USRE46397E1 - Slow release of organic salts of local anesthetics for pain relief - Google Patents

Slow release of organic salts of local anesthetics for pain relief Download PDF

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USRE46397E1
USRE46397E1 US14/933,735 US200814933735A USRE46397E US RE46397 E1 USRE46397 E1 US RE46397E1 US 200814933735 A US200814933735 A US 200814933735A US RE46397 E USRE46397 E US RE46397E
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particles
organic acid
caine
anesthetic
acid
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Samuel P. Sawan
Daniel Jacobs
Tadmor Shalon
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Theracaine LLC
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SVIP5 LLC
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Definitions

  • the field of this invention is the treatment of pain, particularly surgically caused or other type of wound.
  • Local anesthetics of the “caine” family are weak bases.
  • “caine” is intended anesthetics that end in the suffix caine, which will usually include amino acid amides and esters.
  • One of the classes of anesthetics that are amine bases also includes an aromatic ring, for example, a meta-xylyl group and an amide or ester functionality. The aromatic group with the other entities results in hydrophobicity, so that the members of the class are frequently employed as their hydrochloride salts to allow for water solubility.
  • anesthetics of the caine family include lidocaine (lignocaine), procaine, bupivacaine, ropivacaine, butacaine oxybuprocaine mepivacaine, prilocaine, amylocaine chloroprocaine, etidocaine, propoxycaine and tropacocaine.
  • Local anesthetics are usually administered by injection into the area of the nerve fibers to be blocked. Thus, absorption and distribution are not as important in controlling the onset of effect as in determining the rate of offset of anesthesia and the likelihood of central nervous system and cardiac toxicity.
  • Topical application of local anesthetics, where there is an intact skin barrier requires drug diffusion for both onset and offset of anesthetic effect.
  • lidocaine 2-(diethylamino)-N-(2,6-dimethylphenyl)-acetamide
  • ventricular tachycardia an arrythmia of the heart
  • Lidocaine is also used with vasoconstrictors to reduce regional blood flow in topical applications or aerosols (such as nasal aerosols to reduce nasal congestion).
  • aerosols such as nasal aerosols to reduce nasal congestion.
  • lidocaine is known for its therapeutic effects in reducing post-herpetic neuralgia (PHN) nerve injury pain from shingles (herpes zoster and post herpetic neuralgia) and analogous neuropathies.
  • PPN post-herpetic neuralgia
  • U.S. Pat. No. Re 37,727 discloses methods employing lidocaine intradermal administration by transport of lidocaine from the skin surface, using patches and dressings, into the skin.
  • Lidocaine base is freely lipid soluble. It is insoluble in water and thus not suitable for use in an aqueous solution, requiring ethanol or the like to obtain a liquid solution.
  • its salt form, lidocaine-HCl is very soluble in water and alcohol.
  • lidocaine-HCl is the form that is used for preparation of injection solutions.
  • the hydrophilicity of the lidocaine hydrochloride salt inhibits transport across the skin.
  • the action of the lidocaine salt can be short-lived, requiring repeated administrations to relieve the patient.
  • bupivacaine see, for example, U.S. Pat. Nos. 6,699,908, 6,534,081, 6,521,259, 6,514,516, and 6,391,888, while in the scientific literature, Lambert et al. 2007 Arthritis Rheum 56, 2278-87; Ostergaard et al 2005 Eur J Pharm Sci 76, 280-7; and Larsen et al 2007 Eur J Pharm Sci 31, 172-9, as indicative of some of the activity in the field.
  • ropivacaine see, for example, U.S. Pat.
  • Examples of patents and patent applications that use polymeric matrices include U.S. Pat. No. 6,750,291 (Transdermal agent, film forming polyurethane and addition polymer); U.S. Pat. No. 6,699,908 (Bupivacaine in a controlled release polymeric vehicle); U.S. Pat. Nos. 6,534,081 (6,521,259) (6,514,516) (Bupivacaine in a controlled release polymeric vehicle and augmenting agent); U.S. Pat. No. 6,217,911 (Sustained release lidocaine with capped and uncapped PLGA); U.S. Pat. No.
  • 6,086,863 (Microspheres non-biodegradable charged, insoluble in carrier plus pharmaceutical agent); U.S. Pat. No. 5,810,786 (Lidocaine in thermoplastic resin (not PLGA)); U.S. Pat. No. 5,292,512 (Microspheres of PLGA with active ingredient of 3-10 mgs); 2005/0002996 (Cellulose impregnated with drug, coated with polymer or fatty acid); and 2004/0076671 (Lidocaine in carrier applied to wound, also includes an antibiotic and wax matrix).
