A stable emulsion pharmaceutical formulation with sustained release properties.

Abstract

This disclosure discloses a composition for treating pain in a subject requiring it, comprising an emulsion comprising an aqueous carrier; a liquid lipid phase dispersed as droplets in the aqueous carrier; and a first anesthetic in the lipid phase. In certain embodiments, the first anesthetic comprises a plurality of first anesthetic crystals. In certain alternative embodiments, the first anesthetic is dissolved in the lipid phase. In certain embodiments, the composition further comprises a plurality of second anesthetic crystals in the aqueous carrier rather than in the lipid phase, the second plurality of anesthetics dissolve and elute from the emulsion at a faster rate than the first plurality of anesthetic crystals. In certain embodiments, the composition further comprises one or more additional anesthetics different from the first anesthetic.

Description

Technical Field

[0001] Cross - reference to related applications

[0001] This application claims priority to U.S. Provisional Patent Application No. 63 / 458,316, filed on April 10, 2023, entitled "SUSTAINED RELEASE STABLE EMULSION PHARMACEUTICAL FORMULATIONS", under 35 U.S.C. § 119(e), the entire disclosure of which is incorporated herein by reference.

Background Art

[0002]

[0002] Liposomal bupivacaine has been used in peripheral nerve blocks to extend the duration of action of local anesthetics and reduce postoperative pain and perioperative opioid use. In practice, however, its formulation often is not sufficient to eliminate opioid use in surgical patients in many situations. The delivery system of local anesthetics in tissues and the kinetic drug profile of the migrating drug contribute together to limited efficacy and the duration of action at the target site.

[0003]

[0003] Acute postoperative pain is estimated to require pain relief for at least 5 - 7 days. For that purpose, advances in perioperative medicine have tried to eliminate opioids from the postoperative treatment regimen, but so far, without success. Techniques to limit multiple opioids, such as intrathecal morphine, pharmaceutical adjuvants, and local anesthetics in standard sustained - release formulations, have demonstrated limited efficacy up to 24 - 48 hours of effective analgesia and often require narcotics (anesthetics) to supplement the waning analgesia.

[0004]

[0004] There is a need in the art for compositions and methods effective to provide sustained postoperative pain relief without using opioid - based pharmaceuticals.

Summary of the Invention

[0005]

[0005] While multiple embodiments are disclosed, further other embodiments of the Disclosure will become apparent to those skilled in the art from the following detailed description illustrating and describing exemplary embodiments of the disclosed devices, systems and methods. As will be understood, all disclosed devices, systems and methods can be modified in various obvious ways without departing from the spirit and scope of the Disclosure. Accordingly, the drawings and detailed description are to be considered illustrative and not restrictive. [Brief explanation of the drawing]

[0006] [Figure 1]

[0006] This figure shows the plasma concentration (ng / mL) of butaropivacaine after a sciatic nerve block procedure (treatment) using the stable emulsion (6.29 mg / kg formulation) disclosed herein, compared to a 0.5% positive control of naropin, according to a particular embodiment. [Figure 2]

[0007] This figure shows the time-course plasma concentrations (ng / mL) of butaropivacaine after infusion of the stable emulsion (20.44 mg / kg formulation) disclosed herein as a peripheral nerve block or a 0.5% positive control of Naropin, according to a particular embodiment. [Figure 3A]

[0008] This figure shows a microscopic image of sample 1 at 10x magnification according to a specific embodiment. [Figure 3B]

[0009] This figure shows a microscopic image of sample 1 at 20x magnification according to a specific embodiment. [Figure 4A]

[0010] This figure shows a microscopic image of sample 2 at 10x magnification according to a specific embodiment. [Figure 4B]

[0011] This figure shows a microscopic image of sample 2 at 20x magnification according to a specific embodiment. [Figure 5A]

[0012] This figure shows a microscopic image of sample 3 at 10x magnification according to a specific embodiment. [Figure 5B]

[0013] This figure shows a microscopic image of sample 3 at 20x magnification according to a specific embodiment. [Figure 6A]

[0014] This figure shows a microscopic image of sample 4 at 10x magnification according to a specific embodiment. [Figure 6B]

[0015] This figure shows a microscopic image of sample 4 at 20x magnification according to a specific embodiment. [Figure 7A]

[0016] This figure shows a microscopic image of sample 5 at 10x magnification according to a specific embodiment. [Figure 7B]

[0017] This figure shows a microscopic image of sample 5 at 20x magnification according to a specific embodiment. [Figure 8A]

[0018] This figure shows a microscopic image of sample 6 at 10x magnification according to a specific embodiment. [Figure 8B]

[0019] This figure shows a microscopic image of sample 6 at 20x magnification according to a specific embodiment. [Figure 9A]

[0020] This figure shows a microscopic image of sample 7 at 10x magnification according to a specific embodiment. [Figure 9B]

[0021] This figure shows a microscopic image of sample 7 at 20x magnification according to a specific embodiment. [Figure 10A]

[0022] This figure shows a microscopic image of sample 8 at 10x magnification according to a specific embodiment. [Figure 10B]

[0023] This figure shows a microscopic image of sample 8 at 20x magnification according to a specific embodiment. [Figure 11A]

[0024] This figure shows a microscopic image of sample 9 at 10x magnification according to a specific embodiment. [Figure 11B]

[0025] This figure shows a microscopic image of sample 9 at 20x magnification according to a specific embodiment. [Figure 12A]

[0026] It is a diagram showing a microscopic image of sample 10 at a magnification of 10 times according to a specific embodiment. [Figure 12B]

[0027] It is a diagram showing a microscopic image of sample 10 at a magnification of 20 times according to a specific embodiment. [Figure 13A]

[0028] It is a diagram showing a microscopic image of sample 11 at a magnification of 10 times according to a specific embodiment. [Figure 13B]

[0029] It is a diagram showing a microscopic image of sample 11 at a magnification of 20 times according to a specific embodiment. [Figure 14A]

[0030] It is a diagram showing a microscopic image of sample 12 at a magnification of 10 times according to a specific embodiment. [Figure 14B]

[0031] It is a diagram showing a microscopic image of sample 12 at a magnification of 20 times according to a specific embodiment. [Figure 15A]

[0032] It is a diagram showing a microscopic image of sample 13 at a magnification of 10 times according to a specific embodiment. [Figure 15B]

[0033] It is a diagram showing a microscopic image of sample 13 at a magnification of 20 times according to a specific embodiment. [Figure 16A]

[0034] It is a diagram showing a microscopic image of sample 14 at a magnification of 10 times according to a specific embodiment. [Figure 16B]

[0035] It is a diagram showing a microscopic image of sample 14 at a magnification of 20 times according to a specific embodiment. [Figure 17A]

[0036] It is a diagram showing a microscopic image of sample 15 at a magnification of 10 times according to a specific embodiment. [[ID=4l]] [Figure 17B]

[0037] It is a diagram showing a microscopic image of sample 15 at a magnification of 20 times according to a specific embodiment. [Figure 18A]

[0038] It is a diagram showing a microscopic image of sample 16 at a magnification of 10 times according to a specific embodiment. [Figure 18B]

[0039] This figure shows a microscopic image of sample 16 at 20x magnification according to a particular embodiment. [Figure 19A]

[0040] This figure shows a microscopic image of sample 17 at 10x magnification according to a specific embodiment. [Figure 19B]

[0041] This figure shows a microscopic image of sample 17 at 20x magnification according to a specific embodiment. [Figure 20A]

[0042] This figure shows a microscopic image of sample 18 at 10x magnification according to a particular embodiment. [Figure 20B]

[0043] This figure shows a microscopic image of sample 18 at 20x magnification according to a particular embodiment. [Figure 21A]

[0044] This figure shows a microscopic image of sample 19 at 10x magnification according to a specific embodiment. [Figure 21B]

[0045] This figure shows a microscopic image of sample 19 at 20x magnification according to a specific embodiment. [Figure 22A]

[0046] This figure shows a microscopic image of sample 20 at 10x magnification according to a particular embodiment. [Figure 22B]

[0047] This figure shows a microscopic image of sample 20 at 20x magnification according to a specific embodiment. [Figure 23A]

[0048] This figure shows a microscopic image of sample 21 at 10x magnification according to a specific embodiment. [Figure 23B]

[0049] This figure shows a microscopic image of sample 21 at 20x magnification according to a specific embodiment. [Figure 24A]

[0050] This figure shows a microscopic image of sample 22 at 10x magnification according to a specific embodiment. [Figure 24B]

[0051] This figure shows a microscopic image of sample 22 at 20x magnification according to a specific embodiment. [Figure 25A]

[0052] This figure shows a microscopic image of sample 23 at 10x magnification according to a specific embodiment. [Figure 25B]

[0053] This figure shows a microscopic image of sample 23 at 20x magnification according to a specific embodiment. [Figure 26]

[0054] This figure shows a microscopic image of sample 24 at 40x magnification according to a specific embodiment. [Figure 27]

[0055] This figure shows a microscopic image of sample 25 at 40x magnification according to a specific embodiment. [Modes for carrying out the invention]

[0007]

[0056] Before disclosing and describing the compounds, compositions, articles, systems, apparatus, and / or methods of the present invention, it should be understood that they are not limited to specific synthesis methods or specific reagents unless otherwise specified, and may naturally differ. It should also be understood that the terms used herein are intended to describe only specific aspects and are not intended to limit them. Any methods and substances similar to or equivalent to those described herein may be used in the practice or testing of this disclosure, but exemplary methods and substances are described herein.

