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WO2016156470A1 - Formulations vésiculaires à utiliser dans le traitement de la douleur musculaire - Google Patents

Formulations vésiculaires à utiliser dans le traitement de la douleur musculaire Download PDF

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Publication number
WO2016156470A1
WO2016156470A1 PCT/EP2016/057027 EP2016057027W WO2016156470A1 WO 2016156470 A1 WO2016156470 A1 WO 2016156470A1 EP 2016057027 W EP2016057027 W EP 2016057027W WO 2016156470 A1 WO2016156470 A1 WO 2016156470A1
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WIPO (PCT)
Prior art keywords
formulation
soreness
tissue
soft
exercise
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Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
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PCT/EP2016/057027
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English (en)
Inventor
Richard Wolf GARRAWAY
Michael James EARL
William Henry
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Sequessome Technology Holdings Ltd
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Sequessome Technology Holdings Ltd
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Publication of WO2016156470A1 publication Critical patent/WO2016156470A1/fr
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Ceased legal-status Critical Current

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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
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/715—Polysaccharides, i.e. having more than five saccharide radicals attached to each other by glycosidic linkages; Derivatives thereof, e.g. ethers, esters
    • A61K31/739—Lipopolysaccharides
    • 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
    • A61K31/66—Phosphorus compounds
    • A61K31/683—Diesters of a phosphorus acid with two hydroxy compounds, e.g. phosphatidylinositols
    • A61K31/685—Diesters of a phosphorus acid with two hydroxy compounds, e.g. phosphatidylinositols one of the hydroxy compounds having nitrogen atoms, e.g. phosphatidylserine, lecithin
    • 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
    • A61K47/24—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing atoms other than carbon, hydrogen, oxygen, halogen, nitrogen or sulfur, e.g. cyclomethicone or phospholipids
    • 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
    • A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
    • 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
    • A61K9/10—Dispersions; Emulsions
    • 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
    • A61K9/107—Emulsions ; Emulsion preconcentrates; Micelles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/04—Drugs for skeletal disorders for non-specific disorders of the connective tissue
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P21/00—Drugs for disorders of the muscular or neuromuscular system

Definitions

  • the present invention relates to formulations containing ultra-deformable drug- free particles and their use in treating soft-tissue soreness, such as delayed onset muscle soreness (DOMS) and exercise- induced muscle soreness.
  • the formulations of the invention comprise a non-ionic surfactant and/or a phospholipid and are free of any pharmaceutically active agent.
  • GI gastrointestinal
  • renal and cardiovascular side effects are associated with an increased risk of gastrointestinal (GI), renal and cardiovascular side effects, even in healthy individuals including athletes (Al-Saeed, 2011 ; Conaghan, 2012; Harirforoosh & Jamali, 2009; Warden, 2010).
  • Topical application of NSAlDs minimises systemic exposure, thereby improving GI adverse effects, but some safety concerns still remain (Klinge & Sawyer, 2013), as well as uncertainty regarding the extent of absorption (Heyneman, Lawless-Liday & Wall, 2000).
  • Published data also suggest that oral NSAlDs can delay recovery from muscle soreness or injury (Nieman et al., 2006; Nikanne, Kokki, Salo & Linna, 2005).
  • the present invention provides a formulation that is free of NSAlDs and any other pharmaceutically active agent for use in the treatment of soft-tissue soreness.
  • Topical NSAID use demonstrated efficacy in patients with soft tissue inflammation (Kneer, Rother, Rother, Seidel & IDEA-033-III-01 Study Group, 2009) but showed no improvement in efficacy over that of drug-free particles, such as those in accordance with the present invention.
  • Topical therapy with drug-free particles not only avoids the systemic adverse effects of oral NSAlDs but also reduces the burden of polypharmacy for patients.
  • Drug-free ultra-deformable particles in accordance with the present invention are able to penetrate the skin. Similar formulations have been designed to provide targeted delivery of high drug concentrations into deeper subcutaneous tissues (US6165500; Cevc & Blume, 1992; Cevc & Gebauer, 2003). Drug-free particles have since demonstrated efficacy in reducing osteoarthritis-associated pain (WO2010/140061 ; Conaghan et al., 2014; Conaghan et al., 2013).
  • the applicants have now shown that such drug-free particles are able to reduce soft-tissue soreness, such as DOMS and exercise-induced muscle soreness.
  • the particles of the present invention are as effective at reducing soft-tissue soreness as formulations that contain NSAIDs.
  • the particles of the present invention are well tolerated and do not have the side effects associated with using NSAID- containing formulations.
  • the invention provides a formulation of colloidal particles comprising a non-ionic surfactant and/or a phospholipid for use in preventing or treating soft-tissue soreness in a subject, wherein the formulation is free of any pharmaceutically active agent.
  • the colloidal particles are vesicles.
  • the colloidal particles of the formulation may be free of any pharmaceutically active agent i.e. any non-lipid, non-surfactant pharmaceutically active agent.
  • Soft-tissue includes muscle, connective tissue, synovial membranes, fascia, skin, fibrous tissues, fat, nerves and blood vessels.
  • Soft-tissue soreness is any discomfort, soreness, swelling or stiffness in soft-tissues and may be caused by exercise, overuse of the particular soft-tissue, injury, trauma or stress.
  • the soft-tissue soreness may be delayed onset muscle soreness (DOMS).
  • DOMS delayed onset muscle soreness
  • DOMS is the discomfort and stiffness felt in muscles from several hours to a few days after unaccustomed or strenuous exercise. Any activity can cause DOMS, although the main cause is believed to be eccentric (lengthening) contractions of the muscle, which results in microscopic tearing of the muscle fibres and surrounding connective tissues. Examples of activities that involve eccentric contractions include walking down stairs, lowering weights or running downhill.
  • the tissue microtrauma sets off an inflammatory response that leads to the formation of metabolic waste products. These products act as a chemical stimulus to nociceptors causing a sensation of discomfort. The inflammatory response also produces free radicals that potentially cause further damage to the muscle tissue and connective tissue.
  • DOMS can be experienced by all individuals regardless of fitness level and it is the normal response to undertaking unfamiliar physical activities or increasing exertion.
  • DOMS The symptoms of DOMS include discomfort, tenderness, soreness, stiffness, swelling, fatigue and loss of strength, which can impair subsequent physical activity. This is a particular problem for professional athletes as physical training and performance may be impaired.
  • the discomfort associated with DOMS typically peaks forty eight to seventy two hours post-exercise and usually resolves within ninety six hours post-exercise.
  • the soft-tissue soreness may be exercise-induced muscle soreness.
  • Soft-tissue soreness such as DOMS and exercise-induced muscle soreness, as herein described may be due to an increase in, or an uptake of, physical activity.
  • Physical activity or exercise is any bodily movement produced by skeletal muscles that requires energy expenditure. For example, for people unaccustomed to strenuous activity, exercise may simply be standing up, whereas for more active people or athletes, exercise may be running or lifting weights.
  • the formulation of the invention may be beneficial for any person. For example, it may benefit sedentary people that undertake unfamiliar physical activity or professional athletes that undertake regular intense exercise.
  • Soft-tissue soreness may be due to an increase in a subject's physical activity compared to the usual level of physical activity of the subject.
  • the increase may be in duration and/or intensity of the physical activity. For example, an increase in duration may be running for longer than a subject would usually run, climbing more stairs than a subject would usually climb or lifting weights for a longer period of time than a subject would usually lift.
  • An increase in intensity may be, for example, running faster than a subject would usually run, climbing stairs more quickly than a subject would usually climb or lifting heavier weights than a subject usually would lift.
  • the period of time may be 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 1 week, 2 weeks, 3 weeks, 1 month, 2 months, 3 months, 6 months, 9 months, 1 year or more than 1 year.
  • Regular exercise means any activity that requires energy expenditure and/or raises a person's heart rate by 1%> to 100% of their maximum heart rate at least three or more times per week.
  • Intense exercise means any activity that could be defined as vigorous exercise or overexertion as herein described.
  • the soft-tissue soreness as herein described may be due to bruising.
  • Bruising is injury of soft-tissue that results in the breakage of local capillaries and leakage of red blood cells, often causing a red- purple discolouration of the skin that fades to a green-brown discolouration before disappearing.
  • Exercise can cause bruising as tearing of muscle tissue and connective tissue can damage small blood vessels, resulting in local bleeding. Bruising may also be caused by any bumps and knocks that cause damage to soft-tissue.
  • Soft-tissue soreness such as DOMS and exercise-induced muscle soreness
  • these treatments and preventative measures have drawbacks.
  • the effectiveness of nutritional supplementation has been shown to have inconsistent results among several studies.
  • NSAIDs have associated side-effects such as gastrointestinal distress and hypertensive effects. As such, there is a need for an alternative treatment that can be used to effectively manage discomfort on a long-term basis.
  • the formulation of the present invention is effective in the prevention and treatment of exercise and injury induced soft-tissue soreness.
  • the formulation of the present invention does not retard muscle soreness recovery after exercise compared with an oral NSAID and is therefore an improved alternative approach for the treatment of soft-tissue soreness during and post- exercise.