  • 5,635,205 (Anesthetic composition with triglycerides and amphipathic ligand, e.g. phospholipid); U.S. Pat. No. 3,949,071 (Burn treatment, aqueous buffer pH 8-10, base, surface active agent, fatty acid and lidocaine); 2006/0280801 (Analgesic, fatty acid metal salts and other components); 2006/0222687 (Topical anesthetic formulation includes lidocaine and fatty acids as penetration enhancers); 2004/0228884 (Ion pair composition releases active ingredient); 2004/0214215 (Molecular complex of alkaline drug and related acid); 2004/0058994 (Surgical wounds treated with lidocaine free base or salt, includes some carboxylic acids as exemplary); and 2003/0027833 (Anesthetics (includes lidocaine) and penetration enhancers (fatty acids)). (All of these references are incorporated herein by reference to the extent that the references describe methods of preparation of salts and use of the an
  • Idexx Laboratories While not specifically directed to anesthetics, an extensive patent effort has been directed by Idexx Laboratories toward the use of fatty acid salts of amine drugs as slow release compositions. Idexx Laboratories have filed U.S. Pat. Nos. 7,033,599; 6,946,137; 6,887,487; 2007/0141162; and 2005/0075296, disclosing bupivacaine as one of the drugs.
  • Aminoacid amides and esters of the “caine” family of local anesthetics are provided in particle form as salts of organic acids, particularly in a surgical setting.
  • the subject compositions can be in powder, gel, gaseous dispersion or liquid form with intact particles and applied to the exposed tissue, such as surgically exposed, or to the skin in the case of laparoscopy.
  • the particles are designed to provide for enhanced performance of the anesthetic, including extended release of the anesthetic over a prolonged period of time, particularly during the period of pain, for maintaining the anesthetic in the area of interest, and minimizing toxicity.
  • the invention is directed to a method for improving the alleviation of pain of a surgical wound of a mammal.
  • the method comprises administering to the area of the surgical wound a therapeutically effective amount of particles of an organic acid salt of a caine anesthetic, wherein the organic acid is at least 6 carbon atoms, whereby the anesthetic provides improved alleviation of pain.
  • the anesthetic is selected from the group consisting of ropivacaine, bupivacaine and lidocaine.
  • the organic acid is an aliphatic organic acid or an aromatic organic acid and the particles comprise up to 50% equivalent excess of the organic acid.
  • the caine is an amino acid amide or an amino acid ester.
  • the particles are introduced into the bed of the wound, such as, but not limited to, by spraying into the bed. In certain embodiments, the particles are sprayed as an aerosol.
  • the particles are administered topically in a gel or liquid medium.
  • the invention is directed to a method for improving the alleviation of pain of a surgically created wound of a human.
  • the method comprises administering particles of an aliphatic acid salt of a caine to the bed of the wound, wherein the aliphatic acid is of from 6 to 30 carbon atoms, and is present in not more than 50% equivalent excess, and the particles have a median size range in the range of about 50 to 2000 ⁇ m, whereby the caine is released from the salt over at least one day at a therapeutically effective amount and alleviates the pain.
  • the particles are sprayed into the bed of the wound, such as but not limited to a method wherein the particles are mixed with a propellant.
  • the particles are dispersed in a vehicle to form a dispersion.
  • the particles are sprayed by means of a pump.
  • the particles are in a size range of about 100 to 1200 ⁇ m.
  • the particles are painted in the area of the wound.
  • the invention is directed to a for alleviating pain of a surgically created wound of a human.
  • the method comprises topically administering to the skin in proximity to the wound particles of an aliphatic organic acid salt of a caine selected from the group consisting of ropivocaine, bupivacaine or lidocaine, wherein the aliphatic organic acid is of from 6 to 30 carbon atoms and the particles are of median size in the range of 100 to 1200 ⁇ m, whereby the caine is released from the salt and transported transdermally over at least one day at a therapeutically effective amount and alleviates the pain.
  • a caine selected from the group consisting of ropivocaine, bupivacaine or lidocaine
  • FIG. 1 is a graph of the release of the lidocaine over time for the large particle formulation referred to as B16 298-69-1L and the small particle formulation referred to as B16 298-69-1s;
  • FIGS. 2A-2B show the size distribution of the large particles ( FIG. 2A ) and the small particles ( FIG. 2B ) in the formulation.
