WO2014155074A1 - Composition - Google Patents

Composition Download PDF

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Publication number
WO2014155074A1
WO2014155074A1 PCT/GB2014/050907 GB2014050907W WO2014155074A1 WO 2014155074 A1 WO2014155074 A1 WO 2014155074A1 GB 2014050907 W GB2014050907 W GB 2014050907W WO 2014155074 A1 WO2014155074 A1 WO 2014155074A1
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WO
WIPO (PCT)
Prior art keywords
composition
pain
lidocaine
patient
administration
Prior art date
Application number
PCT/GB2014/050907
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English (en)
Inventor
Richard Henry
Original Assignee
Richard Henry
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Richard Henry filed Critical Richard Henry
Publication of WO2014155074A1 publication Critical patent/WO2014155074A1/fr

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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
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
    • A61K31/167—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide having the nitrogen of a carboxamide group directly attached to the aromatic ring, e.g. lidocaine, paracetamol
    • 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
    • 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

Definitions

  • the present invention relates to products, compositions, methods and uses which are useful in the prevention, alleviation or treatment of pain.
  • the present invention relates to topical compositions in the alleviation or treatment of pain associated with an internal organ or mucous membrane or gland of the human or animal body.
  • Lidocaine is an anaesthetic known for the treatment and alleviation of pain.
  • Lidocaine is an amphiphatic compound which exists in an ionised and a non-ionised state.
  • the ionized salt form of local anesthetics is highly water- soluble and poorly suited to penetrate tissue and cross biological membranes. All aqueous preparations of local anesthetics use the ionized, water-soluble form of the drug and maintain the drug in that state by lowering the pH of the solution to below pH 6 with the use of acids such as hydrochloric acid.
  • the ionised form of the anaesthetic is poorly absorbed by the human or animal body.
  • Lidocaine has a pKa of between 7.6 - 7.9 (depending on the information source).
  • the pKa is the pH at which 50% of the drug in an aqueous solution will be in the base form and 50% in the ion or charged form. As the pH of the solution falls, more of the drug converts into the ionised form. Since the pH scale is a logarithmic scale, these changes are quite marked over a small pH range. For example, at a pH of 6.8, 1% of the lidocaine will be in the base form, while at a pH of 5.8, only 0.1% will be in the base form.
  • the ion and base forms of local anesthetics have important physical and physiological differences that greatly affect the pharmaco-kinetics of this class of drugs.
  • the base or non- ionized form is highly lipid soluble and readily crosses biological membranes. It is however poorly soluble in water and will precipitate out of an aqueous solution at room temperature.
  • the ionised form of anaesthetics such as lidocaine cannot easily cross biological membranes and are associated with low uptake into the human or animal body.
  • lidocaine To be dissolved in aqueous solution, lidocaine must be in its ionised state. In its ionised state, lidocaine is water-soluble. Generally 99.9% of lidocaine in aqueous solution will be in the ionised state. In its ionised state, lidocaine will not be absorbed easily into tissue of the human or animal body.
  • Known lidocaine formulations are generally aqueous solutions. It is generally accepted that the bioavailability of topical lidocaine solutions is around 3%.
  • the tissue When an aqueous solution is injected into live tissue to affect anaesthesia, the tissue has a pH of around 7.3 and will buffer the excess hydrogen ions in the lidocaine solution, raising the pH of the solution to 7.3. This in turn will convert the lidocaine molecules into the base form and facilitate diffusion down the concentration gradient into the surrounding tissue and particularly into the nerve cells in the region, where they have their desired effect - numbness. Conversion of the lidocaine to its base form relies on body tissue buffering of the injected solution with with subsequent conversion of the lidocaine to the base form and its diffusion into the target neurons.
  • the urothelium of the bladder is almost impermeable to water, charged ions, and small molecules, such as urea and sodium (Negrete H O, Lavelle J P, Berg J, Lewis S A, & Zeidel M L: Permeability Properties of the Intact Mammalian Bladder Epithelium. Am J Physiol.271 (Renal Fluid Electrolyte Physiol.40) F886-894, 1996).
  • This blood-urine barrier has been documented to provide a high trans-urothelial electrical resistance, which reflects the low ion flux across the urothelial membrane.
  • lidocaine across biological membranes, such as the bladder wall
  • WO00/40234 describes this problem and suggests that this problem may be addressed through the instillation of an alkaline solution in the bladder prior to the administration of an aqueous solution of lidocaine in the bladder.
  • the pH of the lidocaine solution rises, and the lidocaine converts from the ionised to the non-ionised form.
