US20130121930A1 - Use of Glyceryl Trinitrate for Treating Hematomas - Google Patents

Use of Glyceryl Trinitrate for Treating Hematomas Download PDF

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Publication number
US20130121930A1
US20130121930A1 US13/813,685 US201113813685A US2013121930A1 US 20130121930 A1 US20130121930 A1 US 20130121930A1 US 201113813685 A US201113813685 A US 201113813685A US 2013121930 A1 US2013121930 A1 US 2013121930A1
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percent
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composition
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gtn
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Marianne Boskamp
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G Pohl Boskamp GmbH and Co KG
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Assigned to G. POHL-BOSKAMP GMBH & CO. KG reassignment G. POHL-BOSKAMP GMBH & CO. KG ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: BOSKAMP, MARIANNE
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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/44—Oils, fats or waxes according to two or more groups of A61K47/02-A61K47/42; Natural or modified natural oils, fats or waxes, e.g. castor oil, polyethoxylated castor oil, montan wax, lignite, shellac, rosin, beeswax or lanolin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0014—Skin, i.e. galenical aspects of topical compositions
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/06—Ointments; Bases therefor; Other semi-solid forms, e.g. creams, sticks, gels
    • 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
    • A61K9/10—Dispersions; Emulsions
    • A61K9/12—Aerosols; Foams
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

  • the present invention relates to the use of glyceryl trinitrate (GTN) for treating hematomas.
  • GTN glyceryl trinitrate
  • Hematomas are bleeding conditions due to the rupture of blood vessels in the subcutaneous region which result from the external action of force, for example an impact, blow, or fall, or following a surgical procedure. Hematomas may result in intense swelling and cause great pain. A hematoma generally heals on its own over a period of two to three weeks. During the healing phases, various skin discolorations occur due to breakdown of blood residues by the body. A distinction may be made among the following phases:
  • hematomas usually heal within several days to a few weeks without treatment, accelerated healing is often desirable, in particular when the hematomas have a very large area or are located on regions of the skin not normally covered by clothing.
  • heavy hematoma it is important to rapidly reduce the hematoma, in order to alleviate pain, decrease complications of swelling, and restore fitness for work.
  • a required surgical procedure cannot be performed until swelling subsides at the fracture site.
  • hematomas may be treated by applying ointments containing heparin, DMSO, or hirudin, with the objective of accelerating the dissolution of the hematoma.
  • Products containing arnica extract are also used, which have an anti-inflammatory effect, reduce swelling, and relieve pain.
  • Glyceryl trinitrate (nitroglycerin), abbreviated below as GTN, is an active substance used for the treatment of angina pectoris, among other conditions. It is primarily used in emergency situations in the form of chewable capsules or as a sublingual spray, with the active substance penetrating the oral mucosa. Sublingual sprays are commercially marketed as propellant sprays and as pump sprays. Spray compositions containing propellants are disclosed, for example, in U.S. Pat. No. 3,155,574, European patent application EP 0 461 505, and German unexamined patent application DE 32 460 81. Propellant-free compositions containing GTN are described in European patent applications EP 0 448 961 and EP 0 471 161.
  • Agrawal et al. (Agrawal et al., Diabetes Research and Clinical Practice, 77 (2007) 161-167) reports on the successful use of topically applied GTN for treating painful diabetic neuropathy.
  • U.S. Pat. No. 5,698,589 discloses the effectiveness of topically applied GTN for treating male erectile dysfunction and female anorgasmia, and for assisting in wound healing of cuts.
  • International patent application WO 2004/064779 reports on the treatment of nocturnal muscle cramps by topically applying GTN to the affected sites.
  • hematomas are bleeding conditions in the subcutaneous region which result from the external application of force, for example an impact, blow or fall. Hematomas are characterized by closed or unbroken skin, and therefore do not include lesions, wounds, surgical incisions, or other injuries involving broken skin.
  • composition used according to the invention contains GTN in addition to at least one excipient such as a solvent or a solid carrier, for example.
  • the composition may optionally contain further excipients, for example penetration accelerators which promote transfer of the active substance into the damaged tissue, and preservatives and antioxidants which are able to prolong the shelf life of the composition, or, in the case of an aerosol or non-pump spray formulation, propellants which facilitate the application of the active substance.
