US3053255A - Process of percutaneously administering exact doses of physiologically active agents and composite unit therefor - Google Patents

Process of percutaneously administering exact doses of physiologically active agents and composite unit therefor Download PDF

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US3053255A
US3053255A US780795A US78079558A US3053255A US 3053255 A US3053255 A US 3053255A US 780795 A US780795 A US 780795A US 78079558 A US78079558 A US 78079558A US 3053255 A US3053255 A US 3053255A
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layer
carrier
reservoir
active agent
skin
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Meyer Friedrich
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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
    • A61K9/70—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
    • A61F—FILTERS IMPLANTABLE INTO BLOOD VESSELS; PROSTHESES; DEVICES PROVIDING PATENCY TO, OR PREVENTING COLLAPSING OF, TUBULAR STRUCTURES OF THE BODY, e.g. STENTS; ORTHOPAEDIC, NURSING OR CONTRACEPTIVE DEVICES; FOMENTATION; TREATMENT OR PROTECTION OF EYES OR EARS; BANDAGES, DRESSINGS OR ABSORBENT PADS; FIRST-AID KITS
    • A61F13/00—Bandages or dressings; Absorbent pads
    • A61F13/00051—Accessories for dressings
    • A61F13/00063—Accessories for dressings comprising medicaments or additives, e.g. odor control, PH control, debriding, antimicrobic
    • 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
    • A61K9/7084—Transdermal patches having a drug layer or reservoir, and one or more separate drug-free skin-adhesive layers, e.g. between drug reservoir and skin, or surrounding the drug reservoir; Liquid-filled reservoir 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
    • A61M19/00—Local anaesthesia; Hypothermia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61F—FILTERS IMPLANTABLE INTO BLOOD VESSELS; PROSTHESES; DEVICES PROVIDING PATENCY TO, OR PREVENTING COLLAPSING OF, TUBULAR STRUCTURES OF THE BODY, e.g. STENTS; ORTHOPAEDIC, NURSING OR CONTRACEPTIVE DEVICES; FOMENTATION; TREATMENT OR PROTECTION OF EYES OR EARS; BANDAGES, DRESSINGS OR ABSORBENT PADS; FIRST-AID KITS
    • A61F13/00—Bandages or dressings; Absorbent pads
    • A61F2013/00361—Plasters
    • A61F2013/00902—Plasters containing means
    • A61F2013/00906—Plasters containing means for transcutaneous or transdermal drugs application

Definitions

  • the present invention relates to an article of manufacture and a process for dispensing dosed quantities of physiologically active material for percutaneous absorption.
  • salves, ointments, liniments, powders which may contain pastes, cerates, or other externally applicable preparations of physiologically active agents to the outer skin surface
  • This mode of application may have for its purpose to bring about a topical eect, for instance, it may cause local disinfection or it may be intended for a far-reaching absorption effect extending also to other parts of the body than those Where the preparation has been applied topically, such as, for instance, the long known treatment with a mercurial ointment, i.e. with unguentum hydrargyri, used in the treatment of syphilis.
  • Active agents which normally Iare not absorbed by the skin or are only taken up sparingly, are now rendered readily absorbable.
  • the new process according to the present invention has the ⁇ further particular advantage that it permits non-disturbing, convenient, and at the same time safe administration ⁇ of such active agents which on oral administration are partially or totally destroyed in the gastro-intestinal tract, or which for other reasons are not absorbed quickly enough or completely enough.
  • active agents are, for instance, curare, strophanthin, convallatoxin, adrenalin, acetyl choline, or agents which are badly tolerated on oral administration, such as saponin containing drug extracts.
  • the process according to the present invention makes it further possible to vary within wide limits the rate of absorption of active agents.
  • the rate of absorption could be achieved only by enteral administration through the gastro-intestinal tract or parenterally by way of injection.
  • the process according tothe present invention consists in first applying to an absorptive carrier material a measured quantity (dose) of the active agent to be absorbed by the skin.
  • This absorptive carrier material is covered with a non-absorptive, non-permeable separator material.
  • a second layer of absorptive material serving as the reservoir for the active agent is placed on top of said separator layer.
  • This reservoir layer is somewhat thicker than the carrier layer.
  • One or several wicks of absorptive material are provided to make a connection between the reservoir layer and the carrier layer.
  • a liquid vehicle supplied to the reservoir layer is carried through the wicks to the carrier layer wherein it picks up the active agent and causes it to be absorbed by and through the skin in a definite predetermined dose.
  • FIG. 1 is a top plan View of a plaster-like preparation embodied in the present invention
  • FIG. 2 is a cross-sectional view taken along line 2--2 of FIG. l;
  • FIG. 3 is a cross-sectional View taken along line 3-3 of FIG. 2;
  • FIG. 4 is a cross-sectional View of another embodiment of the present invention.
  • FIG. 5 illustrates curves showing the anesthesizing effect of a preparation according to the present invention.
