WO2009103932A1 - Utilisation d’un glycoside cardiaque et/ou d’un diurétique pour le traitement de la douleur neuropathique - Google Patents

Utilisation d’un glycoside cardiaque et/ou d’un diurétique pour le traitement de la douleur neuropathique Download PDF

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WO2009103932A1
WO2009103932A1 PCT/GB2008/000568 GB2008000568W WO2009103932A1 WO 2009103932 A1 WO2009103932 A1 WO 2009103932A1 GB 2008000568 W GB2008000568 W GB 2008000568W WO 2009103932 A1 WO2009103932 A1 WO 2009103932A1
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digoxin
release
furosemide
skin
gel
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PCT/GB2008/000568
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WO2009103932A8 (fr
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Ian Stuart Pardoe
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Henderson Morley Plc
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Publication of WO2009103932A8 publication Critical patent/WO2009103932A8/fr

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    • 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/54—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame
    • A61K31/549—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame having two or more nitrogen atoms in the same ring, e.g. hydrochlorothiazide
    • 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
    • A61K31/63—Compounds containing para-N-benzenesulfonyl-N-groups, e.g. sulfanilamide, p-nitrobenzenesulfonyl hydrazide
    • A61K31/635—Compounds containing para-N-benzenesulfonyl-N-groups, e.g. sulfanilamide, p-nitrobenzenesulfonyl hydrazide having a heterocyclic ring, e.g. sulfadiazine
    • 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
    • A61K31/64—Sulfonylureas, e.g. glibenclamide, tolbutamide, chlorpropamide
    • 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
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7028—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages
    • A61K31/7034—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin
    • A61K31/704—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin attached to a condensed carbocyclic ring system, e.g. sennosides, thiocolchicosides, escin, daunorubicin
    • 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
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
    • A61K31/7048—Compounds having saccharide radicals and heterocyclic rings having oxygen as a ring hetero atom, e.g. leucoglucosan, hesperidin, erythromycin, nystatin, digitoxin or digoxin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • 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
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
    • 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
    • A61K9/70—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
    • A61K9/7038—Transdermal patches of the drug-in-adhesive type, i.e. comprising drug in the skin-adhesive layer
    • A61K9/7046—Transdermal patches of the drug-in-adhesive type, i.e. comprising drug in the skin-adhesive layer the adhesive comprising macromolecular compounds
    • A61K9/7053—Transdermal patches of the drug-in-adhesive type, i.e. comprising drug in the skin-adhesive layer the adhesive comprising macromolecular compounds obtained by reactions only involving carbon to carbon unsaturated bonds, e.g. polyvinyl, polyisobutylene, polystyrene
    • A61K9/7061—Polyacrylates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/02—Drugs for disorders of the nervous system for peripheral neuropathies
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]

Definitions

  • This invention relates to the treatment of pain, for example neuropathic pain.
  • pain for example neuropathic pain.
  • it relates to the therapeutic treatment of neuropathic pain by the topical application of drugs.
  • Neuropathic pain is the result of an injury or malfunction in the peripheral or central nervous system.
  • the pain is often triggered by an injury, but this injury may or may not involve actual damage to the nervous system.
  • Nerves can be infiltrated or compressed by tumors, strangulated by scar tissue, or inflamed by infection.
  • the pain frequently has burning, lancinating, or electric shock qualities.
  • Persistent allodynia pain resulting from a nonpainful stimulus such as a light touch, is also a common characteristic of neuropathic pain. The pain may persist for months or years beyond the apparent healing of any damaged tissues. In this setting, pain signals no longer represent an alarm about ongoing or impending injury, instead the alarm system itself is malfunctioning.
  • neuropathic pain examples include post herpetic (or post-shingles) neuralgia, reflex sympathetic dystrophy / causalgia (nerve trauma), components of cancer pain, phantom limb pain, entrapment neuropathy (e.g., carpal tunnel syndrome), and peripheral neuropathy (widespread nerve damage, most commonly caused by diabetes or chronic alcohol use).
  • neuropathic pain The fundamental characteristic of neuropathic pain is the hypersensitivity of the pain detection mechanism. Actions, such as gentle touching or stroking of affected parts of the body, will result in a massively disproportionate level of pain being felt by the patient. The exact mechanism by which this hypersensitivity develops is unknown, however the fundamental electrical mechanism by which pain is transmitted is the same in all cases- the sensitised nerve more readily fires its action potential than a normal axon, so consequently more pain messages will be received by the central nervous system. In some cases these damaged or sensitised neurons will fire spontaneously, sending painful messages to the brain in the absence of any direct stimulus.
  • neuropathic pain The more detailed patho-physiology of neuropathic pain is not well understood. Neurophysiologic and neuroanatomic changes may occur in some types of neuropathic pain following injury to neural tissue. Injury to peripheral neural axons can result in abnormal nerve regeneration in the weeks to months following injury. The damaged axon may grow multiple nerve sprouts, some of which form neuromas. These nerve sprouts, including those forming neuromas, can generate spontaneous activity, which peaks in intensity several weeks after injury. Unlike normal axons, these structures are more sensitive to physical distention, which is clinically associated with tenderness and the appearance of Tinel's sign (i.e., sensation of tingling or "pins and needles").
  • atypical connections may develop between nerve sprouts or demyelinated axons in the region of the nerve damage, permitting "cross-talk" between somatic or sympathetic efferent nerves and nociceptors. This has been hypothesized as another mechanism sustaining a peripheral generator in some types of neuropathic pain. Dorsal root fibers may also sprout following injury to peripheral nerves.
  • neuropathic pain With respect to pharmacological treatment of neuropathic pain, treatment can be difficult since most of the interventions used have side effects and may not work (for example, only two thirds of patients in controlled clinical trials typically respond, and those patients may only respond by a third). There are major concerns in the treatment of patients with neuropathic pain because good treatment algorithms for treating a broad spectrum of neuropathic pains do not exist. Furthermore, current treatment guidelines are not written in terms of underlying patho-physiology, but rather by disease history (diabetes, herpes). It is difficult to predict whether a patient will respond, and consequently, many agents need to be tried before a patient can be managed appropriately.
  • Acute, inflammatory and neuropathic pain can be attenuated or abolished by local treatment with the sodium channel blocker lidocaine (or lignocaine).
  • lidocaine or lignocaine
  • this is the only licensed topical treatment for neuropathic pain. It is thought to exert its effect by delivering amounts of lidocaine sufficient to block sodium channels on small damaged pain fibres but insufficient to interfere with normal conduction of impulses in larger sensory fibers.
  • lidocaine When applied to painful areas it is able to provide local analgesia. This may lead to the systemic absorption of drug, so some patients, who are taking other forms of treatment such as oral class 1 anti-arrhythmic drugs such as mexiletene may be unable to receive this form of treatment.
  • Medications used to treat neuropathic pain have traditionally been categorized by their drug class (antidepressant, anticonvulsant, anti-arrhythmic, analgesic [opioid or nonsteroidal anti-inflammatory], topicals).
  • drug class anticonvulsant, anti-arrhythmic, analgesic [opioid or nonsteroidal anti-inflammatory], topicals.
  • PPN postherpetic neuralgia
  • Neuropathic pain is frequently chronic, and tends to have a less robust response to treatment with morphine or other systemic opiod drugs. Usually, neuropathic problems are not fully reversible so treatment is aimed at control of pain rather than a cure of the underlying condition.
  • All living cells including cells of the human body, have an uneven distribution of ions between the inside and outside of the cell.
  • the dominant ions outside cells are positively charge sodium ions (Na+) and negatively charged chloride ions (Cl-).
  • the dominant ions inside a cell are the positively charged potassium ions (K+) and negatively charged proteins (Pr-).
  • the concentration of potassium ions is as much as 20 times greater than the extracellular concentrations.
  • the extracellular fluid contains a concentration of sodium ions (Na + ) as much as 10 times greater than that within the cell.
  • the electrical gradient that exists between the inside and outside of a cell is called the resting membrane potential, and in human cells, the inside of the cell is negatively charged relative to the outside of the cell.
  • the resting membrane potential in man is in the order of -7OmVoItS.
  • the sodium-potassium pump maintains this unequal concentration by actively transporting ions against their concentration gradients.
  • Na7K + ATPase also known as the sodium pump
  • concentration gradients are established by the active transport of both ions, and the same transporter, called the Na7K + ATPase (also known as the sodium pump), does both jobs. It uses the energy from the hydrolysis of ATP to actively transport 3 Na + ions out of the cell for each 2 K + ions pumped into the cell.