  • the present invention provides a novel, effective and reliable way to treat soft-tissue soreness, such as DOMS and exercise-induced muscle soreness, without associated side effects and can be used on a long-term basis.
  • All soft-tissue soreness such as DOMS and exercise-induced muscle soreness, involves a repair process that triggers an inflammatory response, resulting in the generation of inflammatory mediators and waste products. These products cause the symptoms of inflammation and sensitise nerve endings in the body, promoting discomfort. It is believed that a formulation in accordance with the present invention is able to reduce this discomfort by physically removing undesirable products.
  • topical application of the formulation allows the particles to traverse the skin and temporarily enter the extracellular interstitial spaces, eventually arriving in the lymph nodes. It is hypothesised, without wishing to be bound by any mechanism of action, that this facilitates drainage of the interstitial fluids to the lymph.
  • Enhanced drainage of the interstitial fluid assists in the removal of undesirable by-products from tissues, preventing toxic build-up of by-products and maintenance of the inflammation cascade, thus reducing the symptoms of soreness and discomfort.
  • a number of inflammatory conditions in tissues can arise as a result of local overproduction and/or accumulation of compounds that initiate the inflammation cascade, causing the normal symptoms of inflammation, pain, heat and redness.
  • overproduction and accumulation of lactate and acidosis can cause soreness at the time of anaerobic exercise and the by-products, metabolites and inflammatory mediators of the muscle repair process can cause DOMS for some time after exercise.
  • the lymphatic system is responsible for collecting and removing unwanted materials and waste products from tissues.
  • the by-products enter the interstitial fluid that surrounds the tissues and this fluid drains into the lymph capillaries where it is carried away by the lymphatic system. Removal of these undesirable by-products into the lymph is essential to prevent unnecessary damage to tissues due to maintenance of the inflammatory cascade and build-up of normal by-products to toxic levels.
  • the particles of the present invention locate in the extracellular spaces of tissues and it is thought that they may act as a form of nano-stent, proppant or scaffold, to facilitate the draining of
  • the particles of the present invention are passively driven to the lymph by muscle movement and the normal flow of the interstitial fluid. However, the particles are able to improve the flow of the interstitial fluid due to their hydration level and their ability to deform and then return to a spherical shape, thereby providing a proppant function.
  • lymphatic vessels For example, during exercise, particularly prolonged or intense periods of exercise, muscle tissues accumulate excessive amounts of respiratory and metabolic waste. The tissue relies on efficient drainage by the lymphatic vessels to expel the waste and maintain normal osmotic and pH conditions. Lymphatic capillaries have no structural component to maintain a clear lumen and are subject to closure upon compression.
  • the presence of the particles of the invention provides a means to maintain an open and fully functional local lymphatic system by entering the small vessels.
  • the internal presence of particles (vesicles) gives structural support as a proppant in which the highly hydrated particles move in response to muscular pressure and thereby maintain an effective drainage flow.
  • any type of soft-tissue soreness disclosed herein may be relieved by the vesicles of the present invention in this way.
  • the particles of the present invention are vesicles that comprise hygroscopic moieties, such as non- ionic surfactants. These moieties enable the maintenance of the essential hydration shell of the particles, thus ensuring that they remain lubricious.
  • the hygroscopic moieties also enable the robust flexibility, elasticity and deformability of the particles. It is these properties that enable the particles to penetrate the skin and enter the extracellular spaces, whilst being able to retain their integrity and return to their normal spherical shape. These properties also enable the particles to move through the extracellular spaces without becoming lodged, keeping the extracellular spaces open and encouraging drainage.
  • the particles are too large (approximately 50nm to 200nm in diameter) to enter cells or blood vessels and therefore do not enter the peripheral circulatory system prior to being transported to the lymph.
  • the particles of the present invention are able to penetrate the skin and other semi-permeable barriers and traverse to the lymph due to their adaptable and deformable nature.
  • the non-ionic surfactant when present provides flexibility to the particles and enables them to penetrate the skin through pores which are smaller in diameter than the particles themselves, whilst maintaining their integrity. Once they pass through the skin, the particles of the invention eventually present as intact particles. Efficient clearance of the particles does not occur via the cutaneous blood microvasculature (capillaries) owing to their relatively large size and as a result prevents systemic delivery. However, due to their adaptability and deformability, the particles are able to traverse quickly and easily to the lymph and through the lymph, without becoming stuck.
  • the adaptability or deformability of the particles may be determined by the ability of the particles to penetrate a barrier with pores having an average pore diameter that is smaller than the average particle diameter before the penetration.
  • the pore diameter may be at least 10%, 20%, 30%>, 40%> or 50%> smaller than the average particle diameter.
  • the particles of the present invention may have a defined non-ionic surfactant and/or phospholipid unilamellar bilayer and range in size from approximately 50nm to 200nm.
  • the formulation may contain the particles (vesicles) suspended in an aqueous buffer. The formulation may be applied topically.
  • the non-ionic surfactant and/or phospholipid have the ability to relieve soft-tissue soreness, such as DOMS and exercise-induced muscle soreness, without the use of a pharmaceutically active agent.
  • the formulation of the invention may consist essentially of a non-ionic surfactant and/or a phospholipid.
  • the formulation of the invention may include one or more of the following ingredients: co-solvents, chelators, buffers, antioxidants, preservatives, microbicides, emollients, humectants, lubricants and thickeners.
  • the formulation does not need to contain any known pharmaceutically active ingredient to achieve effective prevention or treatment of soft-tissue soreness.
  • the formulation may not contain any known pharmaceutically active ingredient acknowledged in the prevention or treatment of soft-tissue soreness, such as NSAIDs and the like.
  • the formulation of the invention and in particular, the colloidal particles of the formulation may be formulated in the absence of any pharmaceutically active agent i.e. any non-lipid non-surfactant pharmaceutically active agent.
  • a pharmaceutically active agent is herein defined as an agent that has pharmacological, metabolic or immunological activity.
  • the particles are able to elicit a therapeutic effect, namely the treatment of soft-tissue soreness, such as DOMS and exercise-induced muscle soreness.
  • a therapeutic effect namely the treatment of soft-tissue soreness, such as DOMS and exercise-induced muscle soreness.
  • the applicant believes that the particle components themselves are responsible for this effect.
  • the formulation of the invention is able (without wishing to be bound by theory) to achieve its function through the unique properties of multi-layer particles, bilayer particles, micelles or aggregates composed of a non-ionic surfactant, such as polysorbate 80 and/or a phospholipid, such as soy phosphatidylcholine.
  • the formulation of the invention may be topically applied to the skin of the subject.
  • the formulation may be topically applied to any external skin surface, in particular, to any external skin surface surrounding the soft-tissue to be treated.
  • the formulation may be topically applied to the skin over the calf, to the area on the back of the leg just below the knee joint and just above the ankle joint.
  • the formulation of the invention may be used to treat any animal.
  • the animal to be treated may be a human, a companion animal (e.g. a cat, a dog or a horse) or an agricultural animal.
  • the invention may be useful for the treatment of patients of any age, for example, patients aged from 15 years old to 100 years old.
  • the human patient may be male or female.
  • the formulation of the invention may be applied before exercise to treat pre-existing soft-tissue soreness, such as muscle soreness, and/or to prevent the onset of soft-tissue soreness, such as muscle soreness, post-exercise.
  • the formulation may be applied after exercise to treat pre-existing soft-tissue soreness and/or to prevent the onset of soft-tissue soreness due to the specific exercise.
  • the formulation may be applied immediately after exercise to treat pre-existing soft-tissue soreness and/or to prevent the onset of soft-tissue soreness due to the specific exercise.
  • immediately after exercise means from about 0, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 90, 120, 240 or 360 minutes from ceasing physical activity.
  • the formulation may also be applied both before exercise and after exercise to treat pre-existing soft-tissue soreness and/or to prevent the onset of soft-tissue soreness pre- and/or post-exercise.
  • the formulation may also be applied at any time after exercise, for example, from one day after exercise to six months after exercise.
  • the formulation may also be applied after the onset of the soft-tissue soreness, such as muscle soreness.
  • the invention comprises a formulation for use as herein described, wherein the formulation of the invention may be topically applied once, twice, three times or more per day. Alternatively the formulation may be administered on alternate days, two or three times per week, once per week or less frequently as needed.
  • the formulation may be administered over a period of one or more weeks, for example, for at least one week, two weeks, three weeks, four weeks, five weeks, six weeks, seven weeks, eight weeks, nine weeks, ten weeks, eleven weeks, or twelve weeks, sixteen weeks, twenty four weeks, four months, six months, eight months, ten months, one year, two or more years, or indefinitely as needed.
  • any amount of the formulation sufficient to treat soft-tissue soreness may be administered to the patient.
  • a 0.1 to 10 gram dose of the formulation of the invention may be administered to the patient.
  • the dose may be 1 to 10 grams, or 1 to 5 grams or about 1 gram, 2 grams, 3 grams, 4 grams, 5 grams, 6 grams, 7 grams, 8 grams, 9 grams or 10 grams.
  • the dose may be measured as the total weight of the formulation.
