the rate of release or delivery will then decrease continuously. The neck of the pore acts as a resistance to or check on the flow of active'substance and lengthens the period of release.

If the dimensions of the necks in the pore system vary widely, the pores with short and wide necks will empty first, while the concentration in the other pores will remain constant for longer. The rate of release from such a pore system will decrease with the passage of time.

3 With a suitable combination. provision can be made for the drugs to be released with any timing, e.g.. in approximately linear progression. By mixing pore systems of different types. filled with different active substances. programmed release of combinations of active substances also are obtained.

The rate of discharge from a carrier system with inkwell pores can be estimated from their dimensions, as demonstrated by the following example. The composition is taken to be a tablet with a volume of l() mm less the cavity volume V of 10 mm. The cavities are connected to the surface by a l0 not very different pore necks with a mean cross-sectional area of A 10 nm and a mean length of 0.] am. The concentration of active substance in the cavities when the starting processes are over is 0.1 ,umol/mm, while the concentration c, in the body in the vicinity of the tablet is 0. Assuming a coefficient of diffusion of l) l0m .s. then according to Ficks Law the following is obtained. in simplified form, for the rate of release f1 (see, e.g., C.D. Hodgman. Handbook of Chemistry and Physics", 44 ed.. Cleveland, Chemical Rubber Publishing 1961, page 2274).:

The rate of discharge of active substance would accordingly remain constant for longer that /2 day. given low solubility.

With a l0- and l am. one would obtain ri l0" mol.s and a period of release t of 1.6 years.

Solids with an inkwell pore structure are known. they are used. for example. as adsorbents, catalysts or catalyst carriers. Suitable materials which can be used as the carrier material having an inkwell pore structure include oxides, ceramic and metallic materials and plastics which are physiologically innocuous. The preparations may be used as a powder or in a compact or compacted form. such as. tablet form.

Oxides such as silicon oxide, aluminium oxide. zirconium oxide, etc.. can be prepared in highly porous form from the corresponding hydroxide gel by dehydration and drying at an elevated temperature (see. e.g.. R.E. Kirk and D.F. Othmer. Encyclopedia of Chemical Technology". Vol. l2. page 345 ff.. New York. lnterscience Publishers 1954); and E. Robens and G. Sandstede. Z. lnstrumentenkunde" 75 (1967). page I77). In another process (see K.S. Mazdiyasny. (.T. Lynch and 1.8. Smith. J. Am. Ceramic Soc. 48 (1965). pages 372 375) alcoholates dissolved in organic solvents are converted, by hydrolysis and subsequent drying. into oxides with crystallites and pores in the sub-micron range.

Metallic anc ceramic substances as well as plastics can be sintered together to form porous bodies by compressing powders. with a simultaneous or subsequent heat treatment. Porous structures of the desired type can be obtained by thermal disintegration of hydrates or salts. e.g.. in the thermal decomposition of nickel formate dihydrate (P.(i. Fox. I. Ehretsmann and CE. Brown. J. Catalysis 20 (1971). pages 67 73). The Rancy process may be used to prepare metallic powders of very high micro-porosity. A metal alloy is first produced and one component of the alloy is then dis solved out. The remaining metal re-crystallizes. and mi cro-crystallites and corresponding pore systems are formed (see. e.g.. H. Krupp. H. Rabenhorst. G. Sandstede. G. Walter and R. McJones. J. Elektrochemical Soc. 109(1962). pages 553 557 Porous plastics can be made by various. already-known methods. e.g.. by using one of the freeze drying techniques. In the processes mentioned herein. the pore structure can be modified by varying the manufacturing conditions.

The active substance may be deposited by steeping the bonding material in the liquid or molten drug. It may be necessary first to cleanse the material of sub stances (such as water) which have been embedded in the cavities during manufacture. This can be done. e.g.. by drying under vacuum at an elevated temperature. Solid drugs may be dissolved and incorporated or placed in the bonding material by steeping the latter in the solution. The solvent can then be removed by vaporization. if the drug is vaporizable or sublimable. it may be deposited or placed in the cavities by condensation out of the gas phase. Finally, the drug may be mixed with the starting materials before the preparation of the carrier material. As the carrier material is made. the drug becomes enclosed in the pores which are formed.