  • FIG. 3 is a graph of the results of a rat test for time to respond with and without treatment with the bupivacine-palmitate particles.
  • anesthetic particles are provided for the treatment of pain causing injury, particularly wounds, where the particles comprise as their major ingredient an organic acid salt of an amino acid amide or ester local anesthetic.
  • an organic acid salt of an amino acid amide or ester local anesthetic examples of the amino acid amide and ester local anesthetics have been indicated above, where of particular interest are lidocaine, bupivacaine and ropivacaine.
  • the organic acid salt will form an ionic species that is substantially neutral and hydrophobic, while the individual components are charged and capable of solvation and being separated at physiological pH.
  • the organic acid salts include pharmacologically acceptable acids that for the most part will be carboxylic acids, particularly aliphatic and sulphonic acids, where the organic acid is of at least about 6, usually at least about 8, carbon atoms, and the like.
  • the aliphatic carboxylic acids that form the salts of particular interest will usually be from about 6 to 30 carbon atoms, more usually 6 to 24, frequently 8 to 24, particularly 12 to 24 carbon atoms.
  • These acids may be aliphatically saturated or unsaturated, usually having no more than three sites of unsaturation, particularly ethylenic, and will be for the most part be even numbered.
  • Illustrative carboxylic acids include capric, caproic, caprylic, lauric, myristic, palmitic, stearic, oleic, linoleic, linolenic, arachadonic and the like and for the most part are selected as being designated as GRAS (generally regarded as safe).
  • the aliphatic acids may be substituted or unsubstituted, but will retain low water solubility, generally being less than about 5 weight % soluble at 25° C. Generally, substituents will include hydroxyl, halo, etc.
  • the sulfonic acids include such acids as benzene sulfonic acid and its derivatives, N-2-hydroxyethyl piperazine-N-2-ethane sulfonic acid, naphthalenesulfonic acid and derivatives thereof, octane-2-sulfonic acid and derivatives thereof, toluene sulfonic acid and derivatives thereofhe salt composition may have a 1:1 equivalent ratio of the anesthetic to the carboxylic acid or one of the components may be in excess, usually not more than about 5-fold excess, generally up to about 0.5, or up to about a 0.2, equivalent excess of either of the components of the salt may be present.
  • excess carboxylic acid the release rate of the caine from the salt may be diminished by virtue of the common ion effect, where the dissolution of the excess carboxylic acid will act to slow or retard the dissolution rate of the caine salt compound in the particles
  • the size distribution of a particle composition will generally have at least about 50 weight % within 75%, more usually within 50%, and desirably within 25% of the median size.
  • the median size will generally range from about 50 to about 2000 ⁇ m, more usually from about 50 to 1500 ⁇ m, desirably from about 100 ⁇ m to 1200 ⁇ m.
  • Individual compositions of interest have median sizes of about 100 to 200 ⁇ m, 300 to 500 ⁇ m and 750 to 1200 ⁇ m.
  • the particles may have a single salt or have a mixture of salts, where a single particle may be a mixture or the composition may be a mixture of particles of different salts.
  • the composition may be a mixture of different sized particles, usually comprising not more than two different distributions, where each of the different distributions has at least about 75% of the weight of the particles within 50%, more usually within 25%, of the median weight.
  • the median weights of the two differently sized compositions will usually differ by at least about 25%, more usually at least about 50% and there may be a two-fold difference or greater. In this way both composition and particle size can be varied to provide the optimum release profile for the particular application for the subject compositions.
  • the particles may be administered directly into the wound bed and onto the tissue for an open wound or onro the raw surface in case of laparoscopy or other minimally invasive procedure.
  • the particles may be administered by spraying, coating, painting, injecting, irrigating, adhered to a substrate, which substrate is placed in the wound, or the like.
  • Spraying may be employed for administration of the particles with or without a vehicle, using a pharmacologically acceptable propellant.
  • Air may be pumped to disseminate the particles.
  • Suitable topical vehicles, vehicles for aerosols and other components for use with the formulations of the present invention are well known in the art. These vehicles may contain a number of different ingredients depending upon the nature of the vehicle, the nature of the wound, the manner of administration, and the like. The vehicles will provide for a convenient method of administration to the wound, while not adversely affecting the controlled release of the anesthetic from the particles.