  • the dose can be measured as the total weight of the phospholipid(s) and/or surfactant(s) in the formulation.
  • the dose may be administered once or twice daily or as often as needed.
  • the dose may be administered once, twice, three, four, five, six, or seven times per week, or as often as needed, in accordance with the invention.
  • the dose may be administered every day, every other day, or two to three times a week, or as often as needed, in accordance with the invention.
  • a “sufficient amount”, “amount effective to”, “amount sufficient to” or “amount of the formulation sufficient to” achieve a particular result refers to an amount of the formulation of the invention is effective to produce a desired effect, which is optionally a therapeutic effect (i.e., by administration of a therapeutically effective amount).
  • a “therapeutically effective” amount is an amount that provides some alleviation, mitigation, and/or decrease in at least one clinical symptom.
  • Clinical symptoms associated with the disorder that can be treated by the methods of the invention are well-known to those skilled in the art. Further, those skilled in the art will appreciate that the therapeutic effects need not be complete or curative, as long as some benefit is provided to the subject.
  • a "sufficient amount” or “an amount sufficient to” can be an amount that is effective to treat the symptoms of soft-tissue soreness, such as DOMS and exercise- induced muscle soreness.
  • the terms “treat”, “treating” or “treatment” of mean that the severity of a subject's condition is reduced or at least partially improved or ameliorated and/or that some alleviation, mitigation or decrease in at least one clinical symptom is achieved and/or there is an inhibition or delay in the progression of the condition and/or delay in the progression of the onset of disease or illness.
  • the terms “treat”, “treating” or “treatment of also means managing the disease state.
  • the term "pharmaceutically acceptable" when used in reference to the formulation of the invention denotes that a formulation does not result in an unacceptable level of irritation in the subject to whom the formulation is administered. Preferably such level will be sufficiently low to provide a formulation suitable for approval by regulatory authorities.
  • the term "about” means a range surrounding a particular numeral value which includes that which would be expected to result from normal experimental error in making a measurement.
  • the term “about” when used in connection with a particular numerical value means +-20%, unless specifically stated to be +-1%, +-2%, +-3%, +-4%, +-5%, +-10%. +-15%, or +-20% of the numerical value.
  • the term “comprising” is inclusive or open- ended and does not exclude additional, un-recited elements or method steps; the term “consisting of excludes any element, step, or ingredient not specified; and the term “consisting essentially of excludes any element, step, or ingredient that materially changes a basic characteristic of the invention.
  • the formulation of the invention may comprise a mixture of more than one non-ionic surfactant and more than one phospholipid.
  • the formulation of the invention may comprise at least one non-ionic surfactant, at least one phospholipid, a pharmaceutically acceptable carrier, and optionally buffers, antioxidants, preservatives, microbicides, antimicrobials, emollients, co- solvents, and/or thickeners.
  • the formulation of the invention may consist essentially of a non-ionic surfactant and a phospholipid, a pharmaceutically acceptable carrier, and optionally buffers, antioxidants, preservatives, microbicides, antimicrobials, emollients, co- solvents, and/or thickeners.
  • the formulation of the invention may consist of at least one non-ionic surfactant, at least one phospholipid, a
  • pharmaceutically acceptable carrier and one or more of the following: buffers, antioxidants, preservatives, microbicides, antimicrobials, emollients, co-solvents, and thickeners.
  • Any lipid known in the art that will form a phospholipid bilayer may be used for making the formulation of the invention.
  • Table 1 lists preferred phospholipids in accordance with the invention. Table 1 :
  • the preferred lipids in the context of this disclosure are uncharged and form stable, well hydrated bilayers; phosphatidylcholines, phosphatidylethanolamme, and sphingomyelins are the most prominent representatives of such lipids. Any of those can have chains as listed in Table 1 ; the ones forming fluid phase bilayers, in which phospholipid chains are in disordered state, being preferred.
  • a preferred phospholipid is, for example, a natural phosphatidylcholine, which was formerly known as lecithin.
  • Preferred phosphatidylserines also typically originate from brain material whereas
  • phosphatidylglycerol is preferentially extracted from bacteria, such as E. coli, or else prepared by way of transphosphatidylation, using phospholipase D, starting with a natural phosphatidylcholine.
  • bacteria such as E. coli
  • phospholipase D phospholipase D
  • the preferably used phosphatidylmositols are isolated from commercial soybean phospholipids or bovine liver extracts.
  • the preferred phosphatidic acid is either extracted from any of the mentioned sources or prepared using phospholipase D from a suitable phosphatidylcholine.
  • Synthetic phosphatidylcholines synthetic phosphatidylethanolammes, synthetic phosphatidic acids, synthetic phosphatidylserines, synthetic phosphatidyl(poly)alcohols, such as phosphatidylinositol, or synthetic phosphatidylglycerol may also be used in accordance with the invention.
  • Suitable lipids furthermore are a lysophosphatidyl choline analog, such as 1- lauroyl-1,3- dihydroxypropane-3-phosphoryl choline, a monoglyceride, such as monoolein or monomyristin, a cerebroside, ceramide polyhexoside, sulfatide, sphingoplasmalogen, a ganglioside or a glyceride, which does not contain a free or esterified phosphoryl or phosphono or phosphino group in the 3 position.
  • a lysophosphatidyl choline analog such as 1- lauroyl-1,3- dihydroxypropane-3-phosphoryl choline
  • a monoglyceride such as monoolein or monomyristin
  • a cerebroside such as monoolein or monomyristin
  • ceramide polyhexoside such as monoolein or monomyristin
  • sulfatide such as a
  • glyceride is diacylglyceride or 1 -alkenyl- l-hydroxy-2-acyl glyceride with any acyl or alkenyl groups, wherein the 3 -hydroxy group is etherified by one of the
  • carbohydrate groups named, for example, by a galactosyl group such as a monogalactosyl glycerin.
  • Lipids with desirable head or chain group properties can also be formed by biochemical means, for example, by means of phospholipases (such as phospholipase Al, A2, B, C and, in particular, D), desaturases, elongases, acyl transferases, etc., from natural or synthetic precursors.
  • phospholipases such as phospholipase Al, A2, B, C and, in particular, D
  • desaturases desaturases
  • elongases acyl transferases, etc.
  • a suitable phospholipid is any phospholipid, which is contained in biological membranes and can be extracted with the help of apolar organic solvents, such as chloroform.
  • lipids also include, for example, steroids, such as estradiol, or sterols, such as cholesterol, beta-sitosterol, desmosterol, 7-keto-cholesterol or beta-cholestanol, fat-soluble vitamins, such as retinoids, vitamins, such as vitamin Al or A2, vitamin E, vitamin K, such as vitamin Kl or K2 or vitamin Dl or D3, etc.
  • the less soluble amphiphilic components comprise or preferably comprise a synthetic phospholipid, such as myristoleoyl, palmitoleoyl, petroselinyl, petroselaidyl, oleoyl, elaidyl, cis- or trans-vaccenoyl, linolyl, linolenyl, linolaidyl, octadecatetraenoyl, gondoyl, eicosaenoyl, eicosadienoyl.
  • a synthetic phospholipid such as myristoleoyl, palmitoleoyl, petroselinyl, petroselaidyl, oleoyl, elaidyl, cis- or trans-vaccenoyl, linolyl, linolenyl, linolaidyl, octadecatetraenoyl, gondoy
  • eicosatrienoyl arachidoyl, cis- or trans-docosaenoyl, docosadienoyl, docosatrienoyl, docosatetraenoyl, lauroyl, tridccanoyl.
  • myristoyl pentadccanoyl, palmitoyl, heptadecanoyl, stearoyl or nonadecanoyl, glycerophospholipid or corresponding derivatives with branched chains or a corresponding dialkyl or sphingosin derivative, glycolipid or other diacyl or dialkyl phospholipid.
  • the more soluble amphiphilic components(s) is/are frequently derived from the less soluble components listed above and, to increase the solubility, substituted and/or complexed and/or associated with a butanoyl, pentanoyl, hexanoyl, heptanoyl, octanoyl, nonanoyl, decanoyl or undecanoyl substituent or several, mutually independent, selected substituents or with a different material for improving the solubility.
  • a further suitable phospholipid is a diacyl- or dialkyl-glycerophosphoetha- nolamine azo
  • polyethoxylene derivative a didecanoylphosphatidyl choline or a
  • the amount of phospholipid in the formulation of the invention may range from about 0% to about 12%, about 0% to about 10%, about 0% to about 4%, about 4% to about 7% or about 7% to about 10% by weight.
  • the phospholipid is a phosphatidylcholine.
  • the formulation of the invention may include a surfactant.
  • surfactant has its usual meaning.
  • a list of relevant surfactants and surfactant related definitions is provided in EP 0 475 160 Al (see, e.g., p. 6, 1. 5 to p.l4. 1.17) and U.S. Pat. No. 6,165,500 (see, e g., col. 7, 1. 60 to col. 19, 1. 64), and in appropriate surfactant or pharmaceutical Handbooks, such as Handbook of Industrial Surfactants or US Pharmacopoeia, Pharm. Eu.