  • Nerve cells or axons are cells with a specific function of propagation of electrical messages. They have several important features which are responsible for their function;
  • a sensory stimulus When a sensory stimulus is received by a nerve cell there is a change in its resting potential- it converts the sensory input into an electrical signal, and in the case of a pain nerve, this will be a nociceptive stimulus.
  • An action potential is a temporary reversal of the electrical potential along the membrane for a few milliseconds.
  • Sodium gates and potassium gates open in the membrane to allow their respective ions to cross.
  • Sodium and potassium ions reverse positions by passing through membrane protein channel gates that can be opened or closed to control ion passage.
  • potassium channels open to allow potassium ions to pass to the outside of the membrane.
  • the action potential begins at one spot on the membrane, but spreads to adjacent areas of the membrane, propagating the message along the length of the cell membrane. After passage of the action potential, there is a brief period, the refractory period, during which the membrane cannot be stimulated. This prevents the message from being transmitted backward along the membrane.
  • the steps in an Action Potential are:
  • neuropathic pain which targets the peripheral sensitization of neurons, invariably targets the propagation of the action potential and more specifically the drugs are designed to aim at disruption of the voltage gated sodium channel. It is an object of this invention to provide a composition for the treatment of neuropathic pain.
  • Yet further objects of the invention relate to methods of treatment of neuropathic pain.
  • the invention provides the use of a cardiac glycoside and/or a diuretic in the manufacture of a composition for the treatment of pain, e.g. neuropathic pain.
  • a second aspect of the invention comprises a composition to treat pain, e.g. neuropathic pain, the composition comprising a cardiac glycoside and/or a loop diuretic and a carrier.
  • a further and/or more specific aspect of the invention provides a topical gel formulation for the treatment of pain, e.g. neuropathic pain, comprising at least one cardiac glycoside and/or diuretic in a gel carrier medium, said formulation being capable of transdermal delivery of the said diuretic and/or glycoside.
  • pain e.g. neuropathic pain
  • a topical gel formulation for the treatment of pain comprising at least one cardiac glycoside and/or diuretic in a gel carrier medium, said formulation being capable of transdermal delivery of the said diuretic and/or glycoside.
  • a yet further aspect of the invention provides a transdermal active principle delivery means comprising a skin adherent or skin-tolerant substrate applicable to a skin area, which substrate includes a composition for treating pain, e.g. neuropathic pain, comprising a transdermal ⁇ effective carrier medium including at least one active principle selected from the group consisting of diuretics and/or cardiac glycosides.
  • a fifth aspect of the invention provides a method of treating pain, for example neuropathic pain, the method comprising applying a composition comprising one or both of at least one cardiac glycoside and/or at least one diuretic to a site on a patient.
  • a sixth aspect of the invention provides a method of affecting the resting potential of a nerve cell, the method comprising applying a composition comprising one or both of at least one cardiac glycoside and/or at least one diuretic to the nerve cell.
  • the neuropathic pain may be selected from post herpetic neuralgia, diabetic neurophathy, allodynia, phantom limb syndrome.
  • the diuretic may be selected from loop diuretics, thiazide diuretics or sulphonylureas.
  • Loop diuretics are substances which act on the ascending loop of Henle in the kidney. They are sulphonamides but may be other substances too. Typical examples include: acetazolamide mefruside ambuside methazolamide azosemide piretanide bumetanide torsemide butazolamide tripamide chloraminophenamide xipamide clofenamide clopamide ethacrynic acid clorexolone etozolin disulfamide ticrynafen ethoxzolamide furosemide
  • the loop diuretic is one or more of furosemide, bumetamide, ethacyrnic acid or torasemide.
  • furosemide which is an anthrilic acid derivative, chemically 4-chloro-N- furfuryl-5-sulfamoylanthranilic acid. It is practically insoluble in water at neutral pH, however is freely soluble in alkali. Furosemide exerts its physiological effect by inhibition of the transport of chloride ions across cell members. Furosemide is a loop diuretic with a short duration of action. It is used for treating oedema due to hepatic, renal, or cardiac failure and treating hypertension. The bioavailability of furosemide is between 60% to 70% and it is primarily excreted by filtration and secretion as unchanged drug. Furosemide acts on the Na+/K+/2CI- cotransformer.
  • Furosemide is extensively bound to plasma proteins, mainly albumin. Plasma concentrations ranging from 1 to 400 mcg/ml are 91-99% bound in healthy individuals. The unbound fraction ranges between 2.3-4.1% at therapeutic concentrations.
  • the terminal half life of furosemide is approximately 2 hours, and it is predominantly excreted in the urine.
  • Thiazide diuretics include the benzothiadriazines derivatives, also known as thiazides. Typical examples are: althiazide hydrobenzthiazide bemetizide hydrochlorothiazide bendroflumethiazide hydrofluoromethiazide benzthiazide indapamide benzylhydrochlorothiazide mebutizide buthiazide methylcyclothiazide chlorothiazide meticane chlorothalidone metalazone cyclopenthiazide paraflutizide cyclothiazide polythiazide epithiazide quinethazone ethiazide teclothiazide fenquizone trichlormethiazide
  • the thiazide diuretic is one or more of chlorothiazide, hydrochlorothiazide, hydroflumethiazide, methyclothiazide, trichlormethazide, benzthiazide, bendroflumethazide, bendrofluazide, polythiazide or cyclothiazide.
  • Sulphonylureas are anti-diabetic drugs which influence ion transport across cell membranes. They are instanced by: acetohexamide glyburide
  • the sulphonylurea is one or more of tolbutamide, tolazamide, tolcyclamide, glibomuridum, acetohexamide, chlorpropamide, carbutamide, glyburide or glipizide .
  • the cardiac glycoside may be selected from digoxin, digitoxin, ovabain, strophanthia and other known cardiac glycosides. Digoxin is preferred
  • Digoxin is a cardiac glycoside obtained from the leaves of Digitalis lanata (Lond, 1994). It contains a steroid nucleus, with an unsaturated lactone essential for activity at the C17 position, and one or more glycoside residues at C3.
  • the pharmacological activity of Digoxin is related to its ability to specifically bind to a site on the extracytoplasmic face of the ⁇ subunit of the enzyme Na+, K+ ATPase (regulates the concentration of sodium and potassium inside cells). This selectively inhibits the cellular active transport Na+ and K+ pump, which leads to an increase in the intracellular concentrations of sodium and calcium, and a decrease in the concentration of intracellular potassium (Henderson Morley, 2003). It is currently indicated in heart failure and supraventricular arrthymias.
  • One main limitation to its clinical use is the risk of side effects such as nausea and vomiting associated with toxicity as it possesses a narrow therapeutic window.
  • VZV Varicella zoster virus
  • VZV infection is an alphaherpesviruses that is characterised by short growth cycle and rapid cell-to-cell spread resulting in cytocidal infection in a wide variety of cells/tissues. Following primary infection, VZV infection establishes a latent infection in sensory ganglia that persists for the lifetime of the host. A variety of stimuli can induce this latent virus to reactivate, travel back down the axons and produce a new round of productive infection at the site of initial infection.
  • VZV is the causative agent of two human diseases: chicken pox following primary infection and herpes zoster or shingles following reactivation from a latent infection in sensory ganglia of affected dermatomes.
  • VZV Herpes zoster is caused by VZV reactivation whereby the virus reactivates in the dorsal root ganglion and moves along the sensory nerve to the periphery. This results in a localised, painful, vesicular rash that can involve adjacent dermatomes. It is associated with more protracted and severe pain than other herpes virus infections during both the prodrome and clinical phase that may last as long as 3 weeks.
  • PPN Postherpetic neuralgia
  • PHN is classed as a neuropathic pain that is associated with mechanical allodynia, where normally non-painful touch sensations are perceived as painful. In addition warm and cold allodynia and spontaneous pain have also been reported. PHN can result in impaired physical activity, disturbed sleep, social withdrawal and depression which many patients suffer for years. This pain state may be so severe that it has a major impact on quality of life and has been associated with suicide. A uniformly effective treatment for PHN is not yet available. Current antiviral agents such as valaciclovir or famciclovir have been shown to reduce pain resulting from VZV providing treatment starts early after onset of the rash.
  • the main risk factor for the development of PHN is age, e.g. it has been reported that the incidence of PHN was 3-4% in the 30-49 age group but rose to 29% in those 70-79 and 34% in the over 80-year-old age group.
  • the overall incidence of PHN in the population is difficult to determine; it has also been suggested that there are approximately 500,000 cases of PHN in the USA at any one time and it has further been suggested that a figure of 200,000 cases occurring at any one time in the UK was a conservative estimate.
