HK1148449A - Narcotic emulsion formulations for treatment of surgical pain - Google Patents

Description

Anesthetic emulsion preparation for treating operation pain

Cross Reference to Related Applications

As per 35u.s.c. § 119(e), the present application claims application date of U.S. provisional patent application serial No. 61/053,571(2008, 5/15) as priority; the disclosure of which is incorporated herein by reference.

Brief introduction to the drawings

Pain can be defined as: unpleasant feelings and emotional feelings related to actual or potential tissue damage. It is a complex process influenced by physiological and psychological factors. Pain is typically a subjective sensation and many health care professionals are not trained to effectively assess or treat pain.

Over twenty million patients undergo surgical procedures each year. Post-operative pain (interchangeably referred to as post-incision pain), or pain that occurs after surgery or traumatic injury, is a serious and often unmanageable medical problem.

Pain is usually localized to the vicinity of the surgical site. Post-operative pain has two clinically important aspects, namely resting pain or pain that occurs when the patient is not moving, and mechanical pain that is exacerbated by movement (coughing/sneezing, getting up, physiotherapy, etc.). For major surgery, the main problem with post-operative pain management is that the currently used drugs have various significant side effects which can delay recovery, prolong hospitalization and risk serious complications for some fragile patients.

The three major classes of pharmaceutical drugs used to treat post-operative pain are opioid analgesics, local anesthetics, and non-steroidal anti-inflammatory drugs (NSAIDs). During surgery, two of these classes of drugs (opioid analgesics and NSAIDs) are typically administered systemically, while local anesthetics (e.g., channel blockers) are not administered systemically.

Systemic administration for pain relief after surgery is often inappropriate. For example, systemic administration of opioids after surgery can result in nausea, suppression of bowel function, urinary retention, suppression of lung function, cardiovascular effects, and sedation.

One opioid analgesic that has been used in post-operative pain treatment is fentanyl. Fentanyl is the generic name for the compound N- (-phenethyl-4 piperidinyl) propionanilide, which is a potent injectable analgesic. See U.S. Pat. No. 3,164,600. Fentanyl is an opioid agonist and has many of the pharmacological effects of opioids such as morphine and meperidine. However, compared to these opioids, fentanyl shows little hypnotic activity, causes little histamine release, and respiratory depression is more transient. Fentanyl is commercially available and can be administered intravenously, buccally (lozenge-transmucosal) and transdermally.

To date, various injectable fentanyl formulations have been developed. One such formulation is a fentanyl citrate composition (sold in the United states under the trade name Sublimize)^TM) Comprising fentanyl citrate, USP water for injection and sufficient sodium hydroxide to raise the pH to 6.5. Various fentanyl citrate compositions have been marketed in Europe (trade name FENTANEST)^TM) Consisting of fentanyl and water for USP injection, completely without taking into account the pH adjustment problem.

While injectable fentanyl formulations have utility, such formulations do have certain disadvantages. For example, injectable fentanyl formulations can lead to undesirable central nervous system mediated side effects, such as respiratory depression, sedation, and vertigo.

Therefore, there is a need to develop injectable formulations that are as effective as current injectable formulations, but have a low incidence of cns-mediated side effects.

SUMMARY

The present invention provides methods and compositions for treating post-operative pain in a patient. In the present method, post-operative pain in a patient is treated by administering to the patient an effective amount of a narcotic emulsion formulation, for example, a fentanyl emulsion formulation. In certain embodiments, the emulsion formulation includes an anesthetic active agent, an oil, water, and a surfactant. The invention also provides a method for preparing the emulsion preparation and a kit containing the emulsion preparation.

Brief description of the drawings

FIG. 1 illustrates Fentanest^TMEffect on pain-related scores (in mice versus time).

Figure 2 illustrates the effect of fentanyl emulsion a on pain-related scores (versus time in mice).

FIG. 3 shows Fentanest^TMAnd inhibition of pain by fentanyl emulsion a. The effect is expressed as the area under the curve (% Fentanest)^TM)。

FIG. 4 shows a graph represented by Fentanest^TMAnd duration of the Strobel reaction elicited by fentanyl emulsion A. The formulation was administered intravenously in a volume of 0.10 ml. The tail reaction was observed for 1 hour after dosing and the duration of the reaction was summed. Results shown are mean ± SEM of animals illustrating the response. The values in the bars represent the number of animals that exhibited the Stroubus reaction. Fentanest was given to six animals per group^TMOr fentanyl emulsion a.

FIG. 5 shows a diagram made by Fentanest^TMThe resulting one-directional motion (lococotor) behavior (e.g., the duration of a round (round) motion behavior). Intravenous administration of Fentanest in a volume of 0.10ml^TMAnd an excipient. Results shown are mean ± SEM of six animals. P < 0.05 (Dunnett's multiple comparison).

Figure 6 shows the one-directional motor behavior (e.g., duration of circular motor behavior) caused by fentanyl emulsion a. Fentanyl emulsion a and vehicle were administered intravenously in a volume of 0.10 ml. Results shown are mean ± SEM of six animals. P < 0.05 (Dunnett's multiple comparison).

FIG. 7 shows a graph represented by Fentanest^TMAnd fentanyl emulsion a, in one direction of motion behavior (e.g., duration of circular motion behavior). Results shown are mean ± SEM of six animals. P < 0.05 (Dunnett's multiple comparison).

