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WO2024215778A1 - Formulations pharmaceutiques en émulsion stables à libération prolongée - Google Patents

Formulations pharmaceutiques en émulsion stables à libération prolongée Download PDF

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Publication number
WO2024215778A1
WO2024215778A1 PCT/US2024/023902 US2024023902W WO2024215778A1 WO 2024215778 A1 WO2024215778 A1 WO 2024215778A1 US 2024023902 W US2024023902 W US 2024023902W WO 2024215778 A1 WO2024215778 A1 WO 2024215778A1
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Prior art keywords
composition
anesthetic
emulsion
crystals
phase
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William Taylor
Kelsey Pflepsen
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Insitu Biologics Inc
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Insitu Biologics Inc
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    • 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
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/24—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
    • A61K47/44—Oils, fats or waxes according to two or more groups of A61K47/02-A61K47/42; Natural or modified natural oils, fats or waxes, e.g. castor oil, polyethoxylated castor oil, montan wax, lignite, shellac, rosin, beeswax or lanolin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/04—Centrally acting analgesics, e.g. opioids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/14—Esters of carboxylic acids, e.g. fatty acid monoglycerides, medium-chain triglycerides, parabens or PEG fatty acid esters
    • 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
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
    • 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
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner

Definitions

  • Acute post-op pain is estimated to need at least 5-7 days of pain relief coverage.
  • Numerous opioid-limiting techniques such as intrathecal morphine, medicinal adjuncts, and regional anesthetics of standard and extended- release preparations demonstrate limited effectiveness to 24-48 hours of effective analgesia—often requiring narcotics to supplement waning analgesia.
  • FIG. 1 shows porcine ropivacaine blood plasma concentration (ng/mL) after sciatic peripheral nerve block procedure with the instantly disclosed stable emulsion (6.29 mg/Kg formulation) compared to Naropin 0.5% positive control, according to certain embodiments.
  • FIG.2 shows porcine ropivacaine blood plasma concentration (ng/mL) over time following injection of instantly disclosed stable emulsion (20.44 mg/Kg formulation) or Naropin 0.5% positive control as peripheral nerve block, according to certain embodiments.
  • FIG.3A shows a microscope image of Sample 1 at 10x magnification, according to certain implementations.
  • FIG.3B shows a microscope image of Sample 1 at 20x magnification, according to certain implementations.
  • FIG.4A shows a microscope image of Sample 2 at 10x magnification, according to certain implementations.
  • FIG.4B shows a microscope image of Sample 2 at 20x magnification, according to certain implementations.
  • FIG.5A shows a microscope image of Sample 3 at 10x magnification, according to certain implementations.
  • FIG.5B shows a microscope image of Sample 3 at 20x magnification, according to certain implementations.
  • FIG.6A shows a microscope image of Sample 4 at 10x magnification, according to certain implementations.
  • FIG.6B shows a microscope image of Sample 4 at 20x magnification, according to certain implementations.
  • FIG.7A shows a microscope image of Sample 5 at 10x magnification, according to certain implementations.
  • FIG.7B shows a microscope image of Sample 5 at 20x magnification, according to certain implementations.
  • FIG.8A shows a microscope image of Sample 6 at 10x magnification, according to certain implementations.
  • FIG.8B shows a microscope image of Sample 6 at 20x magnification, according to certain implementations.
  • FIG.9A shows a microscope image of Sample 7 at 10x magnification, according to certain implementations.
  • FIG.9B shows a microscope image of Sample 7 at 20x magnification, according to certain implementations.
  • FIG. 10A shows a microscope image of Sample 8 at 10x magnification, according to certain implementations.
  • FIG.10B shows a microscope image of Sample 8 at 20x magnification, according to certain implementations.
  • FIG. 11A shows a microscope image of Sample 9 at 10x magnification, according to certain implementations.
  • FIG.11B shows a microscope image of Sample 9 at 20x magnification, according to certain implementations.
  • FIG. 12A shows a microscope image of Sample 10 at 10x magnification, according to certain implementations. [027] FIG.
  • FIG. 12B shows a microscope image of Sample 10 at 20x magnification, according to certain implementations.
  • FIG. 13A shows a microscope image of Sample 11 at 10x magnification, according to certain [029]
  • FIG. 13B shows a microscope image of Sample 11 at 20x magnification, according to certain implementations.
  • FIG. 14A shows a microscope image of Sample 12 at 10x magnification, according to certain implementations.
  • FIG. 14B shows a microscope image of Sample 12 at 20x magnification, according to certain implementations.
  • FIG. 15A shows a microscope image of Sample 13 at 10x magnification, according to certain implementations.
  • FIG. 15A shows a microscope image of Sample 13 at 10x magnification, according to certain implementations.
  • FIG. 15B shows a microscope image of Sample 13 at 20x magnification, according to certain implementations.
  • FIG. 16A shows a microscope image of Sample 14 at 10x magnification, according to certain implementations.
  • FIG. 16B shows a microscope image of Sample 14 at 20x magnification, according to certain implementations.
  • FIG. 17A shows a microscope image of Sample 15 at 10x magnification, according to certain implementations.
  • FIG. 17B shows a microscope image of Sample 15 at 20x magnification, according to certain implementations.
  • FIG. 18A shows a microscope image of Sample 16 at 10x magnification, according to certain implementations. [039] FIG.
  • FIG. 18B shows a microscope image of Sample 16 at 20x magnification, according to certain implementations.
  • FIG. 19A shows a microscope image of Sample 17 at 10x magnification, according to certain implementations.
  • FIG. 19B shows a microscope image of Sample 17 at 20x magnification, according to certain implementations.
  • FIG. 20A shows a microscope image of Sample 18 at 10x magnification, according to certain implementations.
  • FIG. 20B shows a microscope image of Sample 18 at 20x magnification, according to certain implementations.
  • FIG. 21A shows a microscope image of Sample 19 at 10x magnification, according to certain implementations. [045] FIG.
  • FIG. 21B shows a microscope image of Sample 19 at 20x magnification, according to certain implementations.
  • FIG. 22A shows a microscope image of Sample 20 at 10x magnification, according to certain implementations.
  • FIG. 22B shows a microscope image of Sample 20 at 20x magnification, according to certain implementations.
  • FIG. 23A shows a microscope image of Sample 21 at 10x magnification, according to certain implementations.