[0008]

[0057] In this specification, a range can be expressed as "about" (one specific value) and / or "about" (another specific value). When expressing such a range, further embodiments include "from" (one specific value) and / or (another specific value). Similarly, when a value is expressed as an approximation using the antecedent "about", it will be understood that a specific value forms further embodiments. Furthermore, it will be understood that each endpoint of a range is important both in relation to other endpoints and independently of other endpoints. It will also be understood that although there are many values ​​disclosed in this specification, each value is also disclosed in this specification as "about" (its specific value) along with the value itself. For example, if the value "10" is disclosed, "about 10" is also disclosed. It will also be understood that each unit between two specific units is also disclosed. For example, if 10 and 15 are disclosed, then 11, 12, 13, and 14 are also disclosed.

[0009]

[0058] When used herein, names of compounds, including organic compounds, may be given using common names, IUPAC, IUBMB, or CAS nomenclature recommendations. If one or more stereochemical features are present, the Cahn-Ingold-Prelog rules for stereochemistry may be used to indicate stereochemical priority and E / Z notation, etc. A person skilled in the art can readily verify the structure of a compound, given its name, by systematically reducing the compound structure using nomenclature rules, or by using commercially available software, such as CHEMDRAW® (PerkinElmer, USA).

[0010]

[0059] As used herein, the singular forms "a," "an," and "the" include multiple references unless the context clearly indicates otherwise. Therefore, for example, references to "functional group," "alkyl," or "residue" include mixtures of two or more such functional groups, alkyls, or residues.

[0011]

[0060] Unless otherwise specified, references to parts by weight of a particular element or component in a composition herein indicate the weight relationship between the element or component and any other element or component in the composition or article in which the parts by weight are expressed, unless otherwise explicitly stated. Thus, in a compound containing 2 parts by weight of component X and 5 parts by weight of component Y, X and Y exist in a weight ratio of 2:5, and in such a ratio whether or not additional components are present in the compound.

[0012]

[0061] Unless otherwise stated, the weight percentage (wt%) of an ingredient is based on the total weight of the formulation or composition in which the ingredient is contained.

[0062] As used herein, the terms “optional” or “optionally” mean that the events or circumstances described thereafter may or may not occur, and that this description includes both cases in which such events or circumstances occur and cases in which they do not occur.

[0013]

[0063] The terms “anesthetic” or “local anesthetic” (as used interchangeably herein) refer to agents that cause loss of sensation in humans or other mammals, with or without loss of perception (consciousness). More specifically, the term “local anesthetic” refers to an anesthetic that induces local anesthesia by reversibly inhibiting the excitation and / or transmission of peripheral nerves. Suitable local anesthetics 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. Examples of ester-based anesthetics include, but are not limited to, cocaine, procaine, 2-chloroprocaine, tetracaine, benzocaine, ametokine, chlorocaine, butambene, and dibucaine. Examples of amide-based anesthetics include, but are not limited to, lidocaine, prilocaine, mepivacaine, ropivacaine, etidocaine, levobupivacaine, and bupivacaine. Other anesthetics suitable for use in the present invention include, but are not limited to, aconitine, diclonin, ketamine, pramoxin, safrole, and ester analogs of salicylic alcohol. Such ester analogs may contain an ester group somewhere in their structure.

[0014]

[0064] As used herein, the term “subject” refers to the target of administration, e.g., subject. Therefore, the subjects of the methods disclosed herein may be vertebrates, e.g., mammals, fish, birds, reptiles, or amphibians. Alternatively, the subjects of the methods disclosed herein may be humans, non-human primates, horses, pigs, rabbits, dogs, sheep, goats, cattle, cattle, guinea pigs, or rodents. The term does not indicate a specific age or sex. Therefore, it is intended to target adult and neonatal subjects, as well as fetuses, regardless of sex. In one embodiment, the subject is a mammal. “Patient” refers to a subject suffering from a disease or disorder. The term “patient” includes human and veterinary subjects.

[0015]

[0065] As used herein, the terms “treat” and “prevent,” and terms derived therefrom, do not necessarily imply 100% or complete treatment or prevention. Rather, there are varying degrees of treatment or prevention that a person skilled in the art would recognize as having potential benefits or therapeutic effects. In this regard, the methods of the present invention can provide any level of treatment or prevention of any amount of disease or medical condition in mammals. Furthermore, the treatment or prevention provided by the methods may include the treatment or prevention of one or more states or symptoms of a disease or medical condition. For example, with respect to methods for treating pain, the methods of some embodiments achieve a reduction or elimination of pain in the subject. Also, for the purposes of this specification, “prevention” may include delaying the onset of a disease, or its symptoms or condition. The term “treat” includes the prevention of a particular disorder or condition, or the reduction of symptoms associated with a particular disorder or condition, and / or the prevention or elimination of such symptoms. For example, as used herein, the term “postoperative pain” generally refers to a reduction or elimination of pain associated with recovery from a surgical procedure.

[0016]

[0066] As used herein, the term “substantially” refers to the complete or near-complete range or degree of an action, quality, characteristic, state, structure, item, or result. For example, an object “substantially” enclosed means that the object is either completely enclosed or nearly completely enclosed. The exact degree of tolerance for deviation from absolute completeness may, in some cases, depend on the specific context. However, generally speaking, approaching a complete state results in the same overall outcome as if an absolute and complete state had been achieved. The use of “substantially” is equally applicable when used in a negative sense to refer to the complete or near-complete absence of an action, quality, characteristic, state, structure, item, or result. For example, a “substantially particle-free” composition either completely lacks particles or nearly completely lacks particles, so that its effect is the same as if it were completely particle-free. In other words, a “substantially component or element-free” composition may still actually contain such an item, as long as its measurable effect is not present.

[0017]

[0067] As used herein, the terms “effective dose” and “effective amount” refer to an amount sufficient to achieve a desired outcome or to have an effect against an undesirable condition. For example, “therapeutic effective dose” refers to an amount sufficient to achieve a desired therapeutic outcome or to have an effect against an undesirable symptom, but generally insufficient to cause adverse side effects. A specific therapeutic effective dose level for any particular patient depends on a variety of factors, including: the disorder to be treated and its severity; the specific composition used; the patient’s age, weight, overall health, sex, and diet; the time of administration; the route of administration; the elimination rate of the specific compound used; the duration of treatment; drugs used in combination with or concurrently with the specific compound used, and similar factors well known in the medical field. For example, it is well within the scope of the art to start the dose of a compound at a level lower than the level required to achieve the desired therapeutic effect and gradually increase the dose until the desired effect is achieved. If desired, the effective daily dose can be divided into multiple doses depending on the purpose of administration. Thus, a single-dose composition may contain such an amount or a fraction thereof to constitute a daily dose. Dosage may be adjusted by the individual physician if there are contraindications. Dosage may vary and may be administered once or multiple times daily for one or several days. Guidance on appropriate dosages for a given class of pharmaceutical products can be found in printed materials. Furthermore, in various aspects, preparations may be administered in a “preventive effective dose,” i.e., a dose effective for the prevention of disease or condition.

[0018]

[0068] The effective dose can be initially estimated from an in vitro assay. For example, an initial dose for use in animals may be formulated to achieve a circulating blood or serum concentration of the active compound with an IC50 of or greater than that of a particular compound measured in an in vitro assay. Calculating the dose to achieve such a circulating blood or serum concentration, taking into account the bioavailability of a particular active agent, is well within the capabilities of those skilled in the art. For guidance, see Fingl & Woodbury, "General Principles," in The Pharmaceutical Basis of Therapeutics, Chapter 1, pp. 1-46, current edition, Pergamagon Press, by Goodman and Gilman (the entire work and the references cited therein are incorporated herein by reference).