  • an active agent which is to be absorbed by the skin, is measured out (by volume or by weight) in solid form, for instance, 0.1 mg. of gor k-strophanthin, or in liquid form, for instance, 0.04 cc. of an 0.25% alcoholic solution of gstrophanthin, and is applied to an absorptive carrier for the active agent, for instance, paper, cellulose, silk, linen, nylon, and other artiicial fiber tissue, and the like material.
  • the carrier material impregnated with a measured predetermined amount of active agent may then be applied to the skin before or after completing the assembly of the parts of the preparation used in the present invention.
  • This carrier material impregnated with active agent is then covered with a non-absorbent, non-permeable -separator material having about the same surface area as the carrier material.
  • the separator material may consist, for instance of a film or foil of 0.1 mm. to 0.5 mm. thickness and made of rubber, wax paper, a substantially liquid impermeable synthetic resin, such as polyvinyl chloride, and the like. This separator material is preferably provided with one or more openings which have as their purpose to receive the wicks described more in detail hereinafter. Upon the non-permeable separator material there is placed the reservoir material.
  • This reservoir material consists of a layer of absorbent fibrous material, such as cotton, paper, cellulose, linen, silk, nylon, or other natural or synthetic iber material, and serves to take up the solvent, the function of which is also described hereinbelow.
  • This reservoir has also about the same surface area as the carrier layer. However, it is thicker than the latter and has a thickness, for instance, of several mm.
  • the reservoir has sufiicient capacity to take up, for instance, from 0.5 cc. to 1 cc. of a suitable solvent or solvent mixture which is free of active agent.
  • This solvent functions as a guide rail i.e., it causes the active agent to be absorbed by the skin by dissolving it out of the ⁇ active agent carrier.
  • the Wick can be in the form of filaments, for instance, Wool laments, or in the form of bands, for instance, paper strips.
  • These wicks connect the reservoir carrier with the active agent carrier. It is understood that the cross-sectional area of all the Wicks together must be such that at least so much of the vehicle can flow therethrough (including the active agent dissolved therein) as will be absorbed by the skin from the active agent carrier.
  • the aggregate cross-sectional area of the wicks will vary with the size of the skin surface area covered. Thus, for instance, if the carrier has an area of 40 sq. cm., the aggregate crosssectional area of the Wicks will be larger than in the case where the carrier has a surface area of 4 sq. cm.
  • the wicks can be conducted from the reservoir carrier to the active agent carrier either around the separator layer, in the case where no perforations are provided in said separator layer, or through perforations in the separator layer.
  • an adhesive plaster strip 1 is secured to covering 2 made of non-absorbent, substantially liquid and gas impermeable material which is flexible or non-exi'ble, consisting, for instance, of plastic foil, such as polyvinyl chloride film, lacquer, rubber, glass, or other suitable materials.
  • This cover 2 serves to prevent evaporation of the vehicle and/ or to keep out the oxygen of the air, if readily oxidizable active agents and/or vehicles ⁇ are employed.
  • reservoir carrier 6 Disposed right beneath cover 2 is reservoir carrier 6 which, as mentioned above, may be of cotton, paper, cellulose, silk, linen, nylon, or other synthetic fiber material.
  • separator layer 3 which separates reservoir carrier 6 from active agent carrier 4.
  • the separator layer 3 is not perforated and active agent carrier 4 is in communication with reservoir carrier ⁇ 6 through wick 5, which is drawn around the edge of separator layer 3.
  • carrier 4 may have ⁇ an area of 4 sq. cm. and is 0.2 mm. thick.
  • the surface area of the other layers, such as of reservoir layer 6 and separator layer 3 are of substantially the same size.
  • a protective strip 7 of any suitable material is provided to protect the carrier 4 from being soiled and to prevent evaporation of the solvent and/or active agent before use and on storage.
  • FIG. 2 The Various elements as shown in FIG. 2 and described hereinafter, namely active agent carrier 4, separator layer 3, reservoir carrier 6, wicks 5, cover 2, adhesive plaster strip 1, and protective strip 7, are combined into a convenient unit or article of manufacture for carrying out the process according to the present invention.
  • the size and the form of the various elements may be varied and adopted for various uses.
  • a carrier 4 having a small surface area of 4 sq. cm. is used.
  • wicks 5 of paper strips 2 cm. wide are employed, which are conducted around the edges of separator layer 3.
  • a suitable reservoir carrier 6 is used which has an area of 4 sq. cm. and is l mm. to 2 mm. thick and made of a layer of cotton having a capacity of about 0.5 cc. to 1 cc. for the transport substance or vehicle.
  • a definite quantity of active agent or a solution thereof is placed on carrier 4 which is prefer-ably colored to distinguish it from the other layers.
  • 'Ihe vehicle is then introduced in any suitable manner into the reservoir carrier 6 in the desired quantities according to the directions of use.
  • the finally assembled unit of the various elements shown in FIG. 2 is then placed on the skin and secured thereto by a bandage, a strip of adhesive tape, or an adhesive film.
  • the assembly can also be made so that carrier 4 is previously loaded with the necessary dose of active agent.
  • the user need only then apply the transport substance or vehicle to the reservoir carrier 6, for instance, by a pipette, either before or after the assembly is secured to the skin.