  • FIG. 23B shows a microscope image of Sample 21 at 20x magnification, according to certain implementations.
  • FIG. 24A shows a microscope image of Sample 22 at 10x magnification, according to certain implementations. [051] FIG.
  • FIG. 24B shows a microscope image of Sample 22 at 20x magnification, according to certain implementations.
  • FIG. 25A shows a microscope image of Sample 23 at 10x magnification, according to certain implementations.
  • FIG. 25B shows a microscope image of Sample 23 at 20x magnification, according to certain implementations.
  • FIG.26 shows a microscope image of Sample 24 at 40x magnification, according to certain implementations.
  • FIG.27 shows a microscope image of Sample 25 at 40x magnification, according to certain implementations.
  • a further aspect includes from the one particular value and/or to the other particular value.
  • values are expressed as approximations, by use of the antecedent “about,” it will be understood that the particular value forms a further aspect.
  • the endpoints of each of the ranges are significant both in relation to the other endpoint, and independently of the other endpoint.
  • references in the specification to parts by weight of a particular element or component in a composition denotes the weight relationship between the element or component and any other elements or components in the composition or article for which a part by weight is expressed, unless expressly described otherwise.
  • X and Y are present at a weight ratio of 2:5, and are present in such ratio regardless of whether additional components are contained in the compound.
  • a weight percent (wt. %) of a component is based on the total weight of the formulation or composition in which the component is included.
  • the terms “optional” or “optionally” means that the subsequently described event or circumstance can or cannot occur, and that the description includes instances where said event or circumstance occurs and instances where it does not.
  • the term “anesthetic agent” or “local anesthetic agent” refers to an agent that causes loss of sensation in a human or other mammal with or without the loss of consciousness. More particularly, the term “local anesthetic” refers to an anesthetic agent that induces local anesthesia by reversibly inhibiting peripheral nerve excitation and/or conduction. Local anesthetics suitable for use in the present invention include, but are not limited to, ester- based anesthetics, amide-based anesthetics, ester analogs of amide-based anesthetics, and ester analogs of other anesthetics.
  • Ester-based anesthetics include, but are not limited to, cocaine, procaine, 2-chloroprocaine, tetracaine, benzocaine, amethocaine, chlorocaine, butamben, dibucaine, and the like.
  • Amide-based anesthetics include, but are not limited to, lidocaine, prilocaine, mepivacaine, ropivacaine, etidocaine, levobupivacaine, bupivacaine, and the like.
  • anesthetics suitable for use in the present invention include, but are not limited to, ester analogs of aconitine, dyclonine, ketamine, pramoxine, safrole, and salicyl alcohol. Such ester analogs can contain an ester group anywhere within the structure.
  • the term “subject” refers to the target of administration, e.g. a subject.
  • the subject of the herein disclosed methods can be a vertebrate, such as a mammal, a fish, a bird, a reptile, or an amphibian.
  • the subject of the herein disclosed methods can be a human, non-human primate, horse, pig, rabbit, dog, sheep, goat, cow, cat, guinea pig or rodent.
  • the term does not denote a particular age or sex. Thus, adult and newborn subjects, as well as fetuses, whether male or female, are intended to be covered.
  • the subject is a mammal.
  • a patient refers to a subject afflicted with a disease or disorder.
  • patient includes human and veterinary subjects.
  • the methods of the present invention can provide any amount of any level of treatment or prevention of a disease or medical condition in a mammal.
  • the treatment or prevention provided by the method can include treatment or prevention of one or more conditions or symptoms of the disease or medical condition.
  • the method in some embodiments, achieves a diminution in or elimination of pain in a subject.
  • prevention can encompass delaying the onset of the disease, or a symptom or condition thereof.
  • treating includes prophylaxis of the specific disorder or condition, or alleviation of the symptoms associated with a specific disorder or condition and/or preventing or eliminating said symptoms.
  • post-operative pain refers in general to producing a diminution or alleviation of pain associated with recovering from a surgical procedure.
  • substantially refers to the complete or nearly complete extent or degree of an action, characteristic, property, state, structure, item, or result. For example, an object that is "substantially” enclosed would mean that the object is either completely enclosed or nearly completely enclosed. The exact allowable degree of deviation from absolute completeness may in some cases depend on the specific context.
  • the terms “effective amount” and “amount effective” refer to an amount that is sufficient to achieve the desired result or to have an effect on an undesired condition.
  • a “therapeutically effective amount” refers to an amount that is sufficient to achieve the desired therapeutic result or to have an effect on undesired symptoms but is generally insufficient to cause adverse side effects.
  • the specific therapeutically effective dose level for any particular patient will depend upon a variety of factors including the disorder being treated and the severity of the disorder; the specific composition employed; the age, body weight, general health, sex and diet of the patient; the time of administration; the route of administration; the rate of excretion of the specific compound employed; the duration of the treatment; drugs used in combination or coincidental with the specific compound employed and like factors well known in the medical arts. For example, it is well within the skill of the art to start doses of a compound at levels lower than those required to achieve the desired therapeutic effect and to gradually increase the dosage until the desired effect is achieved. If desired, the effective daily dose can be divided into multiple doses for purposes of administration.
  • compositions can contain such amounts or submultiples thereof to make up the daily dose.
  • the dosage can be adjusted by the individual physician in the event of any contraindications. Dosage can vary, and can be administered in one or more dose administrations daily, for one or several days. Guidance can be found in the literature for appropriate dosages for given classes of pharmaceutical products. In further various aspects, a preparation can be administered in a “prophylactically effective amount”; that is, an amount effective for prevention of a disease or condition. [068] Effective dosages may be estimated initially from in vitro assays.
  • an initial dosage for use in animals may be formulated to achieve a circulating blood or serum concentration of active compound that is at or above an IC50 of the particular compound as measured in an in vitro assay.
  • Calculating dosages to achieve such circulating blood or serum concentrations is well within the capabilities of skilled artisans.
  • the reader is referred to Fingl & Woodbury, “General Principles,” In: Goodman and Gilman's The Pharmaceutical Basis of Therapeutics, Chapter 1, pp. 1-46, latest edition, Pergamagon Press, which is hereby incorporated by reference in its entirety, and the references cited therein.
  • a stable emulsion containing solid crystal pharmaceutical agents and or solid phase drug reservoir are contained within a continuous carrier phase that forms a liquid emulsion that allows delivery via syringe and hypodermic needle, through a catheter or through an applicator.