[0019]

[0069] Pharmaceutically active small molecules and biological compounds elute from custom-formulated, multiphase, stable emulsions to induce biological responses in the body, such as peripheral nerve blocks, or, when infiltrated at wound sites, provide long-lasting pain relief for several days. Depending on the active pharmaceutical ingredient contained in the drug reservoir, other useful therapies and clinical applications beyond pain relief may be provided for several days or even longer. Generally, stable emulsions containing solid crystalline pharmaceuticals and / or solid-phase drug reservoirs are contained within a continuous carrier phase that forms a liquid emulsion, which allows for delivery via catheters or via syringes and subcutaneous needles through applicators. Alternative forms may have liquid, solid, or semi-solid drug reservoirs, or mixtures of multiple drug reservoirs formed within the emulsion.

[0020]

[0070] In certain embodiments, the drugs disclosed herein are stable three-phase emulsion formulations that provide excellent sustained-release performance for low molecules such as ropivacaine and bupivacaine, but have the advantage of not having residual active pharmaceutical ingredients (APIs) or excipients that remain in the body after 14 days. As used herein, APIs generally refer to anesthetics, but in certain embodiments, non-anesthetic APIs may also be present. It is advantageous to use body tissues to absorb and remove the drug during movement of adjacent muscles, preventing stimulation or compression of nerves or surrounding tissues. According to certain embodiments, the emulsions disclosed herein are primarily designed to act as peripheral nerve blocks (PNBs), which provide sufficient nerve block within the first hour after administration and can maintain pain block for at least 3 days (72 hours). The ability of a PNB to provide pain block for at least 3 days allows patients to avoid opioids and transition to non-opioid medications after 3 days.

[0021]

[0071] Other drug formulations still cannot provide both a strong nerve block and long-lasting pain relief of at least 72 hours. They may be able to treat pain locally at the wound, or in some cases may require additional / adjunctive anesthetics to provide a strong block. The stable emulsion formulation described herein provides a robust nerve block that starts rapidly and is followed by pain anesthesia for at least 3 days. It is absorbed into the body within 14 days and does not cause compression or inflammation at the injection site.

[0022]

[0072] The inherent composition of the drug allows for the storage and retention of the API, in these examples ropivacaine, and limits its dissolution rate. Solid particles in the emulsion typically allow for the maturation of the lipid and aqueous phases, destabilizing the emulsion. In some embodiments, the solid particles may be drug crystals. In other embodiments, the solid particles may be solid microparticles. In various other embodiments, the solid particles may be various other configurations that will be understood by those skilled in the art to be functionally compatible with the formulation. In the formulation described, the solid particles do not destabilize the emulsion, and the emulsion is a homogeneous liquid that retains the solid particles dispersed throughout the two liquid phases.

[0023]

[0073] Typically, emulsions cannot deliver a sufficient dose of API and persist for several days because they cannot carry solid particles, thus limiting the amount of drug delivered in a single dose. Stable emulsions typically do not contain solid particles that could initiate the maturation of the lipid and aqueous phases. The formulations disclosed herein are unique in that they can hold up to 28% by weight of solid API particles in the emulsion relative to the lipid component, or up to 12% by weight relative to the total drug in the stable emulsion, as defined below. In some formulations, the emulsion can carry up to 30% API, or up to 15% relative to the total drug volume, but these become more viscous and must be delivered through larger gauge needles and applicators. Similarly, many lipid components, such as triglycerides, have low API solubility in the body and at ambient temperatures, preventing the dissolution of pharmaceutically effective amounts of API. Due to their inherent manufacturing process, the formulations disclosed herein produce stable emulsions with solid API crystals.

[0024]

[0074] In certain embodiments, API crystals are suspended in an emulsion along with small amounts of dissolved API present in both the lipid and aqueous phases. One of the main barriers to elution, giving a sustained-release profile, is the physical conversion of the solid API crystal phase to the liquid or continuous aqueous phase of the reservoir lipid droplets. Lipophilic API molecules, such as ropivacaine, may have low solubility in both the lipid and aqueous phases. The dissolved API present in each phase is eluted into the surrounding tissue. Immediately after injection, this conversion of the API crystal occurs at a faster rate due to the chemical gradient between the emulsion (high ropivacaine) and the surrounding tissue (low ropivacaine). The dissolved API quickly elutes into the surrounding tissue, thereby reducing the amount of dissolved API present in the lipid and aqueous phases. This then gives a chemical gradient between the crystal and the lipid and aqueous phases, and the solid API crystal then dissolves in each phase at similar rates, eluting from each phase into the surrounding tissue. In addition to the processes described above, migration of dissolved APIs can also occur at the liquid / liquid interface between one low-solubility liquid phase and the other low-solubility liquid. Once the chemical gradient between the emulsion and the surrounding tissue decreases due to the elution of ropivacaine, the processes described above reach a slow steady state until all API crystals have dissolved, at which point the API elution rate will locally fall below the pharmaceutically effective dose. For typical formulations with ropivacaine as the API, plasma ropivacaine concentrations remain detectable for up to approximately 7 days, and autopsy results indicate that the drug has disappeared or is largely gone from the infusion space within approximately 14 days.

[0025]

[0075] In a particular embodiment, the disclosed stable emulsion comprises an aqueous carrier; a lipid phase dispersed as droplets within the aqueous carrier; and a first plurality of anesthetic crystals within the lipid phase. In a particular embodiment, a second plurality of API crystals are present in the aqueous carrier rather than in the lipid phase, and these second plurality of API crystals dissolve and elute from the stable emulsion at a faster rate than the first plurality of API crystals.

[0026]

[0076] An emulsion can be considered stable if the remaining unmiscible phase remains unseparated for a commercially useful period. The commercially useful period is the period that allows sufficient time to carry out all relevant testing, transport, storage, and use. In some embodiments, the commercially useful period may range from about one week to about five years. In further embodiments, the commercially useful period may range from about one month to about two years. In preferred embodiments, the commercially useful period may range from about six months to about twelve months.

[0027]

[0077] Emulsions can also be reversible. A reversible emulsion is one in which, once emulsified, immiscible phases separate, and can return to a stable, unseparated state with a gentler mixing than was required to initially mix the immiscible phases. In some cases, this mixing required to recombine the separated phases can be achieved by shaking the container, although sometimes more vigorous mixing is necessary.

[0028]

[0078] In some embodiments, the presence of anesthetic crystals can cause an increase in the viscosity of the formulation. In some embodiments, as the presence of anesthetic crystals increases, the viscosity of the formulation can increase from about 150 cP to about 500 cP. In further embodiments, as the presence of anesthetic crystals increases, the viscosity of the formulation can increase to about 220 cP. lipid phase

[0079] In certain embodiments, the lipid phase is dispersed in the aqueous phase, and the dispersed droplets contain an anesthetic. In certain embodiments, the anesthetic is present in the lipid phase in the form of anesthetic crystals. In further embodiments, the anesthetic is dissolved in the lipid phase. The lipid phase may contain one or more triglycerides and is liquid at room temperature. aqueous phase

[0080] According to certain embodiments, the aqueous phase may be dispersed as droplets in a continuous phase of lipid solution. The anesthetic may be present in the aqueous phase as a solute, or in the solid crystalline phase. Multiple anesthetics may be present in droplets of the aqueous phase. Additional lipophilic anesthetics may be present in the continuous lipid phase together with hydrophilic anesthetics in the aqueous droplets. Triglycerides

[0081] Triglycerides are esters of glycerol with three fatty acids, which may be all the same fatty acid or a mixture of different fatty acids. Fatty acids can be saturated (no carbon double bonds in the fatty acid chain), unsaturated (one or more carbon double bonds in the fatty acid chain), or a mixture of both saturated and unsaturated fatty acid chains. Triglycerides are the main components of animal fats and plant-derived oils.

[0029]

[0082] Triglycerides have long been used as carriers for pharmaceutical ingredients. Castor oil, soybean oil, and peanut oil are all used as carriers for hydrophobic anesthetics. These formulations are used when a pharmaceutically effective dose can be dissolved in the carrier volume, and when that volume is small enough not to cause significant discomfort to the recipient.