  • the surfactants may be those described in Tables 1-18 of U.S. Patent Application Publication No. 2002/0012680 Al, published January 31, 2002.
  • surfactants to be used in accordance with the disclosure include those with an HLB greater than 12.
  • the list includes ionized long-chain fatty acids or long chain fatty alcohols, long chain fatty ammonium salts, such as alkyl- or alkenoyl-trimethyl-, -dimethyl- and - methyl- ammonium salts, alkyl- or alkenoyl-sulphate salts, long fatty chain dimethyl- aminoxides, such as alkyl- or alkenoyl-dimethyl-aminoxides, long fatty chain, for example alkanoyl, dimethyl-aminoxides and especially dodecyl dimethyl-aminoxide, long fatty chain, for example alkyl-N-methylglucamide- s and alkanoyl-N-methylglucamides.
  • N-long fatty chain- ⁇ , ⁇ -dimethylglycines for example N-alkyl- N,N-dimethylglycines
  • 3 -(long fatty chain- dimethylammonio)-alkane- sulphonates for example 3-(acyidimethylammonio)-alkanesulphonatcs
  • long fatty chain derivatives of sulphosuccinate salts such as bis(2-ethylalkyl) sulphosuccinate salts
  • long fatty chain- sulphobetaines for example acyl-sulphobetaines, long fatty chain betaines, such as EMPIGEN BB or ZWITTERGENT-3-16, -3-14, -3-12, -3-10, or -3-8
  • polyethylcn-glycol- acylphenyl ethers especially nonaethylen-glycol-octyl
  • polyethyleneglycol-sorbitane-acyl esters and especially polyoxyethylene- monolaurate e.g.
  • polysorbate 20 or Tween 20 polyoxyethylene-sorbitan-monooleate (e.g. polysorbate 80 or Tween 80), polyoxyethylene-sorbitan-monolauroleylate, polyoxyethylene - sorbitan-monopetroselinate, polyoxyethylene -sorbitan- monoelaidate, polyoxyethylene - sorbitan-myristoleylate, polyoxyethylene -sorbitan-palmitoleinylate, polyoxyethylene- sorbitan-p- etroselinylate, polyhydroxyethylene-long fatty chain ethers, for example polyhydroxyethylene-acyl ethers, such as polyhydroxyethylene-lauryl ethers, polyhydroxyethylene-myristoyl ethers, polyhydroxyethylene-cetylst- earyl, polyhyd roxyethylene-palmityl ethers, polyhydroxyethylene-oleoyl ethers, polyhydroxyethylene- palmitoleoyl ethers, polyhydroxyethylene-lino-
  • polyhydroxyethylen-8-stearate Myrj 45 and polyhydroxyethylen-8 -oleate, polyethoxylated castor oil 40 (Cremophor EL), sorbitane-mono long fatty chain, for example alkylate (Arlacel or Span series), especially as sorbitane-monolaurate (Arlacel 20, Span 20), long fatty chain, for example acyl-N- methylglucamides, alkanoyl-N-methylglucamides, especially decanoyl-N-methylglucamide, dodecanoyl-N-methylglucamide, long fatty chain sulphates, for example alkyl-sulphates, alkyl sulphate salts, such as lauryl-sulphate (SDS), oleoyl-sulphate: long fatty chain thioglucosides, such as alkylthioglucosides and especially heptyl-, octyl-
  • the surfactant in the formulation of the invention is a non-ionic surfactant.
  • the surfactant may be present in the formulation in about 0% to about 1%, about 0.1% to about 5%, about 0.2%> to about 4%, about 0.5% to about 10%, about 1% to about 9%, about 1.5% to about 7%, about 2% to about 6% or about 3% to about 8% by weight.
  • the non-ionic surfactant may be selected from the group consisting of: polyoxyethylene sorbitans (polysobate surfactants), polyhydroxyethylene stearates or polyhydroxyethylene laurylethers (Brij surfactants).
  • the surfactant may be a polyoxyethylene- sorbitan- monooleate (e.g.
  • polysorbate 80 or Tween 80) or Tween 20, 40 or 60 can have any chain with 12 to 20 carbon atoms.
  • the polysorbate may be fluid in the formulation, which may contain one or more double bonds, branching, or cyclo-groups.
  • the formulation of the invention may comprise only one non-ionic surfactant.
  • the formulation of the invention may comprise only one non-ionic surfactant and/or only one phospholipid.
  • the formulation of the invention may comprise one or more than one non-ionic surfactant and/or one or more than one phospholipid, e.g., independently one, two, three, four, or more non-ionic surfactants and/or one, two, three, four or more phospholipids.
  • the formulation of the invention may have a range of phospholipid to surfactant ratios.
  • the ratios may be expressed in terms of molar terms (mol phospholipid/mol surfactant). They may also be expressed as % weight.
  • the weight ratio of phospholipid to surfactant in the formulation may be from about 20: 1 to about 5: 1, from about 15: 1 to about 10: 1 , from about 12: 1 to about 9: 1 , from about 18: 1 to about 14: 1.
  • the formulation of the invention may also have varying amounts of total amount of the following components: phospholipid and surfactant combined (TA).
  • the TA amount may be stated in terms of weight percent of the total composition.
  • the TA may be from about 1% to about 40%, about 5% to about 30%), about 7.5% to about 15%, about 6% to about 14%, about 8% to about 12%, about 5% to about 10%, about 10% to about 20% or about 20% to about 30%.
  • the TA may be 6%, 7%, 8%, 9%, 10%, 12%, 14%, 15% or 20%.
  • the molar ratio of phospholipid to surfactant in the formulation of the invention may be from about 1:3 to about 30:0, from about 1:3 to about 30:1, from about 1:2 to about 30:1, from about 1:1 to about 30:0, from about 1:1 to about 30:1, from about 2:1 to about 20:0, from about 2:1 to about 20:1, from about 5:1 to about 30:1, from about 10:1 to about 30:1, from about 15:1 to about 30:1, or from about 20: 1 to about 30:1.
  • the molar ratio of phospholipid to surfactant in the formulation may be from about 1 :2 to about 10:1.
  • the molar ratio may be from about 1 : 1 to about 2: 1 , from about 2: 1 to about 3:1, from about 3:1 to about 4:1, from about 4:1 to about 5:1 or from about 5:1 to about 10:1.
  • the molar ratio may be from about 10.1 to about 30:1, from about 10:1 to about 20:1, from about 10:1 to about 25:1, and from about 20:1 to about 25:1.
  • the phospholipid to surfactant ratio may be about 1.0:1.0, about 1.25:1.0, about 1.5:1.0, about 1.75:1.0, about 2.0:1.0, about 2.5:1.0, about 3.0:1.0 or about 4.0:1.0.
  • Table 2 Total Amount and Phospholipid to Surfactant Ratios.
  • the formulation of the invention may optionally contain one or more of the following ingredients: co- solvents, chelators, buffers, antioxidants, preservatives, microbicides, emollients, humectants, lubricants and thickeners. Preferred amounts of optional components are described as follows in Table 3.
  • the formulation of the invention is typically formulated and/or administered in an aqueous medium.
  • the formulation may be formulated with or without co-solvents, such as lower alcohols.
  • the formulation of the present invention may also comprise a polar liquid medium.
  • the formulation may be in the form of a solution, suspension, emulsion, cream, lotion, ointment, gel, spray, film forming solution or lacquer.
  • the formulation of the present invention is in the form of a gel.
  • the formulation of the invention may include a buffer to adjust the pH of the aqueous solution to a range from pH 3.5 to pH 9, pH 4 to pH 7.5, or pH 6 to pH 7.
  • buffers include, but are not limited to acetate buffers, lactate buffers, phosphate buffers, and propionate buffers.
  • microbicide or “antimicrobial”' agent is commonly added to reduce the bacterial count in pharmaceutical formulations.
  • Some examples of microbicides are short chain alcohols, including ethyl and isopropyl alcohol, chlorbutanol, benzyl alcohol, chlorbenzyl alcohol, dichlorbenzylalcohol, hexachlorophene; phenolic compounds, such as cresol, 4-chloro-m-cresol, p-chloro-m-xylenol.
  • dichlorophene hexachlorophene, povidon- iodine
  • parabenes especially alkyl-parabenes, such as methyl-, ethyl-, propyl-, or butyl- paraben, benzyl paraben
  • acids such as sorbic acid, benzoic acid and their salts
  • quaternary ammonium compounds such as alkonium salts, e.g., a bromide, benzalkonium salts, such as a chloride or a bromide, cetrimonium salts, e.g., a bromide,
  • phenoalkecinium salts such as phenododecinium bromide, cetylpyridinium chloride and other salts; furthermore, mercurial compounds, such as phenylmercuric acetate, borate, or nitrate, thiomersal, chlorhexidine or its gluconate, or any antibiotically active compounds of biological origin, or any suitable mixture thereof.