  • compositions are sprays which may be formulated as a propellant spray as well as propellant-free in the form of a pump spray.
  • the compositions conveniently ensure the uniform application of a homogeneous active substance film to the affected sites on the skin.
  • Gels or ointments, as well as transdermal systems such as patches, are also suitable.
  • composition used is preferably topically applied to the affected areas of the skin.
  • preferred GTN-containing propellant sprays contain, for 100 mg of the overall composition, 0.2 to 2.0 mg (0.2 to 2.0 percent by weight), preferably 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 1.0, 1.2, 1.4, 1.6, or 1.8 mg GTN, 40 to 70 mg (40 to 70 percent by weight), preferably 45, 50, 55, 60, or 65 mg, propellant, and 30 to 60 mg (30 to 60 percent by weight), preferably 35, 40, 50, or 55 mg, of a suitable solvent.
  • Preferred solvents in the propellant sprays are isopropanol, ethanol, n-pentane, propylene glycol, water, medium-chain triglycerides, and mixtures thereof.
  • a suitable preservative and/or fragrances or scents may be added to the composition.
  • a suitable preservative and/or fragrances or scents may be added to the composition.
  • n-butane, isobutane, and propane as well as mixtures thereof are suitable as propellants.
  • Dimethyl ether and monochloroethane as well as noncombustible propellants such as hydrofluoroalkanes 1,1,1,2,3,3,3-heptafluoropropane (HFA 227) or 1,1,1,2-tetrafluoroethane (HFA 134a) may also be used.
  • Pump sprays preferred according to the invention comprise aqueous, oily or alcoholic solutions of the active substance, which in addition to 0.2 to 2.0, preferably 0.3 to 0.6, percent by weight GTN contain 30 to 50 percent by weight water, or 30 to 80 percent by weight of an alcoholic solvent.
  • Preferred quantities of GTN in the pump sprays according to the invention are 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 1.0, 1.2, 1.4, 1.6, or 1.8 percent by weight.
  • Preferred quantities of water in the aqueous solutions are 35, 40, or 45 percent by weight, while preferred quantities of alcoholic solvents in the alcoholic solutions are 40, 50, 60 or 70 percent by weight.
  • alcoholic solvents which are contained in a quantity of 20 to 70 percent by weight, preferably in a quantity of 30, 40, 50, or 60 percent by weight.
  • the solutions may also contain 20 to 30 percent by weight, preferably 22, 24, 26, or 28 percent by weight, glycerol, 5 to 25 percent by weight, preferably 7, 9, 11, 13, 15, 17, 19, 21, or 23 percent by weight, propylene glycol, 10 to 25 percent by weight, preferably 12, 14, 16, 18, 20, 22, or 24 percent by weight medium-chain triglycerides (e.g., C 6 -C 12 saturated fatty acid triglycerides), 5 to 15 percent by weight, preferably 6, 8, 10, 12, or 14 percent by weight triglycerol diisostearate, diethylene glycol monoethylether, or mixtures thereof, and 0.15 to 2.5 percent by weight menthol and/or eucalyptus oil.
  • medium-chain triglycerides e.g., C 6 -C 12 saturated fatty acid triglycerides
  • Suitable alcoholic solvents contain alcohols with 2 to 4 carbon atoms, ethanol and isopropanol or mixtures thereof being particularly suitable.
  • the solutions can optionally contain a buffer, such as sodium lactate, disodium monohydrogen phosphate, sodium phosphate and calcium stearate in a quantity of less than 0.5% by weight as disclosed in US patent U.S. Pat. No. 7,872,049.
  • Gels preferred for the use according to the invention contain 0.5 to 2 percent by weight, preferably 0.6, 0.8, 1.0, 1.2, 1.4, 1.6, or 1.8 percent by weight, GTN, 70 to 95 percent by weight, preferably 75, 80, or 90 percent by weight, of a medium-chain triglyceride marketed, for example, under the name Miglyol® 812, 2 to 6 percent by weight silica, 2 to 12 percent by weight ethanol, and optionally 0.01 to 2 percent by weight of a fragrance and/or scent.