[0030]

[0083] Triglycerides are used as nutritional supplements intravenously or orally and are one of the main energy storage molecules in mammals. Stable emulsions are used in the pharmaceutical industry, but most formulations do not contain solid anesthetic crystals.

[0031] [Table 1-1]

[0032] [Table 1-2]

[0033] [Table 2-1]

[0034] Table 2-2

[0035] Table 2-3

[0036] Table 2-4

[0037] Table 2-5

[0038] Table 2-6

[0039] Table 2-7

[0040] Table 3-1

[0041] Table 3-2

[0042] Table 4

[0043] Table 5

[0044] Table 6

[0045] Conjugated fatty acids can also be used alone or in mixtures with other fatty acids to produce triglycerides.

[0046] [Table 7]

[0047] [Table 8-1]

[0048] [Table 8-2]

[0049] Excipients

[0084] According to certain embodiments, low concentrations of other excipients may be added to supplement or improve stability or to act as antioxidants. Naturally derived triglycerides contain unsaturated moieties, polymerize, and can be oxidized in the presence of oxygen. By adding α-tocopherol to triglycerides before sterile filtration, they can act as antioxidants without affecting the stability or elution properties of the emulsion. Other hydrophobic antioxidants, such as lycopene, retinol, carotenoids, and other tocopherols, can be used.

[0050]

[0085] Similarly, hydrophilic antioxidants, such as ascorbic acid, can be added to protect hydrophilic APIs. Iterations of previous formulations have used sodium hydroxide to control the elution of APIs from lipid excipients, maintaining a desired pH of approximately 8 or lower. It is presumed that other salts or weak acids can be used to adjust and maintain the formulation at the desired pH. Those skilled in the art will know that buffers, if present, are adjusted to ensure a stable pH over time.

[0051]

[0086] In certain embodiments, glycerol is used as an effective aqueous modifier to produce a stable emulsion. In further embodiments, sorbitol, manitol, and other polyol chemical compounds are used to further modify the formulation to obtain similar results.

[0052]

[0087] In certain embodiments, hyaluronic acid, hyaluron, and sodium hyaluronate (collectively referred to herein as "HA") are considered the same compound herein and consist of long-chain polymers containing linear glycosaminoglycans (GAGs). Those skilled in the art will know that hyaluronic acid can have various molecular weights (MW), and that the variation in MW used affects the viscosity of the formulation and the stability of the emulsion. In certain embodiments, hyaluronic acid is used as an emulsifier and aqueous phase thickener. Higher concentrations result in a higher ratio of lipid to aqueous phase that can be achieved, and therefore a higher total amount of API available for elution. In some embodiments, HA may be crosslinked with tyramine.

[0053]

[0088] In further embodiments, amphiphilic polysaccharides having both polar hydroxyl and nonpolar methyl ether moieties, acting as thickeners, are used to achieve effects similar to those of HA. In certain embodiments, polyethylene glycol functions as an emulsifier / thickener. In further embodiments, the aforementioned combinations are used to thicken and stabilize emulsions.

[0054]

[0089] Lecithin, a mixture of phospholipids obtained from soybeans or eggs, can be used to produce the same results. In certain embodiments, lecithin obtained from other sources, such as sunflower seeds or canola seeds, can be used to produce similar results. In this case, phospholipids are referred to as a group of lipids comprising one hydrophilic phosphate group and two hydrophobic fatty acid groups linked by one alcohol residue. Those skilled in the art will know that the hydrophilic phosphate "head" group may contain chemical moieties of different amino acids. Furthermore, those skilled in the art will know that the hydrophobic "tail" groups may contain saturated, monounsaturated, and polyunsaturated fatty acids and may have varying chain lengths of 14 to 18 carbon atoms.

[0055]

[0090] In certain embodiments, phospholipids may be combined with other emulsifiers, such as sorbitan esters, polysorbates, propylene oxides, ethoxylates, copolymers, and macromolecules, to produce similar results, although this is not limited to these.

[0056]

[0091] In certain embodiments, a sufficient amount of aqueous thickener is used to achieve a viscosity of the formulation from about 150 cP to about 500 cP. In further embodiments, the viscosity of the formulation can increase to about 220 cP as the presence of anesthetic crystals increases.

[0057]

[0092] According to a particular embodiment, the emulsion components and the range of amounts of such components are shown in Table 9.

[0058] [Table 9]

[0059] Method for formulating a stable, multiphase emulsion

[0093] There are two main methods for producing a stable emulsion. The first method utilizes a common solvent, such as acetone (acetone is preferred), other ketone solvents, or a mixture thereof, that can dissolve triglyceride oil, lipophilic excipients, and anesthetics. The second method uses heated triglyceride oil to dissolve an effective amount of anesthetic. Solvent method

[0094] Regarding the solvent preparation method, the anesthetic and lipophilic excipient are added to a solvent, such as acetone. Once the anesthetic is completely dissolved and a clear solution is obtained, the solution can be sterile filtered through a filter medium with a pore size of 0.2 microns or less. The resulting solution is then subjected to a crystallization unit operation, where the solvent is removed from the solution and crystallization of the anesthetic component occurs in the liquid triglyceride phase. The solvent can be completely removed by various methods; for example, the solvent can be removed by the steps of drawing a vacuum over the solvent phase and removing the solvent from the liquid lipid phase by draining or condensing it. Heat may be used to increase the vapor pressure of the solvent and facilitate its removal from the solution. Any residual solvent can be volatilized from the liquid lipid phase using air, nitrogen, or other inert gases. Once the solvent is removed from the liquid triglyceride phase, the resulting slurry will contain anesthetic crystals. The aqueous phase, containing all remaining emulsifiers and excipients, is then sterile filtered through a 0.2 μm filter medium and added to the liquid triglyceride phase. The two phases are thoroughly mixed to produce a homogeneous two-phase liquid, which is then exposed to a stator-rotor emulsifier or fed into an in-line emulsifier to produce a stable and homogeneous emulsion containing the anesthetic. The resulting emulsion is then transferred to a stock tank / bag, which can be packaged in vials, syringes, or other delivery devices. One advantage of using the solvent method described above is its ability to dissolve temperature-sensitive anesthetics in solution without the need for heating. This also allows for the formation of high-concentration anesthetic formulations that cannot be created using heating processes. heating method

[0095] The thermal manufacturing method utilizes an unexpected and non-trivial method of dissolving the anesthetic in the lipid phase, which allows for sterile filtration of the solution before emulsion formation. While many solvents can contain more solute in solution as the solvent is heated, in most cases a significant amount of solute remains present in the solution at lower temperatures, such as room temperature (22°C). In the case of triglyceride oil, the anesthetic is almost completely insoluble in the oil at room temperature, but this can increase when the solution is heated. This allows for sterile filtration of the anesthetic in the solution when heated. Another inherent aspect of this formulation is that, when heated, it results in contact with the aqueous component, and as it cools as an emulsion forms, the resulting crystals are smaller, with the majority of the anesthetic molecules remaining in the oil droplets. Without this thermal emulsification, very large amounts of anesthetic would be suspended in the formulation as large crystals, and the desired elution profile to the target site over several days would not be achieved.

[0060]

[0096] In certain embodiments, the composition further comprises a radiopaque contrast agent.

[0097] Furthermore, this specification discloses a method for treating postoperative pain in a subject requiring such treatment, comprising the step of administering an effective amount of a composition comprising a stable multiphase emulsion disclosed herein to the subject.

[0061]

[0098] In certain embodiments, the anesthetic is ambucaine, amoranon, amylocaine, benoxynate, benzocaine, vetoxycaine, bifenamine, bupivacaine, butacaine, butamben, butanilicaine, butetamine, butoxycaine, calticaine, chloroprocaine, cocaethylene, cocaine, cyclomethicaine, dibucaine, dimethisoquine, dimethocaine, diperodon, diclonin, ecgonidine, ecogonin, euprosin, phenalcomine, formocaine, hexylcaine, hydroxytetracaine, isobutyl p-aminobenzoate, leucinocaine, levoxadro The anesthetic is selected from ol, lidocaine, mepivacaine, meprilcaine, metabutoxycaine, methyl chloride, myrtecaine, naepain, octacaine, orthocaine, oxethazaine, parentoxycaine, phenacaine, phenol, pipelocaine, pyridocaine, polidocanol, pramoxin, prilocaine, procaine, propanocaine, proparacaine, propipokaine, propoxycaine, pseudococaine, pyrocaine, ropivacaine, salicylic alcohol, tetracaine, tricaine, trimecaine, zolamine, or a pharmaceutically acceptable salt thereof, or a mixture thereof. In certain embodiments, the anesthetic is ropivacaine. In certain alternative embodiments, the anesthetic is bupivacaine.

