WO2021211575A1

WO2021211575A1 - Compositions comprising propofol, ketamine, and non-opioid analgesic, and methods of use

Info

Publication number: WO2021211575A1
Application number: PCT/US2021/027070
Authority: WO
Inventors: Zhuang T. FANG
Original assignee: The Regents Of The Univefisity Of California
Priority date: 2020-04-13
Filing date: 2021-04-13
Publication date: 2021-10-21

Abstract

The present invention relates to pharmaceutical compositions comprising propofol, ketamine, and a non-opioid analgesic in a ratio of 6:2:2 with a superior therapeutic profile as compared to opioid-based mixtures of the same ratio. The present invention also relates to methods for treating a subject in need of sedation with the pharmaceutical composition of the present invention, comprising administering the composition in a dosage that is adjusted based on the weight and age of the subject.

Description

COMPOSITIONS COMPRISING PROPOFOL, KETAMINE, AND NON-OPIOID ANALGESIC, AND METHODS OF USE

CROSS-REFERENCE TO RELATED APPLICATIONS This application claims priority to U.S. Provisional Patent Application No. 63/009,047 filed on April 13, 2020, the contents of which are incorporated by reference herein in its entirety.

BACKGROUND OF THE INVENTION Monitored Anesthesia Care (MAC), commonly called intravenous sedation, is an anesthesia practice broadly used in diagnostic and surgical procedures. In general, MAC is quite safe, however, patient injury can occur during MAC, which mainly caused by the side effects of sedatives leading to eye injury, hypoxia, respiratory failure, hemodynamic changes, permanent brain damage, or death. So far, there is no standard way to perform MAC other than the general guidelines developed by ASA (American Society of Anesthesiologists). Furthermore, there is no standard dose of medications used in MAC based on patient’s age and weight or underlying medical conditions. Most anesthesia practitioners give small doses of medication(s) over time, a technique called “titrate to effect” according to patient’s response to the medication to reach target level of sedation. Therefore, the current practice is time consuming and not reliably predictable in total dose and time spent for “titration.” In addition, most anesthesia providers use “loss of consciousness” (deep sedation) as the end point of sedation, which may increase the risk of oversedation leading to apnea, respiratory failure, and hypoxic brain injury.

Opioids are a very important component of MAC because of their profound analgesic effect. Opioids have been widely used during surgery to prevent the patient from feeling pain and to prevent the associated adrenal hormone(s) response to pain. Opioids are also used to reduce the dose of general anesthetics required during general anesthesia since a large dose of anesthetics can adversely affect a patient’s heart rate, blood pressure, and blood supply to the brain and other vital organs. However, the current opioid epidemic is a great threat to the health of the general population nationwide and many patients die from addiction to opioids and opioid overdose every year. Approximately 50,000 Americans died from opioid overdose in 2018 according to CDC. Although the causes of the opioid epidemic are multifactorial and whether the intraoperative use of opioids is playing significant role in the addiction of the opioids has been speculated, nonetheless, it would be preferable to avoid using opioids during surgery. It is possible to avoid opioids during general anesthesia since the painless stage can be achieved by the use of volatile agents, such as sevoflurane, dexflurane, and others. However, avoiding opioids is more difficult for MAC since volatile anesthetics are not used. Opioids have been heavily relied on during MAC for their analgesic effect (as well as general anesthesia for pain control after surgery).

Thus, there is an urgent need for a technique for MAC in anesthesia practice which contains no opioids while still providing an adequate level of sedation in a short time with a profound analgesic effect and minimum risk of complications. The present invention addresses this unmet need.

SUMMARY OF THE INVENTION

In one aspect, the present invention relates to a pharmaceutical composition comprising a solution of propofol, ketamine, and a non-opioid analgesic wherein the concentration of propofol is 1 mg/mL - 10 mg/mL, the concentration of ketamine is 1 mg/mL - 10 mg/mL, and the concentration of non-opioid analgesic is 0.1 mg/mL - 2 mg/mL. In one embodiment, the non-opioid analgesic is selected from the group consisting of: ketorolac, clonidine, lidocaine, magnesium sulfate, methylprednisolone, acetaminophen, aminobenzoate potassium, aminobenzoate sodium, phenacetin, etomidate, ibuprofen, fenoprofen, aspirin, indomethacin, naproxen, oxyphenbutazone, phenylbutazone, allopurinol, cholchicine, carbamazepine, methyl sergide, methotrimeprazine, propoxyphene, probenecid, salsalate, sulfinpyrazone, antipyrine, ethoheptazine, amodiaquine, diflunisal, dihydroergotamine, ergotamine, meclofenamate, mefenamic acid, piroxican, sulindac, tolmetin, benoxaprofen, benzydamine, bicifadine decibuprofen, flurbiprofen, ibufenac, indoprofen, ketoprofen, naproxen, naproxol, salicylamide, sodium salicylate, salicylate potassium, and combinations thereof. In one embodiment, the non-opioid analgesic is etomidate. In one embodiment, the concentration of propofol is 5 mg/mL - 7 mg/mL, the concentration of ketamine is 1 mg/mL - 3 mg/mL, and the concentration of non-opioid analgesic is 0.1 mg/mL - 2 mg/mL. In one embodiment, the solution comprises a sterile medium selected from the group consisting of water, deionized water, distilled water, sterilized water, saline solution, dextrose in water solution, Ringer’s lactate solution, soybean oil, egg lecithin, propylene glycol, disodium, and combinations thereof. In one embodiment, the volume ratio of propofol: ketamine: non-opioid analgesic is 6:2:2.

In another aspect, the present invention relates to a method of providing sedation to a subject in need thereof, the method comprising the step of administering to the subject a pharmaceutical composition comprising a solution of propofol, ketamine, and a non-opioid analgesic wherein the concentration of propofol is 1 mg/mL - 10 mg/mL, the concentration of ketamine is 1 mg/mL - 10 mg/mL, and the concentration of non-opioid analgesic is 0.1 mg/mL - 2 mg/mL; and wherein the composition is administered in a dosage based on the weight and age of the subject.