  • the assembly can also be provided with means secured to it for fastening it to the skin, such as with an adhesive strip.
  • the carrier 4 with active ⁇ agent and the adhesive layer 1 are protected from becoming dirty by a common protective layer 7 which is separated before use.
  • an arrangement whereby a complete unit is supplied containing both the active agent carrier 4 impregnated with active agent and vehicle contained in the reservoir carrier 6.
  • This arrangement is made possible through the use of a non-permeable coniining or blocking layer 8 consisting, for instance, of a hlm otE polyvinyl chloride or the like liquid impermeable plastic material which serves to prevent putting into operation diiiusion of the transport substance or vehicle through the wicks 5 into the active agent carrier 4 and dissolution of the ractive agent present in carrier 4.
  • the assembled unit is placed on the skin and then blocking layer 8 is removed or torn, for instance, by pulling itv out sidewardly.
  • wick 5 is brought into communication with reservoir 6 whereby the vehicle contained in the reservoir is conveyed to the carrier 4 and functions as described above.
  • the transport substances or vehicles that may be used in accordance with the present invention are liquids which must meet the following requirements:
  • the low molecular compounds of this group such as dibromo ethane, trichloroethylene, are less suitable because of their low compatibility; however, they may be used in mixtures with other vehicles;
  • Example l To an active agent carrier 4 of the unit illustrated in FIG. 3, which consists of silk strips having a surface area of 2 sq. om., there are applied 0.02 mg. of eserine base dissolved in 10.02 cc. of ethyl alcohol.
  • the alcohol is of the assembled unit according to the present invention.
  • separator lstrip 3 consisting of a polyvinyl chloride iilm of 0.2 mm. thickness and having three perforations, one of them indicated at 9.
  • separator strip 3 On said separator strip 3 there is placed a reservoir 6 consisting of a cellulose layer 3 mm. thick which is connected with carrier layer 4 by three wicks 5 (silk liilaments 0.3 mm. thick) ⁇ which pass through the perforations 9 ⁇ in separator layer 3.
  • the reservoir layer 6 is provided with 0.3 cc. of a vehicle mixture of amyl alcohol, n-hexanol, and cyclohexane in the proportion of 10:25 :65.
  • an ointment consisting of 'one part of yellow Vpetrolatum and one part of lanoline is used as ointment base for the -iirst group of mice, while unguentum cereum (German Pharmacopeia 6th Vedition etc.) consisting of 7 parts of ,peanut oil and 3 parts of yellow waxA is used as ointment for the second group of mice.
  • No eserine effect could be recorded with all six experimental animals on observation for 2 hours, although an amount of eserine is applied to the skin which is about 250 times as large as that applied by means Example 2 Yeter) 8 silk iilaments S of 0.3 mm. thickness were pulled.
  • Said filaments 5 serve to form the Wicks connecting reservoir V6 and carrier 4.
  • AV cellulose layer 0.5 cm. thick and having an area of 4 sq. cm. serves as reservoir 6. It is supplied and impregnated with 1 cc. of a vehicle liquid consisting of cyclohexanone, ethylene glycol, hexanol, and cyclohexane in the proportion of l0:10:-50:30.
  • the outside covering 2 is provided by a flexible polyvinyl chloride iilm having an area of 9 sq. cm.,which is secured to the abdominal skin by means of a muslin bandage. All three animals show 30 to 45 minutes after application the typical, reversible poisoning eiects of strophanthin, such as muscular tremor, convulsions, and respiratory impairment. The assembly is removed after 50 minutes.
  • the assembly is removed after 50 minutes.
  • non-absorbed residue on carrier 4 is determined with the aid of the color reaction agent described by Kedde as cited by J. E. Bush and D. A. H. Taylor in Biochem 1., vol. 52 page 643 (1952).
  • This reagent consists of 3,5- dinitro benzoic acid in alcoholic potassium hydroxide.
  • the test results were only weakly positive as indicated by a slight rose coloration indicating the presence of traces of strophanthin, i.e. less than 0.005 mg. to 0.015 mg. approximately uniformly distributed over carrier 4.
  • the same dose of 0.1 mg. of g-strophanthin, and even a dose of 1 mg. of strophanthin administered orally or, respectively, cutaneously in the form of an ointment has no noticeable effect.
  • Example 3 Three guinea pigs having a body weight between 380 g. and 400 g. receive 0.1 mg. of g-strophanthine by the aid of a unit preparation ready for use according to this invention.
  • the unit is applied to the shaved abdominal skin of the animals.
  • the active agent carrier 4 and the two wicks 5 consist of filter paper strips 2 cm. wide and 6 cm. long (Schleicher & Schuell lter paper No. 2043b). An area of 2 cm. by 2 cm. (4 sq. cm.) in the middle of these strips serves as active agent carrier 4.
  • 0.1 mg. of g-strophanthin dissolved in 0.04 cc. of ethanol are applied to the carrier. Both ends of the strips (likewise 2 cm.