Detailed Description

The present invention provides methods and compositions for treating post-operative pain in a patient. In the present method, post-operative pain in a patient is treated by administering to the patient an effective amount of a narcotic emulsion formulation, for example, a fentanyl emulsion formulation. In certain embodiments, the emulsion formulation includes an anesthetic active agent, an oil, water, and a surfactant. The invention also provides a method for preparing the emulsion preparation and a kit containing the emulsion preparation.

Before the present invention is described in more detail, it is to be understood that this invention is not limited to particular embodiments described, and that modifications may, of course, be made. It is also to be understood that the terminology used herein is for the purpose of describing particular embodiments only, and is not intended to be limiting, since the scope of the present invention will be limited only by the appended claims.

Where a range of values is provided, it is understood that each intervening value, to the tenth of the unit of the lower limit unless the context clearly dictates otherwise, between the upper and lower limit of that range and any other stated or intervening value in that stated range is encompassed within the invention. The upper and lower limits of these smaller ranges may independently be included in the smaller ranges, and are also encompassed within the invention, subject to any specifically excluded limit in the stated range. If the stated range includes one or both of the limits, ranges excluding either or both of those included limits are also included in the invention.

Certain ranges are provided herein with numerical values, and the term "about" is used before numerical values. The term "about" is used herein to provide literal support for the precise numerical value following it, as well as the numerical value that is near or approximate to the numerical value following the term. In determining whether a value is near or similar to a specifically recited value, near or similar to the non-recited value can be the value provided in the context as long as it is substantially equivalent to the specifically recited value.

Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Although any methods and materials similar or equivalent to those described herein can also be used in the practice or testing of the present invention, representative illustrative methods and materials are now described.

All publications and patents cited in this specification are herein incorporated by reference as if each individual publication or patent were specifically and individually indicated to be incorporated by reference and were set forth in its entirety herein to disclose and describe the methods and/or materials in connection with which the publications were cited. The citation of any publication is for its disclosure prior to the filing date and should not be construed as an admission that the present invention is not entitled to antedate such publication by virtue of prior invention. Further, the dates of publication provided may be different from the actual publication dates which may need to be independently determined.

It should be noted that, as used herein and in the appended claims, the singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise. It should be further noted that the claims may be drafted to exclude any optional element. Accordingly, such statements are to be considered as antecedent basis for use of exclusive terminology such as "solely," "only," etc., in connection with the recitation of claim elements, or use of a "negative" limitation.

It will be apparent to those skilled in the art from this disclosure that each of the individual embodiments described and illustrated herein has independent components and features which may be readily distinguished from or combined with the features of any other embodiments without departing from the scope or spirit of the present invention. Any recited method may be performed in the order of the recited events, or in any other order that is logically possible.

In the following sections, the emulsion formulations and methods of using the emulsion formulations are first described in more detail, followed by a review of the methods of making the formulations and kits that may contain the formulations.

Anesthetic emulsion formulations

The present anesthetic emulsion formulation comprises an anesthetic active agent. An interesting narcotic active agent is an opioid receptor agonist. Opioid receptor agonists include opiates and opioids. "opiate" and "opioid" are generally synonymous terms, and generally refer to a class of narcotic compounds characterized by addictive or sustained-addiction properties (similar to morphine), or capable of being converted into drugs having such addictive or sustained-addiction properties. In particular, the term "opiate" refers to a compound that contains an essential morphine or thebaine structure and has some affinity for any or all of the opioid receptor subtypes. Examples of opiates are heroin, buprenorphine and naltrexone. An "opioid" is any compound, peptide, or compound that has some affinity for any or all of the opioid receptor subtypes when not containing the essential morphine or thebaine structure. Non-exclusive examples of opiates and opioids include morphine, heroin, poppy, cocaine, fentanyl, ecgonine, thebaine, and the like. Commercially available opiates and opioids (and exemplary registered trade names available) include: alfentanil ("alfentanta"), buprenorphine ("Temgesic", or "Subutex"), carfentanil ("Carfenta"), codeine, dihydrocodeine, diproporphine, etorphine ("Immobilon"), fentanyl ("Sublimaze" or "Fentanest"), heroin, hydrocodone ("Vicodin"), hydromorphone ("Dilaudi"), LAAM ("Orlaam"), liflofen ("Levo-Dromoran"), meperidine ("Demerol"), methadone ("Dolophine"), morphine, naloxone ("Narcan"), naltrexone ("Trexan"), beta-hydroxy 3-methylfentanyl, oxycodone ("Percodan"), oxymorphone ("oxymorphone"), DarlNurpron ("Darvon"), remifentanil ("Ulva"), sufentanil ("Sunfera"), toleron ("Vatoleron") and tramadol ("Ultrax"). This definition includes all opiates and opioids of any origin, including naturally derived compounds, synthetic compounds and semi-synthetic compounds. The definition also includes all isomers, stereoisomers, esters, ethers, salts and salts of such isomers, stereoisomers, esters and ethers, the presence of which is possible whenever within the specific chemical designation.

The anesthetic formulations described herein are emulsion formulations, which are liquid medicaments that are suspensions of small droplets of one liquid in a second liquid, wherein the first liquid does not mix with the second liquid. In certain embodiments, the present emulsion formulations include an anesthetic active agent, an oil, water, and a surfactant. The narcotic active may include an opioid as described above, wherein in some instances the opioid includes fentanyl, i.e., N- (1-phenylethyl-4-piperidinyl) propionanilide.

