WO1982000005A1 - Polymeric diffusion matrix containing a vasodilator - Google Patents

Polymeric diffusion matrix containing a vasodilator Download PDF

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Publication number
WO1982000005A1
WO1982000005A1 PCT/US1981/000892 US8100892W WO8200005A1 WO 1982000005 A1 WO1982000005 A1 WO 1982000005A1 US 8100892 W US8100892 W US 8100892W WO 8200005 A1 WO8200005 A1 WO 8200005A1
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WIPO (PCT)
Prior art keywords
matrix
diffusion matrix
polymeric diffusion
vasodilator
polymer
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Application number
PCT/US1981/000892
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English (en)
French (fr)
Inventor
Inc Keypharmaceuticals
A Keith
W Snipes
Original Assignee
Key Pharma
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority claimed from US06/163,262 external-priority patent/US4291015A/en
Application filed by Key Pharma filed Critical Key Pharma
Priority to AU74502/81A priority Critical patent/AU7450281A/en
Publication of WO1982000005A1 publication Critical patent/WO1982000005A1/en

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Classifications

    • 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

Definitions

  • the present invention relates to a polymeric diffusion matrix containing a vasodilator. More particularly, the invention relates to a polymeric diffusion matrix containing a vasodilator characterized by a sustained release of the vasodilator. Furthermore, the polymeric diffusion matrix is self-supporting.
  • a polymeric diffusion matrix comprising from about 2 to about 60% glycerol, from about 2 to about 15% polyvinylalcohol, from about 2 to about 10% of a water-soluble polymer with hydration sites which in combination with the remaining ingredients (including a vasodilator) yields a matrix capable of sustained release of a vasodilator dispersed therein, and the balance water, the percentages being by weight.
  • the water-soluble polymer is polyvinylpyrrolidone.
  • the polyvinylalcohol preferably has a molecular weight of from about 50,000 to about 150,000, particularly from about 100,000 to about 150,000 and the polyvinylpyrrolidone preferably has a molecular weight of from about 15,000 to about 80,000, particularly from about 20,000 to about 60,000.
  • the glycerol is preferably present in an amount of about 35% to about 55%.
  • the glycerol (a polar plasticizer) in the diffusion matrix can be replaced in whole or in part with propylene glycol or polyalkylene glycols such as polyethylene glycol and polypropylene glycol.
  • Polyethylene glycols particularly those having molecular weights ranging from about 200 to about 1,000 can be used as the polar plasticizer. If polyethylene glycol is used in admixture with glycerol, the glycol can have a molecular weight of up to about 4,000. It has been found that a polar plasticizer, e.g., glycerol, is a necessary component in the matrix.
  • a diffusion matrix formed with no polar plasticizer is not flexible and has poor diffusional contact with the skin causing unreliable diffusion release.
  • polyvinylalcohol matrix component polymers of hydroxyethylacrylate, polymers of hydroxyethylmethacrylate, polymers of hydroxypropylacrylate, and polymers of hydroxypropylmethacrylate. It is possible to use homopolymers or copolymers of the hydroxyalkyl (meth)-acrylates.
  • the water-soluble polymer can be (in addition to polyvinylpyrrolidone) any of agar, agarose, gum arabic, gum tragacanth, polyacrylic acid, polymethacrylic acid, polyvinyloxazolidone, polyvinylmorpholinone, and polyvinylpiperidone.
  • a polymeric diffusion matrix suitable for the transdermal delivery of a vasodilator comprising from about 2 to about 60% glycerol, from about 2 to about 15% polyvinyl alcohol, from about 2 to about 10% of a water-soluble polymer with hydration sites which in combination with the remaining ingredients yields a matrix capable of sustained release of a vasodilator dispersed therein, and the balance water, the percentages being by weight.
  • the water-soluble polymer is polyvinylpyrrolidone.