In one embodiment, when the subject is younger than 60 years of age, the dosage is 6 mg propofol per 10 kg body weight, 2 mg ketamine per 10 kg body weight, and 0.4 mg non-opioid analgesic per 10 kg body weight; when the subject is between 60 and 70 years of age, the dosage is 4.8 mg propofol per 10 kg, 1.6 mg ketamine per 10 kg, and 0.32 mg non-opioid analgesic per 10 kg; and when the subject is over 70 years of age, the dosage is 3.6 mg propofol per 10 kg, 1.2 mg ketamine per 10 kg, and 0.24 mg non-opioid analgesic per 10 kg. In one embodiment, when the patient is obese, the dosage is adjusted using the formula: Adjusted Weight for Dosing (AWFD) = Ideal Body Weight (IBW) + 30% (actual weight - IBW). In one embodiment, when the subject is younger than 40 years of age, the dosage is 7.2 mg of propofol per 10 kg body weight, 2.4 mg of ketamine per 10 kg body weight, and 0.48 mg of etomidate per 10 kg body weight; and when the subject is older than 85 years of age, the dosage is 3 mg of propofol per 10 kg body weight, 1 mg of ketamine per 10 kg body weight, and 0.2 mg of etomidate per 10 kg body weight. In one embodiment, when the patient is obese, the dosage is adjusted using the formula: Adjusted Weight for Dosing (AWFD) = Ideal Body Weight (IBW) + 30% (actual weight - IBW). In one embodiment, the step of administering a pharmaceutical composition further comprises the step of mixing a solution of propofol with a solution of ketamine and a solution of non-opioid analgesic to form a mixture. In one embodiment, the non opioid analgesic selected from the group consisting of: ketorolac, clonidine, lidocaine, magnesium sulfate, methylprednisolone, acetaminophen, aminobenzoate potassium, aminobenzoate sodium, phenacetin, etomidate, ibuprofen, fenoprofen, aspirin, indomethacin, naproxen, oxyphenbutazone, phenylbutazone, allopurinol, cholchicine, carbamazepine, methyl sergide, methotrimeprazine, propoxyphene, probenecid, salsalate, sulfinpyrazone, antipyrine, ethoheptazine, amodiaquine, diflunisal, dihydroergotamine, ergotamine, meclofenamate, mefenamic acid, piroxican, sulindac, tolmetin, benoxaprofen, benzydamine, bicifadine decibuprofen, flurbiprofen, ibufenac, indoprofen, ketoprofen, naproxen, naproxol, salicylamide, sodium salicylate, salicylate potassium, and combinations thereof. In one embodiment, the non-opioid analgesic is etomidate. In one embodiment, the step of administering a pharmaceutical composition further comprises the step of administering a solution of propofol when a maximum dosage of ketamine or non-opioid analgesic is reached. In one embodiment, the volume ratio of propofol: ketamine: non-opioid analgesic is 6:2:2

DETAILED DESCRIPTION

It is to be understood that the descriptions of the present invention have been simplified to illustrate elements that are relevant for a clear understanding of the present invention, while eliminating, for the purpose of clarity, many other elements used in pharmaceutical compositions and methods. Those of ordinary skill in the art may recognize that other elements and/or steps are desirable and/or required in implementing the present invention. However, because such elements and steps are well known in the art, and because they do not facilitate a better understanding of the present invention, a discussion of such elements and steps is not provided herein. The disclosure herein is directed to all such variations and modifications to such elements and methods known to those skilled in the art.

As used herein, each of the following terms has the meaning associated with it in this section. Unless defined otherwise, all technical and scientific terms used herein generally have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs.

The articles “a” and “an” are used herein to refer to one or to more than one (i.e., to at least one) of the grammatical object of the article. By way of example, “an element” means one element or more than one element. “About” as used herein when referring to a measurable value such as an amount, a temporal duration, and the like, is meant to encompass variations of ±20%, ±10%, ±5%, ±1%, or ±0.1% from the specified value, as such variations are appropriate to perform the disclosed methods. The term “abnormal” when used in the context of organisms, tissues, cells or components thereof, refers to those organisms, tissues, cells or components thereof that differ in at least one observable or detectable characteristic (e.g., age, treatment, time of day, etc.) from those organisms, tissues, cells or components thereof that display the “normal” (expected) respective characteristic. Characteristics which are normal or expected for one cell or tissue type, might be abnormal for a different cell or tissue type.

A “disease” is a state of health of an animal wherein the animal cannot maintain homeostasis, and wherein if the disease is not ameliorated then the animal’s health continues to deteriorate.

In contrast, a “disorder” in an animal is a state of health in which the animal is able to maintain homeostasis, but in which the animal’s state of health is less favorable than it would be in the absence of the disorder. Left untreated, a disorder does not necessarily cause a further decrease in the animal’s state of health.

A disease or disorder is “alleviated” if the severity of a sign or symptom of the disease or disorder, the frequency with which such a sign or symptom is experienced by a patient, or both, is reduced.

An “effective amount” or “therapeutically effective amount” of a compound is that amount of a compound which is sufficient to provide a beneficial effect to the subject to which the compound is administered.

The terms “patient,” “subject,” “individual,” and the like are used interchangeably herein, and refer to any animal, or cells thereof whether in vitro or in vivo, amenable to the methods described herein. In certain non-limiting embodiments, the patient, subject or individual is a human.

A “therapeutic” treatment is a treatment administered to a subject who exhibits signs or symptoms of a disease or disorder, for the purpose of diminishing or eliminating those signs or symptoms.

As used herein, “treating a disease or disorder” means reducing the severity and/or frequency with which a sign or symptom of the disease or disorder is experienced by a patient.

As used herein, the term “pharmaceutical composition” refers to a mixture of at least one compound useful within the invention with a pharmaceutically acceptable carrier. The pharmaceutical composition facilitates administration of the compound to a patient or subject. Multiple techniques of administering a compound exist in the art including, but not limited to, intravenous, oral, aerosol, parenteral, ophthalmic, pulmonary and topical administration.

As used herein, the term “pharmaceutically acceptable” refers to a material, such as a carrier or diluent, which does not abrogate the biological activity or properties of the compound, and is relatively non-toxic, i.e., the material may be administered to an individual without causing an undesirable biological effect or interacting in a deleterious manner with any of the components of the composition in which it is contained.