  • propellants are mixtures of volatile hydrocarbons, typically propane, n-butane and isobutane, or hydrofluoroalkanes (HFA): either HFA 134a (1,1,1,2,-tetrafluoroethane) or HFA 227 (1,1,1,2,3,3,3-heptafluoropropane) or combinations of the two or compressed gases such as nitrogen, carbon dioxide, air and the like.
  • HFA hydrofluoroalkanes
  • HFA 134a 1,1,1,2,-tetrafluoroethane
  • HFA 227 1,1,1,2,3,3,3-heptafluoropropane
  • Liquid media used for dispersing the particles should be highly volatile or miscible with the aqueous environment of the wound and rapidly evaporate or dissipate under the conditions of administration.
  • the liquids will for the most part be non-solvents for the anesthetic salt, although there may be minimal solubility.
  • Such vehicles may include non-solvent liquid media that include water, mixtures of water and organic solvents and mixtures of organic solvents.
  • Other additives may include protein-based materials such as collagen and gelatin; silicone-based materials; stabilizing and suspending agents; emulsifying agents; and other vehicle components that are suitable for administration to the skin, as well as mixtures of these components and those otherwise known in the art.
  • the vehicle can further include components adapted to improve the stability or effectiveness of the applied formulation, such as preservatives, antioxidants, and skin penetration enhancers. Examples of such components are described in the following reference works hereby incorporated by reference: Martindale—The Extra Pharmacopoeia (Pharmaceutical Press, London 1993) and Martin (ed.), Remington's Pharmaceutical Sciences.
  • a suitable vehicle will depend on the particular physical form and mode of delivery that the formulation is to achieve.
  • suitable foams include liquids; solids and semisolids such as gels, foams, pastes, creams, ointments, powders and the like; colloidal drug delivery systems, for example, liposomes, microemulsions, microparticles, or other forms.
  • the topical formulations of the present invention can be prepared in a variety of physical forms.
  • solid particles, pastes, creams, lotions, gels, and liquids are all contemplated by the present invention.
  • a difference between these forms is their physical appearance and viscosity, which can be governed by the presence and amount of emulsifiers and viscosity adjusters present in the formulation.
  • Particular topical formulations can often be prepared in a variety of these forms.
  • Solids are generally firm and will usually be in particulate form; solids optionally can contain liquids, emulsifiers, moisturizers, emollients, fragrances, dyes/colorants, preservatives and other active ingredients that increase or enhance the efficacy of the final product.
  • Creams and lotions are often similar to one another, differing mainly in their viscosity; both lotions and creams may be opaque, translucent or clear and often contain emulsifiers, solvents, and viscosity adjusting agents, as well as moisturizers, emollients, fragrances, dyes/colorants, preservatives and other active ingredients that increase or enhance the efficacy of the final product.
  • Gels can be prepared with a range of viscosities, from thick or high viscosity to thin or low viscosity.
  • These formulations may also contain liquids, emulsifiers, moisturizers, emollients, fragrances, dyes/colorants, preservatives and other ingredients that increase or enhance the efficacy of the final product.
  • Liquids are thinner than creams, lotions, or gels and often do not contain emulsifiers.
  • Suitable emulsifiers for use in the formulations of the present invention include, but are not limited to ionic emulsifiers, behentirmonium methosulfate, cetearyl alcohol, non-ionic emulsifiers like polyoxyethylene oleyl ether, PEG-40 sterate, ceteareth-12, ceteareth-20, ceteareth-30, ceteareth alcohol, PEG-100 stearate, glyceryl stearate, or combinations or mixtures thereof.
  • Suitable viscosity adjusting agents for use in the formulations of the present invention include, but are not limited to protective colloids or non-ionic gums such as hydroxyethylcellulose, xanthan gum, magnesium aluminum silicate, silica, microcrystalline wax, beeswax, paraffin, and cetyl palmitate, or combinations or mixtures thereof.
  • protective colloids or non-ionic gums such as hydroxyethylcellulose, xanthan gum, magnesium aluminum silicate, silica, microcrystalline wax, beeswax, paraffin, and cetyl palmitate, or combinations or mixtures thereof.
  • Suitable liquids for use in the formulations of the present invention will be selected to be non-irritating and include, but are not limited to water, propylene glycol, polyethylene glycols, polypropylene glycols and mixtures thereof. Not more than about 10 weight %, usually not more than 5 weight %, of the anesthetic salt will be soluble in the medium; preferably the anesthetic salt will be insoluble in the medium.