One aspect of the present emulsion formulations is an emulsion formulation comprising an effective amount of an anesthetic active agent. An effective amount is a dosage sufficient to provide the desired effect. For example, if the active agent is an anesthetic, the effective amount is a dose that provides the desired anesthetic effect. It will be apparent to those skilled in the art that the effective amount may vary depending on the particular active agent used, the particular wound being treated, and the like. The amount of anesthetic active agent in the present emulsion formulations may vary, and in certain embodiments, ranges from 0.01 to 100mg/ml, e.g., from 0.1 to 50mg/ml, and including from 0.1 to 10 mg/ml. In certain embodiments, the emulsion formulation comprises an effective amount of fentanyl. Fentanyl may be present in the emulsion formulation as the free base or as a physiologically acceptable salt thereof or as a hydrate thereof. In certain embodiments, fentanyl is present in the composition at a concentration of 0.05mg/ml or greater, including 0.1mg/ml or greater, and in certain embodiments at a concentration in the range of 0.1 to 10mg/ml, such as 0.1 to 2mg/ml, including 0.1 to 1 mg/ml.

In certain embodiments, the emulsion formulation is a water and oil emulsion formulation. Because the formulations are emulsion formulations, they are mixtures of two immiscible (e.g., immiscible) liquids, with one liquid (e.g., oil or water) (the dispersed phase) dispersed in the other liquid (e.g., the other oil or water) (the continuous phase). The water present in the emulsion formulation may be any suitable water, including deionized water, USP water for injection (WFI), and the like.

In certain embodiments of the present emulsion formulations, an oil is also present. Oils of interest are physiologically acceptable oils and include, but are not limited to: simple lipids, derived lipids, complex lipids derived from natural vegetable oils and fats, animal fats and oils and mineral oils, or mixtures thereof. In certain embodiments, oils include, but are not limited to: soybean oil, olive oil, sesame oil, castor oil, corn oil, peanut oil, safflower oil, grapeseed oil, eucalyptus oil, medium chain fatty acid esters, low chain fatty acid esters, and the like. Animal oils and fats of interest include, but are not limited to: cod liver oil, seal oil, sardine oil, docosahexaenoic acid and eicosapentaenoic acid. Mineral oils of interest include, but are not limited to: liquid paraffin (e.g., oils derived from n-alkanes), naphthalene oils (e.g., naphthenic-based oils), and aromatic oils (e.g., aromatic-based oils). One type or a combination of more than one type of such oils may be used. For example, some embodiments of the present emulsion formulations comprise soybean oil, olive oil, sesame oil, or combinations thereof. Another embodiment comprises soybean oil, olive oil, or a combination thereof. In certain embodiments, highly refined oils and fats are used. In some instances, the amount of oil in the emulsion formulation is in the range of 0.05 to 200mg/ml, e.g., 1 to 200mg/ml, and including 10 to 100 mg/ml.

In certain embodiments of the present emulsion formulations, a surfactant is also present. The surfactant may include any type of surfactant used in pharmaceutical formulations, including but not limited to: phospholipids, refined phospholipids, nonionic surfactants, or mixtures thereof. The refined phospholipids may include phosphatidylinositol (phosphatidylinositol), phosphatidylethanolamine, phosphatidylserine and sphingomyelin, in which lecithin is a main component. For example, refined phospholipids include egg yolk lecithin and soybean lecithin. Nonionic surfactants of interest include, but are not limited to: polyethylene glycol, polyoxyalkylene copolymer and sorbitan fatty acid ester. One of these surfactants or a combination of more than one of these surfactants may be used. In certain embodiments, the emulsion formulation comprises a surfactant, e.g., using a refined phospholipid. In some cases, the emulsion formulation comprises a refined or hydrogenated phospholipid derived from egg yolk or soy (lecithin as the major component). In the present emulsion formulation, there is no particular limitation on the combination ratio of the oil and the surfactant as long as a lipid emulsion formulation can be obtained. Thus, the amount of surfactant may vary, and in certain embodiments ranges from 0.1 to 50mg/ml, such as 0.1 to 25mg/ml, including 1 to 20 mg/ml.

In certain embodiments of the present emulsion formulations, one or more emulsification enhancers are also included. Any type of fatty acid that may be used in pharmaceutical formulations may be used as an emulsification enhancer. Of interest are fatty acids containing 6 to 22 carbons. Natural or synthetic and saturated or unsaturated fatty acids may be used, including but not limited to: stearic acid, oleic acid, linoleic acid, palmitic acid, linolenic acid, myristic acid, and the like. In certain embodiments, the emulsion formulation comprises a refined fatty acid, for example, oleic acid. The amount of emulsification enhancer included in the emulsion formulation may range from 0.1 to 10mg/ml, for example 1 to 5 mg/ml.

In addition, the emulsion formulation may have a physiologically acceptable pH. In certain embodiments, the pH of the emulsion formulation is in the range of 3 to 8, such as 5 to 7.5, including 6 to 7. In some instances, the emulsion formulation includes a pH adjuster. Interesting pH adjusting agents include, but are not limited to: sodium hydroxide, hydrochloric acid, phosphoric acid buffer, citric acid buffer, and the like. For example, the pH of the emulsion formulation can be adjusted to the desired range by adding an appropriate amount of a pH adjuster.