  • antioxidants are butylated hydroxyanisol (BHA), butylated hydroxytoluene (BHT) and di-tert-butylphenol (LY178002, LY256548, HWA-131, BF-389, CI-986, PD-127443, E-51 or 19, BI- L-239XX, etc.), tertiary butylhydroquinone (TBHQ), propyl gallate (PG), l-O-hexyl-2,3,5- trimethylhydroquinone (HTHQ); aromatic amines (diphenylamine, p-alkylthio-o-anisidine, ethylenediamine derivatives, carbazol, tetrahydroindenoindol); phenols and phenolic acids (guaiacol, hydroquinone, vanillin, gallic acids and their esters, protocatechuic acid, quinic acid, syringic acid, ellagic acid, salicylic acid
  • tocopheryl-POE-succinate tocopheryl-POE-succinate; trolox and corresponding amide and thiocarboxamide analogues; ascorbic acid and its salts, isoascorbate, (2 or 3 or 6)-o-alkylascorbic acids, ascorbyl esters (e.g., 6-o-lauroyl, myristoyl, palmitoyl-, oleoyl, or linoleoyl-L-ascorbic acid, etc.).
  • tocopheryl-POE-succinate trolox and corresponding amide and thiocarboxamide analogues
  • ascorbic acid and its salts isoascorbate, (2 or 3 or 6)-o-alkylascorbic acids, ascorbyl esters (e.g., 6-o-lauroyl, myristoyl, palmitoyl-, oleoyl, or linoleoyl-L-a
  • oxidised compounds such as sodium bisulphite, sodium metabisulphite, thiourea; chellating agents, such as EDTA, GDTA, desferral: miscellaneous endogenous defence systems, such as transferrin, lactoferrin, ferritin, cearuloplasmin, haptoglobion, heamopexin, albumin, glucose, ubiquinol-10); enzymatic antioxidants, such as superoxide dismutase and metal complexes with a similar activity, including catalase, glutathione peroxidase, and less complex molecules, such as beta- carotene, bilirubin, uric acid; flavonoids (flavones, flavonols, flavonones, flavanonals, chacones, anthocyanins).
  • chellating agents such as EDTA, GDTA, desferral: miscellaneous endogenous defence systems, such as transferrin, lactoferrin, ferr
  • thioethers dithioethers, sulphoxides, tetralkylthiuram disulphides; phytic acid, steroid derivatives (e.g., U74006F); tryptophan metabolites (e.g., 3-hydroxykynurenine, 3-hydroxyanthranilic acid), and organochalcogenides.
  • Thickeners are used to increase the viscosity of pharmaceutical formulations and may be selected from pharmaceutically acceptable hydrophilic polymers, such as partially etherified cellulose derivatives, comprising carboxym ethyl-, hydroxyethyl-, hydroxypropyl-, hydroxypropylmethyl- or methyl-cellulose; completely synthetic hydrophilic polymers such as polyacrylates (e.g. Carbopol®), polymethacrylatcs, poly(hydroxyethyl)-, poly(hydroxypropyl)-,
  • pharmaceutically acceptable hydrophilic polymers such as partially etherified cellulose derivatives, comprising carboxym ethyl-, hydroxyethyl-, hydroxypropyl-, hydroxypropylmethyl- or methyl-cellulose
  • completely synthetic hydrophilic polymers such as polyacrylates (e.g. Carbopol®), polymethacrylatcs, poly(hydroxyethyl)-, poly(hydroxypropyl)-,
  • the invention also provides a method of preventing or treating soft-tissue soreness in a subject, such as DOMS or exercise-induced muscle soreness, the method comprising topically applying a formulation of colloidal particles comprising a non-ionic surfactant and/or a phospholipid to the skin surrounding the soft-tissue to be treated in a subject in need thereof, wherein the formulation is free of any pharmaceutically active agent, and wherein the tissue soreness is prevented or treated.
  • the invention provides a pharmaceutical package or kit comprising one or more containers filled with a formulation of the invention, and instructions for administration of the formulation to a patient or subject in need thereof, for use in the treatment of soft-tissue soreness, such as DOMS or exercise-induced muscle soreness.
  • the container may comprise a formulation formulated as a suspension, emulsion, gel, cream, lotion, spray, film forming solution or lacquer.
  • the invention provides packages or kits that can be used in any of the above-described methods or uses.
  • Figure 1 shows the number of participants that received each treatment arm of the study described in Example 4.
  • Figure 2 shows the mean muscle soreness scores over time for patients that received each treatment arm of the study described in Example 4.
  • the vesicular formulation of the present invention may be prepared by the following procedure:
  • the organic phase is produced by weighing the lipid, the surfactant, any additional lipophilic excipients into suitable containers followed by mixing these components into anoptically isotropic phase which appears as a clear solution. During mixing, the organic phase will be heated up, but temperature must not rise above 45 °C.
  • the aqueous phase is prepared by weighing the non-lipophilic components and water, which serves as solvent, into suitable containers and then mixing these components into a clear solution. During mixing, the temperature will be elevated to 40 °C.
  • the isotropic organic phase and the clear aqueous phase are combined under stirring in a suitable vessel. Before and during the combination the temperature of both phases must be kept between 35 °C and 45 °C.
  • the resulting intermediate is homogenised mechanically at 40 °C. Before starting homogenisation, the pressure in the production vessel is lowered to -0.08 MPa. The desired average carrier size is typically reached after 30 minutes of homogenisation. Three process parameters must be controlled carefully during the production of the concentrated intermediate: temperature, homogeniser circulation velocity, and overall processing time.
  • the concentrated intermediate is diluted with the dilution buffer to the intended final concentration.
  • the mixture is carefully stirred in the mixing vessel at 20 °C to homogeneity.
  • Formulation 1 comprises phosphatidyl choline (50.000 mg/g) as a lipid, Polysorbate 80 (40.000 mg/g) as a surfactant, phosphate (pH 6.5) buffer, benzyl alcohol or paraben (5.000 mg/g) as an
  • BHT (0.200 mg/g) and sodium metabisulfite (0.500 mg/g) as antioxidants
  • glycerol 30.000 mg/g
  • EDTA 3.000 mg/g
  • ethanol 30.000 mg/g
  • Formulation 2 comprises phosphatidyl choline (38.571 mg/g) as a lipid, Polysorbate 80 (51.429 mg/g) as a surfactant, phosphate (pH 6.5) buffer, benzyl alcohol or paraben (5.000 mg/g) as an
  • BHT (0.200 mg/g) and sodium metabisulfite (0.500 mg/g) as antioxidants, glycerol (30.000 mg/g), EDTA (3.000 mg/g), and ethanol (30.000 mg/g).
  • Formulation 3 comprises phosphatidyl choline (41.954 mg/g) as phospholipid, Polysorbate 80 (50.546 mg/g) as surfactant, phosphate (pH 6.5) buffer,benzyl alcohol or paraben (5.000 mg/g) as an antimicrobial, BHT (0.200 mg/g) and sodium metabisulfite (0.500 mg/g) as antioxidants, glycerol (30,000 mg/g), EDTA (3.000 mg/g), and thanol (30.000 mg/g).
  • Example Formulation 4 comprises phosphatidyl choline (41.954 mg/g) as phospholipid, Polysorbate 80 (50.546 mg/g) as surfactant, phosphate (pH 6.5) buffer,benzyl alcohol or paraben (5.000 mg/g) as an antimicrobial, BHT (0.200 mg/g) and sodium metabisulfite (0.500 mg/g) as antioxidants, glycerol (30,000 mg/g), EDTA (3.000 mg/g), and thano
  • Formulation 4 comprises phosphatidyl choline (42.632 mg/g) as a lipid, Polysorbate 80 (47.368 mg/g) as a surfactant, phosphate (pH 6.5) buffer, benzyl alcohol or paraben (5.000 mg/g) as an
  • BHT (0.200 mg/g) and sodium metabisulfite (0.500 mg/g) as antioxidants
  • glycerol 30.000 mg/g
  • EDTA 3.000 mg/g
  • ethanol 30.000 mg/g
  • Formulation 5 comprises phosphatidyl choline (46.098 mg/g) as a lipid, Polysorbate 80 (43.902 mg/g) as a surfactant, phosphate (pH 6.5) buffer, benzyl alcohol or paraben (5.000 mg/g) as an
  • BHT (0.200 mg/g) and sodium metabisulfite (0.500 mg/g) as antioxidants
  • glycerol 30.000 mg/g
  • EDTA 3.000 mg/g
  • ethanol 30.000 mg/g
  • Formulation 6 comprises phosphatidyl choline (39.721 mg/g) as a lipid, Polysorbate 80 (50.279 mg/g) as a surfactant, phosphate (pH 6.5) buffer, benzyl alcohol or paraben (5.000 mg/g) as an
  • BHT (0.200 mg/g) and sodium metabisulfite (0.500 mg/g) as antioxidants
  • glycerol 30.000 mg/g
  • EDTA 3.000 mg/g
  • ethanol 30.000 mg/g
  • Formulation 7 comprises phosphatidyl choline (44.198 mg/g) as a lipid, Polysorbate 80 (50.802 mg/g) as a surfactant, phosphate (pH 6.5) buffer, benzyl alcohol or paraben (5.000 mg/g) as an
  • BHT (0.200 mg/g) and sodium metabisulfite (0.500 mg/g) as antioxidants
  • glycerol 30.000 mg/g
  • EDTA 3.000 mg/g
  • ethanol 30.000 mg/g
  • Formulation 8 comprises phosphatidyl choline (46.453 mg/g) as a lipid, Polysorbate 80 (51.047 mg/g) as a surfactant, phosphate (pH 6.5) buffer, benzyl alcohol or paraben (5.000 mg/g) as an antimicrobial, BHT (0.200 mg/g) and sodium metabisulfite (0.500 mg/g) as antioxidants, glycerol (30.000 mg/g), EDTA (3.000 mg/g) as a chelating agent, and ethanol (30.000 mg/g).