  • the instantly disclosed drug product is a stable 3 phase emulsion formulation that provides excellent sustained release performance for small molecules like ropivacaine and bupivacaine but with the advantages of not having a residual active pharmaceutical ingredient (API) or drug product excipient remaining in the body after 14 days.
  • API generally refers to an anesthetic agent, although in certain embodiments, non- anesthetic agent APIs are possible. It is advantageous to use the body’s tissues to absorb and remove the drug product to prevent irritation or compression of the nerve or surrounding tissues during movement of neighboring muscles.
  • the instantly disclosed emulsion is primarily designed to act as a peripheral nerve block (PNB) in which it can produce a full nerve block within the first hour post administration and maintain a pain block for at least 3 days (72hrs).
  • PNB peripheral nerve block
  • the ability of a PNB to produce a pain block for at least three days allows the patient to avoid opioids and transition to non-opioid medications after 3 days.
  • No other drug formulations have yet been capable of producing both a strong nerve block and prolonged pain relief for at least 72 hours. They may be able to treat pain locally at the wound or in some examples require additional/supplemental anesthetic to produce a strong block.
  • the stable emulsion formulation drug product described herein produces a fast onset robust nerve block followed by at least 3 days pain anesthetic. It is absorbed by the body within 14 days and does not compress or cause inflammation at the injection site.
  • the unique composition of the drug product allows it to store and retain the API, ropivacaine in these examples, and limit its elution rates.
  • Solid particles within emulsions usually allow for coalescence of a lipid phase and aqueous phases and destabilizes emulsions.
  • the solids particles can be drug crystals. In other embodiments, the solid particles can be solid microparticles.
  • the solid particles can be various other configurations that would be understood as functionally compatible with the formulation by those skilled in the art.
  • the solid particles do not destabilize the emulsion and the emulsions retain the solid particles dispersed within and throughout the two liquid phases in a homogenous liquid.
  • emulsions are not able to deliver a sufficient dose of API to last several days as they cannot carry solid particles and are thus limited in the amount of drug carried in a single dose.
  • Stable emulsions typically do not contain solid particles that may initiate coalescence of the lipid and aqueous phases.
  • the instantly disclosed formulation is unique in that it can hold solid API particles in the emulsion up to 28% by weight relative to the lipid components or 12% relative to the entire drug product in a stable emulsion, as defined below.
  • the emulsion can carry up to 30% API, or 15% relative to entire drug product volume, but they become thick and must be delivered through larger gauge needles and applicators.
  • many lipid components such as triglycerides have low API solubility at body and ambient temperatures preventing them from dissolving pharmaceutically effective amounts of API. Due to its unique manufacturing process, the instantly disclosed formulation creates a stable emulsion with solid API crystals.
  • API crystals are suspended in the emulsions with a small amount of dissolved API present in both the lipid and aqueous phases.
  • One of the main barriers to elution, which creates the extended-release profile, is the physical transformation of the solid API crystal phase into the liquid phases of the reservoir lipid droplets or the continuous aqueous phase.
  • a lipophilic API molecule, such as ropivacaine, may have a low solubility in both lipid and aqueous phases. The dissolved API present in each phase is eluted into the surrounding tissue.
  • the disclosed stable emulsion comprises an aqueous carrier; and lipid phase dispersed into droplets within the aqueous carrier, and a first plurality anesthetic agent crystals within the lipid phase.
  • An emulsion can be considered stable if the immiscible phases of the remain unseparated for a commercially useful period.
  • a commercially useful period is one that allows for sufficient time for all relevant testing, shipping, storage, and use to take place.
  • a commercially useful period in some embodiments, can be between about 1 week to about 5 years. In further embodiments, a commercially useful period can be between about 1 month to about 2 years. In a preferred embodiment, a commercially useful period can be between about 6 months to about 12 months.
  • An emulsion can also be reversible. A reversible emulsion is one, whereupon the once- emulsified immiscible phases have separated, they can be returned to a stable, unseparated state with mixing gentler than required to initially combine the immiscible phases.
  • this mixing needed to recombine the separated phases can be accomplished by shaking the container, although more vigorous mixing may be needed.
  • the presence of anesthetic agent crystals can cause an increase in formulation viscosity.
  • the increasing presence of anesthetic agent crystals can increase the viscosity of the formulation to about 150 cP to about 500 cP.
  • the increasing presence of anesthetic agent crystals can increase the viscosity of the formulation to about 220 cP.
  • Lipid phase [079] According to certain embodiments, the lipid phase is dispersed within the aqueous phase and contains anesthetic agent within the dispersed droplets.
  • the anesthetic agent is present in the lipid phase in the form of anesthetic agent crystals. In further embodiments, the anesthetic agent is dissolved within the lipid phase.
  • the lipid phase may comprise one or more triglycerides and is a liquid at room temperature.
  • Aqueous phase [080] According to certain embodiments, the aqueous phase can be dispersed as droplets within a lipid liquid continuous phase.
  • the anesthetic agent may be present in the aqueous phase as a solute and also may be present in solid crystal phase. Multiple anesthetic agents may be present in the aqueous phase droplets.
  • Triglycerides are an ester of glycerol and three fatty acids that can be all the same fatty acid or mixtures of different fatty acids.
  • the fatty acids can be saturated (no double carbon bonds in the fatty acid chain) or unsaturated (one or more carbon double bonds in the fatty acid chain length) or mixtures of both saturated and unsaturated fatty acid chains.
  • Triglycerides are the primary component in animal fats and plant derived oils.
  • Triglycerides have long been used as carriers for pharmaceutical ingredients.
  • Triglycerides have been used as a nutritional supplement intravenously or orally and are one of the main energy storage molecules in mammals. Stable emulsions are used in the pharmaceutical industry, but most do not contain solid anesthetic agent crystals in the formulations. Table 1. Pure Triglycerides F A i F A i 9 Table 2.