Other additives that may be present in the formulation include stabilizers such as, but not limited to: glycerol, propylene glycol, polyethylene glycol (e.g., having an average molecular weight of 400 or less), D-glucose, and maltose. Such agents may be included in the present emulsion formulations in amounts of from 0.1 to 50mg/ml, for example 1 to 25 mg/ml.

With Fentanest^TMFentanyl citrate injectable formulations (0.1mg/2ml, available from Sankyo Corporation, Tokyo, Japan) the fentanyl-containing emulsion formulations may exhibit enhanced efficacy as compared to the fentanyl citrate injectable formulations. Of interest are emulsion formulations, e.g. fentanyl emulsion A, which is comparable to Fentanest^TMThe fentanyl citrate injection formulation showed greater efficacy as demonstrated in the experimental section below. By administering Fentanest at various time points after administration^TMThe effect can be determined by comparing inhibition of pain intensity (e.g., pain-related score) for the fentanyl citrate injection formulation and the emulsion formulation described herein (e.g., fentanyl emulsion a). In certain embodiments, with Fentanest^TMThe emulsion formulations described herein show at least comparable effects compared to fentanyl citrate injection formulations. For example, with Fentanest^TMThe present emulsion formulations may exhibit an increase in potency of 5% or more, for example 10% or more, including 15% or more, over fentanyl citrate injection formulations. In certain embodiments, 15 minutes after administration, Fentanest^TMFentanyl citrate injection formulation and fentanylNile emulsion a inhibited pain intensity (e.g., pain related score) by 61% and 78%, respectively, and 30 minutes after administration by 35% and 49%, respectively, as illustrated in fig. 1 and 2. In addition, in some cases, with Fentanest^TMFentanyl emulsion a can reduce (expressed as the area under the curve) the intensity of pain (e.g., the fraction associated with pain) by 50% or more, such as 75% or more, including 100% or more, compared to the area under the curve for the fentanyl citrate injectable formulation. In some cases, the reduced pain intensity (expressed as the area under the curve) of the present emulsion formulation is Fentanest^TMFentanyl citrate injection formulation reduced pain by twice the intensity of the pain as illustrated in figure 3.

In certain embodiments, with Fentanest^TMThe emulsion formulations described herein have been shown to reduce central nervous system mediated side effects compared to fentanyl citrate injection formulations. By combining the emulsion formulations described herein with Fentanest^TMA reduction in central nervous system mediated side effects can be observed by comparing the incidence of sturobusta tail reactions between fentanyl citrate injection formulations. The tail-lifting response of mice is an S-shaped dorsiflexion of the tail of the mice, which can be used as a biological test for sensitivity and specificity to opioids. The Strausura cauda response is mediated by the effects of opioids on the sacrococcygeal dorsal muscles at the level of the lumbosacral spinal cord. In some cases, with Fentanest^TMThe emulsion formulations described herein have been shown to reduce the incidence of stuart tail reactions compared to fentanyl citrate injection formulations. For example, after administration of a 30 μ g/ml dose of fentanyl emulsion A, as illustrated in Table 5 below, with Fentanest^TMThe incidence of the strombursement reaction in mice was 50% or less, e.g. 33% or less (determined using the test protocol reported in the experimental section below) compared to the fentanyl citrate injectable formulation. In some cases, with Fentanest^TMThe duration of the Strauuer tail reaction is 80% or less, for example 75% or less, for fentanyl emulsion, compared to fentanyl injectable formulationsIncluding 36% or less (as illustrated in fig. 4).

Aspects of the emulsion formulations disclosed herein also include: emulsion formulations (with Fentanest) shown to reduce brain-mediated side effects (e.g., increased one-directional motor behavior, e.g., wraparound behavior)^TMFentanyl citrate injection formulation comparison). For example, at a dose of 30. mu.g/ml Fentanest^TMThe duration of the ringing behavior after fentanyl citrate injection formulation or fentanyl emulsion a was 40 and 27 minutes respectively (as illustrated in figures 5 and 6, determined using the test protocol reported in the experimental section below). In certain embodiments, the duration of the circling action after administration of the present emulsion formulation is 40 minutes or less, such as 35 minutes or less, including 30 minutes or less.

Other aspects of the present emulsion formulations include storage stable emulsion formulations. By stable storage is meant that the composition can be stored for extended periods of time without significant phase separation and/or significant reduction in the activity of the active agent. In certain embodiments, the present compositions are stable for storage for 6 months or more, such as 1 year or more, including 3 years or more, and the like, when maintained at 25 ℃. The phrase "no significant reduction in the activity of the active agent" means that: the activity of the active agent is reduced by 10% or less, such as 5% or less, including 3% or less, at the end of the storage period compared to the activity of the active agent at the beginning of the storage period.