  • the pathology of clinical zoster is characterised by inflammation and severe damage to the nerves (haemorrhagic necrosis) of the ganglia with accompanying degeneration of motor and sensory roots. This suggests that some immune responses play a part in the development of zoster pain.
  • the pathology of PHN is complex and not well understood. The involvement of the immune response in PHN has also been hypothesised, ongoing inflammation has been observed in post-mortem studies of some PHN patients and Gilden has been proposed that PHN may involve the persistence of VZV at levels above those normally seen during latency accompanied by continued inflammation. This point is important with regard to this invention, as antiviral effects of digoxin and furosemide have been demonstrated against VZV. PHN is somewhat resistant to opioid and NSAIDs, which are the most commonly used treatments for acute and inflammatory pain states, suggesting that inflammatory responses per se are not sufficient to induce PHN.
  • Neuropathic pain (such as PHN) is characterised by neuronal hyperexcitability in damaged areas of the nervous system.
  • This hyperexcitability is due to molecular changes (e.g. abnormal expression of sodium channels, changes in gaminobutyric acid (GABA) inhibition) at the level of the peripheral nociceptor, in the dorsal root ganglia (DRG), dorsal horn and brain.
  • GABA gaminobutyric acid
  • VZV has been implicated in the establishment and propagation of PHN. Topically applied cardiac glycosides, loop diuretics or a combination of both, have been demonstrated to inhibit VZV infection. Therefore topically applied drug will prevent the development of chronic VZV infection. 2. By altering the resting potential generated within a peripheral nerve, the perpetuation and propagation of hyperexcitability associated with VZV infection will be prevented and/or treated.
  • Example 1 In order to demonstrate the efficacy of compositions of the invention, reference is made to the following Examples: Example 1 :
  • Furosemide at a concentration of 1.0 mg/ml was very well tolerated by MRC5 cells in vitro; there was no adverse effect on cell morphology and cells replicated. Furosemide inhibited VZV plaque formation by 50% at this concentration.
  • VZV replication was completely inhibited by Furosemide at a concentration of 2.0 mg/ml.
  • Digoxin at a concentration of 0.05 ⁇ g/ml was very well tolerated by MRC5 cells; there was no adverse effect on cell morphology and cells replicated. Digoxin inhibited VZV plaque formation by 50% at this concentration.
  • VZV replication was completely inhibited by Digoxin at a concentration of 0.1 ⁇ g/ml.
  • Example 3 VZV replication was completely inhibited by Furosemide and Digoxin in combination at their individual ID 50 concentrations [see Table 1]. The combined dosage was equally well tolerated by MRC5 cells; there was no adverse effect on cell morphology and cells replicated. Table 1
  • Uninfected MRC5 cells replicated to normal yields in the presence of Furosemide at a concentration of 1.0 mg/ml, the same concentration as the VZV ID50.
  • Uninfected MRC5 cells replicated to normal yields in the presence of Digoxin at a concentration of 0.05 ⁇ g/ml, the same concentration as the VZV ID50.
  • Viruses are intracellular parasites wholly dependent upon the infected host cell for survival.
  • the earliest known anti-viral drugs were cytotoxic drugs, such as those used in cancer chemotherapy. It was postulated that these inhibitors of host cell metabolism would have an adverse effect upon the lifecycle of the virus. In the non-cancer patient cytoxic drugs were too toxic to the host to be of benefit, and as a consequence their use as anti-viral treatments was severely restricted.
  • a topical gel formulation may be applied to the body.
  • stratum corneum of human skin is the rate limiting step in terms percutaneous absorption from topical applied agents.
  • stratum corneum in skin areas populated with viral warts is significantly different from that of 'regular' skin having as it does densely packed corneocytes with limited lipid intracellular pathways. This results in a stratum corneum with potentially even greater drug absorption rate limiting capabilities.
  • lesions are substantially absent in PHN we have sought to provide a topical medicament which can pass through skin with such lesions as well as skin absent such lesions. The rationale being that the passage of a medicament through lesioned skin is inhibited and will represent an arduous route for a medicament.
  • one approach is to chemically modify the barrier properties (making the barrier less efficient) by the incorporation of non- pharmacologically active (and 'skin friendly') excipients.
  • topical formulations that can deliver the or ideally both of a cardiac glycoside (e.g. Digoxin) and a diuretic (e.g. Furosemide) (that, when applied together, act synergistically) to the site of action at efficacious amounts with minimal toxicity.
  • a cardiac glycoside e.g. Digoxin
  • a diuretic e.g. Furosemide
  • these two preferred drugs act synergistically and a primary aim is to provide topical gel formulations which is able to deliver them together in beneficial proportions.
  • An effective way of achieving this is to employ a 'homogenous system' i.e. a single phase formulation.
  • structured matrices e.g. gels
  • the occlusive nature of a gel also assists in coating the treatment site more effectively.
  • UREA BP, EP USP
  • Urea is commonly used in emollient formulations and has been shown to increase hydration of the stratum corneum at concentrations of 2 - 20% becoming keratolvtic at 20%.
  • Urea is incorporated into the gel at 20% therefore providing hydration of the stratum corneum (additional effects on swelling) whilst simultaneously exerting mild keratolytic effects.
  • Another advantage of incorporating this excepient is that it is a natural product of metabolism and is excreted in the urine without systemic toxicity.
  • PROPYLENE GLYCOL (PG) (BP), EP USA)
  • PG is one of the most commonly used formulation excipients available and is frequently used at relatively low to medium concentration. The main reason for its use in topical formulations is excellent properties as a solvation agent. PG also increases water content in the stratum corneum encouraging an osmotic gradient through the stratum corneum.
  • PG is used at concentrations of 40-70% it is acts as a keratolytic agent. PG is minimally absorbed and any systemic absorbance is oxidised in the liver to lactic acid pyruvic acid.
  • STERILE H 2 O BP, EP, USP
  • Swelling (and associated hydration of the tissue) is deemed highly preferred to permit optimal delivery of the two actives through the otherwise densely packed corneocytes/keratin to target zone the basal layer.
  • Ethanol (BP, EP, USP)
  • Ethanol is frequently used in topical formulation predominantly to improve drug solubility within the formulation. When exposed to the skin it causes dehydration, lipid mobilisation and potentially 'skin cracking' at relatively high concentrations.
  • PEG 400 is also known in topical formulations to improve drug solubility within the formulation. There is no scientific evidence that suggests PEG400 exhibits keratolytic activity, but there is some evidence to suggest it aids hydration of the skin.
  • Literature indicates that a 20% urea solution exhibits keratolytic properties, including urea into a gel formulation is preferable for some embodiments (urea also makes gels/creams feel less greasy).
  • urea also makes gels/creams feel less greasy.
  • propylene glycol By maintaining propylene glycol at 40%, excipients mixes were prepared with varying amounts of urea (up to 20%) to determine any effects on swelling. Results showed that urea had no adverse effect on the swelling (amount of uptake of water) of callous skin to any significant extent.
  • the incorporation of 20% urea into the gel is therefore preferred in some embodiments, keeping it at a known (yet minimal) keratolytic concentration.
  • the active or permeant when applied to the skin the active or permeant will be present either dissolved or dispersed in a solvent or vehicle.
  • concentration of permeant present within the skin generally controls the rate of transport, that particular concentration is dependent on the solubility (i.e. thermodynamic activity) of the permeant present in the vehicle present on the surface of the skin.
  • Example 4 Relative solubilities of Digoxin and Furosemide permeant drugs were evaluated in a series of regular solvents/excipients. The solubilities were investigated at, 32°C, the average temperature at the surface of the skin. The results were then used to determine preferred permeant solvent combination for in vitro release and permeation to arrive at preferred gel formulations delivering optimum amounts of the 2 actives.
  • Negative control vials were present, containing each of the solvents with no drug added. For each permeant/solvent combination, a total of four replicates where carried out.
  • the vials were secured into a blood cell rotator. Again this procedure was carried out at the predetermined temperature. An incubator was used to maintain a constant temperature of 32°C. The thermometer readings were periodically noted to ensure a stable consistent temperature was being maintained.
  • the vials were periodically examined to ensure there was excess drug present within the solvent, i.e. visible solid particles or a suspension rather than a clear solution. If any vial visually showed no particles present then additional amounts of permeant where added until complete saturation was achieved for that specific permeant solvent combination was achieved. The vials were allowed to rotate for a total period of 24 hours. Following a final visual inspection to ascertain presence of excess solid and the assumption that the equilibrium had been attained, the vials were immediately transferred to a centrifuge and spun at 12,500rpm for 10 minutes. The centrifuge had been temperature pre-equilibrated at 32 0 C. By centrifuging the vials, separation of saturated permeant solvent from excess permeant was achieved, with the excess solid forming a pellet at the bottom of the vial.