  • Tripropionin (AKA: Glycerol tripropionoate): • Tributyrin: (AKA: Glyceryl tributurate) • Trivelerin: (Glycerol triverlerate) • Tricaproin: (AKA: Trihexanoin, glycerol trihexanoate) • Tripelargonin: (AKA: Trinonanoin, Glyceryl pelargonate) • Triheptanoin: (AKA: Glyceryl triheptanoate) • Tricaprin: (AKA: Trioctanoin, Tricaprilin, Glycerol trioctanoate) • Tricaprin: (AKA: Tridecaoin, Glycerol tridcanoate, Glycerol tricaprate) • Triundecylin: (AKA: Triundecanoin, Glycerol triundecanoate) • Trilaurin: (AKA: Glycerol triuren: (AKA:
  • Naturally sourced triglycerides will contain unsaturated moieties and can polymerize and oxidize in the presence of oxygen.
  • ⁇ - tocopherols can be added to the triglyceride prior to sterile filtration to act as an antioxidant without impacting emulsion stability or elution characteristics.
  • Other hydrophobic antioxidants such as lycopene, retinols, carotenoids, and other tocopherols can be used.
  • hydrophilic antioxidants such as ascorbic acid can be added to protect hydrophilic APIs. Previous iterations of the formulation have used sodium hydroxide to maintain a desired pH of ⁇ 8 in order to control elution of the API from the lipid excipients.
  • glycerol is utilized as an effective aqueous modifier to produce a stable emulsion.
  • sorbitols, manitols, and other polyol chemical compounds are utilized to modify the formulation sufficiently to obtain similar results.
  • hyaluronic acid, hyaluron, and sodium hyaluronate are considered the same compound for this description and is composed of a long chain polymer containing linear glycosaminoglycan (GAG).
  • GAG linear glycosaminoglycan
  • hyaluronic acid can vary in molecular weight (MW) and changes in the MW used will impact formulation viscosity and emulsion stability.
  • hyaluronic acid is used as an emulsifier and aqueous phase thickener.
  • HA may be cross-linked with tyramine.
  • amphipathic polysaccharides that act as a thickener and have both polar hydroxyl and non-polar methyl ether moieties are used to achieve similar effect to HA.
  • polyethylene glycol serves as an emulsifier/thickener.
  • combinations of the foregoing are used to thicken and stabilize the emulsion.
  • Lecithin a mixture of phospholipids, obtained from soy or eggs can be used to produce the same result.
  • lecithin obtained from other sources such as sunflower seed or canola seed could be used to generate a similar result.
  • Phospholipids in this instance, is referring to a class of lipids that contain a hydrophilic phosphate group and two hydrophobic fatty acid groups that are joined by an alcohol residue.
  • the hydrophilic phosphate “head” group can contain different amino acid chemical moieties.
  • the hydrophobic “tail” groups can contain saturated, monounsaturated, and polyunsaturated fatty acids and vary in chain length from 14 to 18 carbons.
  • phospholipids in combination with other emulsifiers such as, but not limited to, sorbitan esters, polysorbates, propylene oxide, ethoxylates, copolymers, and macromolecules would produce similar results.
  • emulsifiers such as, but not limited to, sorbitan esters, polysorbates, propylene oxide, ethoxylates, copolymers, and macromolecules
  • sufficient aqueous phase thickener is used to achieve a viscosity of the formulation to about 150 cP to about 500 cP.
  • the increasing presence of anesthetic agent crystals can increase the viscosity of the formulation to about 220 cP.
  • emulsion components and the range of amount of such components are shown in Table 9. Table 9.
  • Emulsion Stability Summary Component Min Max Soybean Oil % (v/v) 15 80 Medium Chain Triglyceride % (v/v) 15 20 HA % 0 3 Aqueous Buffered to ⁇ 8.0 pH No Yes Tween 80 % (w/v) 0 5 Lecithin % (w/v) 0 5 Glycerol % (w/v) 1.7 2.25 PEG % (w/v) 0 0.5 Sorbitol % (w/v) 0 2 Dextrose % (w/v) 1 2 API (e.g., Ropivacaine) Concentration (mg/gSoybean oil) 0 300 NaCl in Aqueous no Yes Methods of Formulating Multiphase Stable Emulsion [093] There are two main methods of manufacturing stable emulsions.
  • the first method utilizes a common solvent, such as acetone (acetone is preferred), other ketone solvents, or mixtures thereof, that can dissolve the triglyceride oil, the lipophilic excipients, and the anesthetic agent.
  • a common solvent such as acetone (acetone is preferred), other ketone solvents, or mixtures thereof, that can dissolve the triglyceride oil, the lipophilic excipients, and the anesthetic agent.
  • the second method uses hot triglyceride oils to dissolve an effective amount of anesthetic agent.
  • Solvent Method [094]
  • the anesthetic agent and lipophilic excipients are added to a solvent, such as acetone. Once the anesthetic agent is completely dissolved and a clear solution results, the solution can be sterile filtered through a 0.2 micron or smaller pore size filter media.
  • the resulting solution is then subjected to a crystallization unit operation in which the solvent is removed from the solution resulting in the crystallization of the anesthetic agent component in the liquid triglyceride phase.
  • the solvent will be completely removed through various methods, for example the solvent can be removed by pulling vacuum on the solvent phase and exhausting or condensing the solvent to remove it from the liquid lipid phase. Heat may be used to increase the vapor pressure of the solvent, making it easier to remove from the solution. Air, nitrogen, or other inert gases can be used to strip any residual solvent from the liquid lipid phase.
  • aqueous phase containing all remaining emulsifiers and excipients is now sterile filtered through a 0.2um filter media and added to the liquid triglyceride phase and the two phases are well mixed to create a homogenous two-phase liquid that is either exposed to a stator-rotor emulsifier or fed to an inline emulsifier to generate a stable homogenous emulsion containing the anesthetic agent.
  • the resulting emulsion is transferred to an inventory tank/bag where it can be packaged into a vial, syringe, or other delivery device.
  • One advantage of using the above solvent method is its ability to dissolve temperature sensitive anesthetic agents into solution without the need for heating.
  • the heat manufacturing method utilizes an unexpected and nonobvious method of dissolving the anesthetic agent in the lipid phase, which allows the solution to be sterile filtered before creating the emulsion.
  • Many solvents are able to contain more solute in solution as the solvent is heated but, in most cases, a significant amount of the solute is still present in solution at lower temperature such as room temperature (22°C).
  • room temperature 22°C
  • the anesthetic agent is almost completely insoluble in the oil at room temperature but can be increased when the solution is heated. This allows the anesthetic agent in solution to be sterile filtered when heated.
  • composition further comprises a radiopaque contrast agent.