Method of treating post-operative pain with anesthetic emulsion formulations

As summarized above, the present invention provides a method of treating post-operative pain in a patient. "post-operative pain" (interchangeably referred to as "post-incision" or "post-traumatic pain") refers to pain (including pain caused by all surgical procedures, whether aggressive or non-aggressive) caused or resulting from external damage (e.g., cuts, punctures, incisions, tears, or injuries) to the tissue of an individual. As used herein, "post-operative pain" does not include pain that occurs without an external physical injury. In some embodiments, the post-operative pain is internal or external pain, and the wound, cut, injury, tear, or incision can occur accidentally (as with a traumatic wound) or intentionally (as with a surgical incision). As used herein, "pain" includes nociception and pain perception, and pain scores and other methods (e.g., protocols well known in the art) can be used to objectively and subjectively assess pain. Post-operative pain, as used herein, includes allodynia (i.e., pain due to a stimulus that does not normally cause pain) and hyperalgesia (i.e., an increased response to a stimulus that is normally painful), which may also be thermal or mechanical in nature (tactile pain). In some embodiments, the pain is characterized by thermal sensitivity, mechanical sensitivity, and/or resting pain (e.g., persistent pain in the absence of an external stimulus). In some embodiments, the post-operative pain comprises mechanically induced pain or resting pain. In other embodiments, the post-operative pain comprises resting pain. Pain may be primary pain (e.g., caused directly by the pain-causing activity) or secondary pain (e.g., pain associated with, but not directly caused by, the pain-causing activity).

Accordingly, in one aspect, the present invention provides a method of treating post-operative pain in a patient, the method comprising: administering an effective amount of an emulsion formulation of an anesthetic active agent. In some embodiments, the post-operative pain comprises one or more of the following: allodynia, hyperalgesia, heat-induced pain, mechanically-induced pain or resting pain. For example, post-operative pain may include mechanically induced pain and/or resting pain. In some cases, post-operative pain includes resting pain. "treating" or "treating" means: at least inhibiting or ameliorating the symptoms associated with a condition afflicting a patient, where inhibiting and ameliorating is used broadly, refers to a reduction in the magnitude of a parameter (e.g., symptom) associated with the condition being treated (e.g., pain). Thus, treatment also includes conditions in which symptoms are completely suppressed, e.g., prevented from occurring or discontinued, e.g., terminated, such that the patient no longer experiences symptoms. Thus, treatment includes prevention and control of symptoms. In certain embodiments, allodynia is inhibited, ameliorated and/or prevented, and in some embodiments, hyperalgesia is inhibited, ameliorated and/or prevented. In some cases, the pain is chronic pain. In other cases, the pain is at or about, and/or near, one or more sites of an external injury, wound, or incision.

Other aspects of the present methods include methods of ameliorating and/or preventing the development or progression of post-operative pain by administering the present emulsion formulations. In certain embodiments, the present emulsion formulations may be administered prior to an activity (e.g., surgery) that may result in external injury, or incision. For example, the present emulsion formulation may be administered 30 minutes, 1 hour, 2 hours, 5 hours, 10 hours, 15 hours, 24 hours, or longer (e.g., 1 day, several days, or even 1 week, 2 weeks, 3 weeks, or longer) prior to an activity that may cause external injury, or incision (e.g., prior to surgery). In other embodiments, the present emulsion formulations may be administered during and/or after surgery or activity resulting in external injury, or incision. In some instances, the present emulsion formulations are administered 1 hour, 2 hours, 3 hours, 4 hours, 6 hours, 8 hours, 12 hours, 24 hours, 30 hours, 36 hours, or more after surgery or activity that results in external injury, or incision.

In practicing the present methods, the emulsion formulations disclosed herein can be administered parenterally to a patient. By "parenteral administration" is meant administration by a route other than the digestive tract, using a regimen that delivers an amount of the emulsion formulation to a patient (e.g., a patient suffering from post-pain). Examples of parenteral administration include, but are not limited to: intramuscular injection, intravenous injection, transdermal absorption, inhalation, and the like. In certain embodiments, parenteral administration uses an injection delivery device for injection. The amount of emulsion formulation administered to a patient may vary depending on a number of factors, e.g., the patient's characteristics, previous opiate treatments, the nature of the pain, etc. In certain embodiments, the dose of active agent administered per administration ranges from 10 to 250 μ g/dose, for example from 10 to 150 μ g/dose, including from 25 to 100 μ g/dose. For the present emulsion formulation, dosage guidelines for emulsion formulations that have been developed and followed by those skilled in the art may be used.

Further aspects of the method include methods of increasing pain threshold. As used herein, "increasing the pain threshold" means: pain associated with surgery, incision, injury, or injury is reduced, and/or minimized (including reducing, attenuating, and/or minimizing the subjective perception of pain). In yet another aspect, the method provides enhanced surgical recovery, as well as enhanced recovery of wounds, traumatic injuries and/or incisions.

It should be understood that while treatment or prevention of post-operative pain is generally indicated herein, the present emulsion formulations may be administered prior to an activity of external injury (e.g., collision), trauma, or increased risk of injury. As will be appreciated by those skilled in the art, activities of increased risk of external injury, trauma, or injury include dangerous occupational, combat, and/or athletic activities.

In certain embodiments, the method comprises a diagnostic step. The present method may be used to diagnose an individual using any convenient protocol. In addition, prior to practicing the subject methods, individuals may be known to be in need of the subject methods, e.g., they have a targeted disease symptom, or have been determined to be at risk for the targeted disease symptom.

The diagnosis or assessment of pain is well established in the art. The evaluation may be based on objective measures, such as observation of behavior, e.g. response to stimuli, facial expressions, etc. The evaluation may also be based on subjective measures, e.g. pain characterization of patients using various pain classes. See, e.g., Katz et al, surg, clin, north Am, (1999)79 (2): 231-52; caraceni et al, j.pain Symptom Manage (2002)23 (3): 239-55.