  • lidocaine Upon conversion to the non-ionised form lidocaine will precipitate out of solution. Where the precipitated particles are small they may adhere to the walls of the bladder.
  • the precipitated particles are large, they are likely to be precipitated out into the aqueous lidocaine solution and the amount of lidocaine which crosses the bladder wall is limited accordingly.
  • the administration of two solutions results in increased cost and complexity of treatment. A medical practitioner must generally be present to administer two volumes into the bladder, restricting self -treatment or treatment at home.
  • the administration of relatively large volumes of aqueous solution would not be suitable for respiratory passages such as the nasal passages.
  • Lidocaine compositions suitable for systemic administration are also known. However, systemic administration is associated with far higher doses than topical administration. Adverse indications are associated with the systemic administration of anaesthetic including vomiting, lack of hydration, disorientation, confusion, postoperative cognitive decline, anaphylactic reaction, complications associated with all major organs including heart, brain, liver, kidneys and increased blood pressure.
  • a topical composition comprising lidocaine wherein at least 25 wt% of the lidocaine is in its base form.
  • a topical composition comprising lidocaine, wherein the pH of the composition is 6.5 to 7.5 and wherein 10 to less than 50 wt% of the lidocaine is in its base form.
  • the composition of the present invention is generally associated with an optimum pH range of suitably 6 to 8, generally 6.5 to 7.5. This pH range is both safe for use and provides lidocaine in a stable solution.
  • a high proportion (typically 10 to 50%) of the lidocaine in the composition of the present invention is in its base form. The base form of lidocaine is readily absorbed through biological membranes.
  • composition of the present invention is thus effective in administering lidocaine into a human or animal body through topical application to a biological membrane.
  • the composition of the present invention suitably has good bioadhesiveness, allowing the composition prolonged residency at the desired site of action to give time for the lidocaine to be absorbed.
  • the enhanced topical bioavailability (>25%) of the composition of the present invention means it is particularly effective in the prevention or treatment of pain and inflammation such as that associated with diseases like interstitial cystitis, radiation cystitis, proctitis and infections such as found in wounds and the urinary bladder.
  • lidocaine Aqueous compositions of lidocaine and their use in the anaesthesia of the human or animal body are known. However, in aqueous solution, lidocaine is ionized, and in thus not easily absorbed across biological membranes.
  • the present application describes topical lidocaine compositions with extremely good bioavailability. As the lidocaine in the composition is in its base form, it may cross biological membranes easily, diffusing into the surrounding tissue down the concentration gradient.
  • composition of the present invention generally exhibits good bioadhesivity, wherein at least 20 vol. % of the composition generally remains on the biological surface to which it is applied for at least 1 hour after application at temperatures of 35 to 40 °C; typically at least 30 vol. %; suitably at least 50 vol %; more suitably at least 75 vol. %.
  • composition of the present invention generally exhibits good mucoadhesivity, wherein at least 20 vol. % of the composition generally remains on the surface of the mucus membrane to which it is applied for at least 1 hour after application at temperatures of 35 to 40 °C typically at least 30 vol. %; suitably at least 50 vol %; more suitably at least 75 vol. %.
  • composition as described herein for use in the diagnosis of a source of pain also contemplates topical anesthesia of a potential source of pain for diagnostic purposes.
  • topical composition of the present invention is administered to a patient suffering from pain where the origin of the pain is not precisely known. This administration reliably blocks pain from a potential source for a temporary period of time. This allows differentiating this source of pain from pain emanating from other sources such as surrounding organs.
  • a method of preventing, treating or alleviating pain and/or inflammation in a patient suffering therefrom, in particular pain originating from an internal source comprising the topical administration in a therapeutically effective amount of the composition described herein.
  • the pain may originate from inflammation and/or from an infection due to an indwelling medical device, interstitial cystitis, pain associated with, for instance, the urinary tract, bladder, urethra, prostate, intestine, oesophagus, genitals and/or surgical procedures.
  • the present invention provides a method of topically anaesthetizing a part of a patient's body to allow surgical procedures without pain.
  • a method of treating and/or alleviating the symptoms associated with a condition comprising the topical administration in a therapeutically effective amount of the composition described herein wherein the condition is one or more of cystitis (in particular interstitial cystitis and radiation cystitis), infections (in particular those associated with wounds including those relating to breaks in a biological membrane such as skin and/or infections of the urinary bladder); proctitis and premature ejaculation.