  • x 2 cm. serve as band forming wicks 5. They are passed around separator strip 3 having an area of 4 sq. cm. and consisting of a non-perforated film of polyvinyl chloride having a thickness of 0.1 mm. as shown in FIG. 4. A layer of pressed cotton 3 mm. thick and having an area of 4 sq. cm. serves as reservoir carrier 6. Said layer is impregnated with 1 cc. of the transporting liquid or vehicle mentioned in Example 2, i.e. with a mixture of cyclohexanone, ethylene glycol, hexanol, and cyclohexane in the proportion 10:10:5030.
  • the outside covering 2 consists of a flexible polyvinyl chloride film showing an area of 9 sq. cm.
  • a blocking layer 8 is arranged between the reservoir 6 and the wick and carrier zone. Said blocking layer 8 consists of polyvinyl chloride. It is secured at its margins to the outer covering Z and is removed before using the unit so that reservoir 6 communicates with wicks 5.
  • Example 2 Within 45 minutes after the application of such a unit to the ⁇ skin of the three experimental animals there are observed in all the animals the reversible poisoning etects described in Example 2.
  • Analysis of the residue in the carrier in accordance with the Kedde method described hereinabove shows a diiference from the results obtained in Example 2.
  • Non-absorbed residue is found only in the middle of the carrier in an ill defined band of about 2 mm. to 3 mm. width. This finding clearly demonstrates the functioning of the wicks, which are passed around the separator layer 3. They permit the vehicle liquid to flow into the carrier from the two sides, i.e. from the outer portion toward the center.
  • Example 4 Two-groups each of three guinea pigs receive 0.1 mg. of g-strophanthin using a unit ready for use and applying said unit to the shaved abdominal skin of the animals.
  • the same conditions as used in Example 3 are employed.
  • the only ditference is that the vehicle liquid of Examples 2 and 3 is replaced by the same volume of two different mixtures.
  • Example 5 For many purposes itis important to determine whether the quantity of therapeutically active agent applied has been completely taken up by the blood stream, i.e. to ind out whether part of the active agent has been retained by the superficial skin layers. I-f this were the case, the active agent, for instance, the strophanthin, would also not have been detected in the residue on the carrier.
  • the following experiments show that a measured quantity of g-strophanthin, administered according to the present invention, is quantitatively absorbed in the blood stream. As the small therapeutic doses of 0.1 mg.
  • strophanthin as they are conventionally administered, cannot be detected with certainty by chemical analysis in the blood, faeces, or the organs, biological methods must be used to find out how much of the strophanthin has entered the blood stream. ⁇ In these experiments a predetermined quantity of g-strophanthin, such as one half of the lethal dose of intravaneous in- -fusion is applied to the skin. That this amount is quantitatively absorbed and has entered the blood stream can readily be ascertained by subsequently injecting intravenously the other half of the lethal dose. If all the animals are killed, it is obvious that all the strophanthin administered precutaneously must have been absorbed through the skin into the blood stream.
  • guinea pigs under urethane anesthesia 2 g./kg. of body weight
  • rIlhe lethal dose amounts to 0.31 mg./kg.i0.048 rug/kg. at a speed of infusion of 0.0047 mg./min.
  • lethal dose i.e. 0.15 mg. of g-strophanthin per kg. body weight by means of a 4 sq. c-m. ⁇ carrier applied to the skin in accordance Iwith the procedure of Example 3.
  • the assembly is allowed to remain on the skin -for minutes under the conditions of Example 3, to cause absorption of the active agent. Thereafter it was determined which amount of strophanthin intravenously injected, causes death of the thus pretreated animals. It was found that 0.18 mg./kg.i0.08 mg./kg. are required to kill the animals. Thus the sum of the amount of active agent absorbed precutaneously I(0.15 nig/kg.) and that required to kill the animals on intravenous administration (0.18 mg./kg.i0.08 rng/kg.) corresponds approximately to the previously determined lethal dose of 0.31 mg./kg.
  • cardio-active glycoides such as k-strophanthin and convallatoxine
  • various alkaloids such as morphine and strychnine as well as barbiturates, such as phenyl ethyl barbituric acid can be administered percutaneously in therapeutic as well as toxic doses.
  • Example 6 Five guinea pigs receive 0.04 cc. of a 10% solution of procaine in base form in n-hexanol with the aid of a 4 sq. cm. carrier 4 made of linen tissue. These carriers are applied to the shaved abdominal skin in the same manner as described in Example l. Separation layer 3 is placed over the carrier 4 also measuring 2 cm. x 2 cm. It consists of a exible polyvinyl chloride iilm which is provided with 25 round openings of 0.2 mm. diameter. Silk iilament wicks 5 are passed through each of these openings. The wicks 5 communicate with the superposed reservoir 6. Said reservoir is m-ade of a 3 mm.
  • the reservoir 6 contains 1 cc. of a transporting liquid or vehicle consisting of hexanol and cyclohexane in the proportion of 1:4.
  • percutaneous absorption of the procaine is determined by its pain Ikilling elect. Whether anesthesia is achieved, is determined by exposing the animals to niechanical irritation or, respectively, to electrical irritation by means of rectangular electrical impulses of 30 cycles per see. and a duration of 1 msec. with variations in current intensity of from 0.2 ma. to 2.5 ma. and determining the dose required to suppress pain reaction ofthe animals.