  • a medium-chain triglyceride marketed, for example, under the name Miglyol® 812, 2 to 6 percent by weight silica, 2 to 12 percent by weight ethanol, and optionally 0.01 to 2 percent by weight of a fragrance and/or scent.
  • a suitable ointment within the meaning of the invention contains 0.2 to 2.0 percent by weight, preferably 0.3, 0.4, 0.5, 0.6, 0.8, 1.0, 1.4, 1.6, or 1.8 percent by weight GTN, 2 to 10 percent by weight of a suitable medium-chain triglyceride (Miglyol® 812 or 840, for example), and 90 to 98 percent by weight of a water-free ointment base such as lanolin alcohol ointment, white Vaseline, or semisolid hard fat, for example.
  • a suitable medium-chain triglyceride Miglyol® 812 or 840, for example
  • a water-free ointment base such as lanolin alcohol ointment, white Vaseline, or semisolid hard fat, for example.
  • GTN is preferably used as stabilized concentrates in a liquid carrier such as propylene glycol or medium-chain triglycerides.
  • a method is provided of accelerating healing of a hematoma by contacting an external surface at the site of the hematoma with a composition that includes: glyceryl trinitrate in a quantity between about 0.2 percent by weight and about 2.0 percent by weight; a medium chain triglyceride and an alcohol, wherein the medium chain triglyceride and the alcohol are mixed in a ratio of about 10:90 to about 90:10; a component for enhancing penetration of the external surface by glyceryl trinitrate in a quantity between about 5.0 percent by weight and about 20 percent by weight; and, optionally, water.
  • a composition that includes: glyceryl trinitrate in a quantity between about 0.2 percent by weight and about 2.0 percent by weight; a medium chain triglyceride and an alcohol, wherein the medium chain triglyceride and the alcohol are mixed in a ratio of about 10:90 to about 90:10; a component for enhancing penetration of the external surface by glyceryl tri
  • the external surface at the site of the hematoma is contacted with an amount of composition effective to accelerate healing of the hematoma when the skin at the external surface is unbroken.
  • the composition can be in the form of a pump spray solution.
  • the medium chain triglyceride can be a triglyceride of plant or semi-synthetic origin, a saturated C8 to C12 fatty acid triglyceride, a saturated C6 to C12 fatty acid triglyceride, or a combination of any two or more of the foregoing.
  • the alcohol is isopropanol and/or the component for enhancing penetration is triglyceroldiisostearate.
  • a method is provided of accelerating healing of a hematoma by contacting an external surface at the site of the hematoma with a composition that includes: glyceryl trinitrate in a quantity between about 0.2 percent by weight and about 2.0 percent by weight; at least one solvent; a component for enhancing penetration of the external surface by glyceryl trinitrate in a quantity between about 5.0 percent by weight and about 20 percent by weight; and, optionally, water.
  • the external surface at the site of the hematoma is contacted with an amount of composition effective to accelerate healing of the hematoma when the skin at the external surface is unbroken.
  • the composition can be in the form of a pump spray solution.
  • the solvent can be selected from propylene glycol, isopropanol, and combinations of the foregoing, and/or the component for enhancing penetration can be diethylene glycol monoethyl ether.
  • compositions disclosed herein are useful for treating, alleviating and/or diminishing the formation of hematomas, thereby resulting in significant acceleration of the corresponding healing process.
  • Healing progress can be assessed by monitoring tissue volume, subcutaneous microcirculation (e.g., at a tissue depth of 2 mm to 8 mm, post capillary venous filling pressure, capillary blood flow, blood flow velocity, and oxygen saturation in the area of the affected tissue.
  • tissue volume e.g., at a tissue depth of 2 mm to 8 mm
  • post capillary venous filling pressure e.g., at a tissue depth of 2 mm to 8 mm
  • capillary blood flow e.g., at a tissue depth of 2 mm to 8 mm
  • oxygen saturation e.g., oxygen saturation in the area of the affected tissue.
  • percent by weight always refers to the weight of the composition.
  • the GTN was first dissolved in the respective solvents, while stirring. The additional excipients were then added, and the solution was stirred until homogeneous. The solution was filled into suitable containers which were then sealed. The pressure-liquefied propellants were then added via the valves.
  • the active substance was first dissolved in the solvent.