  • cystitis in particular interstitial cystitis and radiation cystitis
  • infections in particular those associated with wounds including those relating to breaks in a biological membrane such as skin and/or infections of the urinary bladder
  • proctitis and premature ejaculation in particular cystitis (in particular interstitial cystitis and radiation cystitis), infections (in particular those associated with wounds including those relating to breaks in a biological membrane such as skin and/or infections
  • composition as described herein for use in the prevention, treatment or alleviation of pain and/or inflammation.
  • composition as described herein for use in the prevention of pain.
  • cystitis in particular interstitial cystitis and radiation cystitis
  • infections in particular those associated with wounds including those relating to breaks in a biological membrane such as skin and/or infections of the urinary bladder
  • proctitis and premature ejaculation in particular those associated with wounds including those relating to breaks in a biological membrane such as skin and/or infections of the urinary bladder.
  • composition as described herein in the manufacture of a medicament for the prevention, treatment or alleviation of pain and/or inflammation.
  • kit of parts for use in the prevention, treatment or alleviation of pain, said kit of parts comprising the composition as described herein and an applicator device such as a syringe, spatula, container comprising an extended nozzle.
  • bioadhesive is used to refer to the force of attraction between a composition and a surface of a human or animal body, in particular the surface of a biological tissue. This is dependent on the properties of the composition and the surface to which it is applied.
  • composition has good bioadhesivity
  • at least 20 vol. % of the composition generally remains on the biological surface to which it is applied for at least 1 hour after application.
  • composition has good mucoadhesivity
  • at least 20 vol. % of the composition generally remains on the surface of the mucus membrane to which it is applied for at least 1 hour after application.
  • an “effective” amount or “therapeutically effective amount” is meant an amount of one or more active substances which, within the scope of sound medical judgment, is sufficient to provide a desired effect without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.
  • a "contact angle" provides a measure of adhesion of a composition to a surface. Strong adhesion and weak cohesion results in a high degree of wetting, a lyophilic condition with low measured contact angles. Conversely, weak adhesion and strong cohesion results in lyophobic conditions with high measured contact angles and poor wetting.
  • Premature ejaculation as used herein is defined as a condition in which ejaculation occurs with minimal sexual stimulation prior to, upon or shortly after vaginal penetration and before the person and/or his partner desires it.
  • a topical composition comprising lidocaine wherein at least 25 wt% of the lidocaine is in its base form, generally at least 50% of the lidocaine is in its base form.
  • lidocaine is readily absorbed through biological membranes such as skin, mucous membranes and the walls of organs such as the bladder and oesophagus.
  • the non-ionised form of lidocaine is lipid-soluble and precipitates out of aqueous solution.
  • a composition for topical administration to the human or animal body comprising lidocaine in its non-ionised form.
  • a topical composition which has good bioadhesive properties comprising at least 5wt% lidocaine in its non-ionised form.
  • the composition comprises at least 0.5 to 15 wt% lidocaine, generally 2 to 15 wt% lidocaine; suitably 5 to 10 wt% lidocaine.
  • at least 25 wt% of the lidocaine contained in the composition is in its base form, generally at least 30 wt%, suitably at least 40 wt%.
  • around 50 wt% of the lidocaine contained in the composition is in its base form.
  • At least 80 wt% of the lidocaine contained in the composition is in its base form; suitably at least 95 wt%.
  • the present invention is based upon the discovery that there is an optimum pH at which absorption of lidocaine is generally around five times greater than at lower pHs. Depending on the area of the body the absorption of the composition may decline at a pH above a certain optimal range. As the pH increases above 8.0 Hdocaine precipitates out of the aqueous solution as a higher percentage of the lidocaine is converted to its lipid soluble base form before it can be absorbed into the body. Precipitation of the lidocaine out of solution markedly decreases the concentration of lidocaine in solution, resulting in slower absorption across biological membranes.
  • the pH of the composition is optimized to maximize the formation of the non-ionised form of lidocaine, and to maximize absorption by the human or animal body accordingly.
  • the composition has a pH of at least 6.5, suitably 6.5 to 8.0, more suitably 6.5 to 7.5.
  • the pH of the composition is 7.5 to 8.0.
  • Known lidocaine compositions comprise lidocaine in its ionised form. Generally at least 90% of the lidocaine in known lidocaine formulations is in its ionised form.
  • the composition of the present invention provides enhanced topical bioavailability of lidocame compared to known lidocaine compositions. Typically the bioavailability of the lidocaine in the composition of the present invention is at least 20% greater than known lidocaine compositions.
  • the composition of the present invention is also generally bioadhesive allowing the lidocaine sufficient time at the desired site of action to maximise absorption of the lidocaine across biological membranes.
  • the effectiveness of the composition of the present invention in the prevention, alleviation or treatment of pain and/or inflammation is thus maximised.