  • Formulation 9 comprises phosphatidyl choline (51.221 mg/g) as a lipid, Polysorbate 80 (43.779 m; as a surfactant, phosphate (pH 6.5) buffer, benzyl alcohol or paraben (5.000 mg/g) as an antimicrobial, BHT (0.200 mg/g) and sodium metabisulfite (0.500 mg/g) as antioxidants, glycerol (30.000 mg/g), EDTA (3.000 mg/g) as a chelating agent, and ethanol (30.000 mg/g).
  • Polysorbate 80 (43.779 m; as a surfactant, phosphate (pH 6.5) buffer, benzyl alcohol or paraben (5.000 mg/g) as an antimicrobial, BHT (0.200 mg/g) and sodium metabisulfite (0.500 mg/g) as antioxidants, glycerol (30.000 mg/g), EDTA (3.000 mg/g) as a chelating agent, and ethanol (30.000 mg/g).
  • Formulation 10 comprises phosphatidyl choline (54.167 mg/g) as a lipid, Polysorbate 80 (43.333 mg/g) as a surfactant, phosphate (pH 6.5) buffer, benzyl alcohol or paraben (5.000 mg/g) as an antimicrobial, BHT (0.200 mg/g) and sodium metabisulfite (0.500 mg/g) as antioxidants, glycerol (30.000 mg/g), EDTA (3.000 mg/g) as a chelating agent, and ethanol (30.000 mg/g).
  • Formulation 11 comprises phosphatidyl choline (40.000 mg/g) as a lipid, Polysorbate 80 (50.000 mg/g) as a surfactant, phosphate (pH 6.5) buffer, benzyl alcohol or paraben (5.000 mg/g) as an antimicrobial, BHT (0.200 mg/g) and sodium metabisulfite (0.500 mg/g) as antioxidants, glycerol (30.000 mg/g), EDTA (3.000 mg/g) as a chelating agent, and ethanol (30.000 mg/g).
  • Example formulation 11 is an emulsion.
  • Formulation 12 comprises phosphatidyl choline (40.000 mg/g) as a lipid, Polysorbate 80 (50.000 mg/g) as a surfactant, phosphate (pH 6.5) buffer, benzyl alcohol or paraben (5.000 mg/g) as an antimicrobial, BHT (0.200 mg/g) and sodium metabisulfite (0.500 mg/g) as antioxidants, glycerol (30.000 mg/g), EDTA (3.000 mg/g) as a chelating agent, and ethanol (30.000 mg/g).
  • Example formulation 12 is a suspension.
  • Formulation 13 comprises phosphatidyl choline (40.000 mg/g) as a lipid, Polysorbate 80 (50.000 mg/g) as a surfactant, phosphate (pH 6.5) buffer, benzyl alcohol or paraben (5.000 mg/g) as an antimicrobial, BHT (0.200 mg/g) and sodium metabisulfite (0.500 mg/g) as antioxidants, glycerol (30.000 mg/g), EDTA (3.000 mg/g) as a chelating agent, and ethanol (30.000 mg/g).
  • Formulation 14 comprises phosphatidyl choline (40.000 mg/g) as a lipid, Polysorbate 80 (50.000 mg/g) as a surfactant, phosphate (pH 6.5) buffer, benzyl alcohol or paraben (5.000 mg/g) as an antimicrobial, BHT (0.200 mg/g) and sodium metabisulfite (0.500 mg/g) as antioxidants, glycerol (30.000 mg/g), EDTA (3.000 mg/g) as a chelating agent, and ethanol (30.000 mg/g).
  • Formulation 15 comprises phosphatidyl choline (39.721 mg/g) as a lipid, Polysorbate 80 (50.279 mg/g) as a surfactant, phosphate (pH 6.5) buffer, benzyl alcohol or paraben (5.25 mg/g) as an antimicrobial, BHT (0.200 mg/g) and sodium metabisulfite (0.500 mg/g) as antioxidants, glycerol (30.000 mg/g), EDTA (3.000 mg/g) as a chelating agent, and ethanol (30.000 mg/g).
  • Formulation 16 comprises phosphatidyl choline (90.000 mg/g) as a lipid, Polysorbate 80 (8.500 mg/g), phosphate buffer (pH 6.5), benzyl alcohol or paraben as an antimicrobial, BHT (0.200 mg/g) and sodium metabisulfite (0.500 mg/g) as antioxidants, glycerol (30.000 mg/g), EDTA (3.000 mg/g) as a chelating agent, and ethanol (30.000 mg/g).
  • Formulation 17 comprises phosphatidyl choline (68.700 mg/g) as a lipid, Polysorbate 80 (8.500 mg/g) as a surfactant, phosphate (pH 7.5) buffer, BHT (0.200 mg/g) and sodium metabisulfite (0.500 mg/g) as antioxidants, benzyl alcohol or paraben (5.000 mg/g) as an antimicrobial, glycerol (30.000 mg/g), EDTA (1.000 mg/g) as a chelating agent, and ethanol (36.51 mg/g).
  • Polysorbate 80 8.500 mg/g) as a surfactant
  • phosphate (pH 7.5) buffer BHT (0.200 mg/g) and sodium metabisulfite (0.500 mg/g) as antioxidants
  • benzyl alcohol or paraben 5.000 mg/g) as an antimicrobial
  • glycerol 30.000 mg/g
  • EDTA 1.000 mg/g
  • ethanol 36.51 mg/g
  • Formulation 18 comprises phosphatidyl choline (71.460 mg/g) as a lipid, Polysorbate 80 (4.720 mg/g) as a surfactant, phosphate (pH 7.8) buffer, BHA (0.200 mg/g) and sodium metabisulfite (0.500 mg/g) as antioxidants, benzyl alcohol or paraben (5.000 mg/g) as an antimicrobial, glycerol (50.000 mg/g), EDTA (3.000 mg/g) as a chelating agent, and ethanol (35.000 mg/g).
  • Formulation 19 comprises phosphatidyl choline (71.460 mg/g) as a lipid, Polysorbate 80 (4.720 mg/g) as a surfactant, phosphate (pH 7.8) buffer, BHA (0.200 mg/g) and sodium metabisulfite (0.500 mg/g) as antioxidants, benzyl alcohol or paraben (5.000 mg/g) as an antimicrobial, glycerol (15.000 mg/g), EDTA (3.000 mg/g) as a chelating agent, and ethanol (35.000 mg/g).
  • Formulation 20 comprises phosphatidyl choline (71.460 mg/g) as a lipid, Polysorbate 80 (4.720 mg/g) as a surfactant, phosphate (pH 7.8) buffer, BHA (0.200 mg/g) and sodium metabisulfite (0.500 mg/g) as antioxidants, glycerol (50.000 mg/g), EDTA (3.000 mg/g) as a chelating agent, and ethanol (15.000 mg/g).
  • Formulation 21 comprises phosphatidyl choline (39.72 mg/g)as a lipid, Polysorbate 80 (50.279 mg/g) as surfactant, phosphate (pH 6.5) buffer, benzyl alcohol or paraben (5.00 mg/g) as an antimicrobial, BHT (0.200 mg/g) and sodium metabisulfite (0.500 mg/g) as antioxidants, glycerol (30.000 mg/g) as emollient, EDTA (3.000 mg/g) as the chelating agent, and ethanol (30.000 mg/g).
  • Example Formulation 22 Example Formulation 22
  • Formulation 22 comprises phosphatidyl choline and lysophospholipid (50.000 mg/g) as a lipid, Polysorbate 80 (40.000 mg/g) as a surfactant, phosphate (pH 6.5) buffer, benzyl alcohol or paraben (5.000 mg/g) as an antimicrobial, BHT (0.200 mg/g) and sodiummetabisulfite (0.500 mg/g) as antioxidants, glycerol (30.000 mg/g), EDTA (3.000 mg/g) as a chelating agent, and ethanol (30.000 mg/g).
  • Formulation 23 comprises phosphatidyl choline and lysophospholipid (38.571mg/g) as a lipid, Polysorbate 80 (51.429 mg/g) as a surfactant, phosphate (pH 6.5) buffer, benzyl alcohol or paraben (5.000 mg/g) as an antimicrobial, BHT (0.200 mg/g) and sodium metabisulfite (0.500 mg/g) as antioxidants, glycerol (30.000 mg/g), EDTA (3.000 mg/g), and ethanol (30.000 mg/g).