As used herein, the language “pharmaceutically acceptable salt” refers to a salt of the administered compound prepared from pharmaceutically acceptable non-toxic acids, including inorganic acids, organic acids, solvates, hydrates, or clathrates thereof. Examples of such inorganic acids are hydrochloric, hydrobromic, hydroiodic, nitric, sulfuric, phosphoric, acetic, hexafluorophosphoric, citric, gluconic, benzoic, propionic, butyric, sulfosalicylic, maleic, lauric, malic, fumaric, succinic, tartaric, amsonic, pamoic, p-tolunenesulfonic, and mesylic. Appropriate organic acids may be selected, for example, from aliphatic, aromatic, carboxylic and sulfonic classes of organic acids, examples of which are formic, acetic, propionic, succinic, camphorsulfonic, citric, fumaric, gluconic, isethionic, lactic, malic, mucic, tartaric, para-toluenesulfonic, glycolic, glucuronic, maleic, furoic, glutamic, benzoic, anthranilic, salicylic, phenylacetic, mandelic, embonic (pamoic), methanesulfonic, ethanesulfonic, pantothenic, benzenesulfonic (besylate), stearic, sulfanilic, alginic, galacturonic, and the like. Furthermore, pharmaceutically acceptable salts include, by way of non-limiting example, alkaline earth metal salts (e.g., calcium or magnesium), alkali metal salts (e.g., sodium-dependent or potassium), and ammonium salts.

As used herein, the term “pharmaceutically acceptable carrier” means a pharmaceutically acceptable material, composition or carrier, such as a liquid or solid filler, stabilizer, dispersing agent, suspending agent, diluent, excipient, thickening agent, solvent or encapsulating material, involved in carrying or transporting a compound useful within the invention within or to the patient such that it may perform its intended function. Typically, such constructs are carried or transported from one organ, or portion of the body, to another organ, or portion of the body. Each carrier must be “acceptable” in the sense of being compatible with the other ingredients of the formulation, including the compound useful within the invention, and not injurious to the patient. Some examples of materials that may serve as pharmaceutically acceptable carriers include: sugars, such as lactose, glucose and sucrose; starches, such as com starch and potato starch; cellulose, and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; powdered tragacanth; malt; gelatin; talc; excipients, such as cocoa butter and suppository waxes; oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, com oil and soybean oil; glycols, such as propylene glycol; polyols, such as glycerin, sorbitol, mannitol and polyethylene glycol; esters, such as ethyl oleate and ethyl laurate; agar; buffering agents, such as magnesium hydroxide and aluminum hydroxide; surface active agents; alginic acid; pyrogen-free water; isotonic saline; Ringer’s solution; ethyl alcohol; phosphate buffer solutions; and other non-toxic compatible substances employed in pharmaceutical formulations. As used herein, “pharmaceutically acceptable carrier” also includes any and all coatings, antibacterial and antifungal agents, and absorption delaying agents, and the like that are compatible with the activity of the compound useful within the invention, and are physiologically acceptable to the patient. Supplementary active compounds may also be incorporated into the compositions. The “pharmaceutically acceptable carrier” may further include a pharmaceutically acceptable salt of the compound useful within the invention.

Other additional ingredients that may be included in the pharmaceutical compositions used in the practice of the invention are known in the art and described, for example in Remington's Pharmaceutical Sciences (Genaro, Ed., Mack Publishing Co., 1985, Easton, PA), which is incorporated herein by reference.

As used herein, the term “potency” refers to the dose needed to produce half the maximal response (ED50).

As used herein, the term “efficacy” refers to the maximal effect (Emax) achieved within an assay.

Ranges: throughout this disclosure, various aspects of the invention can be presented in a range format. It should be understood that the description in range format is merely for convenience and brevity and should not be construed as an inflexible limitation on the scope of the invention. Accordingly, the description of a range should be considered to have specifically disclosed all the possible subranges as well as individual numerical values within that range. For example, description of a range such as from 1 to 6 should be considered to have specifically disclosed subranges such as from 1 to 3, from 1 to 4, from 1 to 5, from 2 to 4, from 2 to 6, from 3 to 6 etc., as well as individual numbers within that range, for example, 1, 2, 2.7, 3, 4, 5, 5.3, and 6. This applies regardless of the breadth of the range.

Description

The present invention is based in part on the unexpected result that a non-opioid mixture comprising propofol, ketamine and a non-opioid analgesic in a volume ratio of 6:2:2 has a superior therapeutic profile (e.g., shorter mean time to readiness, no reduction in MAP, minimal oxygen desaturation, etc.) as compared to opioid-based mixtures of the same ratio.

Pharmaceutical composition

The present invention relates in part to a pharmaceutical composition comprising propofol and ketamine. Such a pharmaceutical composition may consist of at least propofol, or a salt thereof, and ketamine, or a salt form thereof, in a form suitable for administration to a subject, or the pharmaceutical composition may comprise at least propofol, or a salt thereof, ketamine, or a salt form thereof, and one or more pharmaceutically acceptable carriers, one or more additional ingredients, or some combination of these. Propofol and ketamine may be present in the pharmaceutical composition in the form of a physiologically acceptable salt, such as in combination with a physiologically acceptable cation or anion, as is well known in the art.

In one embodiment, the pharmaceutical composition comprises 10 mg to 100 mg of propofol. In one embodiment, the pharmaceutical composition comprises 20 mg to 90 mg of propofol. In one embodiment, the pharmaceutical composition comprises 30 mg to 80 mg of propofol. In one embodiment, the pharmaceutical composition comprises 40 mg to 70 mg of propofol. In one embodiment, the pharmaceutical composition comprises 50 mg to 65 mg of propofol. In one embodiment, the pharmaceutical composition comprises 55 mg to 65 mg of propofol.