  • the water and the other excipients were then added, and the solution was stirred until homogeneous.
  • the solution was filled into suitable spray bottles.
  • a 35-year-old male patient who had sustained several bruises on the lower leg while playing soccer was treated, immediately after the injury occurred, on a portion of the hematomas with a composition containing GTN according to Example 3.
  • 100 mg of solution was applied with each spray burst, corresponding to a quantity of 0.2 mg GTN for a solution density of approximately 0.7 g/mL.
  • the active substance solution was distributed uniformly over the entire affected area of the skin.
  • the patient was initially treated with 10 to 12 spray bursts of the described composition.
  • the treatment of the injured skin areas was continued over a period of 8 days by applying two to four spray bursts twice daily. It was observed that the treated hematomas healed much more quickly.
  • the average healing time i.e., the period of time until the skin discoloration completely disappeared, was reduced by one-half.
  • a 45-year-old female recreational equestrian was treated on a section of the front thigh approximately 100 cm 2 in area with a pump spray containing GTN after being kicked by a horse.
  • 70 mg of the solution according to Example 10 was applied to the injured site in approximately 6-8 spray bursts every 30 minutes. This corresponds to an absolute quantity of approximately 2.4-3.2 mg GTN per application.
  • the treatment was continued, including the second day after the injury, with reduced frequency of application. It was observed that the dark blue coloration of the skin which usually occurs in hematomas was not present. The patient experienced no side effects, in particular no headaches.
  • the topical administration of a composition containing GTN suppresses extend and degree of the hematoma, and advantageously reduces the period needed for its remission. Since the typical coloration associated with a hematoma was not observed, moreover, the interference of biochemical processes associated with the formation and healing of hematoma can be postulated.
  • soft tissue restitution is evaluated after severe soft tissue trauma under standardized conditions.
  • the healing processes of animals treated with a nitroglycerin formulation are compared to those treated with a placebo solution.
  • nitroglycerin results in a positive effect on soft tissue restitution, particularly with respect to the formation and the healing of traumatic edemas and hematomas, resp.
  • an effect could be explained by the vasodilatating properties of nitroglycerin and nitric oxid (NO), resp., e.g. by an increase of post-capillary venous drainage.
  • the effect of a topically applied nitroglycerin formulation on the formation and healing of edemas and hematomas is investigated, and the microcirculation in a tissue depth of 2 mm and 8 mm of traumatized soft tissue of the lower leg of rats is compared to placebo.
  • the primary endpoint is the evaluation of edema and hematoma of the lower leg of the rat by daily measuring the volume of the lower leg and by inspecting the leg visually over a period of 14 days after the injury. Moreover a daily photo documentation of the healing process is carried out.
  • the parameters of the microcirculation in 2 mm and 8 mm tissue depth are determined, these are the post capillary venous filling pressure, the capillary blood flow, the blood flow velocity, and the oxygen saturation of the tissue. These are characteristic data of the proportion of the local blood supply compared to the total volume and a proper means for describing venous stasis, ischemia and hyperemia. The dimensions of these parameters are defined as arbitrary units.
  • Two nitroglycerin formulations and their respective placebo solutions serve as study medication. They are characterized as a non polar formulation according to example 11 and a more polar formulation according to example 12.
  • the microcirculation is determined in a non-invasive manner by the device Oxygen-to-see (O2C, LEA Medizintechnik, Gie ⁇ en, Germany).
  • This device combines the laser Doppler technique with tissue spectrophotometry and determines the relative blood flow, the blood flow velocity, the relative amount of hemoglobin, and the oxygen amount of the hemoglobin simultaneously in two tissue depths (2 and 8 mm) in real time.
  • the animals After arrival the animals are acclimatized for 7 days prior to the study. Throughout the whole study the animals have unrestricted access to fresh water and dry food. A 12/12 hours light and darkness cycle is maintained. The animals are kept according to the appropriate guidelines. During examination the animals are anesthetized.
  • the animals are allocated to the trial medication and the treatment scheme in a randomized way.
  • the treatment algorithm is based on Williams' square. In this design each treatment occurs only once in every sequence and in every period. In this order of treatments a possible period effect is balanced in an optimal manner.