  • Figures 1 to 5 show the results obtained from each of the solubility tests. Figures 6 and 7 highlight comparisons.
  • the solubility test results shown in Figures 1 to 3 indicated that both actives Furosemide (F) and Digoxin (D) were relatively insoluble in water, but their solubility increased in the presence of propylene glycol (PG). The presence of urea reduced solubility of both actives F and D.
  • PG propylene glycol
  • thermodynamic activity or 'chemical potential' of the permeant in the delivery system One means of optimising the delivery of permeants into the skin from dermatological formulations is to improve the thermodynamic activity or 'chemical potential' of the permeant in the delivery system.
  • the respective levels of Digoxin and Furosemide required to achieve saturation in the various co-solvent mixes was investigated in the solubility tests. Other formulation factors must also be considered in addition to the thermodynamic for e.g. Furosemide is amphiphillic in chemical nature and so formulation pH effects could affect performance.
  • gel thickeners for example carbomers such as Carbopol 981NF Carbopol and ULTREZ (presently used in commercially available dermatological preparation due to excellent gelling, stability, and low skin toxicity characteristics).
  • carbomers such as Carbopol 981NF Carbopol and ULTREZ (presently used in commercially available dermatological preparation due to excellent gelling, stability, and low skin toxicity characteristics).
  • the cellulose derivative, Hydroxypropylcellulose was also investigated as a suitable thickening agent.
  • Rationale 1 Gel formulation containing a saturated solution of Digoxin and Furosemide in the 40:40:20 co-solvents mix at a 1 :1 molar ratio
  • the saturation limit of Digoxin in the 40:40:20 (PG: Wata: Urea) co-solvents mix was 433 ⁇ g cm "3 (see saturated solubility results section).
  • the saturation limit of Furosemide in co-solvents 5979 ⁇ g cm "3 .
  • Rationale 2 Gel formulation containing a combined saturated solution of Digoxin and Furosemide in the 40:40:20 co-solvents mix, Molar Ratio 1:14.
  • the 'Max Digoxin' gel formulation was prepared by firstly combining 25Og of Propylene glycol with 20Og of Ethanol and 5Og of Water (to constitute the 50:40:10 ratio). The amounts were weighed accurately on a pre- calibrated electronic balance and continually mixed with the use of a magnetic stirrer. Excess amounts of Furosemide and Digoxin were added to the co-solvent mix, to ensure a saturated solution of both Digoxin and Furosemide was obtained. The beaker was immediately sealed using para-film (to stop any solvent evaporation) and left continually stirring at room temperature over night.
  • the resulting suspension was then centrifuged at 25,000rpm for 20 minutes to separate excess Furosemide and Digoxin drug, from the resultant saturated co-solvent mix.
  • the resultant saturated solution was transferred into another clean one litre beaker, which had been previously placed on an electronic balance, with care taken in ensuring no excess permeant was also transferred, and the total weight of the saturated solution recorded.
  • HPC hydroxypropycellulose
  • In vitro Release testing is a commonly used technique to examine the performance of topical drug formulations. It is a basic requirement as dictated by regulatory bodies such as the FDA and SUPACS. We utilised a recently developed improved in vitro model that eliminated some pitfalls in previously used methods.
  • Diffusion experiments were performed using all glass Franz-type cells (nominal receptor phase volume, 3ml). The membranes were soaked in the receptor medium (appropriate co-solvent mix) for 24 hours prior to commencement. The membranes were then taken out of the receptor fluid, the surface dried and carefully placed onto the pre-greased flange of the receptor compartment. The donor chamber was then placed onto the corresponding receptor compartment and pinch clamped in position. To each receptor compartment a micro stirrer was added. The effectiveness of this technique for PBS and the more viscous PEG400 was previously validated by applying small aliquots of dye to receptor compartments filled with solution.
  • HPLC analysis was performed using a Hewlett Packard 1100 HPLC automated system fitted with a Phenomenex Kingsorb 5 ⁇ m C18 Column (250 x 4.6mm).
  • the mobile phase consisted of 40:30:30 Water: MeOH: MECN.
  • the UV detector was set to 200nm and a 20 ⁇ l injection volume was used.
  • the flow rate was 1ml min "1 , the run time was 10 minutes and the retention time of furosemide was typically 3.2 minutes and Digoxin 5.4 minutes.
  • Standard calibration curves were constructed from standard solutions (range 0.1 , 1 , 10, 20, 40, 80 and 100 ⁇ g ml "1 ) that contained the relative same proportions of the solvents or co-solvent mixes.
  • This value is the total concentration of active per unit area ( ⁇ g cm "2 ) that has been released into the receptor phase in 24 hours.
  • Flux This is concentration of active that has been release per hour per unit area ( ⁇ g cm h-1 ). Calculated by dividing Q24 by 24.
  • % Applied Dose The amount of active present in the receptor phase calculated as a percentage of the dose applied. Assuming the donor phase contains fixed 2g of gel
  • PBS receptor phase phosphate buffered saline
  • HBS HEPES buffer
  • HEPES buffer 1.5mM CaCI 2
  • HEPES buffer 10% Bovine Calf Serum
  • Both gels exemplified used the same improved in vitro release system, in which the co- solvents contained within the topical formulation and the contents of the receptor phase were both the 40:40:20 Water: Propylene Glycol: Urea gel mix.
  • the 40:40:20 gel mix as the receptor phase instead of the traditional phosphate buffered saline (PBS) co-elution of excipients in the formulation are minimal allowing only net translocation of Furosemide and Digoxin from the donor. Also soaking the membranes in this mix prior to cell assembly ensured that the only net migration would be the actives.
  • PBS phosphate buffered saline
  • Digoxin is a neutral permeant the observations of reduced release with increasing pH was attributed to physiochemical properties of the gel (given that thickening characteristics of the gel can be affected via changes in pH). Furosemide is chemically amphiphillic which may explain the less significant changes in the rates of release with changes in pH.
  • the 1 :14 Gel resulted in release rates of 77.482 ⁇ g cm "2 h 0 5 for Furosemide and 430 ⁇ g cm "2 h 05 .
  • release rates produced the 1:1 Gel were significantly lower for Furosemide at 7.18 ⁇ g cm "2 h ⁇ 5 and also lower at 3.48 ⁇ g cm '2 h 05 for Digoxin. This is a respective 10.8 fold and 1.2 fold reduction. This observation was attributed to the applied doses of the two formulations.
  • the Ultrez formulation When observing the Digoxin release rates for the 3 gels, the Ultrez formulation showed the highest rate of release with 274 ⁇ g cr ⁇ 2 h ⁇ 5 , followed by a similar rate of release from the HPC formulation with 245 ⁇ g cm "2 h ⁇ 5 , however significantly lower rates of release were gained from the Ampule gel formulation with 8.1 ⁇ g cm "2 h 05 -
  • the applied gel was occluded with glass cover slips and the cells stirred in a thermostatically controlled water bath, maintaining the skin temperature at 32 0 C.
  • 200 ⁇ l samples were collected at 1 , 3, 6, 12, 24, 36, 48, 72, 96, 120 and 144hrs (6 days total) and replaced with temperature-equilibrated receptor phase. A total of five replicates were carried out for each gel. All samples were immediately analysed by HPLC.
  • the steady state flux of both Digoxin and Furosemide for each gel was calculated from the gradient of the linear section of the cumulative permeation profiles.
  • the breakthrough time was taken from the point at which permeant was first detected in the receptor phase (dependent on the MDL for each permeant).
  • Lag times were calculated by extrapolating the linear section of the cumulative amount permeated (steady state flux) to the X-axis (time).
  • Figures 16 to 20 illustrate the permeation profiles for Furosemide and Digoxin through callous plantar skin from an infinite dose of gel.
  • Furosemide exhibited a typical permeation profile through the plantar skin (Figure 16).
  • First order kinetics were observed between 120 and 312 hours from which a steady state of flux of 13.83 ⁇ 1.18 ⁇ g cm "2 hr "1 was calculated.
  • For Digoxin a typical permeation profile was also obtained. Steady state was attained at 144 hours to which a flux of 1.14 ⁇ 0.28 ⁇ g cm "2 hr '1 was calculated ( Figure 17).
  • the relative steady state flux for Furosemide and Digoxin may not be entirely due to the physical characteristics of the permeants but also the relative keratolytic effects of the formulation.