  • the composition of the present invention generally has good bioadhesivity at a temperature of around 35 to 40 °C.
  • at least 20 vol. % of the composition remains on the biological surface to which it is applied for at least 1 hour after application; typically at least 30 vol. %; generally at least 50 vol. %.
  • at least 90 vol % of the composition remains on the biological surface to which it is applied for at least 1 hour after application.
  • the lidocaine is readily absorbed into the biological tissue.
  • the good bioadhesivity of the present invention allows increased residency times at the site of required action.
  • the composition has good mucoadhesivity at a temperature of 35 to 40 °C, providing good adhesion to mucus membranes and surrounding tissue.
  • at least 20 vol. % of the composition remains on the surface of the mucous membrane to which it is applied for at least 1 hour after application; typically at least 30 vol. %; generally at least 50 vol. %.
  • at least 90 vol % of the composition remains on the surface of the mucous membrane to which it is applied for at least 1 hour after application.
  • the lidocaine is readily absorbed into the biological tissue of the mucous membrane.
  • the bioadhesivity/mucoadhesivity of the composition of the present invention may be thermoreversible.
  • the bioadhesivity/mucoadhesivity of the composition of the present invention is generally good at or around body temperature. At lower or higher temperatures, the bioadhesivity/mucoadhesivity of the composition may decline.
  • the bio/muco adhesiveness of the composition of the present invention allows residency of the composition at the desired site of action, allowing sufficient time for the lidocaine to be absorbed.
  • composition of the present invention has an associated contact angle lower than that of water.
  • composition of the present invention is generally not solid.
  • composition of the present invention does not generally comprise more than 2 wt% particles having a diameter of 1 mm or more, typically no more than 0.05 wt% particles having a diameter of 1 mm or more.
  • the composition of the present invention does not comprise any particles having a diameter of 1 mm or more.
  • the composition of the present invention does not comprise any solid particulate material, such as precipitated lidocaine particles.
  • the composition of the present invention has a viscosity greater than that of water.
  • the composition of the present invention has a viscosity of at least 4 cP at 0 °C.
  • the composition of the present invention has a viscosity of at least 6 cP at 0 °C.
  • the composition of the present invention provides lubricant properties.
  • the composition may comprise a lubricant base.
  • the composition is in the form of a gel, foam, emulsion or paste.
  • the composition is in the form of a gel.
  • the composition of the present invention may have thermoreversible gelling properties, in particular forming a gel at or around temperatures of around 35 to 40 °C, including the normal body temperature range.
  • the composition comprises up to 25 wt% lidocaine, suitably 5 to 15 wt% lidocaine, typically around 10 wt% lidocaine.
  • the composition typically comprises one or more of 1 to 5 wt% anti-inflammatory compound, 1 to 5 wt% antimicrobial, 1 to 5 wt% additional analgesic or anaesthetic.
  • the composition comprises lidocaine, one or more additional anti-inflammatory compound and one or more additional antimicrobial compound.
  • a composition may find utility in the treatment of conditions such as infections associated with wounds or with the presence of an indwelling medical device, such as a catheter, in a human or animal body.
  • an indwelling medical device such as a catheter
  • such a composition is useful in the treatment of conditions such as interstitial cystitis, radiation cystitis and proctitis.
  • the composition of the present invention may include one or more additional analgesic or anaesthetic compound.
  • Suitable analgesic compounds include NSAIDs such as diclofenac and ibuprofen; Cox-2 inhibitors such as celecoxib; weak opiods such as codeine, dihydrocodeine and tramadol; strong opiods such as oxycodone, buprenorphine, morphine, fentanyl and hydromorphone and/or anti neuropathic compounds such as gabapentin, pregabalin, amitryptilline, carbamazepine, topiramate and capsaicin
  • NSAIDs such as diclofenac and ibuprofen
  • Cox-2 inhibitors such as celecoxib
  • weak opiods such as codeine, dihydrocodeine and tramadol
  • strong opiods such as oxycodone, buprenorphine, morphine, fentanyl and hydromorphone and/or anti neuropathic compounds
  • the composition comprises 5 to 15 wt% lidocaine, 1 to 5 wt anti-inflammatory and 1 to 5 wt% anti-neuropathic.
  • the ratio of the lidocaine to other active ingredient administered according to the invention may be at least 1:4 to 4:1.
  • the abovementioned active agents may be administered as free or fixed combinations.
  • Free combinations may be provided as combination packages containing all the active agents in free combinations.
  • the active agents of the product of the invention may be provided as pharmaceutical compositions additionally containing one or more pharmaceutically acceptable diluents, excipients and/or carriers. This applies to both fixed and free combinations.