  • the polyvinylalcohol preferably has a molecular weight of from about 50,000 to about 150,000, particularly from about 100,000 to about 150,000 and the polyvinylpyrrolidone preferably has a molecular weight of from about 15,000 to about 80,000, particularly from about 20,000 to about 60,000.
  • Figure 1 shows a plan view of a. bandage having incorporated therein the vasodilator-containing self-supporting polymeric diffusion matrix of the present invention
  • Figure 2 illustrates a cross-sectional view along line 2-2' in Figure 1.
  • a polymeric diffusion matrix comprising, on a weight basis, from about 2 to about 60% glycerol, from about 2 to about 15% polyvinylalcohol, from about 2 to about 10% of a water- soluble polymer with hydration sites which is compatible with the remainder of the ingredients of the diffusion matrix to permit the sustained release of a vasodilator, the balance being water.
  • This water-soluble polymer complements the polyvinylalcohol by providing retention of shape of the desired diffusion matrix.
  • a representative example of a water-soluble polymer with hydration sites suitable for the present invention is polyvinylpyrrolidone.
  • the matrix contains a therapeutically effective amount of a vasodilator for topical or transdermal application to a patient, thus forming a vasodilator drug delivery device.
  • the present invention provides a diffusion matrix for the application of a vasodilator to a patient (vasodilator drug delivery matrix).
  • a vasodilator drug delivery matrix for the application of a vasodilator to a patient (vasodilator drug delivery matrix).
  • the transdermal or topical application of vasodilator drugs is contemplated via the diffusion matrix.
  • the diffusion matrix of the present invention provides a steady release of the drug to the patient over an extended period of time, typically 24 hours.
  • the glycerol is present in an amount of from about 2 to 60%.
  • the amount of glycerol preferably should be within the range of from about 35 to 55%.
  • the glycerol has a minimum specific gravity of 1.23 g/ml.
  • the polyvinylalcohol is present, in the uncured matrix in an amount of from about 2 to about 15%, preferably from about 4 to about 9% by weight.
  • the polyvinylalcohol has a molecular weight of at least about 70,000. Most preferably, the molecular weight is from about 100,000 to about 150,000.
  • the water-soluble polymer with hydration sites is present in the uncured matrix in an amount of from about 2 to about 10%, preferably from about 2 to about 5%, by weight.
  • polyvinylpyrrolidone is used as the water soluble polymer.
  • the molecular weight for the polyvinylpyrrolidone should be selected to maintain water solubility. In general, this molecular weight should be within the range of from about 15,000 to about 80,000, preferably from about 20,000 to about 60,000, and most preferably from about 35,000 to about 50,000.
  • the polyvinylpyrrolidone may be replaced by other ingredients which permit sustained release.
  • the balance of the matrix comprises essentially water.
  • the polymeric diffusion matrix comprises from about 2 to about 55%, preferably from about 4 to about 35% glycerol, from about 4 to about 30%, preferably from about 8 to about 20% polyvinylalcohol; from about 2 to about 20%, preferably from about 4 to about 10%, of a water-soluble polymer having hydration sites, preferably polyvinylpyrrolidone, and the balance water, all percentages being by weight.
  • the molecular weight ranges for the polyvinylalcohol and polyvinylpyrrolidone are the same for cured and uncured diffusion matrices.
  • the cured matrix has a density of about 1.2 g/ml.
  • the weight ratio of glycerol to water.in the cured matrix is about 0.6-1.8:1, preferably about 1:1.
  • the cured matrix shows little swelling when immersed in water and will not dissolve in water at room temperature. However, if the water is heated to boiling, the diffusion matrix will dissolve.
  • At least one vasodilator is dispersed throughout the diffusion matrix when the diffusion matrix is used as a vasodilator drug delivery device.
  • the type of vasodilator which may be dispersed in the diffusion matrix of the present invention includes any vasodilator which is capable of being transdermally or topically administered to a patient. With the sustained release of the drug at a relatively steady rate over a prolonged period, typically 24 hours, the patient is provided with the benefit of a steady application of the vasodilator over the prolonged period.