  • Figure 19 illustrates the molar permeation of both drugs. It can be seen that the ratio of Furosemide and Digoxin (approx. 10:1) does not differ to any great extent from the molar ratio of the drugs found in the formulation (14:1). The higher concentration of Furosemide in the gel is also mirrored in the relative percentages of drug permeated ( Figure 18). The greater propensity for Furosemide to permeate is expected, given Furosemide has a significantly lower molecular weight relative to Digoxin. This is reflected in the calculated apparent steady state flux values (Table 5). However, this effect may not be solely due to the physical properties of the permeants but may also relate to the relative (and perhaps temporary) pore sizes created by the keratolytic effects of the formulation. The specific diameter/3-dimensional shape of the created pores may allow easier permeation of Furosemide rather than Digoxin relative to the permeant molecular weight.
  • Figures 21 and 22 illustrate the cumulative permeation profiles for both Furosemide and Digoxin respectively, through callous plantar skin from about 1g of each of the three different gel formulations.
  • Figures 23 and 24 provide a direct comparison between the cumulative permeation of both Digoxin and Furosemide from the prototype gel and revised maximum Digoxin gel.
  • Table 6a Summary of the Permeation data for the 'Max' Digoxin Gel Formulation
  • Furosemide and Digoxin exhibited 'typical' permeation profiles through the callous plantar skin ( Figure 2).
  • Figure 2 For the 'Max' Digoxin gel formulation, first order kinetics were observed for Furosemide between 72 and 144 hours, and for Digoxin between 48 and 120 hours from which a steady state of flux of 6.759 and 1.015 ⁇ g cm "2 hr "1 accordingly was calculated.
  • Results provide compelling evidence that Furosemide and Digoxin contained within this specific gel formulation can be delivered through human skin, even human callous plantar skin and be useful for the treatment of PHN and other neuropathic pains.
  • a further formulation route which was considered was the use of an active in, for example, a glue.
  • Examples 10 to 12 are included by way of illustration to show the effects including synergistic effects of compositions comprising Digoxin and Furosemide against cells infected with HSV virus. It should be emphasised here that such examples are not however demonstrating transdermal ⁇ effective delivery means entirely within the scope of the invention, but are nonetheless useful indicators of efficacy.
  • Example 10
  • Bioassays with herpes simplex virus in vitro were undertaken to follow the anti-viral activity of the simultaneous administration of furosemide (1mg/ml) and digoxin (30 mcg/ml). Culture and assay methods follow those described by Lennette and Schmidt (1979) for herpes simplex virus and Vero cells with minor modifications.
  • Type 1 herpes simplex strain HFEM is a derivative of the Rockerfeller strain HF (Wildy 1955), and Type 2 herpes simplex strain 3345, a penile isolate (Skinner et a! 1977) were used as prototype strains. These prototypes were stored at -80 0 C until needed.
  • African Green Monkey kidney cells were obtained from the National Institute of Biological Standards and Control UK and were used as the only cell line for all experiments in the examples.
  • Example 10 The method of Example 10 was repeated using type 1 herpes virus strain kos. Similar results were obtained.
  • compositions were applied to different types of Vero cells (African green monkey kidney cells and BHK1 cells) and infected with type 2 herpes simplex virus (strains 3345 and 180) at low, intermediate, and high multiplicities of infection (MOI). Inhibition of virus replication was scored on the scale:
  • T denotes drug toxicity
  • Digoxin and Furosemide were purchased from Sigma, UK. Durotak acrylic glues were sourced from National Starch and Chemical Company. Duro-tak 87-900A (Glue 1), Duro-tak 87-2052 (Glue 2) and 87-201 A (Glue 3) were used. All solvents and chemicals used for the release and permeability were purchased from Sigma. The silicone sheeting that was used as a synthetic skin barrier was purchased from Advanced Biotechnologies, USA.
  • HPLC offers a reliable means of quantifying the amount of drug that has been released.
  • the HPLC used was Agilent Series 1100 with a Phenomenex C18 (150 x 4.60 mm 5 ⁇ micro) column.
  • the mobile phase was water, methanol and acetonitrile (40:30:30) and flowed at 1 ml/min. 20 ⁇ l of sample was injected and detected at 220 nm with a variable wavelength detector (VWD).
  • VWD variable wavelength detector
  • Figure 25 shows a calibration curve of Digoxin concentration according to the HPLC method used.
  • Figure 26 shows a calibration curve of Furosemide concentration according to the HPLC method used.
  • Example 14 Manufacture of the Delivery Device
  • Acrylic based pressure sensitive adhesives were sourced from National Starch and Chemical Company with properties that would be appropriate for use with Digoxin and Furosemide. A study was performed that measure the solubility of the drugs in a range of solvents.
  • Example 15 Measurement of drug release from formulated patches
  • Drug release studies were performed as a screening exercise prior to penetration studies.
  • a circular patch of 1 cm diameter of the formulation was taken and placed into a sealed container containing an excess of release medium (2mC).
  • the vial was sealed and shaken at a controlled speed and temperature (37 0 C) for a period of 48 hours.
  • a sample 0.5ml was removed for analysis.
  • the formulations were compared to note those that demonstrate the best release. In the clinical setting the patch will be approximately 0.25cm 2 and the release required is 25 ⁇ g per 24 hours thus the release rate must be greater than 100 ⁇ g/cm 2 /24hours.
  • Figure 27 shows the release of both drugs from Glue 1 (87900A);
  • Figure 28 shows the release of both drugs from Glue 2 (872677);
  • Figure 29 shows the release of both drugs from Glue 3 (87201 A);
  • Figures 30 to 34 shows an HPLC trace of the drugs release from the film in the solvent described releasing into a buffer solution as described.
  • the pressure sensitive adhesive incorporating the drug that demonstrates the greatest release was selected and the penetration into skin was evaluated.
  • Franz cell apparatus was used to measure the penetration of the drug from the adhesive formulation into the skin membrane.
  • the upper layer represents the transdermal formulation and the lower layer the skin.
  • the vessel below the skin is filled with fluid (the same as used in the release study) and stirred at a constant rate.
  • fluid the same as used in the release study
  • a sample from the lower vessel is taken using the side port and analysed using HPLC for drug content. The permeation of drug across the membrane over time can thus be calculated.
  • the membrane used in this study was a synthetic silicone based skin membrane purchased from Advanced Biotechnologies, USA.
  • the drug powders were mixed at a 1 :1 ratio and 500mg of this mix was blended with 10m € of Glue 1. This mixture was then cast onto 3M Scotchpak 1020 release liner over an area of 80 by 120 mm. The solvents were left to evaporate and the film was covered with 3M Scotchpak 1109 polyester film laminate backing.
  • the drug loading is there 2.6mg/cm 2 of both drugs within the formulation.
  • the surface area of the 1cm diameter patches is 0.785cm 2 .
  • Each small patch contains 1.02mg of Digoxin and 1.02mg of Furosemide.
  • the aim of these later examples is to show both the feasibility of drug-in-glue formulations based on transdermal adhesive and the feasibility of lacquer/paint formulations based upon flexible collodion BP.
  • Digoxin (D) batch number 181104 and Furosemide (F) batch number 114310 were obtained from BUFA Pharmaceutical Products bv (Vitgeest, Netherlands). Centrimide lot no. A012633401 was obtained from Acros Organics (New Jersey, USA). Duro-tak®
  • the ratios of F: D selected mix were 1 :1 , 1:25 and 1 :100, thus providing a sizeable excess of D. This was based on anecdotal evidence which suggested that D has substantially greater virostatic power than F, indicating that a formulation that delivered an excess of D may be more effective in reducing viral load and thus be effective in treating PHN. The effect each ratio had on the release of D and F is illustrated and ratios investigated which may produce optimum release of each active.
  • a drug-in-adhesive formulation is a type of matrix system in which drug and excipients can be dissolved or dispersed depending on the amount of drug required for the desired delivery profile (Venkatramann and Gale, 1998).
  • the solvent in the adhesive evaporates to form a solid matrix product, the concept of thermodynamic activity does not apply.
  • the solvent is an important component as it creates microchannels in the matrix upon drying, to form a 'pathway' for the drugs to the skin.
  • the limiting factor in the amount of drug that can be incorporated is the point at which bioadhesive properties are lost.
  • the method used to case out the patches was based on trial and error. It was consequently determined that to achieve a constant patch thickness, it was preferable to pour the drug-adhesive mixture onto a polymer-lined paper in a horizontal line and then hold the paper vertically allowing the mixture to flow down the paper. This method was found to be reproducible and the drug-in-adhesive covered a surface area of approximately 8cm 2 with a depth measured to be almost exactly 1mm.