  • compositions depend on the method of administration. However, the composition is typically in the form of a gel, hydrogel, lotion, cream, ointment, foam or liquid including a solution or suspension.
  • composition of the present invention may be lipid based.
  • the composition may be aqueous.
  • the composition of the present invention generally comprises less than 50 vol. % water, typically less than 10 vol. , generally less than 0.05 vol. % water. According to one embodiment, the composition of the present invention does not comprise water.
  • composition of the present invention is generally sterile.
  • composition may be rendered isotonic with sufficient saline or glucose prior to administration.
  • composition of the present invention may be suitable for buccal, sublabial, sublingual, ophthalmic, otologic, pulmonary, nasal, urogenital, intravaginal, intrauterine, intracavernous, intravesical, intraperitoneal, rectal, dermal, intradermal, subcutaneous administration and/or suitable for administration via the digestive tract, in particular through controlled release formulations.
  • the products of the invention can be administered in the form of a suppository or pessary, or they may be applied topically in the form of a gel, hydrogel, lotion, solution, cream, ointment skin patch, depot, subcutaneous injection or powder.
  • the products of the invention may be administered through a biological membrane.
  • the products of the invention can also be administered intranasally or by inhalation and are conveniently delivered in the form of a dry powder inhaler or an aerosol spray presentation from a pressurised container, pump, spray, atomiser, nebuliser, with or without the use of a suitable propellant.
  • sterile media employed in the preparation of suitable formulations are all readily obtainable by standard techniques well-known to those skilled in the art.
  • the composition of the present invention is in the form of a gel, foam or cream suitable for administration to the walls of the bladder.
  • the composition may be administered from its container under slightly increased pressure via an applicator which extends into the bladder.
  • the composition may comprise one or more additional active compounds.
  • additional active compounds include anti-inflammatories, including NSAIDs, anti-microbials such as antibiotic, anti-fungal and analgesics including anti-neuropathic agents.
  • the composition of the present invention comprises lidocaine in its base form.
  • additional components of the composition may be administered in the form of pharmaceutically acceptable salts.
  • the pharmaceutically acceptable salts of the present invention can be synthesized from the parent compound which contains a basic or acidic moiety by conventional chemical methods. Generally, such salts can be prepared by reacting the free acid or base forms of these compounds with a stoichiometric amount of the appropriate base or acid in water or in an organic solvent, or in a mixture of the two; generally, nonaqueous media like ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are preferred.
  • phrases "pharmaceutically acceptable” is employed herein to refer to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings or, as the case may be, an animal without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.
  • the composition of the present invention may find utility in preventing, treating or alleviating pain and/or inflammation, in particular pain and inflammation associated with infection, including preventing, relieving or alleviating the pain and/or inflammation associated with diseases like interstitial cystitis, radiation cystitis, proctitis and infections such as found in wounds and the urinary bladder.
  • infections associated with indwelling medical devices such as stents, catheters, ET tubes, colostomy bags, dialysis tubing, draining devices and the like.
  • Prolonged use of medical devices such as stents, catheters, ET Tubes and colostomy bags is associated with infection which is commonly problematic to treat.
  • the prolonged use of such medical devices is associated with biofilm formation.
  • Biofilm formation plays a key role in many infectious diseases, and as a consequence of the presence of indwelling medical devices.
  • the composition of the present invention may comprise a compound which may inhibit bacterial adhesion, hydrophobicity or slime production.
  • the composition may comprise a dispersant and/or an anti-adhesive agent.
  • the term "dispersant” is intended to include any agent capable of dispersing the particles of a biofilm.
  • the dispersant may promote the dispersion of slime produced by microbes such as bacteria, mucous which forms part of the biofilm for example mucous produced by the cells to which the biofilm microbes adheres, and biofilm microbes such as bacteria.
  • the dispersant may be a mucolytic agent.
  • the mucolytic agent may be an enzyme for example a DNase, alginase, protease or carobohydrase.
  • the mucolytic agent may be a small molecule for example an amine such as an aminothiol or an acid such as ethylenediaminetetraacetic acid (EDTA).
  • EDTA ethylenediaminetetraacetic acid
  • the amine may be selected from acetylcysteine and cysteamine.
  • anti-adhesive agent is intended to include any agent capable of inhibiting adhesion between cells, proteins and organisms e.g. microbes thereby preventing biofilm formation or promoting biofilm self-destruction.
  • the anti-adhesive agent may prevent the adhesion to a surface or substrate of all cell types encountered in microbial biofilms in particular free-living microbes i.e. planktonic cells.