[0062]

[0099] In certain embodiments, the anesthetic is an amide anesthetic. In exemplary embodiments, the amide anesthetic is articaine, bupivacaine, cincocaine, etidocaine, bupivacaine, lidocaine, mepivacaine, prilocaine, ropivacaine, and / or trimecaine.

[0063]

[0100] In certain embodiments, the anesthetic is an ether anesthetic. Examples of ether anesthetics include, but are not limited to, benzocaine, chloroprocaine, cocaine, cyclomethicaine, dimethocaine (larocaine), pipelocaine, propoxycaine, procaine, propalacaine, and / or tetracaine.

[0064]

[0101] In certain embodiments, the anesthetic is derived from natural resources. Exemplary natural anesthetics include, but are not limited to, saxitoxin, neosaxitoxin, tetrodotoxin, menthol, eugenol, cocaine, and spiranthol.

[0065]

[0102] In certain embodiments, the anesthetic is combined with one or more antiemetics. Exemplary antiemetics include, but are not limited to, NK1 receptor antagonists (e.g., aprepitant, casopitant, lorapitant), cannabinoids (e.g., cannabis, cannabidiol, nabilone, dronabinol, THC), and / or benzodiazepines (e.g., midazolam, lorazepam).

[0066]

[0103] In certain embodiments, the anesthetic is combined with one or more vasoconstrictors (e.g., epinephrine).

[0104] In certain embodiments, the anesthetic is combined with one or more antihypertensive drugs (e.g., clonidine and / or dexmedetomidine).

[0067]

[0105] In certain embodiments, the anesthetic is combined with one or more nonsteroidal anti-inflammatory drugs (NSAIDs). Examples include salicylates (e.g., acetylsalicylic acid, diflunisal, salicylic acid / salt, salsalate), propionic acid derivatives (e.g., ibuprofen, fenoprofen, flurbiprofen, perbiprofen, dexibupropfen, ketoprofen, oxaprozin, zaltoprofen, naproxen, dexketoprofen, loxoprofen), and acetic acid derivatives (e.g., indomethacin, sulindac). This includes, but is not limited to, ketorolac, aceclofenac, tolmetin, etodolac, diclofenac, bromfenac, enolic acid derivatives (e.g., piroxicam, tenoxicam, lornoxicam, phenylbutazone, meloxicam, droxicam), selective COX-2 inhibitors (e.g., celecoxib, firocoxib, parecoxib, etoricoxib), sulfonanilides, nimeslides, clonixin, and / or lycopherone.

[0068]

[0106] In further embodiments, the anesthetic is combined with one or more antihistamines / involuntary nervous system blockers. Examples include, but are not limited to, meclizine, hyostine, chlorpheniramine, and / or diphenylhydramine.

[0069]

[0107] In further embodiments, the anesthetic agent is combined with one or more additional agents, including but not limited to antimicrobial agents and anti-inflammatory agents (dexamethasone) and / or blood coagulation agents.

[0070]

[0108] This specification also provides kits of pharmaceutical formulations comprising the disclosed compounds or compositions. The kits may be configured to represent a single formulation or a combination of formulations. The compositions may be subdivided to contain appropriate amounts of the compounds. Unit doses may be in the form of packaged compositions, such as powders, vials, ampoules, pre-filled syringes, or sachets containing liquid.

[0071]

[0109] The compounds or compositions described herein may be in single doses or for continuous or periodic discontinuous administration. For continuous administration, the kit may contain the compound in each dose unit. For periodic interruptions, the kit may contain a placebo during periods when the compound is not delivered. If it is desirable to change the concentration of the composition, the components of the composition, or the relative ratio of the compound or other agents in the composition over time, the kit may contain a series of dose units.

[0072]

[0110] The kit may include packaging or containers containing a compound formulated for a desired route of delivery. The kit may also include instructions for administration, accompanying documents related to the compound, instructions for monitoring the circulating concentration of the compound, or a combination thereof. Further items for carrying out the use of the compound may be included, but are not limited to, reagents, well plates, containers, and markers or labels. Such a kit is packaged in a manner suitable for the treatment of the desired indication. To those skilled in the art, other suitable components to be included in such a kit will be readily apparent, given the desired indication and route of delivery. The kit may also include, or be packaged with, instruments for assisting in the injection / administration or placement of the compound into the subject's body. Such instruments include, but are not limited to, syringes, pipettes, forceps, measuring spoons, eyedroppers, or any such medically approved means of delivery. Other instruments may include tools that enable the reading or monitoring of in vitro reactions.

[0073]

[0111] The compounds or compositions in these kits may also be supplied in dry, lyophilized, or liquid form. When reagents or components are supplied in dry form, reconstitution is generally carried out by the addition of a solvent. The solvent may be supplied in a separate packaging method, which can be selected by those skilled in the art.

[0074]

[0112] Many packages or kits for dispensing pharmaceuticals are known to those skilled in the art. In one embodiment, the package is a labeled blister package, a dial dispenser package, or a bottle.

[0075] Various aspects and embodiments of this disclosure are defined by the following numbered sections. 1. A composition for treating postoperative pain in a subject requiring it, an aqueous carrier; a liquid lipid phase dispersed as droplets in the aqueous carrier; and a first anesthetic agent in the lipid phase. emulsion containing A composition containing the following: 2. The composition according to item 1, wherein the first anesthetic agent comprises a plurality of first anesthetic agent crystals. 3. The composition according to item 1, wherein the first anesthetic agent is dissolved in a lipid phase. 4. The composition according to any one of claims 1 to 3, further comprising a second plurality of anesthetic crystals in an aqueous carrier rather than in a lipid phase, wherein the second plurality of anesthetic crystals dissolve and elute from the emulsion at a faster rate than the first plurality of anesthetic crystals. 5. The composition according to any one of claims 1 to 4, further comprising one or more additional anesthetic agents different from the first anesthetic agent. 6. A composition according to any one of items 1 to 5, wherein the lipid phase comprises triglycerides. 7. The composition according to any one of items 1 to 6, wherein the aqueous carrier further comprises a thickening agent. 8. The composition according to item 7, wherein the thickening agent is sodium hyaluronate, hyaluronan, and / or hyaluronic acid. 9. The composition according to item 7, wherein the aqueous carrier further comprises a polyol. 10. The composition according to item 9, wherein the polyol is glycerol and is present in an amount of about 0.25 to about 2.5% (w / v) of the composition. 11. A composition according to any one of items 1 to 10, having a viscosity of about 150 to about 500 Cp. 12. The composition according to item 11, having a viscosity of about 200 to about 250 Cp. 13. The composition according to any one of items 1 to 12, wherein the lipid phase further comprises phospholipids present in an amount of about 0.1% to about 2.0% of the lipid phase. 14. A composition according to any one of items 1 to 13, wherein the lipid phase is approximately 10% to approximately 40% (w / v). 15. The composition according to any one of claims 1 to 14, wherein the stable emulsion further contains lecithin, the lecithin present in an amount of 0.1 to 20% (w / v) of the emulsion. 16. The composition according to any one of claims 1 to 15, wherein the emulsion further comprises dextrose, the dextrose present in an amount of about 1-2% (w / v) of the emulsion. 17. The composition according to any one of claims 1 to 16, wherein the emulsion further contains sorbitol, which is present in an amount of about 0.1 to 2% (w / v) of the emulsion. 18. The composition according to any one of claims 1 to 17, wherein the lipid phase comprises about 15% to 80% (v / v) of soybean oil and about 15% to about 20% (v / v) of one or more medium-chain triglycerides. 19. The composition according to item 18, wherein the anesthetic is present in an amount ranging from about 0.1 mg / g of soybean oil to about 300 mg / g of soybean oil. 20. A composition according to any one of claims 1 to 19, wherein the first anesthetic is selected from lidocaine, prilocaine, mepivacaine, ropivacaine, etidocaine, levobupivacaine, bupivacaine, cocaine, procaine, 2-chloroprocaine, tetracaine, benzocaine, ametokine, chlorocaine, butambene, dibucaine, and aconitine ester analogs, diclonin, ketamine, pramoxin, safrole, and salicylic alcohol. 21. The composition according to any one of items 1 to 20, wherein the lipid phase comprises triptylate and / or stearate. 22. The composition according to item 2, wherein the lipid phase further comprises, in an amount (w / w) of about 5% to about 30% of the lipid phase, an oil and / or wax that is solid at 25°C, and the oil and / or wax coats an anesthetic crystal. 23. The composition according to any one of items 1 to 22, wherein the emulsion is stable for at least 6 months. 24. The composition according to any one of items 1 to 23, wherein the anesthetic is ropivacaine and / or bupivacaine. 25. A composition for treating pain in a subject that requires it, A lipid carrier phase; an aqueous phase dispersed as droplets in the lipid carrier phase; and a first anesthetic agent in the aqueous phase. emulsion containing A composition containing the following: 26. The composition according to item 25, wherein the first anesthetic agent comprises a plurality of first anesthetic agent crystals. 27. The composition according to claim 25 or 26, further comprising a second plurality of anesthetic crystals present in a lipid carrier rather than in an aqueous phase, wherein the second plurality of anesthetic crystals dissolve and elute from the emulsion at a faster rate than the first plurality of anesthetic crystals. 28. The composition according to item 27, wherein the anesthetic agent is hydrophilic and dissolved in the aqueous phase. 29. The composition according to any one of claims 25 to 28, further comprising one or more additional anesthetic agents different from the first anesthetic agent. 30. The composition according to any one of items 1 to 29, wherein the emulsion is stable for a period of about one month to about two years. 31. The composition according to item 30, wherein the emulsion is stable for a period of about 6 to about 12 months. 32. The composition according to any one of items 1 to 29x2, wherein the emulsion is reversible. 33. A method for treating pain in a person who requires it, an aqueous carrier; a lipid phase dispersed as droplets in the aqueous carrier; and a first anesthetic in the lipid phase. The step of administering an effective amount of a composition comprising an emulsion containing to a subject, wherein the anesthetic elutes from the composition over a period of about 4 to about 7 days. method. 34. The method according to claim 33, wherein the anesthetic agent comprises a plurality of anesthetic crystals, and the composition further comprises a second plurality of anesthetic crystals in an aqueous carrier rather than in a lipid phase, wherein the second plurality of anesthetic crystals dissolve and elute from the emulsion at a faster rate than the first plurality of anesthetic crystals. 35. The method according to item 33, wherein the composition is delivered near a nerve or nerve bundle of subject to innervate a surgical incision area of ​​the subject. [Examples]