  • a method of treating post-surgical pain in a subject in need thereof comprising administering to the subject and effective amount of a composition comprising stable multiphase emulsion disclosed herein.
  • the anesthetic is selected from: ambucaine, amolanone, amylcaine, benoxinate, benzocaine, betoxycaine, biphenamine, bupivacaine, butacaine, butamben, butanilicaine, butethamine, butoxycaine, carticaine, chloroprocaine, cocaethylene, cocaine, cyclomethycaine, dibucaine, dimethisoquin, dimethocaine, diperodon, dyclonine, ecogonidine, ecogonine, euprocin, fenalcomine, formocaine, hexylcaine, hydroxyteteracaine, isobutyl p- aminobenzoate, leucinocaine, levoxadrol, lidocaine, mepivacaine, meprylcaine, metabutoxycaine, methyl chloride, myrtecaine, naepaine, octacaine, orthocaine, chloride, myrtecaine,
  • the anesthetic is ropivacaine. In certain alternative embodiments the anesthetic in bupivacaine.
  • the anesthetic agent is an amide anesthetic. In exemplary implementations the amide anesthetic is articaine, bupivacaine, cinchocaine, etidocaoine, bupivacaine, lidocaine, mepivacaine, prilocaine, ropivacaine, and/or trimecaine.
  • the anesthetic agent is an ether anesthetic.
  • Exemplary ether anesthetics include, but are not limited to benzocaine, chloroprocaine, cocaine, cyclomethycaine, dimethocaine (larocaine), piperocaine, propoxycaine, procaine, proparacaine, and/or tetracaine.
  • the anesthetic agent is from a natural source.
  • Exemplary natural source anesthetics include, but are not limited to: saxitoxin, neosaxitoxin, tetrodotoxin, menthol, eudenol, cocaine, spilanthol.
  • the anesthetic agent is combined with one or more antiemetic agents.
  • antiemetic agents include but are not limited to NK1 receptor antagonists (e.g., Aprepitant, Casopitant, Rolapitant), cannabinoids (e.g., cannabis, cannabidiol, nabilone, dronabinol, THC), and/or benzodiazepine (e.g., midazolam, lorazepam).
  • NK1 receptor antagonists e.g., Aprepitant, Casopitant, Rolapitant
  • cannabinoids e.g., cannabis, cannabidiol, nabilone, dronabinol, THC
  • benzodiazepine e.g., midazolam, lorazepam
  • the anesthetic agent is combined with one or more vasoconstrictors (e.g., epinephrine).
  • the anesthetic agent is combined with one or more anti- hypertensives: (e.g., clonidine, and/or dexmedetomidine).
  • the anesthetic agent is combined with one or more non-steroidal anti-inflammatory (NSAIDS).
  • NSAIDS non-steroidal anti-inflammatory
  • Salicylates e.g., Acetylsalicylic acid, Diflunisal, Salicylic acid / salts, Salsalate
  • propionic acid derivatives e.g., Ibuprofen, Fenoprofen, flurbiprofen, pelubiprofen, dexibupropfen, ketoprofen, oxaprozin, zaltoprofen, naproxen, dexketoprofen, loxoprofen
  • acetic acid derivatives e.g., Indomethacin, sulindac, ketorolac, aceclofenac, tolmetin, etodolac, diclofenac, bromfenac
  • enolic acid derivatives e.g., Piroxicam, Tenoxicam, Lornoxicam, Phenylbutazone, Meloxicam, droxicam
  • Selective COX-2 inhibitors e.g., Celecoxib,
  • the anesthetic agent is combined with one or more antihistamines/Involuntary nervous system blocker. Examples include but are not limited to: Meclizine, hyoscine, chloropeniramine, and/or diphenylhydramine. [0107] According to still further embodiments, the anesthetic agent is combined with one or more additional agent, including but not limited to: an anti-microbial agent, and anti-inflammatory agent (dexamethasone) and/or a procoagulant agent. [0108] Also provided herein are kits of pharmaceutical formulations containing the disclosed compounds or compositions. The kits may be organized to indicate a single formulation or combination of formulations.
  • the composition may be sub-divided to contain appropriate quantities of the compound.
  • the unit dosage can be packaged compositions such as packeted powders, vials, ampoules, prefilled syringes, or sachets containing liquids.
  • the compound or composition described herein may be a single dose or for continuous or periodic discontinuous administration.
  • a kit may include the compound in each dosage unit.
  • the kit may include placebos during periods when the compound is not delivered.
  • a kit may contain a sequence of dosage units.
  • the kit may contain packaging or a container with the compound formulated for the desired delivery route.
  • the kit may also contain dosing instructions, an insert regarding the compound, instructions for monitoring circulating levels of the compound, or combinations thereof.
  • Materials for performing using the compound may further be included and include, without limitation, reagents, well plates, containers, markers or labels, and the like.
  • Such kits are packaged in a manner suitable for treatment of a desired indication.
  • Other suitable components to include in such kits will be readily apparent to one of skill in the art, taking into consideration the desired indication and the delivery route.
  • the kits also may include, or be packaged with, instruments for assisting with the injection/administration or placement of the compound within the body of the subject.
  • Such instruments include, without limitation, syringe, pipette, forceps, measuring spoon, eye dropper or any such medically approved delivery means.
  • Other instrumentation may include a device that permits reading or monitoring reactions in vitro.
  • the compound or composition of these kits also may be provided in dried, lyophilized, or liquid forms. When reagents or components are provided as a dried form, reconstitution generally is by the addition of a solvent. The solvent may be provided in another packaging means and may be selected by one skilled in the art.
  • a number of packages or kits are known to those skilled in the art for dispensing pharmaceutical agents. In one embodiment, the package is a labeled blister package, dial dispenser package, or bottle.
  • a composition for treating post-surgical pain in a subject in need thereof comprising: an emulsion comprising: an aqueous carrier; and liquid lipid phase dispersed into droplets within the aqueous carrier, and a first anesthetic within the lipid phase.
  • the first anesthetic comprises a first plurality of anesthetic crystals.
  • the first anesthetic is dissolved with the lipid phase. 4.
  • composition of any of clauses 1-3 further comprising a second plurality of anesthetic crystals within the aqueous carrier, but not the lipid phase and wherein the second plurality of anesthetic crystals dissolves and elutes from the emulsion at a faster rate than the first plurality anesthetic crystals.