  • Example 7 Two volunteers are used in the following experiment. 1 mg. of procaine per sq. em. of skin surface is applied to the untreated skin of the back of the left hand of each of the persons, whereby the conditions of Example 6 are observed. After 40 minutes a very definite anesthetic eff fect sets in. The intensity of electrical stimulation can be raised many times until pain reaction sets in. While the normal stimulus threshold is attained by the application of impulses of 0.2 ma. to *.3 ma., percutaneous treatment with procaine according to the present invention raises said threshold to about 2 ma, before pain sets in. The unbroken curve illustrated in FIG. shows said anesthesizing effect which subsided only very slowly, i.e. within 60 minutes.
  • nicotinic acid amide or nicotinic acid methyl ester each of which is a vasodilator
  • compositions and sizes of the active agent carrier, the separator layer, the reservoir carrier, the blocking layer, the covering layer, the protective layer, yand the adhesive, in the composition of the transporting liquid or vehicle, in the physiologically active agents, in the mode of impregnating the active agent carrier with the physiologically active agent and the reservoir carrier with the transporting liquid or vehicle, in the mode of applying and securing the assembled unit to the skin, and the like may be made by those skilled in the art in accordance with the principles set forth herein and the claims annexed thereto.
  • a composite unit useful for the administration of measured doses of physiologically active agents by percutaneous absorption comprising ⁇ a carrier layer of absorbent material impregnated with said active agent, a separator layer of non-absorbent, non-permeable material superposed over said carrier layer, a reservoir layer of absorbent material disposed above said separator layer, a non-permeable, non-absorbent blocking layer between said reservoir layer and said separator layer to separate said layers from each other, said blocking layer being adapted to prevent liquid from flowing from said reservoir layer to said carrier layer when intact and adapted to be moved when the unit is to be used so as to bring said reservoir layer into contact with said underlying separator layer, wick means in contact to said carrier layer, said wick means being adapted to be brought into communication with said reservoir layer when said blocking layer is moved, said reservoir layer being charged with a transporting iiuid for said active agent, and a cover layer superposed over said reservoir layer and adapted to prevent evaporation of said transporting uid
  • a composite unit for the administration of a measured dose of a physiologically active agent by percutaneous absorption which unit comprises a carrier layer of absorbent material capable of retaining a measured dose of said active agent and carrying said measured dose, a separator layer of non-absorbent, non-permeable material superposed over said carrier layer, a reservoir layer composed of absorbent material disposed above said separator layer, a liquid vehicle for said active agent, the -absorbent material of the reservoir layer being impregnated with said liquid vehicle, and wick means between the reservoir layer and the carrier layer and bypassing the separator layer to place the reservoir layer in communication with added to the same dose of procaine, i.e. 1 mg. per sq. cm.

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  • Health & Medical Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Animal Behavior & Ethology (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • General Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Chemical & Material Sciences (AREA)
  • Dermatology (AREA)
  • Biomedical Technology (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Anesthesiology (AREA)
  • Vascular Medicine (AREA)
  • Hematology (AREA)
  • Medicinal Preparation (AREA)
US780795A 1957-12-19 1958-12-16 Process of percutaneously administering exact doses of physiologically active agents and composite unit therefor Expired - Lifetime US3053255A (en)

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Cited By (48)

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US3297034A (en) * 1963-05-21 1967-01-10 Peavy Paulina Beneficial skin and tissue cover device
US3598122A (en) * 1969-04-01 1971-08-10 Alza Corp Bandage for administering drugs
US3678151A (en) * 1969-07-25 1972-07-18 Gugol Clini Tex Inc Biological staining method
US3797494A (en) * 1969-04-01 1974-03-19 Alza Corp Bandage for the administration of drug by controlled metering through microporous materials