[0076]

[0113] The following examples are provided to fully disclose and illustrate to those skilled in the art how the compounds, compositions, articles, tools and / or methods described in the claims of this disclosure are prepared and evaluated, and are intended purely to illustrate the invention and not to limit the scope of what the inventors consider to be the invention. However, those skilled in the art will understand that many modifications can be made to the specific embodiments disclosed in light of this disclosure, and still equivalent or similar results can be obtained without departing from the spirit and scope of the invention.

[0077] Example 1 Preparation of stable emulsions

[0114] A stable emulsion containing the anesthetic ropivacaine was prepared according to the following protocol. 1. Ropivacaine was added to soybean oil (up to 13% by weight of the oil). 2.0.75 g of lecithin was added to the soybean oil mixture. 3. The anesthetic / oil slurry was heated to 100°C while vigorously mixing the slurry until the anesthetic crystals were completely dissolved in the solution. 4. The soybean oil containing the anesthetic was sterile filtered at a temperature of 100°C using a 0.2 μm vacuum filter. A 5.0.15% aqueous solution of sodium and 0.51 g (w / v) of glycerol was prepared at 4°C. 6. The aqueous solution was heated to 100°C, sterilized by filtration through a 0.2 μm filter medium, and then mixed with warmed soybean oil, lecithin, and an anesthetic base solution. 7. The two phases in the main mixing vessel were emulsified using a rotor-stator emulsifier or by supplying the two-phase mixture to an in-line emulsifier until a stable emulsion was formed. 8. Continue emulsifying the mixture until it cools to room temperature for subsequent use or storage.

[0078] Example 2 Pig sciatic nerve block

[0115] The stable emulsion disclosed herein was prepared according to the method 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 either an injection of the stable emulsion formulation or a 0.5% positive control of Naropin into the transfacial space around the sciatic nerve, resulting in peripheral nerve block (PNB). Animal behavior was observed and recorded after injection. Figure 1 shows the plasma concentration of ropivacaine over time for the 6.29 mg / kg formulation. The Naropin line represents the standard treatment for peripheral nerve block. The stable emulsion formulation provides significant amounts of ropivacaine for longer than 48 hours.

[0079] [Table 10]

[0080]

[0116] Figure 2 shows the plasma concentrations of the 20.44 mg / kg formulation of the stable emulsion drug. These data indicate that the formulation delivers significant amounts of ropivacaine over 168 hours, suggesting a faster onset of PNB. The formulation offers excellent API elution for over 72 hours and is expected to provide a longer-lasting sensory block than 72 hours.

[0081] [Table 11]

[0082] Variations of formulations

[0117] In Examples 3–6, the base formulation is used with various substitutes prepared for each example. The base formulations are given in Table 12 below. The components of the base formulation are mixed using a benchtop mixer with a standard 5.08 cm (2 inch) head at 6000 RPM. This base formulation, and the various substitutes in these examples, are merely illustrative embodiments and are not intended to be limiting.

[0083] [Table 12]

[0084] Example 3 Types of lecithin

[0118] As is understood, the composition of lecithin varies depending on its origin (plant, animal, egg), whether it is defatted, and the degree of processing. Lecithin with a high percentage of phosphatidylcholine is often used in infusion products and must meet the requirements of the United States Pharmacopeia (USP) National Formulary for infusions, which include a phosphatidylcholine concentration of >70% (greater than 70%). Lecithin with lower concentrations of phosphatidylcholine is typically used for oral and topical medicines, foods, and cosmetics. Lecithin with lower phosphatidylcholine yields more stable emulsions with less energy added during formation, while lecithin with higher phosphatidylcholine concentrations also forms more stable emulsions but requires higher energy to be added during formation. In this example, five samples, Samples 1-5, were developed and analyzed using lecithin with different compositions.

[0085]

[0119] Sample 1 uses the base formulation, but instead of lecithin, it uses Spectrum NF (50-60% phosphatidylcholine). Images of the obtained substance are shown in Figure 3A at 10x magnification and in Figure 3B at 20x magnification. The oil droplets are small, and the API crystals are elongated needle-shaped. The emulsion remained stable for 14 days. The sample forms a white, impermeable emulsion / suspension.

[0086]

[0120] Sample 2 uses the base formulation, but instead of lecithin, it uses Cargill Metarin lecithin (19-27% phosphatidylcholine). Images of the obtained substance are shown in Figure 4A at 10x magnification and in Figure 4B at 20x magnification. The oil droplets are small, and the API crystals are long, needle-shaped. The emulsion remained stable for 1 day. The sample forms a white, impermeable emulsion / suspension.

[0087]

[0121] Sample 3 uses the base formulation, but instead of lecithin, it uses Cargill Epikuron lecithin (19-27% phosphatidylcholine). Images of the obtained substance are shown at 10x magnification in Figure 5A and 20x magnification in Figure 5B. The oil droplets are small, and the API crystals are long, needle-shaped. The emulsion remained stable for 1 day, but can be resuspended or reemulsified into an acceptable emulsion by stirring, such as by shaking. The sample forms a white, impermeable emulsion / suspension.

[0088]

[0122] Sample 4 uses the base formulation, but instead of lecithin, it uses Lipoid S75 (>70% phosphatidylcholine). Images of the obtained substance are shown at 10x magnification in Figure 6A and 20x magnification in Figure 6B. The oil droplets are small, and the API crystals are elongated needle-shaped. The emulsion remained stable for 4 days, but can be resuspended or reemulsified into an acceptable emulsion by stirring, such as by shaking. The sample forms a white, impermeable emulsion / suspension.

[0089]

[0123] Sample 5 uses the base formulation, but instead of lecithin, it uses Lipoid S80 (73-79% phosphatidylcholine). Images of the obtained substance are shown at 10x magnification in Figure 7A and 20x magnification in Figure 7B. The oil droplets are small, and the API crystals are long, needle-shaped. The emulsion remained stable for 1 day, but can be resuspended or reemulsified into an acceptable emulsion by stirring, such as by shaking. The sample forms a white, impermeable emulsion / suspension.