  • Suitable surfactants for use in the formulations of the present invention include, but are not limited to nonionic surfactants.
  • nonionic surfactants dimethicone copolyol, polysorbate 20, polysorbate 40, polysorbate 60, polysorbate 80, lauramide DEA, cocamide DEA, and cocamide MEA, are contemplated for use is with the formulations of the present invention.
  • lauramide DEA, cocamide DEA, and cocamide MEA are contemplated for use is with the formulations of the present invention.
  • combinations or mixtures of these surfactants can be used in the formulations of the present invention.
  • Suitable preservatives for use in the formulations of the present invention include, but are not limited to antimicrobials such as methylparaben, propylparaben, sorbic acid, benzoic acid, and formaldehyde, as well as physical stabilizers and antioxidants such as vitamin E, sodium ascorbate/ascorbic acid and propyl gallate.
  • antimicrobials such as methylparaben, propylparaben, sorbic acid, benzoic acid, and formaldehyde
  • physical stabilizers and antioxidants such as vitamin E, sodium ascorbate/ascorbic acid and propyl gallate.
  • combinations or mixtures of these preservatives can be used in the formulations of the present invention.
  • Suitable moisturizers for use in the formulations of the present invention include, but are not limited to lactic acid and other hydroxy acids and their salts, glycerin, propylene glycol, and butylene glycol.
  • Suitable emollients include lanolin alcohol, lanolin, lanolin derivatives, cholesterol, petrolatum, isostearyl neopentanoate and mineral oils.
  • combinations or mixtures of these moisturizers and emollients can be used in the formulations of the present invention.
  • Suitable additional ingredients include, but are not limited to, abrasives, absorbents, anticaking agents, anti-foaming agents, anti-static agents, astringents, binders/excipients, buffering agents, chelating agents, film forming agents, conditioning agents, opacifying agents, pH adjusters and protectants.
  • CTFA Cosmetic, Toiletry, and Fragrance Association
  • the health care professional administering the particle formulation is able to insure uniform coverage or otherwise be able to see what areas have been covered and how extensively the particle formulation has been distributed. Therefore, one may include a detectable composition with the particles so that they can be visualized.
  • This may include colored compounds or dyes, fluorescent compounds and even luminescent compounds.
  • the dyes should be highly colored and visible in the presence of blood, while the fluorescent compounds should fluoresce under ultra-violet light. See, for example, Richard P. Hangland; Molecular Probes—Handbook of Fluorescent Probes and Research Chemicals; 5th Edition 1992-94; Molecular Probes, Inc.
  • the particles will be at least about 1 weight %, usually at least 2 weight %, and up to 100 weight % of the non-volatile portion of the composition.
  • the weight % of the particles will generally be in the range of about 1-75 weight %, more usually about 1-50 weight %.
  • the minor ingredients except for the medium will generally range from about 0.01 weight % to about 10 weight %, the amount generally being conventional for the purpose of the ingredient.
  • the particles are sprayed as an aerosol, generally the particles will be present in the range of about 1 to 99 weight % of the composition.
  • the composition may be sprayed, wiped, smeared, painted, transferred from a template onto or proximal to the wound or may be made into a patch where the composition will be separate from or part of the adhesive.
  • the composition may be applied to the wound and a dressing or other protective layer added to prevent contamination and abrasion.
  • the composition may be injected, particularly where a minimally invasive surgical technique is employed and the rate of transdermal transport is insufficient to provide the pain relief required.
  • Not more than one application should be required per 6 hours, usually per half-day, and times between applications may vary from 6 hours to 7 days, usually 12 hours to 4 days, where frequently by 7 days further treatment will not be required. During this time a therapeutically effective amount of the caine will be released from the particles.
  • the amount of the anesthetic salt applied to the wound area will be a therapeutically effective amount to minimize pain to a level that the patient can tolerate and preferably substantially eliminate any sense of pain.
  • the amount of pain will usually vary with time, so that the amount of anesthetic that will be required can be diminished over time. Therefore, the profile of anesthetic release from the salt can be a diminishing amount of anesthetic being released over time.
  • the large initial release coincides with the high levels of pain in the early post-operative period. After the initial release, generally not more than 60 weight %, more usually not more than about 50 weight %, will be released in 24 hours, where the pain alleviation is to occur over generally greater than two days, with diminishing percentages as the time for relief is extended.