  • Patches were prepared by the direct addition of 0.5g of drug mix, to 5g of adhesive (wet weight). Three drug mixes were prepared containing different molar ratios of F: D, the compositions of the drug mixes are displayed in Table 2.1. The appropriate amounts of drug mix and adhesive wee accurately weighed directly into glass vials using an analytical balance and 2.5ml of methanol was added to the mixture. Each vial was vortex-mixed for three minutes and left to rotate on a blood serum rotator overnight, ensuring that the drug mixture was homogeneously dispersed. Control patches were also prepared by the same method, containing no drug mix. Each adhesive mixture was then cast out onto polymer-lined paper as described above.
  • a receptor phase The function of a receptor phase is to provide an efficient sink for the released or permeated drug.
  • a rule of thumb is that the amount of drug should not exceed 10% of its solubility in a given sink.
  • the sink must not interfere with the release or permeation process (Heard et al, 2002).
  • Two receptor phases wee considered in this work. These were aqueous cetrimide 30 mg ml, an ionic surfactant and EtOH/water 10:90 v/v, chosen as both drugs wee known to be freely soluble in each medium.
  • Example 19 patches Diffusional release of D and F mix from Example 19 patches
  • the aim of this example was to determine whether or not different molar ratios of the two drugs would affect the extent and rate of the release of each drug.
  • the polymer- lined paper was prized from the patches to expose one side of the patch.
  • Each patch was then individually immobilised to the bottom of a general 7ml glass screw cap vial with a small daub of Duro-tak® 387-2287 adhesive to the polymer film and allowed to dry for 30 minutes.
  • the dissolution media used were cetrimide 30mg mt 1 or EtOH/water 10:90 v/v, 5 mt of each was added individually to each vial.
  • the vials were then placed on a Stuart Scientific Gyro-Rocker (Fisher, UK) set at 70rpm to ensure adequate mixing of the dissolution medium and incubated at 32 0 C (the temperature of the skin) in a laboratory incubator (Genlab).
  • O. ⁇ mt of dissolution medium was sampled and placed in HPLC auto sampler vials.
  • the receptor phase was replenished with 0.5mf of stock dissolution medium also at 32 0 C.
  • the samples were refrigerated at 2 - 4 0 C until HPLC analysis 24 hrs later. A total of 3 replicates were performed for each treatment in each receptor phase.
  • the formulation that demonstrated the optimum release was used during permeation examples.
  • the ears were washed under running water and full-thickness dorsal skin was separated from the cartilage via blunt dissection using a scalpel, then hair was removed using an electric razor.
  • the skin was cut into samples of approximately 2cm 2 and visually inspected to ensure that each piece was free from abrasions and blood vessels. Specimens were then stored in a crease free state on aluminium foil at -20 0 C until required.
  • Example 22 Permeation of D and F mix across pig ear skin from patches
  • the skin samples were removed from the freezer and left to fully defrost.
  • the donor and receptor compartments of Franz-type diffusion cells (see Figure 13) were greased, to provide a tight seal and prevent any leakage from the receptor phase.
  • the polymer- lined paper was removed from the patches to expose one side and firmly pressed centrally onto the surface of each piece of skin. After adhesion was established, the skin was mounted onto the flange of a receptor compartment (nominal volume 2.5ml) of the diffusion sell, ensuring that the patch was placed directly over the flange aperture.
  • the donor compartment was then placed on top and clamped to the receptor compartment using a pinch clamp.
  • EtOH/water 10:90 receptor phase (maintained at 37°C) was used to fill the receptor compartment carefully to ensure that no air bubbles were in contact with the underside of the skin and the receptor phase was in contact with the skin.
  • a small magnetic stirrer was added to ensure homogeneous mixing of the receptor phase.
  • the Franz cells were placed on a magnetic stirrer immersed in a water bath (containing vercon) and maintained at a constant temperature of 37 0 C (therefore the surface of the skin was approximately 32 0 C).
  • the donor aperture was occluded to mimic the backing layer of a commercial patch protecting it from moisture and the sampling arms were occluded to prevent evaporation of the receptor phase.
  • Collodion BP is a liquid, with a high solvent content (mainly diethyl ether).
  • a high solvent content mainly diethyl ether.
  • the volatile components of the collodion rapidly evaporate transforming the liquid solution into a dry, solid film which will adhere to the skin.
  • the change in physical state of the vehicle means that the thermodynamic activity, of liquid/semi-solid dermatological systems, only applies to the initial liquid formulation and is irrelevant to the formulation in a solid state. Therefore, the solubility of the actives to a certain extent is arbitrary, as more drug mix can be added by increasing the proportion of solvent to the liquid formulation.
  • the drug mix did not easily re-suspend on shaking; meaning that only a small amount of drug mix would dissolve in the collodion.
  • various amounts of ethanol were added to the formulations until a balance between drug dissolving/reduced rate of sedimentation (which would increase if viscosity decreased) and the rate of drying (solvent evaporating) was found. It was concluded that 0.01 g of drug mix in 5 ml of collodion and 5 ml of ethanol was a good compromise. This formulation also showed good adhesive properties.
  • Drug mix (for composition see Table 7) 0.02g (a stock was made) was weighted on an analytical balance (accurate to 5 decimal places) and added directly to 10m£ of collodion and 10mi of ethanol in a McCartney bottle.
  • the molar ratios used were F: D; 1 :1 , 1:2.5 (2:5) and 1 :10 because a smaller amount of drug mix was used, compared to the drug-in-adhesive and this allowed measurable amounts of F to be used.
  • Each of the McCartney bottles was vortexed for three minutes and left to rotate on a blood serum rotator overnight, to ensure that the mixture was homogeneous and that any air bubbles present had dispersed. Control collodions were also prepared by the same method, however, no drug mix was added.
  • Example 25 The method was essentially the same as described in Example 25. Mounted skin membranes were does with 200 ⁇ l of collodion and left for thirty minutes to dry before the receptor phase was added. A total number of 4 replicates were performed for each treatment.
  • HPLC analysis was performed using the same method as described previously i.e. an Agilent series 1100 automated system, fitted with a Phenomenex Kingsorb 5mm C18 Column 250 x 4.6mm (Phenomenex, Macclesfield, UK) and a Phenomenex Securiguard guard column. D and F were detected using an ultraviolet (UV) detector set at wavelength 220 nm.
  • the mobile phase consisted of 40:30:30 Water: MeOH:MeCN, de-gassed by drawing through a 0.45 membrane and run isocratically for 10min at a flow rate of 1 ml min "1 .
  • the injection volume of each sample was 20 ⁇ l.
  • the retention time of F and D was typically 2.6 minutes and 5.2 minutes respectively.
  • Chromatogram peaks were integrated manually, and the data corrected for dilution effects. Cumulative release was determined and plotted against the square route of time to determine release rates. Cumulative permeation data were determined and plotted against time to order to obtain flux. Excel was used for data processing and Minitab for statistical analysis.
  • Example 27 Diffusional release of D from patches Cumulative mass of Digoxin (D) released Cumulative release (mass/area) profiles of D from adhesive containing molar ratios of F: D; 1:1, 1:25, 1:100 were determined over 24hr and are illustrated in Figure 14. D was released from all the patches. The trend in the greatest cumulative release after 24hr (table 3) was 1 :100>1 :1>1 :25. The patches containing ratios of 1:1 and 1 :100 had similar profiles, and up to 12hr the greatest release was observed form the patches containing a molar ratio of 1 :1. Error bars were small.
  • the main effects plot illustrated in Figure 43 summaries the data from the diffusional release of F from model patches. It illustrates the trend in ratio of percentage release of loading dose of F and how percentage release of loading of F increased over time.
  • Permeation of D across pig skin is illustrated as both cumulative mass/area and percentage permeation of loading of D and is shown in Figures 44 and 45 respectively.
  • the profiles are of a similar shape and are atypical permeation profiles. However, they do illustrate that D is permeated the pig skin. Error bars are larger than for release results. Apparent maximum flux (Table 12 along with maximum permeation values) was calculated from Figure 45 however lag time and Kp could not be calculated from these profiles-.
  • Permeation of F across pig skin is illustrated as both cumulative release (mass/area) of loading and percentage permeation of loading of F and is shown in Figures 46 and 47 respectively. Both of the profiles are of a similar shape and are atypical permeation profiles. However, they do show that F permeated the pig skin. Error bars are larger than for release and permeation of D across pig skin. Apparent flux maximum (Table 8 and maximum permeation values) was calculated, however lag time and Kp could not be calculated from Figure 46.
  • Example 35 Comparison between mass released from the patches containing a F: D in a 1:1 ratio and mass permeated through the skin
  • Figure 48 illustrates the mass/area of D released from the patches and also the mass/area of D that permeated the skin and allows a comparison to be made. A larger mass of D was released from the patches that permeated the skin.