  • An exemplary design of the trial for four days is given in the following table:
  • the preparations are pipetted to the healthy skin of the left hind shank of the rats. At time 0 (before the application of the preparations) a baseline measurement is carried out followed by repeated measurements starting 30 seconds until 30 minutes after application. The microcirculation of the skin of the living rat is analysed using the Oxygen-to-see device (see above). Only one daily treatment with the preparations is carried out assuring a wash-out period of 24 hours. Thus any carry-over-effect can be excluded.
  • the animals are anesthetized and the left hind legs are shaved.
  • the biometric data of the left shank are determined as baseline value for the clinical trauma evaluation.
  • a baseline measurement of the microcirculation in the predefined area of the antero-lateral shank compartment for 2 minutes is carried out.
  • a defined beat to the middle part of the antero-lateral compartment of the left shank is applied using the Controlled Impact Injury Technique with a gas-powered metal bolt (diameter: 1 cm, velocity 7 m/s, time of contact with the tissue: 1 s).
  • a severe blunt, but closed tissue injury (no fracture, no perforation of the skin) is formed with this established method.
  • the measurement of the microcirculation with the Oxygen-to-see device is repeated for 5 minutes in all groups.
  • test animals are set back to their cages and wake up from the narcosis.
  • the first clinical evaluation of the trauma is accomplished and the topical application of either the nitroglycerin formulation in the therapeutic group or placebo in the control group resp. to the traumatized area with a pump spray is carried out.
  • the treatment is continued three times a day with three hour intervals for two weeks. Every day before the first treatment the extent of edemas and hematomas is documented by photography, the volume of the shank is examined by archimedic volumetry, the skin tolerance is evaluated, and the microcirculation is measured with the Oxygen-to-see device.
  • compositions and methods of the present invention will alleviate and/or diminish the formation of a hematoma and/or induce a faster breakdown of hematomas resulting in a significant acceleration of the corresponding healing process. It is further expected that one or more of the clinical endpoints will be improved, thereby showing the effectiveness of the preparations.
  • compositions are described as having, including, or comprising specific components, or where processes are described as having, including or comprising specific process steps, it is contemplated that compositions of the present teachings also consist essentially of, or consist of, the recited components, and that the processes of the present teachings also consist essentially of, or consist of, the recited process steps.
  • an element or component is said to be included in and/or selected from a list of recited elements or components, it should be understood that the element or component can be any one of the recited elements or components and can be selected from a group consisting of two or more of the recited elements or components.
  • each intervening integer and, where appropriate, decimal between the endpoints of that range or list of values is individually contemplated and is encompassed within the invention as if each value were specifically enumerated herein.
  • smaller ranges between and including the endpoints of a given range are contemplated and encompassed within the invention.
  • the listing of exemplary values or ranges is not a disclaimer of other values or ranges between and including the endpoints of a given range.

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  • Health & Medical Sciences (AREA)
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US13/813,685 2010-08-03 2011-08-03 Use of Glyceryl Trinitrate for Treating Hematomas Abandoned US20130121930A1 (en)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
DE102010033182.1 2010-08-03
DE102010033182 2010-08-03
PCT/EP2011/003888 WO2012016690A1 (en) 2010-08-03 2011-08-03 Use of glyceryl trinitrate for treating hematomas

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US13/813,676 Expired - Fee Related US9180109B2 (en) 2010-08-03 2011-08-03 Use of glyceryl trinitrate for treating traumatic edema
US14/870,870 Expired - Fee Related US9693983B2 (en) 2010-08-03 2015-09-30 Use of glyceryl trinitrate for treating traumatic edema

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US14/870,870 Expired - Fee Related US9693983B2 (en) 2010-08-03 2015-09-30 Use of glyceryl trinitrate for treating traumatic edema

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US (3) US20130121930A1 (pl)
EP (3) EP2600837A1 (pl)
AU (1) AU2011287948B2 (pl)
CA (1) CA2806636C (pl)
ES (1) ES2582309T3 (pl)
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AT513312A1 (de) * 2012-08-17 2014-03-15 Gebro Holding Gmbh Antiseptische Zusammensetzung
WO2014193804A1 (en) * 2013-05-28 2014-12-04 Biogen Idec Ma Inc. Method of assessing risk of pml
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