In one embodiment, the pharmaceutical composition comprises 1 mg to 100 mg of ketamine. In one embodiment, the pharmaceutical composition comprises 1 mg to 90 mg of ketamine. In one embodiment, the pharmaceutical composition comprises 1 mg to 80 mg of ketamine. In one embodiment, the pharmaceutical composition comprises 1 mg to 70 mg of ketamine. In one embodiment, the pharmaceutical composition comprises 1 mg to 60 mg of ketamine. In one embodiment, the pharmaceutical composition comprises 1 mg to 50 mg of ketamine. In one embodiment, the pharmaceutical composition comprises 1 mg to 40 mg of ketamine. In one embodiment, the pharmaceutical composition comprises 1 mg to 30 mg of ketamine. In one embodiment, the pharmaceutical composition comprises 10 mg to 30 mg of ketamine. In one embodiment, the pharmaceutical composition comprises 15 mg to 25 mg of ketamine.

In one embodiment, the pharmaceutical composition comprises at least one non-opioid analgesic. The analgesic can be any non-opioid analgesic known to a person of skill in the art. Exemplary non-opioid analgesics include, but are not limited to, ketorolac, clonidine, lidocaine, magnesium sulfate, methylprednisolone, acetaminophen, aminobenzoate potassium, aminobenzoate sodium, phenacetin, etomidate, ibuprofen, fenoprofen, aspirin, indomethacin, naproxen, oxyphenbutazone, phenylbutazone, allopurinol, cholchicine, carbamazepine, methyl sergide, methotrimeprazine, propoxyphene, probenecid, salsalate, sulfinpyrazone, antipyrine, ethoheptazine, amodiaquine, diflunisal, dihydroergotamine, ergotamine, meclofenamate, mefenamic acid, piroxican, sulindac, tolmetin, benoxaprofen, benzydamine, bicifadine decibuprofen, flurbiprofen, ibufenac, indoprofen, dexmedetomidine, ketoprofen, naproxen, naproxol, salicylamide, sodium salicylate, salicylate potassium, and combinations thereof. In one embodiment, the pharmaceutical composition comprises 0.02 mg to 20 mg of non-opioid analgesic. In one embodiment, the pharmaceutical composition comprises 0.02 mg to 18 mg of analgesic. In one embodiment, the pharmaceutical composition comprises 0.02 mg to 16 mg of analgesic. In one embodiment, the pharmaceutical composition comprises 0.02 mg to 14 mg of analgesic. In one embodiment, the pharmaceutical composition comprises 0.02 mg to 12 mg of analgesic. In one embodiment, the pharmaceutical composition comprises 0.02 mg to 10 mg of analgesic. In one embodiment, the pharmaceutical composition comprises 0.02 mg to 8 mg of analgesic. In one embodiment, the pharmaceutical composition comprises 0.02 mg to 6 mg of analgesic. In one embodiment, the pharmaceutical composition comprises 2 mg to 6 mg of analgesic. In one embodiment, the pharmaceutical composition comprises 2 mg to 6 mg of etomidate.

In one embodiment, the pharmaceutical composition is a liquid solution. The liquid may be any liquid known by a person of skill in the art. Exemplary liquids include, but are not limited to, water, deionized water, distilled water, sterilized water, saline solution, dextrose in water solution, Ringer’s lactate solution, soybean oil, egg lecithin, propylene glycol, and combinations thereof. In one embodiment, the liquid pharmaceutical solution comprises propofol which has been dissolved/dispersed in a mixture of water, soybean oil, egg lecithin, and disodium. In one embodiment, the liquid pharmaceutical solution comprises ketamine which has been dissolved/dispersed in water. In one embodiment, the liquid pharmaceutical solution comprises etomidate which has been dissolved/dispersed in 35% v/v propylene glycol. In one embodiment, the milligram amounts disclosed elsewhere herein refer to the milligram amount of each of propofol, ketamine, and analgesic in a 10 mL liquid solution. In one embodiment, the amounts of each propofol, ketamine, and analgesic are doubled in a 20 mL liquid solution, tripled in a 30 mL liquid solution, and quadrupled in a 40 mL liquid solution.

In one embodiment, the concentration of propofol in the liquid solution is between 100 pg/mL and 100 mg/mL. In one embodiment, the concentration of propofol in the liquid solution is between 150 pg/mL and 90 mg/mL. In one embodiment, the concentration of propofol in the liquid solution is between 200 pg/mL and 80 mg/mL. In one embodiment, the concentration of propofol in the liquid solution is between 250 pg/mL and 70 mg/mL. In one embodiment, the concentration of propofol in the liquid solution is between 300 pg/mL and 60 mg/mL. In one embodiment, the concentration of propofol in the liquid solution is between 350 pg/mL and 50 mg/mL. In one embodiment, the concentration of propofol in the liquid solution is between 400 pg/mL and 40 mg/mL. In one embodiment, the concentration of propofol in the liquid solution is between 450 pg/mL and 30 mg/mL. In one embodiment, the concentration of propofol in the liquid solution is between 500 pg/mL and 20 mg/mL. In one embodiment, the concentration of propofol in the liquid solution is between 550 pg/mL and 20 mg/mL. In one embodiment, the concentration of propofol in the liquid solution is between 600 pg/mL and 20 mg/mL. In one embodiment, the concentration of propofol in the liquid solution is between 650 pg/mL and 20 mg/mL. In one embodiment, the concentration of propofol in the liquid solution is between 700 pg/mL and 20 mg/mL. In one embodiment, the concentration of propofol in the liquid solution is between 750 pg/mL and 20 mg/mL. In one embodiment, the concentration of propofol in the liquid solution is between 800 pg/mL and 20 mg/mL. In one embodiment, the concentration of propofol in the liquid solution is between 850 pg/mL and 20 mg/mL. In one embodiment, the concentration of propofol in the liquid solution is between 900 pg/mL and 20 mg/mL. In one embodiment, the concentration of propofol in the liquid solution is between 950 pg/mL and 20 mg/mL. In one embodiment, the concentration of propofol in the liquid solution is between 1 mg/mL and 20 mg/mL. In one embodiment, the concentration of propofol in the liquid solution is between 1 mg/mL and 15 mg/mL.

In one embodiment, the concentration of propofol in the liquid solution is between 5 mg/mL and 12 mg/mL. In one embodiment, the liquid solution comprises 6 mL of propofol at a concentration of 10 mg/mL.