  • Anti-adhesive agents may include, but are not limited to, hyaluronan, heparin or Carbopol 934.
  • the composition may comprise an antibacterial agent.
  • the antibacterial agent may be a mucolytic agent for example a mucolytic agent having both mucolytic and antibacterial activity.
  • the composition may be used to provide topical anaesthesia prior to surgical procedures.
  • the composition may include additional anaesthetics and/or analgesics.
  • composition of the present invention finds utility in the treatment of interstitial cystitis.
  • the composition may include one or more anti-inflammatory, antihistamine and antimicrobial compound.
  • composition of the present invention may include conventional additives such as lactose; mannitol, corn starch or potato starch; binders such as crystalline cellulose, cellulose derivatives, acacia, corn starch or gelatins; disintegrators such as corn starch, potato starch or sodium carboxymethylcellulose; and lubricants such as talc or magnesium stearate.
  • conventional additives such as lactose; mannitol, corn starch or potato starch; binders such as crystalline cellulose, cellulose derivatives, acacia, corn starch or gelatins; disintegrators such as corn starch, potato starch or sodium carboxymethylcellulose; and lubricants such as talc or magnesium stearate.
  • the products of the invention may also find application as/in an oral formulation wherein the product is formulated in a carrier, for example selected from films, tapes, gels, microspheres, lozenges, chewing gum, dentrifices and mouthwash.
  • a carrier for example selected from films, tapes, gels, microspheres, lozenges, chewing gum, dentrifices and mouthwash.
  • composition of the present invention may be in the form of a pessary, ointment, suppository, enema, ointment, cream, lotion, paste, gel, emulsion or foam.
  • compositions may include flavour enhancers.
  • the composition of the present invention is in the form of a nasal spray, ear drops or eye drops.
  • the composition may be in the form suitable for application to the genitals of the user, in particular the penis of a mammal.
  • a method of preventing pain and/or inflammation in a patient suffering therefrom comprising the topical administration in a therapeutically effective amount of the composition described herein.
  • a method of treating or alleviating pain and/or inflammation in a patient suffering therefrom, in particular pain and/or inflammation originating from an internal source comprising the topical administration in a therapeutically effective amount of the composition described herein.
  • a method of treating a patient suffering from cystitis including interstitial cystitis, acute bacterial cystitis and systemic lupus erythematosis (SLE) cystitis or alleviating the symptoms associated therewith comprising the topical administration in a therapeutically effective amount of the composition described herein to the urothelial wall of the patient.
  • cystitis including interstitial cystitis, acute bacterial cystitis and systemic lupus erythematosis (SLE) cystitis or alleviating the symptoms associated therewith
  • a method of treating a patient suffering from urinary stress incontinence or alleviating the symptoms associated therewith comprising the topical administration in a therapeutically effective amount of the composition described herein to the urothelial wall of the patient.
  • a method of treating a patient suffering from proctitis or alleviating the symptoms associated therewith comprising the topical administration in a therapeutically effective amount of the composition described herein to the rectal wall of the patient.
  • a method of treating a patient suffering from premature ejaculation or alleviating the symptoms associated therewith comprising the topical administration in a therapeutically effective amount of the composition described herein to the penis or surrounding area of the patient.
  • a method of treating a patient suffering from an infection associated with an indwelling medical device or alleviating the symptoms associated therewith comprising the topical administration in a therapeutically effective amount of the composition described herein to the infected area of the patient's body.
  • the method of treatment generally involves the topical administration of the composition to the urinary tract.
  • the method of treatment generally involves the topical administration of the composition to the walls of the passage or conduit in the patient's body surrounding the stent.
  • a method of topically anaesthetizing part of a patient's body comprising the step of topically administering the composition as described herein to the part of the patient's body.
  • cystoscopic surgical procedures such as biopsies and cautery of tumors.
  • the method and composition of the present invention may be used in the prevention of pain and/or inflammation. This is commonly used where a patient has undergone a procedure which is associated with the onset of pain and/or inflammation, or is associated with the onset of an infection.
  • the preventative method of the present invention may be used where the patient has a propensity to develop conditions such as infections of the urinary bladder, interstitial cystitis, radiation cystitis or proctitis; for instance where the patient has previously suffered from such conditions.
  • the preventative method of the present invention may be used upon or following the use of an indwelling medical device, or after a wound has been sustained.
  • the method involves the topical administration of the composition of the present invention to the site associated with an increased risk of developing pain and/or inflammation.