  • vasodilators employed in the present invention generally include those agents suitable for systemic absorption through the external body skin in accordance with their known dosages and uses.
  • Representative vasodilators are compounds having nitrate ion.
  • Representative vasodilators include amyl nitrate, nitroglycerin (trinitroglycerol), sodium nitrate, erythrityl tetranitrate, pentaerythritol tetranitrate, isosorbide dinitrate, mannitol hexanitrate, trolnitrate phosphate (triethanolamine biphosphate), and the like.
  • trinitroglycerol When trinitroglycerol is used, it is ordinarily present in the form of lactose triturate. It is necessary to have an active adsorbent surface for the trinitroglycerol.
  • the active adsorbent surface can be supplied by lactose, insolubilized starch, micronized cellulose, silica gel, di- and oligosaccharides having a degree of solubility from lower than to up to twice that of lactose, and cyclitols.
  • lactose When lactose is employed as the insoluble active adsorbent surface material, it is necessary to make certain there is enough polar plasticizer, e.g., glycerol, and not too much water, as this would cause the lactose to become solubilized. Solubilization will prolong the setting time and may decrease adhesion to the backing.
  • polar plasticizer e.g., glycerol
  • the amount of the vasodilator dispersed in the diffusion matrix can be varied. in accordance with the desired dosage and the length of time the matrix is to remain on the skin. However, the amount of the vasodilator included in the matrix should generally be In excess of the amount which is to be delivered to the patient. If the diffusion matrix is to be used for 24 hours, a suitable excess of the vasodilator should be included to assure appropriate release kinetics. For example, if it is desired to apply about 10 mg. of trinitroglycerol to a patient over 24 hours, a roughly six-fold excess of the trinitroglycerol should be included in the diffusion matrix. Accordingly, from 50 to 70 mg. is considered a preferred amount to provide a 10 mg. release of trinitroglycerol over a 24-hour period. Quite obviously, the optimum amount that should be included in the diffusion matrix will vary according to factors such as the period of release of the drug.
  • trinitroglycerol also known as 1,2,3,-propanetriol trinitrate or nitroglycerin
  • nitroglycerin a preferred lactose triturate
  • lactose triturate is a composition comprising 10% nitroglycerin and 90% betalactose.
  • this matrix comprises from about 35 to about 60%, preferably from about 45 to about 55% glycerol; from about 2 to about 15%, preferably from about 4 to about 9% polyvinylalcohol; from about 2 to about 10% , preferably from about 2 to about 5% polyvinylpyrrolidone, and the balance being essentially water, all percentages being by weight.
  • the amount of water evaporated from the uncured matrix is negligible, hence the higher percentage for the glycerol.
  • the weight ratio of glycerol to total polymers is usually greater than 1, preferably from about 1.4 to 15:1.
  • the amount of trinitroglycerol which should be used is based upon a desired delivery of about 5 or 10 mg. per patient over a 24-hour period.
  • the diffusion matrix drug delivery system of the present invention to deliver the 5 or 10 mg. in the 24-hour period should contain about 40 to 60 mg. of the trinitroglycerol.
  • the concentration of the trinitroglycerol in the diffusion matrix and the area of the diffusion matrix are factors to consider.
  • from about 0.1 to about 4.0% by weight trinitroglycerol is included in the diffusion matrix.
  • 80 ml. of the solution is mixed with 20 gm.
  • the matrix is formed at atmospheric pressure.
  • Water and glycerol are first mixed together. Since alkaline solutions of nitroglycerin or other organic nitrates have relatively poor stability, the pH of the glycerol/water mixture is adjusted so that it is either neutral or slightly acidic, i.e., the pH ranging from about 6.5 to about 7.0. In a preferred embodiment, the pH is adjusted to within the above-mentioned range by adding sodium citrate and citric acid to the mixture.