Pain relief is also characterized by the time course of relief. Accordingly, in some embodiments, pain reduction is observed subjectively or objectively after 1, 2, or several hours (in some embodiments, peaking at about 12-18 hours). In other embodiments, pain reduction is observed subjectively or objectively 24, 36, 48, 60, 72 or more hours after surgery (or activity associated with injury or injury).

Preparation method

The present emulsion formulations may be prepared using any convenient emulsification protocol. In certain embodiments, the method of making comprises: the active agent, water and oil are mixed and the mixture is emulsified. For example, an injection solvent (e.g., WFI) may be added to a homogeneous mixture of suitable oils. Initially, the mixture may be approximately emulsified. For example, for the purpose of substantial emulsification, a homogenizing mixer (Mizuho Industrial co., Ltd.) or a highly flexible disperser (SMT) may be used. After the mixture is roughly emulsified, the mixture may be finely emulsified, for example, using a high-pressure emulsifying machine. For fine emulsification, high pressure homogenizers such as Gaulin homogenizers (APV-SMT) and Microfluidics (Microfluidics, Newton, Mass.) may be used. In addition, for fine emulsification, the emulsion preparation may be mechanically treated with emulsification more than once, for example, 2 to 50 times, for example, 5 to 20 times, at a pressure of 500 to 850kg/cm²The range of (1). The preparation process can be carried out at room temperature or at a temperature lower than room temperature. In certain embodiments, the method of making comprises flushing the emulsification machine with nitrogen.

Practicality of use

The present emulsion formulations and methods can be used in a variety of applications, including the prevention or treatment of post-operative pain. Accordingly, the present emulsion formulations and methods are useful for treating, delaying the progression of, and/or preventing post-operative pain in patients, including all mammals (human and non-human), including carnivores (e.g., dogs and cats), rodentia (e.g., mice, guinea pigs, and rats), lagomorpha (e.g., rabbits) and primates (e.g., humans, chimpanzees, and monkeys). In certain embodiments, the subject (e.g., patient) is a human. In addition, the present emulsion formulations and methods may be used for individuals with tissue incision wounds, whether cut, prick, or lacerate, whether internal or external. Such incision wounds may arise accidentally (as with traumatic wounds), or intentionally (as with surgical wounds).

Medicament box

The invention also provides kits that may find use in practicing the subject methods, as described above. For example, kits for practicing the present methods may include some of the emulsion formulations (in unit dosage form, e.g., in ampoules, or in multi-dose form). Thus, in certain embodiments, the kit may comprise one or more unit doses (e.g., ampoules) of the emulsion formulation. The term "unit dose" as used herein refers to physically discrete units suitable as unitary dosages for human and animal patients, each unit containing a predetermined quantity of the subject emulsion formulation (calculated in an amount sufficient to produce the desired effect). The number of unit doses of the present emulsion formulation depends on various factors, such as the particular active agent used, the effect to be obtained, and the pharmaceutical effect associated with the active agent in the formulation. In other embodiments, the kit may comprise a single multi-dose amount of the emulsion formulation.

In addition to the components described above, the kit may further include instructions for practicing the method. These instructions may be present in the present kits in various forms, one or more of which may be present in the kit. One form in which these instructions may be present is information printed on a suitable medium or substrate, for example, one or more sheets of paper on which the information is printed (in the packaging of the kit, in the form of a package insert, etc.). The instructions may reside in a computer readable medium, such as a floppy disk, a CD, a DVD, etc., on which information is recorded. The instructions may be presented at a website that is accessible via the internet so that the information may be obtained at a remote location. Other convenient means are possible and may be included in the kit.

The following examples are put forth so as to provide those of ordinary skill in the art with a complete disclosure and description of how to make and use the present invention, and are not intended to limit the scope of what the inventors regard as their invention nor are they intended to represent that the experiments below are all or the only experiments performed. Although efforts have been made to ensure accuracy with respect to numbers used (e.g., amounts, temperature, etc.), some experimental errors and deviations should be accounted for. Unless otherwise indicated, parts are parts by weight, molecular weight is weight average molecular weight, temperature is in degrees Celsius, and pressure is at or near atmospheric.

Experiment of

I. Fentanyl emulsion formulations and preparation

A. Preparation

(emulsion formulation, 250ml)

Table 1: components of the oil phase

	Emulsion A
		Soybean oil	25g
Refined yolk phospholipid	4.5g
		Oleic acid	0.6g

Table 2: composition of the aqueous phase (Glycerol solution)

	Emulsion A
		Glycerol	5.52g
Purified water	200ml

B. Process for preparing fentanyl emulsion A

The components of the oil phase were added to a beaker and heated to 60 ℃ while stirring (7,000rpm) to dissolve the components.

25mg of fentanyl was added, and the mixture was stirred. (the process takes approximately 10 minutes.)

50ml of a glycerol solution was added dropwise to the mixture, and stirred at 10,000rpm for 10 minutes.

The solution was transferred to a separable flask. The remaining glycerol solution was added while stirring in an emulsifier at 12,000rpm for 30 minutes.

Purified water was added to adjust the total volume of the emulsion to 250 ml.

The emulsion was emulsified 20 times with a high-pressure emulsifier LAB-1000(APV, Denmark) while the mixture was cooled at a pressure of 650 Bar.

If the pH of the emulsion is between 6 and 7, no pH adjustment is necessary. If the pH is not between 6 and 7, the pH is adjusted with hydrochloric acid solution or sodium hydroxide solution. In this experiment, no pH adjustment was used, as the pH was between 6.3 and 6.7.