In one embodiment, the concentration of ketamine in the liquid solution is between 100 pg/mL and 50 mg/mL. In one embodiment, the concentration of ketamine in the liquid solution is between 200 pg/mL and 50 mg/mL. In one embodiment, the concentration of ketamine in the liquid solution is between 300 pg/mL and 50 mg/mL. In one embodiment, the concentration of ketamine in the liquid solution is between 400 pg/mL and 50 mg/mL. In one embodiment, the concentration of ketamine in the liquid solution is between 500 pg/mL and 50 mg/mL. In one embodiment, the concentration of ketamine in the liquid solution is between 600 pg/mL and 50 mg/mL. In one embodiment, the concentration of ketamine in the liquid solution is between 700 pg/mL and 50 mg/mL. In one embodiment, the concentration of ketamine in the liquid solution is between 800 pg/mL and 50 mg/mL. In one embodiment, the concentration of ketamine in the liquid solution is between 900 pg/mL and 50 mg/mL. In one embodiment, the concentration of ketamine in the liquid solution is between 1 mg/mL and 50 mg/mL.

In one embodiment, the concentration of ketamine in the liquid solution is between 1 mg/mL and 40 mg/mL. In one embodiment, the concentration of ketamine in the liquid solution is between 1 mg/mL and 30 mg/mL. In one embodiment, the concentration of ketamine in the liquid solution is between 1 mg/mL and 20 mg/mL. In one embodiment, the concentration of ketamine in the liquid solution is between 1 mg/mL and 10 mg/mL. In one embodiment, the concentration of ketamine in the liquid solution is between 1 mg/mL and 5 mg/mL. In one embodiment, the liquid solution comprises 2 mL of ketamine at a concentration of 10 mg/mL.

In one embodiment, the concentration of non-opioid analgesic in the liquid solution is between 1 pg/mL and 100 mg/mL. In one embodiment, the concentration of analgesic in the liquid solution is between 1 pg/mL and 90 mg/mL. In one embodiment, the concentration of analgesic in the liquid solution is between 1 qg/mL and 80 mg/mL. In one embodiment, the concentration of analgesic in the liquid solution is between 1 qg/mL and 70 mg/mL. In one embodiment, the concentration of analgesic in the liquid solution is between 1 qg/mL and 60 mg/mL.

In one embodiment, the concentration of analgesic in the liquid solution is between 1 qg/mL and 50 mg/mL. In one embodiment, the concentration of analgesic in the liquid solution is between 1 qg/mL and 40 mg/mL. In one embodiment, the concentration of analgesic in the liquid solution is between 1 qg/mL and 30 mg/mL.

In one embodiment, the concentration of analgesic in the liquid solution is between 1 qg/mL and 20 mg/mL. In one embodiment, the concentration of analgesic in the liquid solution is between 1 qg/mL and 10 mg/mL. In one embodiment, the concentration of analgesic in the liquid solution is between 1 qg/mL and 5 mg/mL. In one embodiment, the concentration of analgesic in the liquid solution is between 0.1 mg/mL and 5 mg/mL. In one embodiment, the concentration of analgesic in the liquid solution is between 0.1 mg/mL and 2 mg/mL. In one embodiment, the concentration of analgesic in the liquid solution is between 0.1 mg/mL and 1 mg/mL. In one embodiment, the liquid solution comprises 2 mL of non-opioid analgesic at a concentration of 2 mg/mL. In one embodiment, the liquid solution comprises 2 mL of etomidate at a concentration of 2 mg/mL. In one embodiment, the liquid solution comprises 2 mL of the stock concentration of a commercially available non-opioid analgesic.

In one embodiment, the weight ratio of propofol to ketamine in the pharmaceutical composition is between 1:1 and 100:1. In one embodiment, the weight ratio of propofol to ketamine in the pharmaceutical composition is between 1 : 1 and 90: 1. In one embodiment, the weight ratio of propofol to ketamine in the pharmaceutical composition is between 1 : 1 and 80: 1. In one embodiment, the weight ratio of propofol to ketamine in the pharmaceutical composition is between 1 : 1 and 70: 1. In one embodiment, the weight ratio of propofol to ketamine in the pharmaceutical composition is between 1:1 and 60:1. In one embodiment, the weight ratio of propofol to ketamine in the pharmaceutical composition is between 1 : 1 and 50:1. In one embodiment, the weight ratio of propofol to ketamine in the pharmaceutical composition is between 1:1 and 40:1. In one embodiment, the weight ratio of propofol to ketamine in the pharmaceutical composition is between 1 : 1 and 30:1. In one embodiment, the weight ratio of propofol to ketamine in the pharmaceutical composition is between 1:1 and 20:1. In one embodiment, the weight ratio of propofol to ketamine in the pharmaceutical composition is between 1 : 1 and 10:1.

In one embodiment, the weight ratio of propofol to non-opioid analgesic in the pharmaceutical composition is between 1 : 1 and 200: 1. In one embodiment, the weight ratio of propofol to analgesic in the pharmaceutical composition is between 1 : 1 and 90:1. In one embodiment, the weight ratio of propofol to analgesic in the pharmaceutical composition is between 1 : 1 and 80: 1. In one embodiment, the weight ratio of propofol to analgesic in the pharmaceutical composition is between 1:1 and 70:1. In one embodiment, the weight ratio of propofol to analgesic in the pharmaceutical composition is between 1 : 1 and 60: 1. In one embodiment, the weight ratio of propofol to analgesic in the pharmaceutical composition is between 1:1 and 50:1. In one embodiment, the weight ratio of propofol to analgesic in the pharmaceutical composition is between 1 : 1 and 40: 1. In one embodiment, the weight ratio of propofol to analgesic in the pharmaceutical composition is between 1:1 and 30:1. In one embodiment, the weight ratio of propofol to analgesic in the pharmaceutical composition is between 5:1 and 25: 1. In one embodiment, the weight ratio of propofol to analgesic in the pharmaceutical composition is between 10:1 and 20:1.