  • the polyvinylalcohol and pplyvinylpyrrolidone are then added to the glycerol-water mixture at room temperature, with agitation.
  • the mixture is heated to a temperature within the range of from about 90 to about 95°C at atmospheric pressure to extend the polymers.
  • the mixture is held at this temperature for about one hour. If desired, the mixture may be maintained at this temperature for a period of about 48 hours prior to the addition of the drug.
  • the mixture is stable for a period of about 48 hours and may be kept for such a period before being mixed with the drug to be delivered to the patient. Thereafter, the mixture is cooled to 80°C and stirred for an additional hour to remove bubbles from the mixture.
  • the drug to be applied to the patient is then added to the mixture, with thorough agitation. Once a homogeneous mixture of the polymer solution and drug is obtained, the mixture is ready to be cast into sheets of the drug-containing diffusion matrix.
  • the drug may be dissolved or dispersed by agitation in a suitable solvent such as glycerin and water. The thus-obtained solution can be maintained at room temperature for prolonged periods without deterioration.
  • water and glycerol are mixed, with the pH of the mixture adjusted to a desired value by adding suitable amounts of sodium citrate and citric acid. Thereafter, the polyvinylalcohol and polyvinylpyrrolidone are added.
  • the resulting mixture is then heated to a temperature of about 120°C at a pressure of about 2 atmospheres absolute. The temperature is maintained for about 1 hour without any mechanical agitation. In a preferred embodiment, the heating may be performed in an autoclave. Since bubbles are not formed when the heating is conducted in an autoclave, such a procedure is preferred. Thereafter, the temperature is lowered to about 20 to about 80°C whereupon the drug to be applied to the patient is added. After the drug has been homogeneously dispersed in the fluid mixture, the mixture is poured into molds to form sheets of the drug-containing diffusion matrix.
  • the drug must be added and mixed thoroughly when the polymer mixture is in the liquid state.
  • the mixture should be cast within about 30 minutes after the drug has been introduced into the polymer solution. This is important in order to avoid the setting of the polymer solution prior to casting.
  • the temperature at which the drug is to be added to the matrix solution depends on the stability and volatility of the drug. For example, trinitroglycerol begins to decompose at a temperature of above about 50°C. Accordingly, in preparing a trinitroglycerol-containing diffusion matrix, the matrix solution mixture is cooled to about 50°C, whereupon the trinitroglycerol is added. The drug-containing diffusion solution is then cast into molds to form sheets of the final product.
  • the pH of the solution mixture should be kept slightly acidic, i.e., between 6.5 and 7.0 since trinitroglycerol is stabilized within this pH range.
  • Sodium dodecyl sulfate or sorbitan (Tween-20) or other detergents may be added in an amount of 0.1 to 10% by weight, based on the matrix, as a dispersing agent, if desired.
  • vasodilators that are alcohol-soluble, it may be desirable to add in the initial mixture of glycerol and water, ethanol or is ⁇ propanol in an amount of from 2 to 40% by weight, based on the matrix, to facilitate the preparation of a diffusion matrix for such alcohol-soluble drugs.
  • An absorption facilitator to insure skin penetration such as dimethylsulfoxide, decylmethylsulfoxide, or other penetration enhancers may be added. If it is desired to increase the effective lifetime of the diffusion matrix, a drug reservoir may also be attached to the diffusion matrix.
  • the diffusion matrix may also be used to help with local vasodilation to assist in the solution of physiological problems resulting from local circulatory deficiencies, for example, to promote circulation in the extremities of a patient.
  • the present drug delivery device comprises the drug-containing diffusion matrix and means for fastening the matrix to the skin of a patient.
  • Such means can take various forms, such as an occlusive backing layer forming a kind of "bandage" with the diffusion matrix being held against the skin of a patient being treated.
  • a polyethylene or Mylar tape is contemplated as one form of occlusive layer in accordance with the present invention.