  • the subject treatment may be used with ancillary treatments, such as an initial conventional anesthetic administration prior to or concurrent with the application of the subject composition.
  • any mammal that has been injured or undergone surgery can enjoy the benefits of the anesthetic salt. Therefore, included as patients are domestic animals, e.g. horses, dogs, cats; wild animals, particularly wild animals found in zoos, and the like.
  • the subject compositions can be prepared in accordance with known techniques.
  • the anesthetic base and organic acid can be brought together in an appropriate medium where the two components are dissolved and form the salt. Dissolution may be a result of a temperature increase, generally a temperature below about 60° C., where cooling results in precipitation of the salt.
  • a solvent can be used in which the components are soluble, but the salt is not, so that the salt precipitates upon formation.
  • Another technique is to add a non-solvent that results in the precipitation of the salt, where the salt is the least soluble of the three components in the solution.
  • Another technique is to remove the solvent that allows for the dissolution of the anesthetic base, the organic acid and the resulting salt.
  • Another technique is to combine the anesthetic base and organic acid in the molten state to allow reaction to occur. There are numerous other approaches that may also be used to prepare such salts that are known to those skilled in the art.
  • the precipitate is then isolated and may be treated in a variety of ways to achieve the desired size composition.
  • the precipitate may be ground and then the particles size selected, dissolved in a volatile solvent and sprayed from a nozzle into a vacuum where the solvent evaporates leaving particles of the desired site, dissolved in an appropriate solvent and precipitated in a non-solvent in a manner know to those skilled in the art to prepare microparticles or other conventional technique.
  • these ingredients may be included in the solvent used to spray the solution of the salt, or in the precipitation method, etc.
  • the particles can be blended with an appropriate agent, such as talc, sodium bicarbonate, magnesium carbonate, etc.
  • the particles are then packaged and stored at room or lower temperature or are mixed with a propellant and, as appropriate, a vehicle, and stored in a pressure container. Instead, a pump bottle may be used where only a vehicle would be required. Alternatively, the particles may be kept separate from the vehicle and combined with the vehicle shortly prior to or at time of administration.
  • a drug product can be prepared containing 50% of the organic acid caine salt and 50% of the organic acid. The amount of added organic acid to the composition will be determined by calculation to provide the desired composition for the release rate and profile.
  • the above drug product preparation routes may be equally applied for the preparation of microparticles that contain both the organic acid caine salt and the organic acid.
  • the particles are sized and fractioned typically by sieving operations, although other methods may be employed.
  • a typical sieving operation would employ at least 2 sieves of the appropriate size.
  • the larger sieve size would allow for the rejection of particles larger then the specified maximum while the lower sieve size would serve to retain the particles of the specified size.
  • the selection of the sieves determines the particle size distribution. Using this approach one can also prepare multimodal distributions to obtain different release profiles of drug. Nominal particle size and particle size distribution is determined by an instrument such as a Coulter LS13 on suspensions of the microparticles.
  • Drug dissolution kinetics is evaluated using an LC method employing an infinite sink concept.
  • a known amount of microparticles are suspended in a defined volume of a suitable test medium, for example a phosphate buffer solution containing 1% Tween 80, meant to simulate in vivo release kinetics.
  • the suspension of microparticles is kept at a constant temperature, typically 37° C. for a period of time, for example, about 12 hours, with constant agitation.
  • the particles are removed from the solution by filtration and resuspended in another fresh amount of the test media.
  • the original solution is assayed for the amount of drug product in solution by an appropriate quantitative method, typically an LC method employing UV detection or MS.
  • a fluorescent product a compound such as fluorescein is added to the mixture before the precipitation or preparation of the microparticle is attempted. If a colored product is required a food safe dye such as FD&C Blue No 1 or Blue No 2 is used.
  • Drug product of the appropriate size is combined with other agents that may be appropriate to provide free flowing stable microparticles and added to an appropriate aerosol container.
  • the aerosol container is subsequently pressurized with a high purity propellant and sealed under pressure with the appropriate spray nozzle to provide the spray pattern desired and in some cases to provide a metered dose of the drug.
  • the drug product can be suspended into a PBS solution or other suitable vehicle just prior to application to the wound.