US3828777A (en) * 1971-11-08 1974-08-13 Alza Corp Microporous ocular device
US3853116A (en) * 1971-06-21 1974-12-10 Investors In Ventures Inc Implant methods and devices for influencing body fluids
US3896819A (en) * 1969-04-01 1975-07-29 Alejandro Zaffaroni IUD having a replenishing drug reservoir
US3921636A (en) * 1973-01-15 1975-11-25 Alza Corp Novel drug delivery device
US3961628A (en) * 1974-04-10 1976-06-08 Alza Corporation Ocular drug dispensing system
US3964482A (en) * 1971-05-17 1976-06-22 Alza Corporation Drug delivery device
US3972995A (en) * 1975-04-14 1976-08-03 American Home Products Corporation Dosage form
US3996934A (en) * 1971-08-09 1976-12-14 Alza Corporation Medical bandage
US4039653A (en) * 1974-01-23 1977-08-02 Defoney, Brenman, Mayes & Baron Long-acting articles for oral delivery and process
JPS5416566B1 (de) * 1971-06-30 1979-06-23
US4230105A (en) * 1978-11-13 1980-10-28 Merck & Co., Inc. Transdermal delivery of drugs
DE3205258A1 (de) * 1981-02-17 1982-09-16 Alza Corp., 94304 Palo Alto, Calif. Dosierungseinheit zur gleichzeitigen verabreichung von wirkstoffen und die perkutane absorption verstaerkenden mitteln
FR2534140A1 (fr) * 1982-10-12 1984-04-13 Fournier Laboratoires Nouveau dispositif pour l'administration percutanee de medicaments
EP0112176A1 (de) * 1982-12-16 1984-06-27 Almedco, Inc. Transdermale Arzneizelle
FR2562800A1 (fr) * 1984-04-11 1985-10-18 Fournier Laboratoires Dispositif pour l'administration percutanee de medicaments
FR2567761A1 (fr) * 1984-07-23 1986-01-24 Alza Corp Dispositif d'apport transdermique pour l'administration de fentanyl
US4655766A (en) * 1985-08-01 1987-04-07 Alza Corporation Fluid imbibing pump with self-regulating skin patch
EP0246385A1 (de) * 1986-05-23 1987-11-25 New Mexico Tech Research Foundation Transdermale Applikation von Nikotin
US4743232A (en) * 1986-10-06 1988-05-10 The Clinipad Corporation Package assembly for plastic film bandage
EP0273004A2 (de) * 1986-11-20 1988-06-29 Ciba-Geigy Ag Benutzer-aktivierte Therapeutische Systeme
US4813942A (en) * 1987-03-17 1989-03-21 Bioderm, Inc. Three step wound treatment method and dressing therefor
US4911707A (en) * 1987-02-13 1990-03-27 Ciba-Geigy Corporation Monolithic user-activated transdermal therapeutic system
US4917688A (en) * 1987-01-14 1990-04-17 Nelson Research & Development Co. Bandage for transdermal delivery of systemically-active drug
US5026556A (en) * 1988-11-10 1991-06-25 Norwich Eaton Pharmaceuticals, Inc. Compositions for the transdermal delivery of pharmaceutical actives
US5139023A (en) * 1989-06-02 1992-08-18 Theratech Inc. Apparatus and method for noninvasive blood glucose monitoring
US20030078293A1 (en) * 1999-07-23 2003-04-24 The Regents Of The University Of California Use of etodolac for the treatment of chronic lymphocytic leukemia
WO2004041137A1 (fr) * 2002-10-30 2004-05-21 D-Lab Applicateur de produits pharmaceutiques ou cosmetiques jetable
FR2848535A1 (fr) * 2002-12-17 2004-06-18 D Lab Conditionnement a usage unique pour produit liquide, pateux ou pulverulent
US20040127431A1 (en) * 2002-09-19 2004-07-01 Carson Dennis A. Use of etodolac to treat hyperplasia
US6921772B2 (en) 1998-07-09 2005-07-26 Salmedix, Inc. Methods and compositions for the treatment of chronic lymphocytic leukemia
US20050239752A1 (en) * 1999-07-23 2005-10-27 Carson Dennis A Indole compounds useful for the treatment of cancer
US7105560B1 (en) 1999-07-23 2006-09-12 The Regents Of The University Of California Use of etodolac in the treatment of multiple myeloma
US7151100B1 (en) 1999-07-23 2006-12-19 The Regents Of The University Of California Indole compounds useful for the treatment of cancer
US20060293253A1 (en) * 1999-07-23 2006-12-28 The Regents Of The University Of California Indole compounds useful for the treatment of cancer
US20070071706A1 (en) * 2005-09-28 2007-03-29 Filiberto Zadini Lipodissolving dermatological topical preparation
US20070129425A1 (en) * 2005-11-22 2007-06-07 Filiberto Zadini Dissolution of arterial cholesterol plaques by pharmacological preparation
US20070249543A1 (en) * 2006-04-19 2007-10-25 Filiberto Zadini Dissolution of arterial cholesterol plaques by phytochemical emulsifiers
US20080187569A1 (en) * 2005-11-22 2008-08-07 Z & Z Medical Holdings, Inc. Dissolution of arterial plaque
US20080287429A1 (en) * 2007-05-15 2008-11-20 Z & Z Medical Holdings, Inc. Dissolution of Arterial Cholesterol Plaques by Pharmacologically Induced Elevation of Endogenous Bile Salts
US20090035348A1 (en) * 2005-11-22 2009-02-05 Z & Z Medical Holdings, Inc. Dissolution of arterial plaque