  • Example 36 Comparison between the mass/area of Furosemide released from the patches and mass/area of Furosemide that permeated the skin
  • Figure 49 illustrates the mass/area of F released from the patches and also the mass/area of F that permeated the skin and allows a comparison to be made. A larger mass of F was released from the patches that permeated the skin.
  • Cumulative release profiles of D from collodions containing molar ratios of F: D, 1:1 , 1 :2.5 and 1 :10 were determined over 24hr and are illustrated in Figure 50 released from each of the collodions.
  • the trend the in greatest cumulative release after 24hr was 1 :100.1 :2.5>1 :10.
  • the shape of the three profiles were similar and error bars small.
  • Example 38 Percentage release of loading dose of D from collodion
  • the percentage release of the loading dose of D from collodions containing molar ratios of F: D; 1 :1, 1 :2.5 and 1 :10 was determined over 24hr and are displayed in Figure 51. The percentage release mimics the trend observed in Figure 50. Maximum percentage release values of D after 24hr are illustrated in table 13. Error bars were small.
  • Figure 52 illustrates the cumulative release of Digoxin from the three different collodions plotted against the square root of time. Linearity of the plots indicates first order release kinetics, 1 :10 shows the greatest rate of release. R 2 and rate of rate of release are illustrated in table 11.
  • Example 40 Diffusional release of Furosemide from collodion Cumulative mass/area released of F from collodion
  • Example 41 Percentage release of loading dose of F from collodions
  • the trend in percentage release of loading dose of F (Figure 54) mimics that of cumulative release. For maximum percentage release after 24hr see table 12. Error bars were small. Table 15 Maximum release values of F from collodion after 24hr
  • Example 42 - Release rates of Furosemide from collodion Figure 55 depicts cumulative release of F from the collodions containing the three different molar ratios plotted against the square root of time. Linearity was reported from reported from 1 :1 indicating first order kinetics. For release values refer to Table 16.
  • Permeation of D across pig skin is illustrated as both cumulative mass/area and cumulative percentage of loading of D and are illustrated in Figures 56 and 57 respectively. Both of the profiles are similar in shape and are atypical of permeation profiles. However they do illustrate that D from collodion is permeated the skin. Error bars were larger than for collodion release results. For AFM and maximum permeation values refer to Table 17. Lag time and Kp could not be calculated from these profiles.
  • Example 44 - Permeation of Furosemide across pig ear skin from collodion Permeation of F across pig ear skin is illustrated as both cumulative mass/area and cumulative percentage and shown in Figure 58 and 59 respectively.
  • the profiles are of a similar shape and are atypical permeation profiles. However, they do show that F permeated the pig skin. Error bars are large. AFM and maximum permeation values are displayed in Table 17. However, lag time and Kp could not be calculated from Figure 58.
  • Example 45 Comparison between mass released from the collodion containing F: D in a 1:1 molar ratio and mass permeated through the pig skin
  • Controls were used throughout this work. During the release studies, formulations containing no actives were used as controls. The corresponding chromatograms illustrated no peaks at the wavelength of detection. During permeation studies formulations containing no actives and skin without a formulation applied to it were used as controls. The corresponding chromatograms illustrated no peaks at the wavelength of detection.
  • Dermatological formulations are required to release the active compound(s) at the surface of the skin.
  • the rate-limiting step in skin permeation is transport across the stratum corneum, although in some cases the rate-limiting step can be release of the active compound(s) from the formulation. If this occurs the bioavailability of the compound(s) may be affected. This is less likely to happen during the permeation of D and F through callous material.
  • Percentage release of the loading dose was calculated to allow, for slight variation in patch preparation, and comparison between the formulations. Percentage release was expected to be small with a large amount of drug retained in the matrix.
  • the rate of release was examined, in order to distinguish between 1:1 and 1:100 in terms of which formulation would give the maximum delivery of D in the shortest time period. Although the rate of release from 1 :100 was the greatest at 5.19 ⁇ g cm "2 h '1 it was surprisingly similar to that of 1 :1 at 4.84 ⁇ g cm "2 h "1 .
  • Dermal absorption involves several processes. Firstly the actives are released from the formulation; they then encounter the surface of the skin and establish a SC reservoir. This leads to penetration of the barrier and finally diffusion into another compartment of the skin (Schaefer and Redelmeler, 1996).
  • Permeation profiles were presented as cumulative mass/area and cumulative percentage permeation of total loading. Cumulative permeation results illustrated that both D and F permeated the skin and therefore have potential as a future localised neuropathic pain treatment. Permeation through the skin can predict localisation and therefore it is possible that both D and F are coming in to contact with the basal layer of the epidermis. Comparison between the mass of Digoxin and Furosemide released from model patches containing F: D 1:1 and mass permeated through the skin
  • the release of D and F from the collodion could be potentially limited by three parameters, molar ratio, drug loading and interaction between the drugs and the collodion matrix.
  • the aim of this experiment was to establish which collodion contained the molar ratio of D: F that released the maximum amount of D and a sufficient amount of F. This would be used for further permeation studies. Overall the release of D would have a larger influence in choice of ratio over release of F (Example 23).
  • Release profiles for percentage release of loading dose were also plotted, to allow for variation in volume of collodion pipette into each vial and to allow comparison between formulations. Percentage release ranged from 25.54 - 30.36%, which was relatively high compared to approximate 10%, expected and compared to the patches. This suggested that differences between the adhesive and collodion matrix could be responsible. A possible explanation could be the formation of larger micro channels in the matrix of the collodion as the solvent evaporates on drying, or a greater number may be formed than in the patches due to the higher solvent content of collodion.
  • Percentage release of loading dose did not follow the same trend as cumulative release mass/area, and instead was 1 :1>1 :10>1.2.5. This was no pattern was followed. However, this trend correlated with the trend in cumulative mass/area released of D from the patches. This suggested that the effect of the vehicle would only have an influence on the over all extent of release from all three of the collodions, and that the difference in molar ratios contribute towards the trend.
  • Furosemide was released form all the collodions, indicating that all the collodions could be potentially used in permeation studies, as they illustrated simultaneous release of Digoxin and Furosemide. Maximal dose released after 48hr was in the order of 6.02 ⁇ g cm "2 .
  • Cumulative release (mass/area) of Furosemide from collodion was lower than that of Digoxin, unlike the patches, thereby potentially delivering more of Digoxin to the site of infection or pain, which was desirable.
  • the profiles from all the molar ratios were typical of release, an initial burst was observed between 1-6hr, and plateau in the profile at 6hrs, which was comparable with the Digoxin release profiles. This was most likely to be due to depletion, because it was observed from both drugs and to a lesser extent in the patches (which contained a higher dose of D and F).
  • the trend in cumulative release (mass/area) was 1:1>1:2.5>1:100 and was unexpected as 1:1 contained the lowest (mass/area) of F. This trend was also observed in the percentage release data which indicates that D having an effect on the release of F as otherwise one would expect the percentage release of F to be the same for each ratio.
  • Permeation data was shown as cumulative mass/area and percentage permeation of total loading. The permeation data illustrated that both F and D simultaneously permeated the skin, and can be used as a prediction of localisation.
  • the permeation profiles for both D and F were atypical as were the permeation profiles for the patches. Therefore suggests this could be related to the nature of the actives individually or in combination.
  • the profile for D is however different to that of F differing from a typical profile only during phase 1.
  • the percentage release profile for D mimicked this shape.
  • the profiles for F were a similar shape to that seen from the patches.
  • the SEM for the permeation profiles was larger in magnitude than those for the release profiles. This indicated less reproducibility in data compared to the release data. The major difference between the release experiments and the permeation was the introduction of the skin, therefore this may have had an impact on the results.
  • the SEM was also of a larger magnitude for F compared to D. A reason for this could be the amount of solvent present in the liquid state of the collodion (all solvent had evaporated from the patches during preparation) could affect the integrity of the skin and reduce reproducibility between replicates.
  • the mass/area of D that permeated the skin was 8.02 ⁇ g cm “2 (1.03 x 10 '8 ⁇ g cm “2 ) compared to 28.49 ⁇ g cm “2 (8.62 x 10 "8 ⁇ g cm “2 ) of F, suggesting that drug delivery to the basal layers is a reality.
  • the observation that a greater mass/area of F permeated may be associated with the large SEM indicating that these results lacked reproducibility between samples. If integrity of the skin had decreased as F is smaller than D it is possible that it would penetrate the skin more effectively. It is also less lipophilic and therefore less likely to become trapped in a compartment of the skin. A larger percentage of loading of F permeated the skin than D, which was the same for the patches.
  • the ratio of moles that permeated the skin was D: F 1 :8, supporting suggestions that F permeated the skin more easily.