  • It can also take the form of an elastic band, such as a cloth band, a rubbery band or other material.
  • the diffusion matrix is placed directly on the skin and held in place by such elastic band which typically will be placed over the arm or wrist of the patient.
  • An intermediate adhesive layer between the diffusion matrix and the skin capable of permitting the transdermal application of the drug can also be used.
  • the drug-containing diffusion matrix is placed in a cavity provided in an inert backing material.
  • useful backing materials include metal foils such as aluminum foil, polyolefins such as polyethylene and polypropylene, polyesters such as Mylar (polyethylene terephthalate), polyamides such as nylon, and the like.
  • the drug-containing diffusion matrix can be poured in its molten state into the cavity and permitted to cool.
  • An adhesive layer is provided on the backing material surrounding the cavity. To prevent evaporative loss in the surface of the matrix, the adhesive layer and the matrix are sealed with a release layer. To use the device, the patient peels off the release layer and places the device in intimate contact with his skin. The exposed adhesive layer secures the device to the patient.
  • a concentration gradient existing normal to the surface of the matrix and the patient's skin facilitates diffusion of the drug through the matrix into the patient's body.
  • the package comprises a bandage having cover layer 12 and backing member 10.
  • the diffusion matrix 14 having a vasodilator (e.g., trinitroglycerol) dispered therein is placed in cavity 16 in backing member 10.
  • the diffusion matrix may be poured in its molten state into cavity 16 in backing member 10 and permitted to cure.
  • the molten polymeric mixture (with or without a drug) is cast to form a thin sheet which is cut, after curing, into smaller sheets to fit the particular application of the matrix. Individual smaller sheets may then be placed in cavity 16 in backing member 10.
  • the area 18 surrounding the matrix in the backing member 10 is heat-sealed to prevent the matrix from being removed from the backing member.
  • the backing member 10 is formed of a laminate comprising an outer layer 20 made of a polyester, such as polyethylene terephthalate, an intermediate layer 22 made of a metallic foil, e.g., aluminum foil, and an inner layer 24 made of an ionomer, such as Surlyn.
  • a layer of pressure-sensitive adhesive 26 is provided on the surface of the inner layer surrounding the heat-sealed portion. It is noted that the adhesive does not cover the matrix.
  • the matrix is prevented from coming into contact with the atmosphere by placing cover layer 12 thereon, which seals the matrix.
  • the cover layer is also, formed of a laminate having the same construction as the backing layer, i.e., an outer layer 28 made of a polyester, e.g., polyethylene terephthalate; an intermediate layer 30 made of a metallic foil, e.g., aluminum foil; and an inner layer 32 of an ionomer, e.g., Surlyn.
  • the surface 34 of the inner layer coming into contact with the pressure-sensitive adhesive 26 on the backing member 10 is coated with a release layer to permit easy removal of the cover layer.
  • the cover layer is peeled off.
  • the exposed matrix is then taped onto a suitable portion of the patient's body, e.g., arm or wrist, to allow the drug to diffuse thereinto.
  • the molten matrix is cast into cavities provided in the backing member.
  • the matrix is permitted to cure for a short period (e.g. about 10 minutes to about one hour) and is sealed by placing the cover layer over the backing member.
  • the method of administration of this invention is suitable also for adaptation to buccal and especially to sublingual administration. Because of the much higher rate of absorption through the mucosa by that route, much shorter periods of administration are required.
  • Glycerol (45 ml.), water (45 ml.) and 1% by weight sodium citrate are mixed together and the pH adjusted to 7 through addition of sodium citrate and citric acid.
  • This mixture is heated to 90°C; after reaching at least 70°C, there are slowly added 7 gm. polyvinyl alcohol (PVA 100% hydrolyzed, molecular weight 115,000) and 5 gm. polyvinylpyrrolidone (mw. 40,000).