After high-pressure emulsification, the emulsion was filtered (pore size of 0.4 μm), added to an ampoule and N was added simultaneously₂A gas.

The ampoules were sterilized by autoclaving (121 ℃, 10 minutes).

After sterilization, the ampoules were cooled and stored.

The mean particle size of the sterilised samples was determined using a light-dependent method using a Zetasizer 3000HS (Malvern Instruments, Worcestershire, UK).

Postoperative pain testing of fentanyl formulations

In mice, Fentanest was examined^TMAnd analgesic effect of fentanyl emulsion a on postoperative pain.

A. Feedstock and method

Animal(s) production

Male C57BL/6Cr mice were used.

Test formulations

1)Fentanest^TMInjection (fentanyl citrate, 0.1mg/2ml fentanyl)

2) Fentanyl emulsion a (0.1mg/ml fentanyl; average particle size 181nm)

Administration of drugs

Each formulation was prepared with the appropriate solvent. Each preparation was injected intravenously in an amount of 0.05ml/10g of body weight.

Preparation of postoperative pain model

Under pentobarbital (50mg/kg, i.p.) anesthesia, an incision of approximately 1cm was made from the heel towards the tip of the toe. Another 1cm incision was made with a stainless steel scalpel on the skin, membrane and muscle while avoiding the vessels and nerves under the skin. The two incision areas were sutured twice with No. 7 sutures, and the wound was disinfected with Isodine (Meiji Seika Kaisha ltd., Tokyo, Japan).

Postoperative pain test

The reaction of the hind legs to mechanical stimulation is used as a marker for post-operative pain. Postoperative pain was measured with two hind legs (i.e., ipsilateral and contralateral to the wound area). Von Frey filaments (North Coast Medical, San Jose, CA, USA) with an intensity of 1.6mN were used for the determination. After Von Frey filaments were applied to the plantar portion of the hind legs, the reaction was divided into three stages (0 ═ no reaction; 1 ═ lifting of hind legs; 2 ═ shaking of hind legs and licking of hind legs). Stimulation was given with Von Frey filaments while avoiding the wound area. This procedure was repeated six times and the average was taken as the pain response score.

Performing postoperative pain test by blind method; the experimenters know that all formulations contain fentanyl, but they do not know the differences in the characteristics of these formulations.

B result

SUMMARY

Dose-dependent inhibition of postoperative pain (peaking at 15 minutes after dosing) was observed, and the effect was observed for approximately 60 minutes (figures 1 and 2). In Fentanest^TMIn both groups, injection and fentanyl emulsion A (16. mu.g/kg and 48. mu.g/kg dose), significant inhibition of post-operative pain was observed (FIGS. 1 and 2).

Comparison of inhibitory Effect following fentanyl administration or formulation

After administration, in Fentanest^TMNo difference in inhibitory effect was observed between the injection and fentanyl emulsion a (two-way RM ANOVA) (table 4). No significant difference in area under the curve was observed (one-way ANOVA) 60 minutes after dosing (figure 3).

Table 4: two-way RM ANOVA

	P	F
			Therapy (primary effect)	2.141	0.127
Treatment x time (interaction)	0.447	0.9737

	p＜0.05
		Fentanyl citrate injection contrast emulsion A	Is not provided with

15 minutes after dosing, comparative Fentanest^TMThe inhibitory effect between the injection and the fentanyl emulsion a,no significant difference was observed (figures 1 and 2). However, a substantial inhibitory effect of the fentanyl emulsion a formulation was observed (Bonferroni t test) compared to the reference standard (fig. 2).

Comparison of Fentanest 30 minutes after dosing^TMNo significant difference was observed in the inhibitory effect between the injection and fentanyl emulsion a (figures 1 and 2). However, a long-lasting effect of the fentanyl emulsion a formulation was observed (Bonferroni t test) compared to the reference standard (fig. 2).

Evaluation of CNS-mediated adverse effects of fentanyl emulsion formulations

A. Strobel tail lift reaction

When mice were given opioids, their tails stood upright and tended to be rostral (Rostrally). This response is called the Stroubral tail response and may be mediated by the central nervous system, particularly the spinal cord. Fentanest in mice tested at doses of 30 and 50. mu.g/ml^TMCausing a strouhal tail reaction (table 5). In comparison, the incidence of the Stroubott tail reaction decreased after injection of the fentanyl emulsion A at doses of 30 and 50 μ g/ml (Table 5). Similar results were observed in terms of duration of the tail reaction in the strouhal process (fig. 4).

Table 5: stroup lifting reaction caused by Fengdani preparation

Concentration (μ g/ml)	Observed mice	Responder (%) FentanestTM	Responder (%) emulsion a
				0	6	0(0)	0(0)
10	6	3(50)	2(33)
				30	6	5(83)	2(33)
50	6	6(100)	4(80)

B. Effect of exercise activity

When mice are given high doses of opioids, motor activity is increased by the effect of opioids on the central nervous system. This increase in athletic activity may be observed by an increase in unidirectional athletic activity (i.e., circling behavior). Fentanest at doses of 30 and 50. mu.g/ml^TMLocomotor activity could be significantly increased, but there was no significant effect at a dose of 10 μ g/ml (fig. 5). With Fentanest^TMIn contrast, the increase ratio of motor activity decreased after the administration of fentanyl emulsion a (fig. 6). Fentanest is mixed^TMThe effect of fentanyl emulsion a was compared as shown in figure 7.