Preparations made in this way can be used in powder form. The powder may be processed as an emulsion in a liquid in which the drug is insoluble or compressed into tablets. The carrier material in pellet or tablet form may be coated in a known manner with lacquers in order to achieve a further delay in the action of the drug.

As used herein the term drug includes medicaments. drugs, pharmaceutically active substances. etc.

The drug can be. for example: laxatives. such as. oxyphenisatin acetate; vitamins and nutrients; parasympatholytics. such as homatropine methylbromide or phenobarbital; hormones; steroids; anti-infectives; analgesics. such as, phenacetin. aspirin and caffeine; narcotics; anesthetics; sedatives and tranquilizers, such as, chlordiazepoxide HCl and diazepam; antihallucinatory agents; sympathominetics; hypo-allergenic agents; antigens; antihistamines. such as. bromodiphenhydramine hydrochloride. methapyrilene fumarate and chlorpheniramine maleate'. vasoconstrictors; antibiotics; enzymes; anticoagulants. vasodilators; lipotropic agents; cerebral stimulants; bronchodilators; muscle relaxants;

diuretics; etc.

The carrier material consists of physiologically harmless inorganic or organic materials which cannot be absorbed or only very slightly absorbed in the body. Its special porous structure is critical for its use as a carrier of pharmaceutically active ingredients. It contains socalled inkwell pores. that is to say it contains cavities or hollow spaces. which are connected by channels (necks of the pores). which are narrow in relation to their diameter of the main cavity bodies, with the outside surface of the carrier material. The drug is housed in the hollow spaces.

DETAILED DESCRIPTION OF THIS INVENTION In the following examples and throughout the rest of this document, all parts. percentages and ratios are on a weight basis unless otherwise stated or obviously so to one ordinarily skilled in the art.

EXAMPLE I Ben/.oie acid in silica gel An excess quantity of waterglass solution was stirred drop by drop into dilute hydrochloric acid at 5()"C. A jelly formed, which was washed free of electrolyte and dried first at 100C, then at 300C. A piece of the resultant lumps of silica gel was degassed under vacuum and, again under vacuum, impregnated with molten benzoic acid (as a sample drug). The lump was then compressed in polyethylene powder in such a way that the silica gel was completely sheathed with a porous film of polyethylene. 'Ihe tablet was put into water and the timing of the variation in conductivity resulting from the escape of benzoic acid was measured. A uniform increase in conductivity was observed over several hours.

EXAMPLE 2 l-Propyll -cyclohcxyl-2-methylaminopropane-hydrochloride in aluminium oxide By the method of Mazdyiasni. Lynch and Smith, aluminium-iso-propylate was dissolved in benzene, and a mixture of water and iso-propanol were added dropwise while stirring. Both mixtures contained the drug almost to the point of saturation. The jelly which formed was dried at l()l)c. As in Example I the rate of 6 discharge was ascertained by measuring the conductivity, and the lump disintegrated into small particles. As first there was a strong discharge of the drug, which changed to a slow discharge after about a quarter of an hour. A constant rate of discharge could be observed for 2 days.

The initial strong discharge was decreased by washing and then drying the lump of the preparation.

What is claimed is:

l. A carrier system for a drug which allows the sustained and prolonged release of the drug which consists of i. a porous carrier aluminium oxide material which is insoluble or only slightly soluble in the body which is in dried jelly lump form which disintegrates into small particles and which contains inkwell pore cavities which are connected to the outer surface by narrow pore necks. the mean diameters of the inkwell pore cavities in section being over twice as large as the mean internal widths of the necks of the inkwell pores, and the internal width of the necks of the inkwell pores being preponderantly less than 0.1 pm and ii. a drug or pharmaeeutically active substance which is embedded or contained only in said inkwell pore cavities, and which jelly has been formed by stirring together dropwise a mixture of aluminum isoproponatc dissolved in benzene and a mixture of water and isopropanol, both mixtures containing the drug almost to the point of saturation. and drying the jelly which formed. to a lump which disintegrates into small particles.