  • the patch offers a thicker film than the collodion, meaning that a larger mass of one or both of the binary drug combination can be incorporated into the formulation, and perhaps offer a prolonged duration of treatment, increasing compliance.
  • Thickness of film of collodion is approximately 5 - 20 ⁇ cl limiting the amount of actives applied to the skin (Schaefer and Redelmirer, 1996) compared to approximately 1mm of the patches. This suggests that movement of molecules from the upper surface of the patch through the bulk matrix to a greater extent in the patches, reducing frequency of dosing and aiding compliance. Both dosage forms are flexible. The suitability of these patches in the treatment of neuropathic pain has been demonstrated and will be further established in forthcoming clinical trials. Overall the formulation determines the kinetics and extent of percutaneous absorption, which has an impact upon the onset of action, duration and extent of a biological response.
  • the following additional embodiments demonstrate the in vitro release and permeation of Digoxin and Furosemide from transdermal delivery devices.
  • Several drug-in-glue formulations containing differing amounts of Digoxin and Furosemide were compared for their rates of drug release, rates of drug permeation through porcine skin and the concentration of drug within the skin sample.
  • the ratios of the active principles were varied to investigate optimum formulations for delivery of Furosemide and Digoxin to provide dermal saturation.
  • Digoxin and Furosemide were purchased from Sigma, UK.
  • Glue 1 was sourced from National Starch and Chemical Company. All solvents and chemicals used for the release and permeability studies were purchased from Sigma.
  • the porcine ear skin that was used as a skin barrier was purchased from a local abattoir.
  • a convenient drug loading is 25mg/m£ of both Digoxin and Furosemide within the acrylate glue at a 1:1 ratio. If the total concentration of drug is maintained at 50mg/mJ! then the following systems can be examined: 50mg/mJ! Digoxin
  • Drug release from the patches into a solution of mobile phase was measured for the nine mass-ratio formulations. This was done to compare how the drug loading affects drug release.
  • Table 19 shows that at similar concentration values, furosemide is released to a greater extent than digoxin, e.g. compare formulations 1 and 9.
  • the steady state flux for each drug increases as the initial loading of drug within the patch increases. This is as expected as the drug is released from the patch due to a concentration gradient that exists between the drug loading and release medium.
  • the permeation coefficient is a measure of the rate of drug release in cm per second of each drug from the patch. These values are relatively constant for all formulations which indicates that the two drugs do not interfere in the release of one another.
  • the Kp values for each drug alone are similar to the values in patches that contain both drugs. Kp for furosemide is approximately four times greater than Kp for digoxin, this is likely to be due to the comparatively smaller size of furosemide.
  • Table 20 below shows the data for the drug released from the patches that has penetrated the skin.
  • Table 20 shows the penetration of the skin, both the flux values and permeation coefficient values are much lower than the release of the drug from the formulations listed in the table above. This is expected and reflects the barrier properties of the skin. Furosemide penetrates the skin to a greater extent than digoxin as demonstrated by the permeation coefficient which is nearly eight times higher than digoxin. The drug that accumulated in the skin was also measured. The drug that was present in a 2 cm diameter cross section of skin was calculated for all four formulations.
  • the level of digoxin appeared to be independent of the loading formulation, indicating that the skin was saturated with digoxin at a concentration of 40 ⁇ g over 3.14 cm 2 or 12.73 ⁇ g/cm 2 . Furosemide did not accumulate within the skin and permeated directly through the skin. The concentration measured at 72 hours was a transient indication of furosemide within the skin that was dependant upon the loading concentration. Results are shown in Figure 65.
  • the rate of furosemide release from the patch, Kp for the patch was 6.53 x10 "10 cm per second, this was not greatly faster than the rate of furosemide penetrating porcine ear skin at 4.32 x10 "8 cm/second.
  • the initial patch concentration for digoxin is plotted against the steady state flux rate through the skin, as shown in Figure 66, it can be seen that for the flux to be greater than 0 the initial concentration within the patch must be 804.5 ⁇ g/cm 3 .
  • this study enhanced the overall penetration of digoxin through the skin as a very lipophilic substance was used in the donor phase to enhance the concentration gradient to maximise skin penetration of both digoxin and furosemide.
  • ICVT Ionic contra viral therapy
  • Digoxin solution prepared from powder was as effective as Lanoxin (circles) ( Figure 68).
  • Digitoxin is more soluble than Digoxin; preparation of a saturated solution (17.5mg per ml) in 90% ethanol will enable use at a maximum concentration of 486 ⁇ g per ml in a 'safe-ocular- concentration (2.5%) of ethanol.
  • Digoxin was previously used at a concentration of 62.5 ⁇ g per ml.
  • HSV Herpes simplex virus
  • ID50 50% plaque inhibitory dose
  • Hvdrochiorothiazide Solvent Ethanol 10% 5 mg/ml HSV Plaque 1 D50 Negative @ 2.5 mg/ml Solvent: NaOH 1 % aqueous 1 0 mg/ml
  • Bumetanide Solvent (IV) Aqueous 500 ⁇ g/ml
  • neuropathic pain Other delivery methods may be used to treat neuropathic pain. Depot applications which release actives to alter the central nervous system, spinal cord or the principal or major nerve groups which extend from the spinal column.

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Abstract

L’invention concerne des compositions pharmaceutiques pour le traitement de la douleur neuropathique, p. ex. associée à la névralgie, la dystrophie ou la douleur du membre fantôme. La composition pharmaceutique comprend des glycosides cardiaques et/ou des diurétiques et est de préférence appliquée topiquement, p. ex. sous la forme d’un gel. L’invention concerne également des procédés de préparation de telles compositions.
PCT/GB2008/000568 2008-02-19 2008-02-19 Utilisation d’un glycoside cardiaque et/ou d’un diurétique pour le traitement de la douleur neuropathique WO2009103932A1 (fr)

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20110182912A1 (en) * 2010-01-26 2011-07-28 Evans Michael A Agents and methods for denervation
EP3302439A4 (fr) * 2015-06-08 2018-12-26 Dermac, LLC Composition thérapeutique

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US6306845B1 (en) * 1999-01-29 2001-10-23 The Trustees Of Columbia University In The City Of New York Method for treating demyelinating disease
WO2003103696A1 (fr) * 2002-06-06 2003-12-18 Charles Laudadio Glucosides cardiaques pour le traitement des douleurs et des spasmes musculaires
US20050267103A1 (en) * 1998-12-23 2005-12-01 Cytoscan Sciences Llc Methods and compositions for the treatment of neuropathic pain and neuropsychiatric disorders
WO2007026124A2 (fr) * 2005-09-02 2007-03-08 Henderson Morley Plc Moyens d'administration transdermique de principes actifs
WO2007026125A2 (fr) * 2005-09-02 2007-03-08 Henderson Morley Plc Formulations topiques
WO2007081061A1 (fr) * 2006-01-16 2007-07-19 Japan Science And Technology Agency Agent therapeutique utilise contre les douleurs neurogenes
GB2441011A (en) * 2006-08-18 2008-02-20 Henderson Morley Plc Pharmaceutical composition for the treatment of neuropathic pain

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US20050267103A1 (en) * 1998-12-23 2005-12-01 Cytoscan Sciences Llc Methods and compositions for the treatment of neuropathic pain and neuropsychiatric disorders
US6306845B1 (en) * 1999-01-29 2001-10-23 The Trustees Of Columbia University In The City Of New York Method for treating demyelinating disease
WO2003103696A1 (fr) * 2002-06-06 2003-12-18 Charles Laudadio Glucosides cardiaques pour le traitement des douleurs et des spasmes musculaires
WO2007026124A2 (fr) * 2005-09-02 2007-03-08 Henderson Morley Plc Moyens d'administration transdermique de principes actifs
WO2007026125A2 (fr) * 2005-09-02 2007-03-08 Henderson Morley Plc Formulations topiques
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Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20110182912A1 (en) * 2010-01-26 2011-07-28 Evans Michael A Agents and methods for denervation
US20120108517A1 (en) * 2010-01-26 2012-05-03 Evans Michael A Agents and methods for denervation
JP2013517847A (ja) * 2010-01-26 2013-05-20 エイ． エヴァンズ，マイケル 除神経のための方法、装置、及び薬剤
US8975233B2 (en) * 2010-01-26 2015-03-10 Northwind Medical, Inc. Methods for renal denervation
US9056184B2 (en) * 2010-01-26 2015-06-16 Northwind Medical, Inc. Methods for renal denervation
EP3302439A4 (fr) * 2015-06-08 2018-12-26 Dermac, LLC Composition thérapeutique

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