  • the product is distributed over the wound by spraying using a variety of possible propulsion systems e.g. an air brush type of system, pump sprayer system, etc., whereby drug product suspended in the PBS is aspirated through a tube using the Venturi concept with a propellant container.
  • the amount dispensed per unit time and spray pattern are determined by the nozzle selected at the time of application by the health care professional.
  • a general procedure is provided for any of the members of the caine family.
  • the caine as the hydrochloride salt is dissolved in a suitable organic solvent such as chloroform that dissolves both the hydrochloride form as well as the free base.
  • the hydrochloride salt is neutralized by addition of a stoichiometric amount of triethyl amine producing the free base of the caine.
  • the synthesis is started using the commercially obtained free base form of the caine.
  • the hydrochloride salt is dissolved into water and a stoichiometric amount of sodium hydroxide is added dropwise with stirring.
  • the free base form of the caine is essentially insoluble in water and precipitates during the course of the addition of the strong base.
  • the free base may be extracted from the aqueous phase using a solvent that is immiscible with water and dissolves the free base caine, using such solvents as chloroform, methylene chloride, diethyl ether and the like providing such properties.
  • a solution of the free base of the appropriate caine is treated with a stoichiometric amount of a solution of the carboxylic acid in a solvent that completely dissolves both the free base form of the caine and the carboxylic acid.
  • Solvents such as alcohols or chlorinated solvents are employed.
  • the solution is heated for varying times depending upon the caine and carboxylic acid chosen until the reaction is complete and the product isolated either by precipitation into a non-solvent or by evaporating the solvent to dryness and isolating the product as a dry solid.
  • the dry solid is recrystallized to remove any unreacted carboxylic acid by dissolving the product in 2-propanol and adding water to the solution to cause crystallization of the product.
  • Other solvents such as N-methyl pyrrolidone (NMP), tetrahrydofuran (THF), acetonitrile (ACN) and other organic water miscible solvents are suitable for this purpose.
  • NMP N-methyl pyrrolidone
  • THF tetrahrydofuran
  • ACN acetonitrile
  • the product may be recyrstallized from 1 to 2 times depending upon the purity of the compound that is desired. Purification by chromatographic techniques such as reverse phase chromatography is performed by dissolving the product in acetonitrile and applying the solution to C18 modified silica, and eluted using a mobile phase with an isocratic or gradient eluent. If desired, the compound may be purified by simple precipitation of the dissolved product in dieth
  • the purified fatty acid salt of the caine is converted to microparticles of known size and size distribution through the process of controlled precipitation.
  • a solution of the drug is prepared in ethyl acetate and filtered to remove undissolved particulates. The solution is added slowly with vigorous stirring to aqueous methanol, a nonsolvent for the drug but one miscible with the ethyl acetate, causing controlled precipitation of the microparticles.
  • Polyvinyl alcohol is conveniently employed to allow for the generation of particles that do not adhere to one another.
  • the microparticles are prepared by dissolving the drug product into an aqueous immiscible solvent such as methylene chloride. This solution is added with vigorous agitation to a methylene chloride pre-saturated aqueous solution containing a surfactant such as polyvinyl alcohol. The drug product separates as insoluble particles that are subsequently filtered from the medium and dried to remove traces of solvent.
  • an aqueous immiscible solvent such as methylene chloride.
  • This solution is added with vigorous agitation to a methylene chloride pre-saturated aqueous solution containing a surfactant such as polyvinyl alcohol.
  • the drug product separates as insoluble particles that are subsequently filtered from the medium and dried to remove traces of solvent.
  • the drug product is dissolved in methylene chloride.
  • the solution is sprayed through an appropriately sized nozzle at predetermined rates into a heated and/or vacuum chamber allowing for the rapid volatilization of the solvent leaving the insoluble drug product microparticles.
  • the appropriate nozzle size, temperature and drying conditions are known to those skilled in the art.
  • the salt bupivacaine palmitate was prepared by dissolving 18.3% w/v bupivacaine free base and 16.7% w/v palmitic acid.
  • Particle size characteristics of bupivacaine palmitate particles were determined using a Coulter LS13230 static light scattering instrument. A mass of 100 mg of particles was suspended in 2 ml of 0.1% Tween 80 in water. The micro-volume module attachment was filled with deionized water. The stir speed was set at 32%, and alignment and background corrections were performed. Using a transfer pipette, particle suspension was added to the micro-volume cell until obscuration was between 8 and 12%. Particle size data collection was performed for 60 seconds, and particle size was estimated using the Fraunhofer approximation.