C. Discussion of the related Art

Since the strophant tail reaction and increased locomotor activity can be mediated primarily by the central nervous system, fentanyl formulations are believed to have central nervous system mediated side effects from this result. With Fentanest^TMIn comparison, fentanyl emulsion A had a greater proportion of CNS mediated side effects than Fentanest^TMThe resulting side effects are less severe. For fentanyl emulsion a, the incidence of the strophant tail reaction and the duration of the wraparound behavior was significantly less in mice.

Although the foregoing invention has been described in some detail by way of illustration and example for purposes of clarity of understanding, it will be readily apparent to those of ordinary skill in the art in light of the teachings of this invention that certain changes and modifications may be made thereto without departing from the spirit or scope of the appended claims.

Accordingly, the foregoing merely illustrates the principles of the invention. It will thus be appreciated that those skilled in the art will be able to devise various arrangements which, although not explicitly described or shown herein, embody the principles of the invention and are included within its spirit and scope. Furthermore, all examples and conditional language recited herein are principally intended expressly to aid the reader in understanding the principles of the invention and the concepts contributed by the inventor to furthering the art, and are to be construed as being without limitation to such specifically recited examples and conditions. Moreover, all statements herein reciting principles, aspects, and embodiments of the invention, as well as specific examples thereof, encompass both structural and functional equivalents thereof. Additionally, such equivalents include both currently known equivalents as well as equivalents developed in the future, i.e., any elements developed that perform the same function, regardless of structure. Accordingly, the scope of the present invention is not limited to the exemplary embodiments shown and described herein. Rather, the scope and spirit of the invention is embodied by the appended claims.

Claims (30)

1. A method of treating post-operative pain in a patient, the method comprising:

administering to the patient an amount of a narcotic emulsion formulation effective to treat post-operative pain in the patient.

2. The method according to claim 1, wherein said narcotic emulsion formulation includes an opioid.

3. The method according to claim 2 wherein said opioid is fentanyl.

4. The method according to claim 3, wherein the anesthetic emulsion comprises:

fentanyl;

an oil;

water; and

a surfactant.

5. The method according to claim 4 wherein said fentanyl is present in an amount in the range of 0.1 to 10 mg/ml.

6. A method according to claim 5 wherein the oil is present in an amount in the range 0.05 to 200 mg/ml.

7. The method according to claim 4, wherein the surfactant is selected from egg yolk phospholipids or soybean phospholipids.

8. The method according to claim 4, wherein the emulsion formulation further comprises an emulsification enhancer.

9. The method according to claim 8, wherein said emulsification enhancer is oleic acid.

10. The method according to claim 4, wherein the emulsion formulation further comprises glycerol or propylene glycol.

11. A process according to claim 4, with Fentanest^TMThe emulsion formulations showed similar effects compared to fentanyl citrate injection formulations.

12. A process according to claim 4, with Fentanest^TMThe fentanyl citrate injectable formulation wherein the emulsion formulation exhibits reduced central nervous system mediated side effects as compared to the formulation.

13. An emulsion formulation comprising:

fentanyl;

an oil;

water; and

a surfactant.

14. An emulsion formulation according to claim 13 wherein said fentanyl is present in an amount in the range of 0.1 to 10 mg/ml.

15. The emulsion formulation according to claim 13, wherein said oil is present in an amount ranging from 0.05 to 200 mg/ml.

16. The emulsion formulation according to claim 13, wherein said surfactant is selected from egg yolk phospholipids or soybean phospholipids.

17. The emulsion formulation according to claim 13, wherein said emulsion formulation further comprises an emulsification enhancer.

18. The emulsion formulation according to claim 17, wherein said emulsification enhancer is oleic acid.

19. The emulsion formulation according to claim 13, wherein said emulsion formulation further comprises glycerol.

20. An emulsion formulation according to claim 13, in combination with Fentanest^TMThe emulsion formulations showed similar effects compared to fentanyl citrate injection formulations.

21. An emulsion formulation according to claim 13, in combination with Fentanest^TMThe fentanyl citrate injectable formulation wherein the emulsion formulation exhibits reduced central nervous system mediated side effects as compared to the formulation.

22. A kit comprising an emulsion formulation, wherein the emulsion formulation comprises:

fentanyl;

an oil;

water; and

a surfactant.

23. The kit according to claim 22, wherein said fentanyl is present in an amount ranging from 0.1 to 10 mg/ml.

24. Kit according to claim 22, wherein the oil is present in an amount ranging from 0.05 to 200 mg/ml.

25. Kit according to claim 22, wherein the surfactant is selected from egg yolk phospholipids or soy phospholipids.

26. The kit according to claim 22, wherein said emulsion formulation further comprises an emulsification enhancer.

27. The kit according to claim 26 wherein said emulsification enhancer is oleic acid.

28. The kit according to claim 22, wherein said emulsion formulation further comprises glycerol.

29. The kit according to claim 22, in combination with Fentanest^TMThe emulsion formulations showed similar effects compared to fentanyl citrate injection formulations.

30. The kit according to claim 22, in combination with Fentanest^TMThe fentanyl citrate injectable formulation wherein the emulsion formulation exhibits reduced central nervous system mediated side effects as compared to the formulation.