In one embodiment, the weight ratio of ketamine to non-opioid analgesic in the pharmaceutical composition is between 1 : 1 and 100: 1. In one embodiment, the weight ratio of ketamine to analgesic in the pharmaceutical composition is between 1:1 and 90:1. In one embodiment, the weight ratio of ketamine to analgesic in the pharmaceutical composition is between 1 : 1 and 80: 1. In one embodiment, the weight ratio of ketamine to analgesic in the pharmaceutical composition is between 1:1 and 70:1. In one embodiment, the weight ratio of ketamine to analgesic in the pharmaceutical composition is between 1 : 1 and 60: 1. In one embodiment, the weight ratio of ketamine to analgesic in the pharmaceutical composition is between 1:1 and 50:1. In one embodiment, the weight ratio of ketamine to analgesic in the pharmaceutical composition is between 1 : 1 and 40: 1. In one embodiment, the weight ratio of ketamine to analgesic in the pharmaceutical composition is between 1:1 and 30:1. In one embodiment, the weight ratio of ketamine to analgesic in the pharmaceutical composition is between 1 : 1 and 20: 1. In one embodiment, the weight ratio of ketamine to analgesic in the pharmaceutical composition is between 1:1 and 10:1.

In one embodiment, the volume ratio of propofol to ketamine in the pharmaceutical composition is between 1:1 and 50:1. In one embodiment, the volume ratio of propofol to ketamine in the pharmaceutical composition is between 1 : 1 and 45: 1. In one embodiment, the volume ratio of propofol to ketamine in the pharmaceutical composition is between 1:1 and 40:1. In one embodiment, the volume ratio of propofol to ketamine in the pharmaceutical composition is between 1 : 1 and 35:1. In one embodiment, the volume ratio of propofol to ketamine in the pharmaceutical composition is between 1:1 and 30:1. In one embodiment, the volume ratio of propofol to ketamine in the pharmaceutical composition is between 1 : 1 and 25: 1. In one embodiment, the volume ratio of propofol to ketamine in the pharmaceutical composition is between 1:1 and 20:1. In one embodiment, the volume ratio of propofol to ketamine in the pharmaceutical composition is between 1 : 1 and 15:1. In one embodiment, the volume ratio of propofol to ketamine in the pharmaceutical composition is between 1 : 1 and 5:1. In one embodiment, the volume ratio of propofol to non-opioid analgesic in the pharmaceutical composition is between 1:1 and 50:1. In one embodiment, the volume ratio of propofol to analgesic in the pharmaceutical composition is between 1 : 1 and 45: 1. In one embodiment, the volume ratio of propofol to analgesic in the pharmaceutical composition is between 1:1 and 40:1. In one embodiment, the volume ratio of propofol to analgesic in the pharmaceutical composition is between 1 : 1 and 35:1. In one embodiment, the volume ratio of propofol to analgesic in the pharmaceutical composition is between 1:1 and 30:1. In one embodiment, the volume ratio of propofol to analgesic in the pharmaceutical composition is between 1 : 1 and 25: 1. In one embodiment, the volume ratio of propofol to analgesic in the pharmaceutical composition is between 1:1 and 20:1. In one embodiment, the volume ratio of propofol to analgesic in the pharmaceutical composition is between 1 : 1 and 15:1. In one embodiment, the volume ratio of propofol to analgesic in the pharmaceutical composition is between 1:1 and 5:1.

In one embodiment, the volume ratio of ketamine to non-opioid analgesic in the pharmaceutical composition is between 0.1:1 and 50:1. In one embodiment, the volume ratio of ketamine to analgesic in the pharmaceutical composition is between 0.1:1 and 45: 1. In one embodiment, the volume ratio of ketamine to analgesic in the pharmaceutical composition is between 0.1:1 and 40: 1.

In one embodiment, the volume ratio of ketamine to analgesic in the pharmaceutical composition is between 0.1:1 and 35:1. In one embodiment, the volume ratio of ketamine to analgesic in the pharmaceutical composition is between 0.1:1 and 30:1.

In one embodiment, the volume ratio of ketamine to analgesic in the pharmaceutical composition is between 0.1:1 and 25: 1. In one embodiment, the volume ratio of ketamine to analgesic in the pharmaceutical composition is between 0.1:1 and 20: 1.

In one embodiment, the volume ratio of ketamine to analgesic in the pharmaceutical composition is between 0.1:1 and 15:1. In one embodiment, the volume ratio of ketamine to analgesic in the pharmaceutical composition is between 0.1:1 and 10:1.

In one embodiment, the volume ratio of ketamine to analgesic in the pharmaceutical composition is between 0.5:1 and 5:1.

In one embodiment, the pharmaceutical composition comprises a 10 mL solution comprising 6 mL of 10 mg/mL propofol, 2 mL of 10 mg/mL ketamine, and 2 mL of 2 mg/mL non-opioid analgesic. In one embodiment, the pharmaceutical composition comprises a 10 mL solution comprising 6 mL of 10 mg/mL propofol, 2 mL of 10 mg/mL ketamine, and 2 mL of 2 mg/mL etomidate.

Method of treating a subject with the pharmaceutical composition

The present invention also relates to a method of providing sedation to a subject in need thereof, the method comprising the step of administering to the subject a pharmaceutical composition comprising a solution of propofol and ketamine. In one embodiment, the pharmaceutical composition also comprises a non opioid analgesic. The non-opioid analgesic may be any non-opioid analgesic known to a person of skill in the art. Exemplary non-opioid analgesics are described elsewhere herein. In one embodiment, the non-opioid analgesic is etomidate. In one embodiment, the pharmaceutical composition may comprise any active ingredients, solvents, excipients, carriers, or “additional” ingredients described elsewhere herein.

In one embodiment, the liquid pharmaceutical composition is administered in a bolus dose. In one embodiment, the bolus dose of the liquid pharmaceutical compositions is based on the weight and age of the subject. In one embodiment, the dosage of a 10 mL liquid pharmaceutical composition comprising 6 mL of 10 mg/mL propofol, 2 mL of 10 mg/mL ketamine, and 2 mL of 2 mg/mL non opioid analgesic is as follows: for a patient younger than 60 years of age with a normal weight the dosage is 1 mL per 10 kg of body weight, for a patient between 60 and 70 years of age with a normal weight the dosage is 0.8 mL per 10 kg of body weight, and for a patient older than 70 years of age with a normal weight the dosage is 0.6 mL per 10 kg of body weight. In one embodiment, the dosage of a 10 mL liquid pharmaceutical composition comprising 6 mL of 10 mg/mL propofol, 2 mL of 10 mg/mL ketamine, and 2 mL of 2 mg/mL non-opioid analgesic is as follows: for a patient younger than 40 years of age with a normal weight the dosage is 1.2 mL per 10 kg of body weight and for a patient older than 85 years of age with a normal weight the dosage is 0.5 mL per 10 kg of body weight.