US7569612B1 (en) 2006-08-21 2009-08-04 Mutual Pharmaceutical Company, Inc. Methods of use of fenofibric acid
US20130276974A1 (en) * 2008-05-08 2013-10-24 Changlin Pang Drug-delivery pumps and methods of manufacture
US20180280316A1 (en) * 2017-03-28 2018-10-04 Global Biomedical Technologies, Llc High-Efficiency Transdermal Patches
USD1014764S1 (en) * 2021-11-16 2024-02-13 Raymond Lovell Francis Skin-attachable block set that provides no-touch protection for skin insults

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EP0218759B1 (de) * 1985-09-10 1989-05-24 Yasuro Kuratomi Vorrichtung und Verfahren von der Moxibustion
DE3903794A1 (de) * 1989-02-09 1990-08-16 Lohmann Therapie Syst Lts Therapeutisches system zur transdermalen oder transmucosalen verabreichung von wirkstoffen und seine verwendung

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US3797494A (en) * 1969-04-01 1974-03-19 Alza Corp Bandage for the administration of drug by controlled metering through microporous materials
US3598122A (en) * 1969-04-01 1971-08-10 Alza Corp Bandage for administering drugs
US3678151A (en) * 1969-07-25 1972-07-18 Gugol Clini Tex Inc Biological staining method
US3964482A (en) * 1971-05-17 1976-06-22 Alza Corporation Drug delivery device
US3853116A (en) * 1971-06-21 1974-12-10 Investors In Ventures Inc Implant methods and devices for influencing body fluids
JPS5416566B1 (de) * 1971-06-30 1979-06-23
US3996934A (en) * 1971-08-09 1976-12-14 Alza Corporation Medical bandage
US3828777A (en) * 1971-11-08 1974-08-13 Alza Corp Microporous ocular device
US3921636A (en) * 1973-01-15 1975-11-25 Alza Corp Novel drug delivery device
US4039653A (en) * 1974-01-23 1977-08-02 Defoney, Brenman, Mayes & Baron Long-acting articles for oral delivery and process
US3961628A (en) * 1974-04-10 1976-06-08 Alza Corporation Ocular drug dispensing system
US3972995A (en) * 1975-04-14 1976-08-03 American Home Products Corporation Dosage form
US4230105A (en) * 1978-11-13 1980-10-28 Merck & Co., Inc. Transdermal delivery of drugs
DE3205258A1 (de) * 1981-02-17 1982-09-16 Alza Corp., 94304 Palo Alto, Calif. Dosierungseinheit zur gleichzeitigen verabreichung von wirkstoffen und die perkutane absorption verstaerkenden mitteln
FR2534140A1 (fr) * 1982-10-12 1984-04-13 Fournier Laboratoires Nouveau dispositif pour l'administration percutanee de medicaments
EP0107575A1 (de) * 1982-10-12 1984-05-02 Laboratoires Fournier S.A. Vorrichtung zur perkutanen Verabreichung von aktiven Grundstoffen
EP0112176A1 (de) * 1982-12-16 1984-06-27 Almedco, Inc. Transdermale Arzneizelle
FR2562800A1 (fr) * 1984-04-11 1985-10-18 Fournier Laboratoires Dispositif pour l'administration percutanee de medicaments
FR2567761A1 (fr) * 1984-07-23 1986-01-24 Alza Corp Dispositif d'apport transdermique pour l'administration de fentanyl
US4655766A (en) * 1985-08-01 1987-04-07 Alza Corporation Fluid imbibing pump with self-regulating skin patch
EP0246385A1 (de) * 1986-05-23 1987-11-25 New Mexico Tech Research Foundation Transdermale Applikation von Nikotin
EP0498468A1 (de) * 1986-05-23 1992-08-12 New Mexico Tech Research Foundation Vorrichtung zur transdermalen Applikation von Nikotin
US4743232A (en) * 1986-10-06 1988-05-10 The Clinipad Corporation Package assembly for plastic film bandage
EP0273004A2 (de) * 1986-11-20 1988-06-29 Ciba-Geigy Ag Benutzer-aktivierte Therapeutische Systeme
EP0273004A3 (en) * 1986-11-20 1988-07-13 Ciba-Geigy Ag User-activated therapeutical system
US4917688A (en) * 1987-01-14 1990-04-17 Nelson Research & Development Co. Bandage for transdermal delivery of systemically-active drug
US4911707A (en) * 1987-02-13 1990-03-27 Ciba-Geigy Corporation Monolithic user-activated transdermal therapeutic system
US4813942A (en) * 1987-03-17 1989-03-21 Bioderm, Inc. Three step wound treatment method and dressing therefor
US5026556A (en) * 1988-11-10 1991-06-25 Norwich Eaton Pharmaceuticals, Inc. Compositions for the transdermal delivery of pharmaceutical actives
US5139023A (en) * 1989-06-02 1992-08-18 Theratech Inc. Apparatus and method for noninvasive blood glucose monitoring
US5291887A (en) * 1989-06-02 1994-03-08 Anesta Corporation Apparatus and methods for noninvasive blood substance monitoring
US20050261356A1 (en) * 1998-07-09 2005-11-24 Nardella Francis A Methods and compositions for the treatment of chronic lymphocytic leukemia
US6921772B2 (en) 1998-07-09 2005-07-26 Salmedix, Inc. Methods and compositions for the treatment of chronic lymphocytic leukemia
US7105561B2 (en) 1999-07-23 2006-09-12 The Regents Of The University Of California Use of etodolac for the treatment of prostate cancer