  • the particles were irradiated with a sterilizing dose of gamma-radiation. No change was observed in the nature or the in vitro release kinetics of the particles.
  • the serum filter was used to remove all but approximately 0.2 ml supernatant. A portion of the supernatant was collected for analysis and the remaining amount was discarded. A new volume of 5 ml of PBS was added to the test tube, and the same serum filter was replaced. After the first day, release samples were collected once or twice for a period of approximately 9 days. Collected samples were stored refrigerated until analyzed.
  • UV/Vis ultraviolet/visible spectrophotometer
  • ELSD evaporative light scattering detector
  • a typical experimental setup consists of the following instrumental components: Waters 1525 Binary Pump, Waters 2487 Dual Wavelength Absorbance Detector, Waters 717plus Autosampler and Alltech ELSD 2000. Ambient temperature was used with the autosampler and a Phenomenex Gemini C18 110A (150 mm length, 4.6 mm i.d., 3 ⁇ m packing) was used also at ambient temperature.
  • the flow rate was adjusted to 1 ml/min with a isocratic mobile phase consisting of a binary mixture comprised of 45% of 0.1% triethanol amine (TEA) in water at a pH 10 and 55% acetonitrile (ACN).
  • TEA triethanol amine
  • ACN acetonitrile
  • UV detection was performed at 220 nm and the ELSD detector was set to 80° C. with a nebulizer flow of 1.5 L/min. An injection volume of 25 ⁇ l was used. Typical runs times were 20 minutes.
  • System calibration was performed using pure bone fide bupivacaine and palmitic acid components.
  • a treatment and control side in a male, Sprague-Dawley rat 250-300 g was employed.
  • the animal was anesthetized with isoflurane inhalation (2.5-3%), whereupon the back was partly shaved.
  • a 16 g needle was introduced deep to the shaved skin on the left mid paraspinal back and moved side to side to clear a small (1.0 cm diameter) pocket.
  • a similar procedure was performed on the right side. The needle was then used to introduce test local anesthetic bupivacaine palmitate particles into the pocket on the right side.
  • the rat was awakened and placed in a Decapicone for restraint. As restraint itself can produce endogenous analgesic effects, the animal was allowed to rest quietly in the cone for 15 min prior to any testing. Radiant heat from a focused projection bulb with area of approximately 0.5 cm 2 was then directed to the test areas to assess the pain threshold several times on each side. The light was applied until the rat attempted to move within the restraint cone, at which time the light heat stimulus was turned off. The light heat stimulus was never allowed to exceed a 20 seconds interval in order to avoid permanent damage to the skin or undue discomfort.
  • the post-procedural results at 15 min, 1 and 2 days are represented in average number of seconds before movement:
  • the subject invention provides a substantial advance over present compositions and procedures for alleviating pain, particularly during and after surgical procedures.
  • the compositions of the subject invention are formulated for ease of use by the surgeon and efficacy over an extended period of time.
  • the subject compositions are particularly suitable for introduction into the wound bed. After closing the wound, the subject particles will continue to release an effective amount of the anesthetic for a prolonged period, alleviating the pain and diminishing or obviating the need for systemic pain killers.
  • the components are safe and will readily be metabolized by the body leaving no residue.
  • the compositions have low, if any, toxicity and can provide for enhanced localization of the anesthetic.
  • the subject compositions are easily prepared, handled and formulated to provide the desired anesthetic activity.
  • the formulations can provide for transdermal transport of the anesthetic to provide anesthetic effect at the site of injury.

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SG11201407323WA (en) * 2012-05-10 2014-12-30 Cellix Bio Private Ltd Compositions and methods for the treatment of local pain
EP3242869B1 (fr) * 2015-01-06 2021-10-27 Cellixbio Private Limited Compositions et méthodes pour le traitement d'une inflammation et de la douleur
WO2017082121A1 (fr) * 2015-11-12 2017-05-18 テルモ株式会社 Agent administré par voie topique à libération prolongée
RU2021114918A (ru) * 2016-12-26 2021-07-09 Целликс Био Прайвет Лимитед Композиции и способы лечения хронической боли
HUE053472T2 (hu) 2017-03-27 2021-06-28 Fruithy Holdings Ltd Gyengén oldódó komplex vagy szolvátja, gyógyászati készítmény és alkalmazása

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US8920843B2 (en) 2014-12-30

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