[0090] Example 4 Lecithin concentration in soybean oil

[0124] Those skilled in the art will understand that lecithin concentration can affect a formulation by altering the interaction between the aqueous and lipid phases at their boundary. Typically, a higher lecithin ratio compared to the lipid phase concentration results in smaller, discontinuous phase droplets. However, higher lecithin concentrations may also prevent API crystal aggregation. Higher lecithin concentrations can also make the formulation highly viscous. In the case of pain-relieving agents, higher viscosity may be acceptable because the delivery needle can be a larger gauge needle for drug placement. In this example, five samples, samples 6–10, were developed and analyzed using different concentrations of lecithin.

[0091]

[0125] Sample 6 uses the base formulation, but the lecithin component was reduced to 0.5% and replaced with soybean oil. Images of the resulting substance are shown at 10x magnification in Figure 8A and 20x magnification in Figure 8B. The oil droplets are small, and the API crystals are long, needle-shaped. The emulsion remained stable for 3 days, but can be resuspended or reemulsified into an acceptable emulsion by stirring, such as by shaking. The sample forms a white, impermeable emulsion / suspension. Note that the large voids in Figures 8A and 8B are air pockets (air reservoirs) trapped in the sample.

[0092]

[0126] Sample 7 uses the base formulation, but the lecithin component is slightly reduced to 2.5% and replaced with soybean oil. Images of the resulting substance are shown at 10x magnification in Figure 9A and 20x magnification in Figure 9B. The oil droplets are small, and the API crystals are elongated needle-shaped. The emulsion remained stable for 4 days, but can be resuspended or reemulsified into an acceptable emulsion by stirring, such as by shaking. The sample forms a white, impermeable emulsion / suspension. Note that the large voids in Figures 9A and 9B are air pockets trapped in the sample.

[0093]

[0127] Sample 8 uses the base formulation, but the lecithin component is increased to 5%, and soybean oil is removed to balance the composition. Images of the resulting substance are shown at 10x magnification in Figure 10A and 20x magnification in Figure 10B. The oil droplets are small, and the API crystals are elongated needle-shaped. The emulsion remained stable for 9 days, but can be resuspended or reemulsified into an acceptable emulsion by stirring, such as by shaking. The sample forms a white, impermeable emulsion / suspension. Note that the large voids in Figures 10A and 10B are air pockets trapped in the sample.

[0094]

[0128] Sample 9 used the base formulation, but the lecithin component was increased to 10%, and soybean oil was removed to balance the mixture. Images of the resulting substance are shown at 10x magnification in Figure 11A and 20x magnification in Figure 11B. The oil droplets were very small, and the API crystals were long, needle-shaped. The crystals in the sample had aggregated into clumps. The emulsion remained stable for 23+ days (more than 23 days). The sample forms a white, impermeable emulsion / suspension. Note that the large voids in Figures 11A and 11B are trapped air pockets in the sample.

[0095]

[0129] Sample 10 uses the base formulation, but the lecithin component is increased to 20%, and soybean oil is removed to balance it. Images of the resulting substance are shown at 10x magnification in Figure 12A and 20x magnification in Figure 12B. The oil droplets are very small, and the API crystals are in a long needle-like morphology. The crystals in the sample are separated from each other and show very slight aggregation. The emulsion remained stable for 15 days. The sample forms a very viscous, white, impermeable emulsion / suspension, which would be difficult to inject.

[0096] Example 5 Thickening of the aqueous phase

[0130] In this embodiment, sodium hyaluronate was used as a thickener for the aqueous phase to delay or hinder the interaction between droplets in the lipid discontinuous phase and stabilize the emulsion. Hyaluronic acid from sodium hyaluronate can also act as an emulsifier because its molecule has both polar and nonpolar parts. In this embodiment, the sodium hyaluronate concentration is measured relative to the aqueous phase, not relative to the total drug.

[0097]

[0131] Sample 11 uses the base formulation but does not contain sodium hyaluronate in the aqueous phase. Images of the obtained substance are shown in Figure 13A at 10x magnification and in Figure 13B at 20x magnification. The oil droplets are large, and the API crystals are elongated needle-shaped. The emulsion of the sample broke down rapidly (within minutes) and separated into an oil phase and an aqueous phase.

[0098]

[0132] Sample 12 uses the base formulation but has a 0.1 percent concentration of sodium hyaluronate in the aqueous phase. Images of the obtained substance are shown at 10x magnification in Figure 14A and 20x magnification in Figure 14B. The oil droplets are smaller than those of Sample 11. The API crystals are elongated needle-shaped. The emulsion remained stable for 2 days, but can be resuspended or reemulsified into an acceptable emulsion by stirring, such as by shaking.

[0099]

[0133] Sample 13 uses the base formulation but has a 0.15 percent sodium hyaluronate concentration in the aqueous phase. Images of the obtained substance are shown at 10x magnification in Figure 15A and 20x magnification in Figure 15B. The oil droplets are small and relatively uniform. The API crystals are elongated needle-shaped. The emulsion showed higher stability than sample 11.

[0100]

[0134] Sample 14 uses the base formulation but contains a 1% concentration of sodium hyaluronate in the aqueous phase. Images of the obtained substance are shown at 10x magnification in Figure 16A and 20x magnification in Figure 16B. The oil droplets are small and relatively uniform. The API crystals are elongated needle-shaped. The emulsion remained stable for 8 days.

[0101]

[0135] As observed, at concentrations below 0.1 percent, the emulsion rapidly broke down and separated. At concentrations above 0.1 percent, the emulsion gradually became more stable.

[0102] Example 6 Adding glycerol

[0136] In this example, glycerol was added as an aqueous phase modifier for the aqueous phase, which tended to increase the viscosity of the aqueous phase. The glycerol concentration in this example is measured for the entire formulation, rather than for any specific phase.

[0103]

[0137] Sample 15 uses the base formulation but has a glycerol concentration of 1.7% relative to the total formulation. Images of the obtained substance are shown in Figure 17A at 10x magnification and in Figure 17B at 20x magnification. The oil droplets are small and relatively uniform. The API crystals are elongated needle-shaped. The emulsion remained stable for 1 day.

[0104]

[0138] Sample 16 uses the base formulation but has a glycerol concentration of 3.0% relative to the total formulation. Images of the obtained substance are shown at 10x magnification in Figure 18A and 20x magnification in Figure 19B. The oil droplets are small and relatively uniform. The API crystals are elongated needle-shaped. The emulsion remained stable for 1 day.

[0105]

[0139] Sample 17 uses the base formulation but has a glycerol concentration of 5.0% relative to the total formulation. Images of the obtained substance are shown at 10x magnification in Figure 19A and 20x magnification in Figure 19B. The oil droplets are small and relatively uniform. The API crystals are elongated needle-shaped. The emulsion remained stable for 1 day.

[0106]

[0140] Sample 18 uses the base formulation but has a glycerol concentration of 10% of the total formulation. Images of the obtained substance are shown at 10x magnification in Figure 20A and 20x magnification in Figure 20B. The oil droplets are smaller and more uniform than those of samples 18, 19, and 20. The API crystals are elongated needle-shaped. The emulsion remained stable for 1 day.

[0107]

[0141] Since sample 18 showed improvement in oil droplet size and uniformity, there is a positive correlation between the concentration of glycerol or a similar solvent and droplet uniformity. A negative correlation can be observed between the glycerol / solvent concentration and droplet size.

[0108] Example 7 Lipid phase thickening

[0142] In this example, either coconut oil or carnauba wax was added to the lipid phase of the formulation to increase its viscosity. Coconut oil or carnauba wax was added to the formulation as a thickener, and the mass of added soybean oil was reduced to an equivalent amount to maintain the total amount of lipid phase in the formulation. In this example, the thickener concentration is measured for the entire formulation, not for any specific phase.

[0109]

[0143] Sample 19 used the base formulation, but with 10% coconut oil and an equal amount of soybean oil removed. Images of the resulting substance are shown at 10x magnification in Figure 21A and 20x magnification in Figure 21B. The oil droplets were generally small, but an increase in size and the number of larger droplets could be observed. The API crystals were elongated needle-shaped. The product was a stable emulsion.

[0110]

[0144] Sample 20 used the base formulation, but with 1.0% of the formulation consisting of carnauba wax and an equal amount of soybean oil. Images of the resulting substance are shown at 10x magnification in Figure 22A and 20x magnification in Figure 22B. The API crystals were elongated needle-shaped, and the wax and lipids tended to coat the crystals. The product was a stable emulsion.

[0111]

[0145] Sample 21 used the base formulation, but 2.5% of the formulation consisted of carnauba wax, with an equal amount of soybean oil reduced. Images of the resulting substance are shown at 10x magnification in Figure 23A and 20x magnification in Figure 23B. The API crystals were elongated needle-shaped. The wax and lipid coatings on the crystals were thicker than those observed in Sample 20. The product was a stable emulsion.