  • Formulation 24 comprises phosphatidyl choline and lysophospholipid (41.954 mg/g) as phospholipid, Polysorbate 80 (50.546 mg/g) as surfactant, phosphate (pH 6.5) buffer, benzyl alcohol or paraben (5.000 mg/g) as an antimicrobial, BHT (0.200 mg/g) and sodium metabisulfite (0.500 mg/g) as antioxidants, glycerol (30.000 mg/g), EDTA (3.000 mg/g), and ethanol (30.000 mg/g).
  • Formulation 25 comprises phosphatidyl choline and lysophospholipid (42.632 mg/g) as a lipid, Polysorbate 80 (47.368 mg/g) as a surfactant, phosphate (pH 6.5) buffer, benzyl alcohol or paraben (5.000 mg/g) as an antimicrobial, BHT (0.200 mg/g) and sodium metabisulfite (0.500 mg/g) as antioxidants, glycerol (30.000 mg/g), EDTA (3.000 mg/g) as a chelating agent, and ethanol (30.000 mg/g).
  • Example Formulation 26 Example Formulation 26
  • Formulation 26 comprises phosphatidyl choline and lysophospholipid (46.098 mg/g) as a lipid, Polysorbate 80 (43.902 mg/g) as a surfactant, phosphate (pH 6.5) buffer, benzyl alcohol or paraben (5.000 mg/g) as an antimicrobial, BHT (0.200 mg/g) and sodium metabisulfite (0.500 mg/g) as antioxidants, glycerol (30.000 mg/g), EDTA (3.000 mg/g) as a chelating agent, and ethanol (30.000 mg/g).
  • Formulation 27 comprises phosphatidyl choline and lysophospholipid (39.721mg/g) as a lipid, Polysorbate 80 (50.279 mg/g) as a surfactant, phosphate (pH 6.5) buffer, benzyl alcohol or paraben (5.000 mg/g) as an antimicrobial, BHT (0.200 mg/g) and sodium metabisulfite (0.500 mg/g) as antioxidants, glycerol (30.000 mg/g), EDTA (3.000 mg/g) as a chelating agent, and ethanol (30.000 mg/g).
  • Formulation 28 comprises phosphatidyl choline and lysophospholipid (44.198 mg/g) as a lipid, Polysorbate 80 (50.802 mg/g) as a surfactant, phosphate (pH 6.5) buffer, benzyl alcohol or paraben (5.000 mg/g) as an antimicrobial, BHT (0.200 mg/g) and sodium metabisulfite (0.500 mg/g) as antioxidants, glycerol (30.000 mg/g), EDTA (3.000 mg/g) as a chelating agent, and ethanol (30.000 mg/g).
  • Formulation 29 comprises phosphatidyl choline and lysophospholipid (46.453 mg/g) as a lipid, Polysorbate 80 (51.047 mg/g) as a surfactant, phosphate (pH 6.5) buffer, benzyl alcohol or paraben (5.000 mg/g) as an antimicrobial, BHT (0.200 mg/g) and sodium metabisulfite (0.500 mg/g) as antioxidants, glycerol (30.000 mg/g), EDTA (3.000 mg/g) as a chelating agent, and ethanol (30.000 mg/g).
  • Example Formulation 30 comprises phosphatidyl choline and lysophospholipid (46.453 mg/g) as a lipid, Polysorbate 80 (51.047 mg/g) as a surfactant, phosphate (pH 6.5) buffer, benzyl alcohol or paraben (5.000 mg/g) as an antimicrobial, BHT (0.200 mg/g) and sodium metabisulfite (0.500 mg/
  • Formulation 30 comprises phosphatidyl choline and lysophospholipid (51.221 mg/g) as a lipid, Polysorbate 80 (43.779 mg/g) as a surfactant, phosphate (pH 6.5) buffer, benzyl alcohol or paraben (5.000 mg/g) as an antimicrobial, BHT (0.200 mg/g) and sodium metabisulfite (0.500 mg/g) as antioxidants, glycerol (30.000 mg/g), EDTA (3.000 mg/g) as a chelating agent, and ethanol (30.000 mg/g).
  • Formulation 31 comprises phosphatidyl choline (54.167 mg/g) as a lipid, Polysorbate 80 (43.333 mg/g) as a surfactant, phosphate (pH 6.5) buffer, benzyl alcohol or paraben (5.000 mg/g) as an antimicrobial, BHT (0.200 mg/g) and sodium metabisulfite (0.500 mg/g) as antioxidants, glycerol (30.000 mg/g), EDTA (3.000 mg/g) as a chelating agent, and ethanol (30.000 mg/g).
  • Formulation 32 comprises phosphatidyl choline (68.700 mg/g) as a lipid, Polysorbate 80 (8.500 mg/g) as a surfactant, phosphate (pH 7.5) buffer, BHT (0.200 mg/g) and sodium metabisulfite (0.500 mg/g) as antioxidants, benzyl alcohol or paraben (5.000 mg/g) as an antimicrobial, glycerol (30.000 mg/g), EDTA (1.000 mg/g) as a chelating agent, ethanol (36.51 mg/g) and Carbopol® (12.500 mg/g).
  • Formulation 33 comprises phosphatidyl choline (71.460 mg/g) as a lipid, Polysorbate 80 (4.720 mg/g) as a surfactant, phosphate (pH 7.8) buffer, BHA (0.200 mg/g), benzyl alcohol or paraben (10.0 mg/g) as an antimicrobial, glycerol (50.000 mg/g), EDTA (3.000 mg/g) as a chelating agent, and ethanol (30.000 mg/g).
  • Formulation 34 comprises phosphatidyl choline (68.700 mg/g) as a lipid, phosphate (pH 7.5) buffer, BHT (0.200 mg/g) and sodium metabisulfite (0.500 mg/g) as antioxidants, benzyl alcohol or paraben (5.000 mg/g) as an antimicrobial, glycerol (30.000 mg/g), EDTA (1.000 mg/g) as a chelating agent, ethanol (36.51 mg/g) and Carbopol® (12.500 mg/g).
  • Formulation 35 comprises Polysorbate 80 (8.500 mg/g) as a surfactant, phosphate (pH 7.5) buffer, BHT (0.200 mg/g) and sodium metabisulfite (0.500 mg/g) as antioxidants, benzyl alcohol or paraben (5.000 mg/g) as an antimicrobial, glycerol (30.000 mg/g), EDTA (1.000 mg/g) as a chelating agent, ethanol (36.51 mg/g) and Carbopol® (12.500 mg/g).
  • Formulation 36 comprises phosphatidyl choline (71.460 mg/g) as a lipid, phosphate (pH 7.8) buffer, BHA (0.200 mg/g), benzyl alcohol or paraben (10.0 mg/g) as an antimicrobial, glycerol (50.000 mg/g), EDTA (3.000 mg/g) as a chelating agent, and ethanol (30.000 mg/g).
  • Formulation 37 comprises Polysorbate 80 (4.720 mg/g) as a surfactant, phosphate (pH 7.8) buffer, BHA (0.200 mg/g), benzyl alcohol or paraben (10.0 mg/g) as an antimicrobial, glycerol (50.000 mg/g), EDTA (3.000 mg/g) as a chelating agent, and ethanol (30.000 mg/g).
  • the amount antimicrobial may be anywhere from about 1 mg/g to about 15 mg/g, or about 5 m/g to about 12 mg/g, or 5.25 mg/g, 6, mg/g, 7 mg/g, 8 mg/g, 9 mg/g, 10 mg/g, or 10.25 mg/g.
  • the antimicrobial can be a combination of ingredients, for example benzyl alcohol and parabens (e.g., ethyl and/or propyl).
  • Example Formulations 1 through 37 may also optionally include thickeners such as pectin, xanthan gum, HPMC gel, methylcellulose or Carbopol®.
  • Example 3 Bio distribution of ultra-deformable drug-free particles
  • Formulation A a formulation in accordance with the present invention labelled with cyclosporine A as a traceable marker
  • Sandimmun® a drug containing cyclosporine A (CsA)
  • the CsA oral solution was administered to six male DL x DE hybrid pigs (Wolfgang Giinther, Tierhandel & Transport, Am Why 13a, 15366 Neuenhagen, Germany).
  • the CsA oral solution was dosed individually at 2.5 mg CsA/kg body weight, mixed with food and applied twice daily with approx. 8 h in between. Complete intake of food was controlled by visual inspection of food trays and recorded. The dose was adjusted to increased body weight once weekly.
  • Tissue sampling Prior to skin sampling the respective application area was cleaned with cotton swabs soaked with ethanol 70%. A piece of skin (approx. 1 cm 2 ) with subjacent subcutaneous (s.c.) fat tissue and subdermal muscle tissue was then carefully excised with a scalpel from the application area. After each skin biopsy routine wound care was performed (with sutures) plus post-surgery analgesia (meloxicam). The s.c. fat tissue was carefully and as thoroughly as possible separated from the dermis.
  • the epidermis was thermally separated from the dermis of excised skin samples immediately after biopsy sampling. A biopsy from the de-epidermised dermis was taken inversely to the assumed CsA skin concentration gradient with a single-use 8 mm biopsy punch. All single tissue samples were stored in 2 mL vials and immediately frozen at -20°C. The tissue sampling areas in both studies were identical.
  • tissue samples skin, s.c. fat, subdermal muscle, and local lymph nodes [Lymphonodi cervicalis superficiales dorsales, Lymphonodi subiliaci] were taken.