Claims (1)

1. A CARRIER SYSTEM FOR A DRUG WHICH ALLOWS THE SUTAINED AND PROPLONGED RELEASE OF THE DRUG WHICH CONSISTS OF I. A POROUS CARRIER ALUMINUM OXIDE MATERIAL WHICH IS INSOLUBLE OR ONLY SLIGHTLY SOLUBLE IN THE BODY WHICH IS IN DIRED JELLY LUMP FORM WHICH DISINTEGRATES INTO SMALL PARTICLES AND WHICH CONTAINS INKWELL PORE CAVITIES WHICH ARE CONNECTED TO THE OUTER SURFACE BY NARROW PORE NECKS, THE MEANS DIAMETERS OF THE INKWELL PORE CAVITIES IN SECTION BEING OVER TWICE AS LARGE AS THE MEANS INTERNAL WIDTHS OF THE NECKS OF THE INKWELL PORES, AND THE INTERNAL WIDTH OF THE NECKS OF THE INKWELL PORES BEING PREPONDERANTLY LESS THAN 0.1 UM AND II. A DRUG OR PHARMACETICALLY ACTIVE SUBSTANCE WHICH IS EMBEDDED OR CONTAINED ONLY IN SAID INKWELL PORE CAVITIES, AND WHICH JELLY HAS BEEN FORMED BY STIRRING TOGETHER DROPWISE A MIXTURE OF ALUMINUM ISOPROPONATE DISSOLVED IN VENZENE AND A MIXTURE OF WATER AND ISOPROPANOL, BOTH MIXTURES CONTAINING THE DRUG ALMOST TO THE POINT OF SATURATION, AND DRYING THE JELLY WHICH FORMED, TO A LUMP WHICH DISINTEGRATES INTO SMALL PARTICLES.
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Cited By (20)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4013785A (en) * 1975-03-21 1977-03-22 Bristol-Myers Company Apap tablet containing fumed silica and process for manufacturing same
DE3005350A1 (en) * 1979-02-13 1980-08-21 Kyoto Ceramic Grained ceramic carrier for administration of medicines and accommodated therein drug
US4254099A (en) * 1978-10-18 1981-03-03 Beiersdorf Aktiengesellschaft Pharmaceutical tablet composition
US4282202A (en) * 1978-10-27 1981-08-04 Beecham Group Limited Intramammary compositions
US4587267A (en) * 1983-09-15 1986-05-06 Standard Telephones And Cables, Plc Controlled release system
US4617294A (en) * 1985-04-22 1986-10-14 Ppg Industries, Inc. Animal feed supplement
US4720384A (en) * 1985-05-03 1988-01-19 E. I. Du Pont De Nemours And Company Manufacture of hollow fine tubular drug delivery systems
EP0336014A1 (en) * 1988-04-08 1989-10-11 VECTORPHARMA INTERNATIONAL S.p.A. Pharmaceutical compositions with controlled release, and a method for their preparation
US5170801A (en) * 1990-10-02 1992-12-15 Glaxo Inc. Medical capsule device actuated by radio-frequency (rf) signal
US5248700A (en) * 1982-05-14 1993-09-28 Akzo Nv Active agent containing solid structures for prolonged release of active agents
US5298252A (en) * 1991-03-22 1994-03-29 Hagiwara Research Corp. Antimicrobial composition having resistance to heat and weathers
US6521464B1 (en) * 1999-04-17 2003-02-18 Genevac Limited Methods and apparatus for preventing sample loss
US6602523B1 (en) * 2000-08-17 2003-08-05 Technology Holding, Llc. Composite material and process for increasing bioavailability and activity of a beneficial agent
US20040148015A1 (en) * 2002-11-13 2004-07-29 Setagon, Inc. Medical devices having porous layers and methods for making same
US6831058B1 (en) * 1993-05-31 2004-12-14 Kaken Pharmaceutical Co., Ltd. Crosslinked gelatin gel preparation containing basic fibroblast growth factor
US20050070989A1 (en) * 2002-11-13 2005-03-31 Whye-Kei Lye Medical devices having porous layers and methods for making the same
US20060121080A1 (en) * 2002-11-13 2006-06-08 Lye Whye K Medical devices having nanoporous layers and methods for making the same
EP1786363A2 (en) * 2004-08-13 2007-05-23 Setagon, Inc. Medical devices having nanoporous layers and methods for making the same
US20070292525A1 (en) * 2000-02-21 2007-12-20 Australian Nuclear Science & Technology Organisation Controlled release ceramic particles, compositions thereof, processes of preparation and methods of use
US20080086198A1 (en) * 2002-11-13 2008-04-10 Gary Owens Nanoporous stents with enhanced cellular adhesion and reduced neointimal formation