  • the present invention provides a method of diagnosing a potential source of pain comprising the steps of administering the composition as described herein to a potential source of pain, thus allowing this source of pain to be differentiated from pain emanating from other sources such as surrounding organs.
  • the present invention also provides a method of diagnosing the source of pain comprising the steps of isolating a possible source of pain by topically administering a therapeutically effective amount of the bioadhesive composition described above to the possible source of pain wherein where the pain is greatly alleviated within 10 minutes of administration, the possible source of pain may be identified as the or one of the origins of the pain, and wherein where the pain is not greatly alleviated within 10 minutes of administration, the possible source of pain is identified as not being the origin of the pain.
  • the method of the present invention may provide an indication of a possible source of the pain. Further investigations may be undertaken to provide a definitive diagnosis of the source of the pain.
  • the composition of the present invention provides topical anaesthesia within less than 30 minutes of administration, generally within less than 10 minutes of administration, typically within around 5 minutes of administration.
  • the duration of anaesthesia provided by the composition of the present invention depends on many factors including the type of tissue to which the composition is applied, the amount of composition applied thereto and the concentration of lidocaine in the composition.
  • composition provides topical anaesthesia for at least 30 minutes; typically at least 40 minutes; generally for at least 1 hour.
  • the active agents of the present invention may be administered by any suitable route known to those skilled in the art, preferably in the form of a pharmaceutical composition adapted to such a route, and in a dose effective for the treatment or prevention intended.
  • the method of the present invention may include administering 0.5 to 20 ml of composition per administration, generally at least 1 ml per administration, typically around 10 ml per administration.
  • the active agents of the present invention may be administered by any suitable route known to those skilled in the art, preferably in the form of a pharmaceutical composition adapted to such a route, and in a dose effective for the treatment intended.
  • the active compounds and composition may, for example, be administered by parenteral, oral, intranasal, intrabronchial, enteral, transdermal, sublingual, rectal, vaginal, urethral or ocular route.
  • the compounds and/or composition may be applied topically to the genitals of the patient.
  • the amount of therapeutically active compound that is administered and the dosage regimen for treating a disease condition with the compounds and/or compositions of this invention depends on a variety of factors, including the age, weight, sex and medical condition of the subject, the severity of the disease, the route and frequency of administration, and the particular compound employed, as well as the pharmacokinetic properties of the individual treated, and thus may vary widely.
  • the dosage will generally be lower if the compounds are administered locally rather than systemically, and for prevention rather than for treatment. Such treatments may be administered as often as necessary and for the period of time judged necessary by the treating physician.
  • the active agents may be administered simultaneously or sequentially. According to one embodiment, the active agents are administered simultaneously.
  • the active agents may be administered separately, for instance, the lidocaine composition may be applied topically and the anti-neuropathic compound may be systemically administered.
  • composition is generally suitable for topical administration, typically via administration to a biological membrane such as the urinary tract, the urothelial wall, the intestine wall, mucous membranes and surrounding passages.
  • a biological membrane such as the urinary tract, the urothelial wall, the intestine wall, mucous membranes and surrounding passages.
  • the products of the invention may be administered to the respiratory tract.
  • the present invention also provides aerosol pharmaceutical formulations comprising a product of the invention.
  • a nebuliser or inhaler containing a product of the invention is also provided.
  • the products of the invention may be suited to formulation as sustained release dosage forms and the like.
  • the formulations can be so constituted that they release the active agents, for example, in a particular part of the intestinal or respiratory tract, possibly over a period of time.
  • Coatings, envelopes, and protective matrices may be made, for example, from polymeric substances, such as polylactide-glycolates, liposomes, microemulsions, microparticles, nanoparticles, or waxes. These coatings, envelopes, and protective matrices are useful to coat indwelling devices, e.g. stents, catheters, peritoneal dialysis tubing, draining devices and the like.
  • a substrate to which a product of the invention is applied or attached.
  • the substrate is suitable for application to wounds or delivery to wound sites.
  • the substrate allows for the transfer of the active agents of the product of the invention from the substrate to a wound bed to achieve their analgesic and anti-inflammatory effects.
  • the substrate may be a dressing, for example, wound dressing.
  • the dressing may comprise a fabric material or it may be a collagen-like material. Where the composition is administered to the bladder, the total volume administered is generally 5 - 10 ml.
  • the method generally involves the administration of 10ml of 4% lidocaine.
  • the active agents may be administered simultaneously or sequentially. Where the active agents are administered sequentially, the administration of all of the active agents is generally within 2 minutes, typically within 1 minute.
  • the method of the present invention may be undertaken whenever required.
  • the active agents may be administered up to three times daily.