  • Oral Sandimmun® 3208.6 mg; increasing CsA doses due to increasing body weight during the 4 week treatment period are shown in Table 4.
  • Table 5 Mean CsA concentrations ( ⁇ SD) in skin tissues after 1 week of repeated application of Formulation A and Sandimmun ® , resp.
  • Table 6 Mean CsA concentrations ( ⁇ SD), CsA concentration ratios, and dose adjusted CsA concentration ratios in target tissues after 4 weeks of repeated e.c. application of Formulation A
  • Example 4 Topical application of Formulation B reduces muscle soreness following exercise
  • Formulation B i.e. a formulation in accordance with the present invention
  • Formulation C i.e. a formulation containing ketoprofen
  • Polysorbate 80 (Tween80) 8.500
  • composition of Formulation C is the same as the composition of Formulation B above, with the addition of 22.9 mg/g (or 2.29%) ketoprofen and a commensurate reduction in water to amount to lOOOmg/g (or 100%).
  • Medical history-related exclusion criteria included: history of dermal allergic reactions; known hypersensitivity or allergy to NSAIDs (including ketoprofen); malignancy within the last 2 years; skin lesions; dermatological diseases or tattoo in the treatment area; major surgery 3 months prior to enrolment; major heart disease/uncontrolled hypertension; gastric and duodenal ulcers or bleeding; renal or hepatic failure; vascular disorders of the lower extremities; HIV, hepatitis B or C infection and bronchial asthma.
  • NSAIDs including ketoprofen
  • Participants with a soreness score of >3 on a 10-point categorical soreness scale 12-16 hours after exercise (Day 1) were randomised to receive twice-daily, 7-days' treatment with one of the following: 50mg Formulation C applied epicutaneously on both calves plus one placebo capsule; 1 OOmg Formulation C applied epicutaneously on both calves plus one placebo capsule; one 1 OOmg ketoprofen capsule (Spondylon ® , Riemser Arzneistoff AG, Greifswald, Germany) plus Formulation B; or one placebo capsule plus Formulation B.
  • Study drugs were taken or applied by the participants at home in the morning and evening of Day 1 to Day 6 and in the morning of Day 7.
  • Formulation C was applied over the entire surface of the calves.
  • Oral medication was taken with 250ml of water. Participants had to return all used and unused study drugs and packages. Compliance was determined at the final study visit by weighing returned tubes of study drug.
  • PK ketoprofen pharmacokinetics
  • AEs adverse events
  • body weight body temperature
  • the intent-to-treat (ITT) population included all randomised participants who received at least one application of study drug; participants were analysed according to the treatment to which they were randomised.
  • the safety population included all randomised participants who received at least one application of study drug; participants were analysed according to the treatment they actually received. Since study drugs were taken or applied at home, participants with ⁇ 80% compliance for any of the investigational agents were considered protocol violators and were not included in the per- protocol (PP) analysis. Blinding was guaranteed by using Formulation C and matching Formulation B, as well as ketoprofen and matching placebo capsules, together with a site-specific randomisation procedure. Study personnel had no access to the randomisation list.
  • the primary efficacy endpoint was the change in muscle soreness scores over the 7-day treatment period [AUC(0-7D)].
  • the secondary efficacy endpoint was the change in muscle soreness scores within the first 12 hours of dosing [AUC(0-12h)].
  • the primary efficacy analysis was performed on the ITT population and the secondary efficacy analysis was conducted in the PP population. The primary and secondary efficacy parameters were compared between treatment groups using the
  • Plasma concentration measurements were performed by a certified laboratory (Covance Laboratories, Madison, USA or IDEA AG, Munich, Germany). AUC values were calculated using the linear trapezoidal rule. PK parameters were compared between groups using parametric 2-sided 95% confidence intervals (CI) after log-transformed data. Laboratory and safety parameters were analysed descriptively.
  • the treatment groups were generally balanced with respect to age, height, weight and body mass index at baseline (Table 7). The majority of participants in each treatment group exercised at the highest altitude of 400m. Mean muscle soreness scores were balanced across the treatment groups at baseline (Table 7).
  • Formulation B oral placebo 0.3426 0.0240
  • Gastrointestinal disorders 2 (4.2) 1 (2.1) 1 (4.2) 3 (6.3)
  • the formulations containing ketoprofen (Formulation C) and the drug-free formulation in accordance with the present invention (Formulation B) were both superior to oral ketoprofen in reducing muscle soreness after exercise. Participants taking oral ketoprofen had more soreness over the 7 test days and took longer to recover than participants using the Formulation B or Formulation C. Evaluation of further efficacy parameters indicated that the negative effect of oral ketoprofen was caused by a delay of recovery. Compared with the use of Formulation B or Formulation C, oral ketoprofen increased the time taken to recover from muscle soreness post-exercise by approximately 12 hours. By the end of the study, several participants on oral ketoprofen and Formulation C still had soreness, whereas nearly all of the participants using Formulation B had recovered. No significant effects of
  • cyclooxygenase-2 inhibitors impairs ligament, muscle, and tendon healing in rats and mice (Elder, Dahners & Weinhold, 2001; Shen, Li, Tang, Cummins & Huard, 2005; Ferry, Dahners, Afshari & Weinhold, 2007).
  • Nieman et al. (2006) reported elevated indicators of endotoxemia and inflammation in athletes using ibuprofen both prophylactically and therapeutically, versus non-users, for muscle soreness following a 160km marathon (Nieman et al., 2006).
  • Nikanne et al. reported better initial pain relief with oral ketoprofen, but delayed overall recovery from muscle injury versus celecoxib (Nikanne, Kokki, Salo & Linna, 2005).
  • Formulation C and Formulation B were generally well tolerated by participants in this study. There was a low incidence of AEs overall and no serious or severe events reported. Drug-related treatment emergent AEs were recorded more frequently in participants receiving Formulation C versus oral ketoprofen or Formulation B, and were most often application site or dermal AEs. No study drug- induced changes in laboratory parameters, vital signs, or physical findings were observed.
  • Formulation C and Formulation B were superior to oral ketoprofen in reducing muscle soreness following exercise. Furthermore, oral ketoprofen delayed recovery from muscle soreness but Formulation B and Formulation C did not.
  • Formulation C i.e. a formulation containing ketoprofen
  • Formulation B i.e. a formulation in accordance with the present invention
  • Formulation B improves muscle soreness and is an effective treatment for muscle soreness during and post- exercise.

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Abstract

La présente invention concerne des formulations contenant des particules ultra-déformables exemptes de médicament, et leur utilisation dans le traitement de la douleur des tissus mous, telle que la survenue de courbatures du lendemain (DOMS) et des douleurs musculaires induites par l'exercice physique. Les formulations selon l'invention comprennent un tensioactif non ionique et/ou un phospholipide et sont exemptes de tout agent pharmaceutiquement actif.
PCT/EP2016/057027 2015-03-31 2016-03-31 Formulations vésiculaires à utiliser dans le traitement de la douleur musculaire Ceased WO2016156470A1 (fr)

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Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2010140061A2 (fr) * 2009-06-03 2010-12-09 John Charles Mayo Formulations destinées au traitement de la douleur de tissus profonds
WO2013153221A1 (fr) * 2012-04-12 2013-10-17 Sequessome Technology Holdings Limited Formulations vésiculaires destinées à être utilisées dans le traitement de la douleur ou de la mobilité réduite d'une articulation

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2010140061A2 (fr) * 2009-06-03 2010-12-09 John Charles Mayo Formulations destinées au traitement de la douleur de tissus profonds
WO2013153221A1 (fr) * 2012-04-12 2013-10-17 Sequessome Technology Holdings Limited Formulations vésiculaires destinées à être utilisées dans le traitement de la douleur ou de la mobilité réduite d'une articulation

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
COLLINS J, ROTHNER, M: "ultra deformable drug-free sequessome vesicles for the treatment of joint pain following exercise", BRITISH JOURNAL OF SPORTS MEDICINE, vol. 49, no. suppl 2, A3, 20 October 2015 (2015-10-20), XP002758209 *
P. G. CONAGHAN ET AL: "A multicentre, randomized, placebo- and active-controlled trial comparing the efficacy and safety of topical ketoprofen in Transfersome gel (IDEA-033) with ketoprofen-free vehicle (TDT 064) and oral celecoxib for knee pain associated with osteoarthritis", RHEUMATOLOGY, vol. 52, no. 7, 28 March 2013 (2013-03-28), GB, pages 1303 - 1312, XP055276077, ISSN: 1462-0324, DOI: 10.1093/rheumatology/ket133 *
SEIDEL EGBERT J ET AL: "A randomised trial comparing the efficacy and safety of topical ketoprofen in Transfersome((R)) gel (IDEA-033) with oral ketoprofen and drug-free ultra-deformable Sequessome(TM) vesicles (TDT 064) for the treatment of muscle soreness following exercise.", JOURNAL OF SPORTS SCIENCES 2016, vol. 34, no. 1, 2016, pages 88 - 95, XP009190232, ISSN: 1466-447X *

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