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US2038694A (en) * 1930-10-15 1936-04-28 Davision Chemical Corp Medicament
US3148124A (en) * 1962-06-12 1964-09-08 William E Gaunt Method of preparing sustained release pharmaceutical tablets

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US2038694A (en) * 1930-10-15 1936-04-28 Davision Chemical Corp Medicament
US3148124A (en) * 1962-06-12 1964-09-08 William E Gaunt Method of preparing sustained release pharmaceutical tablets

Cited By (48)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4013785A (en) * 1975-03-21 1977-03-22 Bristol-Myers Company Apap tablet containing fumed silica and process for manufacturing same
US4254099A (en) * 1978-10-18 1981-03-03 Beiersdorf Aktiengesellschaft Pharmaceutical tablet composition
US4282202A (en) * 1978-10-27 1981-08-04 Beecham Group Limited Intramammary compositions
USRE31301E (en) * 1978-10-27 1983-07-05 Beecham Group P.L.C. Intramammary compositions
DE3005350A1 (en) * 1979-02-13 1980-08-21 Kyoto Ceramic Grained ceramic carrier for administration of medicines and accommodated therein drug
US4293540A (en) * 1979-02-13 1981-10-06 Kyoto Ceramic Co., Ltd. Granular ceramic carrier for administration of medicines and medicine supported therein
US5248700A (en) * 1982-05-14 1993-09-28 Akzo Nv Active agent containing solid structures for prolonged release of active agents
US4587267A (en) * 1983-09-15 1986-05-06 Standard Telephones And Cables, Plc Controlled release system
US4617294A (en) * 1985-04-22 1986-10-14 Ppg Industries, Inc. Animal feed supplement
US4720384A (en) * 1985-05-03 1988-01-19 E. I. Du Pont De Nemours And Company Manufacture of hollow fine tubular drug delivery systems
US5008114A (en) * 1988-04-08 1991-04-16 Vectorpharma International S.P.A. Pharmaceutical compositions with controlled release, and a method for their preparation
EP0336014A1 (en) * 1988-04-08 1989-10-11 VECTORPHARMA INTERNATIONAL S.p.A. Pharmaceutical compositions with controlled release, and a method for their preparation
US5170801A (en) * 1990-10-02 1992-12-15 Glaxo Inc. Medical capsule device actuated by radio-frequency (rf) signal
US5298252A (en) * 1991-03-22 1994-03-29 Hagiwara Research Corp. Antimicrobial composition having resistance to heat and weathers
US6831058B1 (en) * 1993-05-31 2004-12-14 Kaken Pharmaceutical Co., Ltd. Crosslinked gelatin gel preparation containing basic fibroblast growth factor
US6521464B1 (en) * 1999-04-17 2003-02-18 Genevac Limited Methods and apparatus for preventing sample loss
US20070292525A1 (en) * 2000-02-21 2007-12-20 Australian Nuclear Science & Technology Organisation Controlled release ceramic particles, compositions thereof, processes of preparation and methods of use
US7585521B2 (en) 2000-02-21 2009-09-08 Australian Nuclear Science & Technology Organisation Controlled release ceramic particles, compositions thereof, processes of preparation and methods of use
US7354602B2 (en) 2000-02-21 2008-04-08 Australian Nuclear Science & Technology Organisation Controlled release ceramic particles, compositions thereof, processes of preparation and methods of use
US20080274199A1 (en) * 2000-02-21 2008-11-06 Autralian Nuclear Science & Technology Organisation Controlled release ceramic particles, compositions thereof, processes of preparation and methods of use