US20070111950A1 (en) * 1999-07-23 2007-05-17 Carson Dennis A Indole compounds useful for the treatment of cancer
US7189752B2 (en) 1999-07-23 2007-03-13 Carson Dennis A Use of etodolac for the treatment of chronic lymphocytic leukemia
US20040147582A1 (en) * 1999-07-23 2004-07-29 University Of California Regents Use of etodolac for the treatment of chronic lymphocytic leukemia
US20060293253A1 (en) * 1999-07-23 2006-12-28 The Regents Of The University Of California Indole compounds useful for the treatment of cancer
US20050239752A1 (en) * 1999-07-23 2005-10-27 Carson Dennis A Indole compounds useful for the treatment of cancer
US20030078293A1 (en) * 1999-07-23 2003-04-24 The Regents Of The University Of California Use of etodolac for the treatment of chronic lymphocytic leukemia
US7151100B1 (en) 1999-07-23 2006-12-19 The Regents Of The University Of California Indole compounds useful for the treatment of cancer
US7361680B2 (en) 1999-07-23 2008-04-22 The Regents Of The University Of California Indole compounds useful for the treatment of cancer
US7129262B2 (en) 1999-07-23 2006-10-31 The Regents Of The University Of California Indole compounds useful for the treatment of cancer
US7105560B1 (en) 1999-07-23 2006-09-12 The Regents Of The University Of California Use of etodolac in the treatment of multiple myeloma
US20040127431A1 (en) * 2002-09-19 2004-07-01 Carson Dennis A. Use of etodolac to treat hyperplasia
US20070299042A1 (en) * 2002-09-19 2007-12-27 Carson Dennis A Use of etodolac to treat hyperplasia
US7211599B2 (en) 2002-09-19 2007-05-01 The Regents Of The University Of California Use of etodolac to treat hyperplasia
US20060155251A1 (en) * 2002-10-30 2006-07-13 Taiki Corporation, Ltd. Disposable pharmaceutical or cosmetic product applicator
WO2004041137A1 (fr) * 2002-10-30 2004-05-21 D-Lab Applicateur de produits pharmaceutiques ou cosmetiques jetable
US7650995B2 (en) 2002-10-30 2010-01-26 Taiki Corporation, Ltd. Disposable pharmaceutical or cosmetic product applicator
FR2848535A1 (fr) * 2002-12-17 2004-06-18 D Lab Conditionnement a usage unique pour produit liquide, pateux ou pulverulent
US20060163101A1 (en) * 2002-12-17 2006-07-27 Jean-Louis Assie Disposable package for liquid, pasty or powder product
US7523821B2 (en) 2002-12-17 2009-04-28 Taiki Corporation, Ltd. Disposable package for liquid, pasty or powder product
WO2004056345A1 (fr) * 2002-12-17 2004-07-08 D-Lab Conditionnement a usage unique pour produit liquide, pateux ou pulverulent
US20070071706A1 (en) * 2005-09-28 2007-03-29 Filiberto Zadini Lipodissolving dermatological topical preparation
US8304383B2 (en) 2005-11-22 2012-11-06 Atheronova Operations, Inc. Dissolution of arterial plaque
US20080187569A1 (en) * 2005-11-22 2008-08-07 Z & Z Medical Holdings, Inc. Dissolution of arterial plaque
US8697633B2 (en) 2005-11-22 2014-04-15 Atheronova Operations, Inc. Dissolution of arterial plaque
US20090035348A1 (en) * 2005-11-22 2009-02-05 Z & Z Medical Holdings, Inc. Dissolution of arterial plaque
US20070129425A1 (en) * 2005-11-22 2007-06-07 Filiberto Zadini Dissolution of arterial cholesterol plaques by pharmacological preparation
US20070249543A1 (en) * 2006-04-19 2007-10-25 Filiberto Zadini Dissolution of arterial cholesterol plaques by phytochemical emulsifiers
US7569612B1 (en) 2006-08-21 2009-08-04 Mutual Pharmaceutical Company, Inc. Methods of use of fenofibric acid
US7741373B1 (en) 2006-08-21 2010-06-22 Mutual Pharmacuetical Company, Inc. Methods of use of fenofibric acid
US7915247B1 (en) 2006-08-21 2011-03-29 Mutual Pharmaceutical Company, Inc. Methods of use of fenofibric acid
US7741374B1 (en) 2006-08-21 2010-06-22 Mutual Pharmaceutical Company, Inc. Methods of use of fenofibric acid
US20080287429A1 (en) * 2007-05-15 2008-11-20 Z & Z Medical Holdings, Inc. Dissolution of Arterial Cholesterol Plaques by Pharmacologically Induced Elevation of Endogenous Bile Salts
US20130276974A1 (en) * 2008-05-08 2013-10-24 Changlin Pang Drug-delivery pumps and methods of manufacture
US9107995B2 (en) * 2008-05-08 2015-08-18 Minipumps, Llc Drug-delivery pumps and methods of manufacture
US20180280316A1 (en) * 2017-03-28 2018-10-04 Global Biomedical Technologies, Llc High-Efficiency Transdermal Patches
USD1014764S1 (en) * 2021-11-16 2024-02-13 Raymond Lovell Francis Skin-attachable block set that provides no-touch protection for skin insults

Also Published As

Publication number Publication date
NL107185C (de)
DE1071897B (de) 1959-12-24
BE573712A (fr) 1959-04-01
CH366127A (de) 1962-12-15

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