  • the mixture is stirred at 90°C until solution is effected, which may take about 10 minutes, it being appreciated that with larger quantities, a considerably longer period of time may be needed. 80 ml. of this solution are then mixed with 20 gm.
  • lactose triturate (10% nitroglycerin and 90% lactose), this mixture then being mechanically stirred until homogeneous.
  • the homogeneous mixture is then poured into forms made of glass or stainless steel which serve as templates to produce a diffusion matrix having a thickness of about 3 to 4 mm. This diffusion matrix is then cut into square pieces of about 1 inch on each side, i.e., to provide a total surface area of about 6.5 cm 2 .
  • a polar plasticizer such as glycerol is a necessary matrix component
  • a drug-free diffusion matrix of Example I and a drug-free matrix of Example I without a glycerol component were prepared. Both matrices were doped with crystal violet.
  • the matrix containing glycerol displayed a uniform color transfer from the surface of the diffusion matrix to the surface of the skin.
  • the glycerol-free matrix when applied to human skin, gave a spotty diffusion pattern. This is believed to establish that a polar plasticizer is a necessary element of the diffusion matrix of the instant invention in order to achieve uniform diffusion characteristics.
  • injection molding can be used.
  • the foil backing is placed in a series of molds and the polymeric mixture is injection molded therein to form the final product.
  • a preferred foil is a "polyfoil” having consecutive layers of polyethylene, aluminum, polyethylene, polyester (polyethylene terephthalate). The first polyethylene layer has the diffusion matrix adhered thereto and the polyester layer represents the backing layer.
  • a particularly preferred "polyfoil” is Ludlow CX-220 available from the Ludlow Co., Ludlow, Massachusetts.
  • Example I Although the polyvinylalcohol of Example I was 100% hydrolyzed, it is possible to use partially hydrolyzed polyvinylalcohols. Tests have been conducted using 75, 88, 96, 97, 98, and 99% hydrolyzed polyvinylalcohols . With hydrolysis levels below 90%, some structural weakness, shrinkage, and even some phase separation are observed. It is preferred to use polyvinylalcohols that are at least 90%, preferably 95%, hydrolyzed.
  • Example I is repeated with the exception that 3 gm. of agar is used instead of polyvinylpyrrolidone. Calcium chloride is included in the mixture also and is present in an amount of 1% by weight.
  • Example I The diffusion matrix of Example I is applied to a patient by placing it against the wrist, shoulder or other sites of the patient.
  • the diffusion matrix of Example I is applied to a patient by first attaching the diffusion matrix to a Mylar or polyethylene backing layer.
  • This occlusive backing layer is provided with an adhesive whereby the diffusion matrix is held in contact with the skin as part of this "bandage".
  • lactose triturate (10% nitroglycerin and 90% lactose) is dispersed in 315 g. glycerol and 214 g. water with agitation at room temperature.
  • the lactose triturate dispersion is poured therein.
  • the mixture is mixed thoroughly at a temperature range of between 50 and 55°C to form a homogeneous mixture.
  • the container is kept covered.
  • the homogeneous mixture is poured into forms made of glass or stainless steel which serve as templates to produce a drug-containing diffusion matrix having a thickness of about 3 to 4 mm. This diffusion matrix is then cut into square pieces of about 1 inch on each side, i.e., to provide a total surface area of about 6.5 cim 2 .
  • Example V is repeated except that sodium polyacrylate having a molecular weight of 100,000 (a preferred molecular weight range of the polyacrylic acid or salt polymer) is used instead of polyvinylpyrrolidone.
  • Male dogs are anesthetized with sodium pentothal. Through surgical incisions, catheters are positioned in the femoral veins of each hind leg and in the abdominal arota. Flow gauges are placed on the internal iliacs of both hind limbs. On a well-shaved area of the medial surface of the left thigh, a nitroglycerin-containing polymer matrix obtained in Example I is taped in place and remains undisturbed for 4 hours. The right hind limb receives no matrix or treatment of any kind. After application of the matrix, blood samples (5 ml .