  • the composition further comprises one or more additional anesthetics, different from the first anesthetic.
  • the lipid phase comprises a triglyceride.
  • the aqueous carrier further comprises a thickener. 8.
  • composition of clause 7, wherein the thickener is sodium hyaluronate, hyaluronan, and/or hyaluronic acid.
  • aqueous carrier further comprises a polyol.
  • the polyol is glycerol and is present in an amount of from about 0.25 to about 2.5% (w/v) of the composition.
  • composition has a viscosity of from about 150 to about 500 Cp.
  • composition of clause 11 wherein the composition has a viscosity of from about 200 to about 250 Cp. 13.
  • sorbitol is present in amount of from about 0.1-2% (w/v) of the emulsion.
  • the lipid phase comprises soybean oil in an amount from about 15% to 80% (v/v) and one or more medium chain triglycerides in amount from about 15% to about 20% (v/v).
  • the anesthetic agent is present in an amount from about 0.1 mg/g soybean oil to about 300 mg/g soybean oil.
  • composition of any of clauses 1-19 wherein the first anesthetic is selected lidocaine, prilocaine, mepivacaine, ropivacaine, etidocaine, levobupivacaine, bupivacaine, cocaine, procaine, 2-chloroprocaine, tetracaine, benzocaine, amethocaine, chlorocaine, butamben, dibucaine, and ester analogs of aconitine, dyclonine, ketamine, pramoxine, safrole, and salicyl alcohol. 21. The composition of any of clauses 1-20, wherein the lipid phase comprises tributyrate and/or stearate. 22.
  • composition of clause 2 wherein the lipid phase further comprises an oil and/or wax that is solid at 25°C in an amount of from about 5% to about 30% of the lipid phase (w/w) and wherein the oil and/or wax coats the anesthetic crystals.
  • the lipid phase further comprises an oil and/or wax that is solid at 25°C in an amount of from about 5% to about 30% of the lipid phase (w/w) and wherein the oil and/or wax coats the anesthetic crystals.
  • 23 The composition of any of clauses 1-22, wherein the emulsion is stable for at least six months.
  • 24. The composition of any of clauses 1-23, wherein the anesthetic is ropivacaine and/or bupivacaine. 25.
  • a composition for treating pain in a subject in need thereof comprising: an emulsion comprising: a lipid carrier phase; and an aqueous phase dispersed into droplets within the lipid carrier phase, and a first anesthetic within the aqueous phase.
  • the first anesthetic comprises a first plurality of anesthetic crystals.
  • 27. The composition of clauses 25 or 26, further comprising a second plurality of anesthetic crystals present within the lipid carrier, but not the aqueous phase, and wherein the second plurality of anesthetic crystals dissolves and elutes from the emulsion at a faster rate than the first plurality anesthetic crystals.
  • composition of clause 27 wherein the anesthetic is hydrophilic and is dissolved within the aqueous phase. 29.
  • 30. The composition of any of clauses 1-29, wherein the emulsion is stable for a period of about 1 month to about 2 years. 31.
  • 32. The composition of any of clauses 1-29x2, wherein the emulsion is reversible. 33.
  • a method of treating pain in a subject in need thereof comprising administering to the subject and effective amount of a composition comprising: an emulsion comprising: an aqueous carrier; and lipid phase dispersed into droplets within the aqueous carrier, and a first anesthetic within the lipid phase and wherein the anesthetic is eluted from the composition over a period of between about 4 and about 7 days.
  • the anesthetic comprises a plurality of anesthetic crystals
  • the composition further comprises a second plurality of anesthetic crystals within the aqueous carrier, but not the lipid phase and wherein the second plurality of anesthetic crystals dissolves and elutes from the emulsion at a faster rate than the first plurality anesthetic crystals.
  • the composition is delivered near a nerve or nerve bundle of a subject and wherein the nerve or nerve bundle innervates the surgical incision area of the subject.
  • Ropivacaine was added to soy oil. (up to 13% by weight of oil). 2. 0.75 g of lecithin was added to the soy oil mixture. 3. Anesthetic agent /Oil slurry was heated to 100C with mixing the slurry vigorously until the crystals of anesthetic agent are completely dissolved into solution. 4. Soybean oil containing the anesthetic agent was sterile filtered using 0.2 ⁇ m vacuum filter at temperature (100C). 5. An aqueous solution of 0.15% sodium and 0.51 g glycerol (w/v) was prepared at 4°C. 6.
  • the aqueous solution was heated to 100°C and sterile filtered by passing it through a 0.2um filter media before combining it with the hot soy oil, lecithin, and anesthetic agent base solution. 7.
  • the two phases in the main mixing vessel were emulsified with a rotor-stator emulsifier or by feeding the two-phase mixture to an in line emulsifier until a stable emulsion formed. 8. Emulsification was continued until mixture cooled to room temperature for subsequent use or storage.
  • Example 2-Porcine Sciatic Peripheral Nerve Block The instantly disclosed stable emulsion was prepared according to the methods of Example 1 as either a 6.29 mg/Kg (40 mg ropivacaine/g lipid) formulation or a 20.44 mg/Kg (130 mg ropivacaine/g lipid dose) formulation. Pigs received injection of either one of the stable emulsion formulations or a Naropin 0.5% positive control into the transfacial space surrounding the sciatic nerve to produce a peripheral nerve block (PNB). Animal behavior was observed and recorded following the injections.
  • FIG.1 shows the ropivacaine blood plasma concentration over time for a 6.29 mg/Kg formulation.
  • the Naropin line shows standard of care for peripheral nerve block.
  • the stable emulsion formulation provides a significant amount of ropivacaine for greater than 48 hours.
  • Table 10 Behavioral observations for animals that received peripheral nerve block of sciatic nerve with 40 mg Ropivacaine/g lipid dose. s [01 e stable emulsion drug product. These data show the formulation provides a significant dose of ropivacaine for over 168 hours and suggest a faster onset to PNB. The formulation provides excellent elution of API out beyond 72 hours and likely provides sensory block for greater than 72 hours.
  • Table 11 Behavioral observations for animals that received peripheral nerve block of sciatic nerve with 130mg Ropivacaine/g lipid dose.
  • Formula Variations [0117] In Examples 3-6, a base formula is used with various alternations made for each example. The base formulation is given below in Table 12.
  • Lecithin with lower concentrations of phosphatidylcholine is typically used for oral and topical drug products, food, and cosmetics.