US20080118565A1 (en) * 2000-02-21 2008-05-22 Australian Nuclear Science & Technology Organisation Controlled release ceramic particles, compositions thereof, processes of preparation and methods of use
US7357948B2 (en) 2000-02-21 2008-04-15 Australian Nuclear Science & Technology Organisation Controlled release ceramic particles, compositions thereof, processes of preparation and methods of use
US7354603B2 (en) 2000-02-21 2008-04-08 Australian Nuclear Science & Technology Organisation Controlled release ceramic particles, compositions thereof, processes of preparation and methods of use
US20080003298A1 (en) * 2000-02-21 2008-01-03 Australian Nuclear Science & Technology Organisation Controlled release ceramic particles, compositions thereof, processes of preparation and methods of use
US20040071784A1 (en) * 2000-08-17 2004-04-15 Joshi Ashok V. Composite material and process for increasing bioavailability and activity of a beneficial agent
US6602523B1 (en) * 2000-08-17 2003-08-05 Technology Holding, Llc. Composite material and process for increasing bioavailability and activity of a beneficial agent
US20060193886A1 (en) * 2002-11-13 2006-08-31 Owens Gary K Medical devices with nanoporous layers and topcoats
US20060276884A1 (en) * 2002-11-13 2006-12-07 Whye-Kei Lye Nanoporous stents with magnesium leaching
US20060276879A1 (en) * 2002-11-13 2006-12-07 Whye-Kei Lye Medical devices having porous layers and methods for making the same
US20060276885A1 (en) * 2002-11-13 2006-12-07 Whye-Kei Lye Nanoporous stents with improved radiolucency
US20060276877A1 (en) * 2002-11-13 2006-12-07 Gary Owens Dealloyed nanoporous stents
US8449602B2 (en) 2002-11-13 2013-05-28 Medtronic Vascular, Inc. Methods for using a stent having nanoporous layers
US7294409B2 (en) 2002-11-13 2007-11-13 University Of Virgina Medical devices having porous layers and methods for making same
US20060276878A1 (en) * 2002-11-13 2006-12-07 Gary Owens Dealloyed nanoporous stents
US20060271169A1 (en) * 2002-11-13 2006-11-30 Whye-Kei Lye Stent with nanoporous surface
US8124166B2 (en) 2002-11-13 2012-02-28 Medtronic Vascular, Inc. Method for loading nanoporous layers with therapeutic agent
US20060193889A1 (en) * 2002-11-13 2006-08-31 Joshua Spradlin Nanoporous layers using thermal dealloying
US20060193890A1 (en) * 2002-11-13 2006-08-31 Owens Gary K Method for loading nanoporous layers with therapeutic agent
US20080086198A1 (en) * 2002-11-13 2008-04-10 Gary Owens Nanoporous stents with enhanced cellular adhesion and reduced neointimal formation
US20060193887A1 (en) * 2002-11-13 2006-08-31 Owens Gary K Medical devices having nanoporous bonding layers
US7713573B2 (en) 2002-11-13 2010-05-11 Medtronic Vascular, Inc. Method for loading nanoporous layers with therapeutic agent
US20060121080A1 (en) * 2002-11-13 2006-06-08 Lye Whye K Medical devices having nanoporous layers and methods for making the same
US20050070989A1 (en) * 2002-11-13 2005-03-31 Whye-Kei Lye Medical devices having porous layers and methods for making the same
US20040148015A1 (en) * 2002-11-13 2004-07-29 Setagon, Inc. Medical devices having porous layers and methods for making same
US9770349B2 (en) 2002-11-13 2017-09-26 University Of Virginia Patent Foundation Nanoporous stents with enhanced cellular adhesion and reduced neointimal formation
EP1786363A4 (en) * 2004-08-13 2008-04-23 Setagon Inc Medical devices having nanoporous layers and methods for making the same
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