  • Dectection (A Hewlett-Packard 4610A Gas chromatograph equipped with a 63 Ni-electron capture detector.) Separation is achieved on a 4 foot x 3 mm. I.D. glass column packed with 10% SE-30 on 100/120 mesh GAS-CHROM Q TM . The column is maintained at 140°C while the injection-port temperature is 170°C and the detector temperature is 220°C. A nitroglycerin calibration curve is constructed from the analyses of nitroglycerin-spiked blank plasma.
  • nitroglycerin absorption rate appears to be fairly constant from 30-240 minutes as depicted by the essentially non-varying arterial nitroglycerin plasma levels.
  • the animals are allowed to recover from the anesthetic and are studied 24 hours later in the fasted, conscious state while resting comfortably in a supporting harness.
  • a 20 ml. reference blood sample is obtained from the right heart catheter.
  • a 1.0" x 1.0" square of the nitroglycerin-containing polymer matrix obtained in Example I is then applied to a well-shaved area of the right lateral chest wall. The matrix is held securely in place with surgical tape.
  • 5.0 ml. blood samples are obtained at: 15 min., 30 min., 45 min., 1 hr., 2 hr. , 3 hr., 4 hr., 5 hr., 6 hr., 7 hr. , 8 hr.
  • blood samples are put in ice and transferred to a walk-in refrigerator and centrifuged for 10 minutes at 0°C.
  • a 2 ml. aliquot of plasma is taken from each specimen and transferred to individual silanized (with an alkylated silicone oil) glass tubes.
  • a 5 ml. volume of npentane is added to each tube and the nitroglycerin is extracted for 60 minutes with gentle shaking at 0°C.
  • the pentane phase is transferred to a 5 ml. capacity Reacti-Vial and evaporated to near dryness. The residue is dissolved in 30 microliters of benzene containing 2 nanograms of para-nitro- anisole used as the external standard.
  • the column is maintained at 140°C while the mjection-port temperature is 170°C and detector temperature:
  • a nitroglycerin calibration curve is constructed from the analyses of nitroglycerin-spicked blank plasma.
  • Table 2 summarizes the plasma nitroglycerin data from the dogs. At each time point the mean ⁇ the standard deviation is listed in the Table.

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PCT/US1981/000892 1980-06-26 1981-06-26 Polymeric diffusion matrix containing a vasodilator WO1982000005A1 (en)

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US06/163,262 US4291015A (en) 1979-08-14 1980-06-26 Polymeric diffusion matrix containing a vasodilator
US163262800626 1980-06-26

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FR2532546A1 (fr) * 1982-09-07 1984-03-09 Biotrol Sa Lab Pate pour la protection de la peau
EP0246385A1 (en) * 1986-05-23 1987-11-25 New Mexico Tech Research Foundation Transcutaneous application of nicotine
EP0421454A3 (en) * 1989-10-06 1991-06-12 Lts Lohmann Therapie-Systeme Gmbh & Co.Kg Dressing containing estrogen
WO1994001103A1 (en) * 1992-07-02 1994-01-20 Baker Norton Pharmaceuticals, Inc. Sustained release organic nitrite therapy
WO2009112258A1 (de) * 2008-03-14 2009-09-17 G. Pohl-Boskamp Gmbh & Co. Kg Langzeitstabile pharmazeutische zubereitung mit dem wirkstoff glyceroltrinitrat
US9101592B2 (en) 2011-02-25 2015-08-11 G. Pohl-Boskamp Gmbh & Co. Kg Stabilized granules containing glyceryl trinitrate