  • the lecithin with lower phosphatidylcholine results in more stable emulsions with lower energy input during formation, but higher phosphatidylcholine concentration Lecithin still form stable emulsions but require higher energy input during formation.
  • five samples, samples 1-5, were developed and analyzed using lecithin of differing composition.
  • Sample 1 uses the base formulation but with Spectrum NF (50-60% phosphatidylcholine) replacing the lecithin component. Images of the resulting material are shown under 10x magnification in FIG.3A and under 20x magnification in FIG. 3B.
  • Sample 2 uses the base formulation but with Cargill Metarin Lecithin (19-27% phosphatidylcholine) replacing the lecithin component. Images of the resulting material are shown under 10x magnification in FIG.4A and under 20x magnification in FIG. 4B. The oil droplets are small, and the API crystals are long needle form. The emulsion remained stable for 1 day. The sample forms a white opaque emulsion/suspension.
  • Sample 3 uses the base formulation but with Cargill Epikuron Lecithin (19-27% phosphatidylcholine) replacing the lecithin component. Images of the resulting material are shown under 10x magnification in FIG. 5A and under 20x magnification in FIG. 5B. The oil droplets are small, and the API crystals are long needle form. The emulsion remained stable for 1 day but can be re-suspended or re-emulsified into an acceptable emulsion through agitation, such as shaking. The sample forms a white opaque emulsion/suspension.
  • Sample 4 uses the base formulation but with Lipoid S75 (>70% phosphatidylcholine) replacing the lecithin component.
  • the oil droplets are small, and the API crystals are long needle form.
  • the emulsion remained stable for 1 day but can be re- suspended or re-emulsified into an acceptable emulsion through agitation, such as shaking.
  • the sample forms a white opaque emulsion/suspension.
  • Example 4 Lecithin Concentration Relative to Soybean Oil
  • lecithin concentration may affect the formulation by changing the interaction between the aqueous and lipid phases at the boundaries between them. Typically, a higher lecithin ratio relative to the lipid phase concentration results in smaller non-continuous phase droplets.
  • the higher lecithin concentration may prevent the API crystals from aggregating.
  • the higher lecithin concentration may also make the formulation very viscous. In the use case of pain therapeutics, the higher viscosity may be acceptable as the delivery needle can be a large gauge needle for placement of the drug product.
  • samples 6-10 were developed and analyzed using differing concentrations of lecithin.
  • Sample 6 uses the base formulation but with the lecithin component being reduced to 0.5% and replaced with soybean oil. Images of the resulting material are shown under 10x magnification in FIG.8A and under 20x magnification in FIG.8B. The oil droplets are small, and the API crystals are long needle form.
  • Sample 7 uses the base formulation but with the lecithin component being slightly reduced to 2.5% and replaced with soybean oil. Images of the resulting material are shown under 10x magnification in FIG. 9A and under 20x magnification in FIG. 9B. The oil droplets are small, and the API crystals are long needle form.
  • Sample 8 uses the base formulation but with the lecithin component being increased to 5%, with soybean oil being removed to compensate. Images of the resulting material are shown under 10x magnification in FIG. 10A and under 20x magnification in FIG. 10B. The oil droplets are small, and the API crystals are long needle form.
  • Sample 9 uses the base formulation but with the lecithin component being increased to 10%, with soybean oil being removed to compensate. Images of the resulting material are shown under 10x magnification in FIG. 11A and under 20x magnification in FIG. 11B. The oil droplets are very small, and the API crystals are long needle form. The crystals in the sample have aggregated into clumps.
  • Sample 10 uses the base formulation but with the lecithin component being increased to 20%, with soybean oil being removed to compensate. Images of the resulting material are shown under 10x magnification in FIG. 12A and under 20x magnification in FIG. 12B. The oil droplets are very small, and the API crystals are long needle form. The crystals in the sample are separated from each other and show very little aggregation. The emulsion remained stable for 15 days.
  • Example 5 Aqueous Phase Thickening
  • sodium hyaluronate was used as a thickening agent for the aqueous phase to slow or impede the interaction between the lipid non continuous phase droplets and stabilize the emulsion.
  • Hyaluronic acid, from sodium hyaluronate may also act as an emulsifier, as the molecule has both polar and nonpolar moieties.
  • sodium hyaluronate concentration is measured relative to the aqueous phase, not the whole drug.
  • Sample 11 uses the base formulation but has no sodium hyaluronate in the aqueous phase. Images of the resulting material are shown under 10x magnification in FIG. 13A and under 20x magnification in FIG. 13B. The oil droplets are large, and the API crystals are long needle form. The emulsion of the sample broke quickly – within minutes – and separated into oil and aqueous phases.
  • Sample 12 uses the base formulation but has a sodium hyaluronate concentration of 0.1 percent in the aqueous phase. Images of the resulting material are shown under 10x magnification in FIG. 14A and under 20x magnification in FIG. 14B. The oil droplets are smaller than those of sample 11. The API crystals are long needle form.
  • Sample 13 uses the base formulation but has a sodium hyaluronate concentration of 0.15 percent in the aqueous phase. Images of the resulting material are shown under 10x magnification in FIG. 15A and under 20x magnification in FIG. 15B. The oil droplets are small and relatively uniform. The API crystals are long needle form. The emulsion showed increased stability over sample 11.
  • Sample 14 uses the base formulation but has a sodium hyaluronate concentration of 1 percent in the aqueous phase.
  • Glycerol concentration in this Example is measured relative to the whole formulation, rather than any particular phase.
  • Sample 15 uses the base formulation but has a glycerol concentration of 1.7% relative to the whole formulation. Images of the resulting material are shown under 10x magnification in FIG. 17A and under 20x magnification in FIG. 17B. The oil droplets are small and relatively uniform. The API crystals are long needle form. The emulsion remained stable for 1 day.
  • Sample 16 uses the base formulation but has a glycerol concentration of 3.0% relative to the whole formulation. Images of the resulting material are shown under 10x magnification in FIG. 18A and under 20x magnification in FIG. 19B. The oil droplets are small and relatively uniform.
  • Sample 17 uses the base formulation but has a glycerol concentration of 5.0% relative to the whole formulation. Images of the resulting material are shown under 10x magnification in FIG. 19A and under 20x magnification in FIG. 19B. The oil droplets are small and relatively uniform. The API crystals are long needle form. The emulsion remained stable for 1 day.