In one embodiment, the dosages of a 10 mL liquid pharmaceutical composition comprising 6 mL of 10 mg/mL propofol, 2 mL of 10 mg/mL ketamine, and 2 mL of 2 mg/mL non-opioid analgesic described above are adjusted for administration to an obese patient, having a Body Mass Index (BMI) greater than 25, using the following formula:

Adjusted Weight for Dosing (AWFD) = Ideal Body Weight (IBW) + 30% (actual weight - IBW).

The bolus dosages can be determined for solutions other than the 10 mL pharmaceutical composition described above. For example, for a patient younger than 60 years of age with a normal weight, the bolus dose comprises 6 mg of propofol, 2 mg of ketamine, and 0.4 mg of non-opioid analgesic. In one embodiment, the non-opioid analgesic is etomidate.

In one embodiment, the bolus dose of the pharmaceutical composition is delivered all at once. In one embodiment, the pharmaceutical composition is delivered as a bolus dose. In one embodiment, the bolus dose is delivered via infusion pump. In one embodiment, the bolus dose is delivered via syringe. In one embodiment, the syringe is pushed by hand. In one embodiment, the pharmaceutical composition is delivered via a continuous infusion. In one embodiment, the composition is delivered via both a bolus dose and a continuous infusion. In one embodiment, the composition is delivered intravenously. In one embodiment, the pharmaceutical composition is administered to the patient as a bolus dose immediately before nerve blocks.

In one embodiment, the pharmaceutical composition is administered to a patient continuously. In one embodiment, the continuous dose is administered to a patient after the bolus dose. In one embodiment, the pharmaceutical composition is administered continuously after nerve blocks. In one embodiment, the pharmaceutical composition is administered continuously after both the bolus dose and nerve blocks. In one embodiment, the pharmaceutical composition is administered continuously to a patient during surgery. In one embodiment, the pharmaceutical composition is administered continuously to a patient intravenously. In one embodiment, the pharmaceutical composition is administered continuously to a patient via an infusion pump. In one embodiment, the pharmaceutical composition is administered continuously to a patient during surgery via an infusion pump.

In one embodiment, the infusion rate of the pharmaceutical composition is between 1 mL/hr and 100 mL/hr. In one embodiment, the infusion rate of the pharmaceutical composition is between 1 mL/hr and 90 mL/hr. In one embodiment, the infusion rate of the pharmaceutical composition is between 1 mL/hr and 80 mL/hr. In one embodiment, the infusion rate of the pharmaceutical composition is between 1 mL/hr and 70 mL/hr. In one embodiment, the infusion rate of the pharmaceutical composition is between 1 mL/hr and 60 mL/hr. In one embodiment, the infusion rate of the pharmaceutical composition is between 1 mL/hr and 50 mL/hr. In one embodiment, the infusion rate of the pharmaceutical composition is between 5 mL/hr and 45 mL/hr.

In one embodiment, for the induction of general anesthesia, the liquid pharmaceutical composition is administered such that about 0.2 to 0.6 mg/kg of non opioid analgesic is delivered to the patient, which is equivalent to about 14 to 42 mg for a 70 kg person. In one embodiment, for sedation, the liquid pharmaceutical composition is administered such that about 0.1 mg/kg of non-opioid analgesic is delivered to the patient in 1 to 3 bolus doses, with total dose of 7 mg to 21 mg for a 70 kg person.

In one embodiment, the infusion rate of the pharmaceutical composition will be determined by the patient’s age, weight, or anxiety level. In one embodiment, the infusion rate of the pharmaceutical composition will be determined by duration or extensiveness of the surgery. In one embodiment, the infusion rate of the pharmaceutical composition will be determined by more than one of the above factors.

In one embodiment, a continuous dose of between 5 mg and 400 mg of propofol is administered to a patient per hour. In one embodiment, a continuous dose of between 5 mg and 380 mg of propofol is administered to a patient per hour. In one embodiment, a continuous dose of between 5 mg and 360 mg of propofol is administered to a patient per hour. In one embodiment, a continuous dose of between 5 mg and 340 mg of propofol is administered to a patient per hour. In one embodiment, a continuous dose of between 5 mg and 320 mg of propofol is administered to a patient per hour. In one embodiment, a continuous dose of between 5 mg and 300 mg of propofol is administered to a patient per hour. In one embodiment, a continuous dose of between 15 mg and 300 mg of propofol is administered to a patient per hour. In one embodiment, a continuous dose of between 15 mg and 280 mg of propofol is administered to a patient per hour. In one embodiment, a continuous dose of between 20 mg and 280 mg of propofol is administered to a patient per hour.

In one embodiment, a continuous dose of between 1 mg and 200 mg of ketamine is administered to a patient per hour. In one embodiment, a continuous dose of between 1 mg and 190 mg of ketamine is administered to a patient per hour. In one embodiment, a continuous dose of between 1 mg and 180 mg of ketamine is administered to a patient per hour. In one embodiment, a continuous dose of between 1 mg and 170 mg of ketamine is administered to a patient per hour. In one embodiment, a continuous dose of between 1 mg and 160 mg of ketamine is administered to a patient per hour. In one embodiment, a continuous dose of between 1 mg and 150 mg of ketamine is administered to a patient per hour. In one embodiment, a continuous dose of between 1 mg and 140 mg of ketamine is administered to a patient per hour. In one embodiment, a continuous dose of between 1 mg and 130 mg of ketamine is administered to a patient per hour. In one embodiment, a continuous dose of between 1 mg and 120 mg of ketamine is administered to a patient per hour. In one embodiment, a continuous dose of between 1 mg and 110 mg of ketamine is administered to a patient per hour. In one embodiment, a continuous dose of between 1 mg and 100 mg of ketamine is administered to a patient per hour.