US9180109B2 (en) 2010-08-03 2015-11-10 G. Pohl-Boskamp Gmbh & Co. Kg Use of glyceryl trinitrate for treating traumatic edema
US9248099B2 (en) 2012-05-31 2016-02-02 Desmoid Aktiengesellschaft Use of stabilized granules containing glyceryl trinitrate for arteriogenesis
US10034850B2 (en) 2013-11-29 2018-07-31 G. Pohl-Boskamp Gmbh & Co. Kg Sprayable aqueous composition comprising glyceryl trinitrate
US11166931B2 (en) 2012-05-31 2021-11-09 G. Pohl-Boskamp Gmbh & Co. Kg Induction of arteriogenesis with an NO (nitric oxide) donor

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Publication number Priority date Publication date Assignee Title
JPH07116032B2 (ja) * 1990-04-06 1995-12-13 積水化学工業株式会社 ニトログリセリン貼付剤

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FR2532546A1 (fr) * 1982-09-07 1984-03-09 Biotrol Sa Lab Pate pour la protection de la peau
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US4503034A (en) * 1982-09-07 1985-03-05 Laboratoires Biotrol S.A Paste for protecting the skin
EP0246385A1 (en) * 1986-05-23 1987-11-25 New Mexico Tech Research Foundation Transcutaneous application of nicotine
EP0498468A1 (en) * 1986-05-23 1992-08-12 New Mexico Tech Research Foundation Device for transcutaneous application of nicotine
EP0421454A3 (en) * 1989-10-06 1991-06-12 Lts Lohmann Therapie-Systeme Gmbh & Co.Kg Dressing containing estrogen
US5393529A (en) * 1989-10-06 1995-02-28 Lts Lohmann Therapie-Systeme Gmbh & Co. Kg Estrogen-containing active substance plaster
WO1994001103A1 (en) * 1992-07-02 1994-01-20 Baker Norton Pharmaceuticals, Inc. Sustained release organic nitrite therapy
WO2009112258A1 (de) * 2008-03-14 2009-09-17 G. Pohl-Boskamp Gmbh & Co. Kg Langzeitstabile pharmazeutische zubereitung mit dem wirkstoff glyceroltrinitrat
AU2009224968B2 (en) * 2008-03-14 2014-01-16 G. Pohl-Boskamp Gmbh & Co. Kg Long-term stable pharmaceutical preparation having the active ingredient glycerol trinitrate
US9180109B2 (en) 2010-08-03 2015-11-10 G. Pohl-Boskamp Gmbh & Co. Kg Use of glyceryl trinitrate for treating traumatic edema
US9693983B2 (en) 2010-08-03 2017-07-04 G. Pohl-Boskamp Gmbh & Co. Kg Use of glyceryl trinitrate for treating traumatic edema
US9101592B2 (en) 2011-02-25 2015-08-11 G. Pohl-Boskamp Gmbh & Co. Kg Stabilized granules containing glyceryl trinitrate
US9616023B2 (en) 2011-02-25 2017-04-11 G. Pohl-Boskamp Gmbh & Co. Kg Stabilized granules containing glyceryl trinitrate
US9248099B2 (en) 2012-05-31 2016-02-02 Desmoid Aktiengesellschaft Use of stabilized granules containing glyceryl trinitrate for arteriogenesis
US9675552B2 (en) 2012-05-31 2017-06-13 Desmoid Aktiengesellschaft Use of stabilized granules containing glyceryl trinitrate for arteriogenesis
US11166931B2 (en) 2012-05-31 2021-11-09 G. Pohl-Boskamp Gmbh & Co. Kg Induction of arteriogenesis with an NO (nitric oxide) donor
US10034850B2 (en) 2013-11-29 2018-07-31 G. Pohl-Boskamp Gmbh & Co. Kg Sprayable aqueous composition comprising glyceryl trinitrate
US10987332B2 (en) 2013-11-29 2021-04-27 G. Pohl-Boskamp Gmbh & Co. Kg Sprayable aqueous composition comprising glyceryl trinitrate

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CA1163195A (en) 1984-03-06
JPS57500831A (enrdf_load_stackoverflow) 1982-05-13

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