[0112]

[0146] Sample 22 used the base formulation, but 5.0% of the formulation consisted of carnauba wax, with an equal amount of soybean oil reduced. Images of the obtained substance are shown at 10x magnification in Figure 24A and 20x magnification in Figure 24B. The API crystals were elongated needle-shaped. The wax and lipids coated the crystals and formed fine particles separated from the crystals. The product was a stable emulsion.

[0113]

[0147] The carnauba wax appeared to coat most of the crystal surface. At higher concentrations, e.g., 5%, the carnauba wax also detached from the crystal, forming fine particles. As can be understood, this tendency of waxes and lipids to coat the API crystals may result in an increased barrier to the diffusion of the API from the formulation to the target. This increased barrier to diffusion may result in a slower, more consistent release of the API to the target. This slower, more consistent release of the API allows for the administration of more formulation at once, due to a slower rate of introduction into the target.

[0114]

[0148] Example 8 Continuous lipid phase

[0149] In some embodiments, and in this embodiment, it may be preferable to disperse the aqueous phase in the continuous lipid phase rather than the lipid phase in the continuous aqueous phase, as in other embodiments. Having a continuous lipid phase may be beneficial when the API used is hydrophilic rather than hydrophobic. The formulation for sample 23 consisted of 60 vol% lipid phase and 40 vol% aqueous phase, with the components of each phase maintaining relative proportions unless otherwise stated. The sodium hyaluronate in the formulation was 0.15 wt% relative to the aqueous phase.

[0115]

[0150] Images of the obtained material are shown in Figure 25A at 10x magnification and in Figure 25B at 20x magnification. The API crystals have a long, needle-like morphology. The aqueous droplets were of various sizes.

[0116] Example 9 Increase in mixed energy

[0151] Sample 24 used the base formulation but employed a 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 in Figure 26 at 40x magnification. The oil droplets are smaller than those found in formulations prepared using standard mixing energies. Smaller oil droplets are more likely to coat the surface of the API crystal. The emulsion remained stable for longer than 7 months.

[0117]

[0152] Sample 25 used the base formulation, but was prepared using a 3 / 4 horsepower Silverson high-shear rotor-stator homogenizer at 12,000 RPM. An image of the obtained material is shown in Figure 27 at 40x magnification. API crystal aggregates formed as a result of higher mixing energy. These aggregates remained stable and did not separate. Increased mixing energy also increased the size distribution of API crystals and the amount of crystal aggregates.

[0118] Example 12 Increased stability due to increased API load

[0153] In a comparison between a formulation without API (placebo) and a formulation containing API (active), it was observed that the placebo formulation broke down, while the active formulation did not. However, samples with higher API concentrations in the ropivacaine form were less stable than samples with lower concentrations. The sample with 29.34 mg / mL of ropivacaine was more stable than the sample with 38.51 mg / mL of ropivacaine. The sample with 38.51 mg / mL of ropivacaine was more stable than the sample with 47.69 mg / mL of ropivacaine. The sample with 47.69 mg / mL of ropivacaine was more stable than the placebo. The 29.34 mg / mL of ropivacaine sample was stable for at least 7 months.

[0119] Example 13 Increase in viscosity due to API loading.

[0154] In the series of samples shown in Table 13, in certain embodiments, it can be observed that the addition of an API, such as ropivacaine, may result in an increase in the overall viscosity of the formulation. All of these samples in Table 13 use the base formulation with the various API loads described.

[0120] [Table 13]

[0121]

[0155] While this disclosure has been described with reference to preferred embodiments, those skilled in the art will recognize that modifications may be made in form and detail without departing from the spirit and scope of the disclosed devices, systems and methods.

Claims

1. A composition for treating postoperative pain in a subject requiring it, an aqueous carrier; a liquid lipid phase dispersed as droplets in the aqueous carrier; and a first anesthetic agent in the lipid phase. emulsion containing A composition containing the following:

2. The composition according to claim 1, wherein the first anesthetic agent comprises a plurality of first anesthetic agent crystals.

3. The composition according to claim 1, wherein the first anesthetic agent is dissolved in the lipid phase.

4. The composition according to claim 2, further comprising a second plurality of anesthetic crystals in an aqueous carrier rather than in a lipid phase, wherein the second plurality of anesthetic crystals dissolve and elute from the emulsion at a faster rate than the first plurality of anesthetic crystals.

5. The composition according to claim 1, further comprising one or more additional anesthetic agents different from the first anesthetic agent.

6. The composition according to claim 1, wherein the lipid phase comprises triglycerides.

7. The composition according to claim 1, wherein the aqueous carrier further comprises a thickener and a polyol, the thickener being hyaluronic acid and the polyol being glycerol, present in an amount of about 0.25 to about 2.5% (w / v) of the composition, and the thickener increases the viscosity of the composition.

8. The composition according to claim 1, wherein the lipid phase further comprises phospholipids present in an amount of about 0.1% to about 2.0% of the lipid phase.

9. The composition according to claim 1, wherein the lipid phase is approximately 10% to approximately 40% (w / v).

10. The composition according to claim 1, wherein the stable emulsion further contains lecithin, the lecithin present in an amount of 0.1 to 20% (w / v) of the emulsion.

11. The composition according to claim 1, wherein the emulsion further comprises dextrose, the dextrose present in an amount of about 1-2% (w / v) of the emulsion.

12. The composition according to claim 1, wherein the emulsion further contains sorbitol, the sorbitol present in an amount of about 0.1 to 2% (w / v) of the emulsion.

13. The composition according to claim 1, wherein the lipid phase comprises about 15% to 80% (v / v) of soybean oil and about 15% to about 20% (v / v) of one or more medium-chain triglycerides.

14. The composition according to claim 13, wherein the anesthetic is present in an amount ranging from about 0.1 mg / g of soybean oil to about 300 mg / g of soybean oil.

15. The composition according to claim 1, wherein the first anesthetic is selected from lidocaine, prilocaine, mepivacaine, ropivacaine, etidocaine, levobupivacaine, bupivacaine, cocaine, procaine, 2-chloroprocaine, tetracaine, benzocaine, ametokine, chlorocaine, butambene, dibucaine, and ester analogs of aconitine, diclonin, ketamine, pramoxin, safrole, and salicylic alcohol.

16. The composition according to claim 1, wherein the lipid phase comprises triptylate and / or stearate.

17. The composition according to claim 2, wherein the lipid phase further comprises an oil and / or wax that is solid at 25°C in an amount (w / w) of about 5% to about 30% of the lipid phase, the oil and / or wax coating an anesthetic crystal.

18. The composition according to claim 1, wherein the emulsion is stable for at least six months.

19. The composition according to claim 1, wherein the anesthetic agent is ropivacaine and / or bupivacaine.

20. A composition for treating pain in a subject requiring it, A lipid carrier phase; an aqueous phase dispersed as droplets in the lipid carrier phase; and a first anesthetic agent in the aqueous phase. emulsion containing A composition containing the following:

21. The composition according to claim 20, wherein the first anesthetic agent comprises a plurality of first anesthetic agent crystals.

22. The composition according to claim 21, further comprising a second plurality of anesthetic crystals present in a lipid carrier rather than in an aqueous phase, wherein the second plurality of anesthetic crystals dissolve and elute from the emulsion at a faster rate than the first plurality of anesthetic crystals.

23. The composition according to claim 22, wherein the anesthetic is hydrophilic and dissolved in the aqueous phase.

24. The composition according to claim 20, further comprising one or more additional anesthetic agents different from the first anesthetic agent.

25. A method for treating pain in a person who requires it, an aqueous carrier; a lipid phase dispersed as droplets in the aqueous carrier; and a first anesthetic in the lipid phase. emulsion containing The step includes administering an effective amount of a composition containing to a subject, wherein the anesthetic agent elutes from the composition over a period of about 4 to about 7 days. method.

26. The method according to claim 25, wherein the anesthetic agent comprises a plurality of anesthetic crystals, and the composition further comprises a second plurality of anesthetic crystals in an aqueous carrier rather than in a lipid phase, wherein the second plurality of anesthetic crystals dissolve and elute from the emulsion at a faster rate than the first plurality of anesthetic crystals.

27. The method according to claim 25, wherein the composition is delivered near a nerve or nerve bundle of interest, and the nerve or nerve bundle innervates a surgical incision area of ​​the interest.

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