  • Sample 18 uses the base formulation but has a glycerol concentration of 10% relative to the whole formulation. Images of the resulting material are shown under 10x magnification in FIG. 20A and under 20x magnification in FIG.20B. The oil droplets are smaller and more uniform than samples 18, 19, and 20.
  • Example 7 Lipid Phase Thickening
  • coconut oil or carnauba wax was added to the lipid phase of the formulation to increase its viscosity.
  • the thickening agent coconut oil or carnauba wax, is added to the formulation, the added mass of soy oil was equally reduced to maintain the total amount of lipid phase in the formulation.
  • Sample 19 uses the base formulation but with 10% of the formulation consisting of coconut oil and an equal reduction in soy oil. Images of the resulting material are shown under 10x magnification in FIG.21A and under 20x magnification in FIG.21B. The oil droplets are generally small, but an increase in the size and number of large droplets can be observed. The API crystals are long needle form. The product was a stable emulsion.
  • Sample 20 uses the base formulation but with 1.0% of the formulation consisting of carnauba wax and an equal reduction in soy oil. Images of the resulting material are shown under 10x magnification in FIG. 22A and under 20x magnification in FIG.
  • Sample 21 uses the base formulation but with 2.5% of the formulation consisting of carnauba wax and an equal reduction in soy oil. Images of the resulting material are shown under 10x magnification in FIG. 23A and under 20x magnification in FIG. 23B.
  • the API crystals are long needle form. The wax and lipids coating on the crystals is thicker than seen in sample 20.
  • the product was a stable emulsion.
  • Sample 22 uses the base formulation but with 5.0% of the formulation consisting of carnauba wax and an equal reduction in soy oil.
  • the API crystals are long needle form.
  • the wax and lipids have coated the crystals and have formed microparticles separate from the crystals.
  • the product was a stable emulsion.
  • the carnauba wax appeared to coat much of the surface of the crystals. In higher concentrations, such as 5%, the carnauba wax also formed microparticles apart from the crystals.
  • this tendency for the wax and lipids to coat the API crystals can lead to an increased barrier to diffusion of the API from the formulation into the subject. This increased barrier to diffusion can lead to a slower, more consistent release of the API into the subject.
  • Example 8 Continuous Lipid Phase
  • the formulation for sample 23 consisted of 60% lipid phase and 40% aqueous phase, by volume, with components of each phase kept in relative proportion, except where noted.
  • the sodium hyaluronate in the formulation was 0.15% by weight, relative to the aqueous phase.
  • Images of the resulting material are shown under 10x magnification in FIG.25A and under 20x magnification in FIG.25B.
  • the API crystals are long needle form.
  • the aqueous phase droplets were varied in size.
  • Example 9 – Increased Mixing Energy [0151] Sample 24 uses the base formulation but used more aggressive mixing energy. This was achieved by using a 3/4 horsepower Silverson high-shear rotor-stator homogenizer at 6000 RPM.
  • An image of the resulting material is shown under 40x magnification in FIG. 26.
  • the oil droplets are smaller than those found in formulations made with standard mixing energy.
  • Sample 25 uses the base formulation but used the 3/4 horsepower Silverson high-shear rotor-stator homogenizer at 12,000 RPM. An image of the resulting material is shown under 40x magnification in FIG.27. API crystal aggregations formed as a result of the higher mixing energy. These aggregations remain stable and do not separate. The increased mixing energy also increased the size distribution of the API crystals and crystal agglomerates.
  • Example 12 Increasing Stability with Increasing API Loading
  • placebo no API
  • active active
  • samples with higher API concentrations, in the form of ropivacaine were less stable than those of lower concentrations.
  • a sample with 29.34 mg/mL ropivacaine had greater stability than a sample with 38.51 mg/mL ropivacaine, which had greater stability than a sample with 47.69 mg/mL ropivacaine, which had greater stability than placebo.
  • the 29.34 mg/mL ropivacaine sample is stable for at least 7 months.
  • Example 13 – Increasing Viscosity with API Loading [0154] In a set of samples shown in Table 13, it can be seen that in certain embodiments, addition of an API, such as Ropivacaine, can lead to an increase in viscosity in the overall formulation. All of these samples in Table 13 use the Base Formulation, with the API loading varying as noted. Table 13. Viscosity measurements. API Concentration (mg/mL) 0 29.3 38.5 47.6 . [0155] Although erred embodiments, persons skilled in the art will recognize that changes may be made in form and detail without departing from the spirit and scope of the disclosed apparatus, systems and methods.

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Abstract

Est divulguée dans la présente invention une composition permettant de traiter la douleur chez un sujet dont l'état le nécessite, qui contient une émulsion comprenant : un vecteur aqueux ; et une phase lipidique liquide dispersée dans des gouttelettes à l'intérieur du support aqueux, et un premier agent anesthésique dans la phase lipidique. Dans certains modes de réalisation, le premier agent anesthésique contient une première pluralité de cristaux d'agent anesthésique. Dans des modes de réalisation alternatifs, le premier agent anesthésique est dissous avec la phase lipidique. Dans des modes de réalisation supplémentaires, la composition contient également une deuxième pluralité de cristaux d'agent anesthésique à l'intérieur du vecteur aqueux, mais pas la phase lipidique, et dans laquelle la deuxième pluralité de cristaux d'agent anesthésique se dissout et s'élue à partir de l'émulsion à une plus grande vitesse que la première pluralité de cristaux d'agent anesthésique. Dans d'autres modes de réalisation, la composition contient en outre un ou plusieurs agents anesthésiques supplémentaires, différents du premier agent anesthésique.
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Citations (3)

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US20030072793A1 (en) * 1998-12-09 2003-04-17 Chiron Corporation Method for administering agents to the central nervous system
US20170143692A1 (en) * 2005-05-17 2017-05-25 Sarcode Bioscience Inc. Compositions and methods for treatment
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US20030072793A1 (en) * 1998-12-09 2003-04-17 Chiron Corporation Method for administering agents to the central nervous system
US20170143692A1 (en) * 2005-05-17 2017-05-25 Sarcode Bioscience Inc. Compositions and methods for treatment
US20220241200A1 (en) * 2021-01-29 2022-08-04 Insitu Biologics, Inc. Compositions and methods for sustained treatment of pain

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