  • the duration of the course of treatment depends on the condition to be treated and its severity.
  • condition to be treated is a bacterial infection, such as that associated with an indwelling medical device or a wound
  • a course of treatment will generally last up to two weeks.
  • condition to be treated is a moderate cystitis condition (for instance interstitial cystitis or radiation cystitis)
  • a course of treatment will generally last up to six months, and this can be extended where required.
  • proctitis a course of treatment will generally last up to six months (extendable as required).
  • condition to be treated is severe, for example severe IC or systemic lupus erythematosis (SLE) cystitis
  • the course of treatment may be ongoing, generally lasting up to several years.
  • the patient is generally a human although in some embodiments, an animal may be treated. Kit of Parts
  • kits of parts for use in the treatment or alleviation of pain, said kit of parts comprising the composition as described herein and an applicator device such as a syringe, spatula or a container comprising an extended nozzle.
  • the kit of parts may comprise the active agents in dosage units containing a particular amount of the active agent.
  • the dosage units may comprise one or more active agents.
  • kit includes instructions for use, for example the nature of administration.
  • the composition may be expelled from the container under pressure.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pain & Pain Management (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicinal Preparation (AREA)

Abstract

La présente invention concerne une composition topique comprenant de la lidocaïne, le pH de la composition étant de 6,5 à 7,5 et de 10 à moins de 50 % en poids de la lidocaïne se trouvant dans sa forme de base. L'invention concerne également un composé tel que celui destiné à être utilisé dans le traitement, la prévention ou le soulagement de la douleur et/ou de l'inflammation. Selon un autre aspect, l'invention concerne le composé destiné à être utilisé dans le traitement d'une pathologie telle qu'une cystite, une rectite, des infections associées à des plaies et/ou la vessie urinaire et l'éjaculation précoce.
PCT/GB2014/050907 2013-03-27 2014-03-24 Composition WO2014155074A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
GB1305622.1 2013-03-27
GBGB1305622.1A GB201305622D0 (en) 2013-03-27 2013-03-27 Composition

Publications (1)

Publication Number Publication Date
WO2014155074A1 true WO2014155074A1 (fr) 2014-10-02

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GB (1) GB201305622D0 (fr)
WO (1) WO2014155074A1 (fr)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2021201680A1 (fr) * 2020-03-31 2021-10-07 Hasan Djohan Traitement du syndrome hyper-inflammatoire

Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2000069471A1 (fr) * 1999-05-19 2000-11-23 The University Of Georgia Research Foundation, Inc. Anesthesie transcutanee amelioree au moyen d'agents anesthesiques locaux
US20040067890A1 (en) * 2002-10-04 2004-04-08 Gupta Shyam K. Ascorbic acid salts of organic bases with enhanced bioavailability for synergictic anti-aging and skin protective cosmetic compositions
WO2006080924A1 (fr) * 2005-01-27 2006-08-03 C.B. Fleet Company Incorporated Gel feminin anti-demangeaisons
WO2007134071A2 (fr) * 2006-05-08 2007-11-22 The University Of Mississippi Formule stabilisée de triamcinolone acétonide
WO2010054093A1 (fr) * 2008-11-06 2010-05-14 Nuvo Research Inc. Formulations destinées au traitement des douleurs de l’herpès-zona aigu
WO2011121074A1 (fr) * 2010-04-01 2011-10-06 Pharmanest Ab Compositions d'anesthésique thermogélifiantes

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2000069471A1 (fr) * 1999-05-19 2000-11-23 The University Of Georgia Research Foundation, Inc. Anesthesie transcutanee amelioree au moyen d'agents anesthesiques locaux
US20040067890A1 (en) * 2002-10-04 2004-04-08 Gupta Shyam K. Ascorbic acid salts of organic bases with enhanced bioavailability for synergictic anti-aging and skin protective cosmetic compositions
WO2006080924A1 (fr) * 2005-01-27 2006-08-03 C.B. Fleet Company Incorporated Gel feminin anti-demangeaisons
WO2007134071A2 (fr) * 2006-05-08 2007-11-22 The University Of Mississippi Formule stabilisée de triamcinolone acétonide
WO2010054093A1 (fr) * 2008-11-06 2010-05-14 Nuvo Research Inc. Formulations destinées au traitement des douleurs de l’herpès-zona aigu
WO2011121074A1 (fr) * 2010-04-01 2011-10-06 Pharmanest Ab Compositions d'anesthésique thermogélifiantes

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2021201680A1 (fr) * 2020-03-31 2021-10-07 Hasan Djohan Traitement du syndrome hyper-inflammatoire

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