In one embodiment, a continuous dose of between 0.1 mg and 34 mg of non-opioid analgesic is administered to a patient per hour. In one embodiment, a continuous dose of between 0.1 mg and 32 mg of analgesic is administered to a patient per hour. In one embodiment, a continuous dose of between 0.1 mg and 30 mg of analgesic is administered to a patient per hour. In one embodiment, a continuous dose of between 0.1 mg and 28 mg of analgesic is administered to a patient per hour. In one embodiment, a continuous dose of between 0.1 mg and 26 mg of analgesic is administered to a patient per hour. In one embodiment, a continuous dose of between 0.1 mg and 24 mg of analgesic is administered to a patient per hour. In one embodiment, a continuous dose of between 0.1 mg and 22 mg of analgesic is administered to a patient per hour. In one embodiment, a continuous dose of between 0.1 mg and 20 mg of analgesic is administered to a patient per hour.

In one embodiment, the continuous dose is administered until surgery is complete. In one embodiment, the continuous dose is administered until a maximum dose of ketamine or non-opioid analgesic is reached. In one embodiment, the maximum dosage of ketamine is between 50 mg and 150 mg. In one embodiment, the maximum dosage of ketamine is between 50 mg and 140 mg. In one embodiment, the maximum dosage of ketamine is between 50 mg and 130 mg. In one embodiment, the maximum dosage of ketamine is between 50 mg and 120 mg. In one embodiment, the maximum dosage of ketamine is between 50 mg and 110 mg. In one embodiment, the maximum dosage of ketamine is between 60 mg and 110 mg. In one embodiment, the maximum dosage of ketamine is between 70 mg and 110 mg. In one embodiment, the maximum dosage of ketamine is between 80 mg and 110 mg. In one embodiment, the maximum dosage of ketamine is between 90 mg and 110 mg. In one embodiment, the maximum dosage of ketamine is between 95 mg and 110 mg.

In one embodiment, 50 mg of ketamine, 50 mg of propofol, and 10 mg of etomidate can be used to make 50 mL of the liquid pharmaceutical composition. In one embodiment, 100 mg of ketamine, 100 mg of propofol, and 20 mg of etomidate can be used to make 100 mL of the liquid pharmaceutical composition. In one embodiment, between about 50 mL and 100 mL of the liquid pharmaceutical composition provides about 1 to 3 hours of sedation for most patients.

In one embodiment, 50 mg of ketamine can be used to make 25 mL of the liquid pharmaceutical composition. In one embodiment, 100 mg of ketamine can be used to make 50 mL of the liquid pharmaceutical composition. In one embodiment, the 25 mL or 50 mL liquid pharmaceutical composition further comprises propofol and etomidate at a dosage described elsewhere herein. In one embodiment, between about 50 mL and 100 mL of the liquid pharmaceutical composition provides about 1 to 3 hours of sedation for most patients. In one embodiment, the continuous dose is administered until a maximum dosage of non-opioid analgesic is reached. In one embodiment, the continuous dose is administered until a maximum dosage of etomidate is reached. In one embodiment, the maximum dosage of etomidate is between 2 mg and 100 mg. In one embodiment, the maximum dosage of etomidate is between 2 mg and 90 mg. In one embodiment, the maximum dosage of etomidate is between 2 mg and 80 mg. In one embodiment, the maximum dosage of etomidate is between 2 mg and 70 mg. In one embodiment, the maximum dosage of etomidate is between 2 mg and 60 mg. In one embodiment, the maximum dosage of etomidate is between 2 mg and 50 mg. In one embodiment, the maximum dosage of etomidate is between 2 mg and 40 mg. In one embodiment, the maximum dosage of etomidate is between 2 mg and 30 mg. In one embodiment, the maximum dosage of etomidate is between 10 mg and 30 mg. In one embodiment, the maximum dosage of etomidate is between 15 mg and 25 mg.

In one embodiment, when the maximum dosage of ketamine or non opioid analgesic is reached, a solution propofol without ketamine or analgesic is administered to the patient. In one embodiment, the solution of propofol is administered continuously. In one embodiment, the propofol is administered intravenously. In one embodiment, the solution of propofol is administered from when the maximum dosage of ketamine or analgesic is reached until the end of surgery. In one embodiment, propofol is administered at a dosage of between 1 and 200 pg/kg/min. In one embodiment, propofol is administered at a dosage of between 1 and 190 pg/kg/min. In one embodiment, propofol is administered at a dosage of between 1 and 180 pg/kg/min. In one embodiment, propofol is administered at a dosage of between 1 and 170 pg/kg/min. In one embodiment, propofol is administered at a dosage of between 1 and 160 pg/kg/min. In one embodiment, propofol is administered at a dosage of between 1 and 150 pg/kg/min. In one embodiment, propofol is administered at a dosage of between 1 and 140 pg/kg/min.

In one embodiment, propofol is administered at a dosage of between 1 and 130 pg/kg/min. In one embodiment, propofol is administered at a dosage of between 1 and 120 pg/kg/min. In one embodiment, propofol is administered at a dosage of between 1 and 110 pg/kg/min. In one embodiment, propofol is administered at a dosage of between 10 and 110 pg/kg/min. In one embodiment, propofol is administered at a dosage of between 20 and 110 pg/kg/min. In one embodiment, propofol is administered at a dosage of between 20 and 105 pg/kg/min. Pharmaceutical compositions and formulations

The relative amounts of the propofol and ketamine, the pharmaceutically acceptable carrier, and any additional ingredients in a pharmaceutical composition of the invention will vary, depending upon the identity, size, and condition of the subject treated and further depending upon the route by which the composition is to be administered. By way of example, the composition may comprise between 0.1% and 100% (w/w) propofol and ketamine. The composition may additionally comprise between 0.1% and 100% (w/w) of anon- opioid analgesic described elsewhere herein. The composition may comprise between 0.1% and 100% (w/w) of one or more additional active ingredients described elsewhere herein.

In one embodiment, the compositions of the invention comprise one or more pharmaceutically acceptable excipients or carriers. In one embodiment, the pharmaceutical compositions of the invention comprise a therapeutically effective amount of propofol, ketamine, and a pharmaceutically acceptable carrier. In one embodiment, the pharmaceutical compositions of the invention comprise a therapeutically effective amount of propofol, ketamine, a non-opioid analgesic, and a pharmaceutically acceptable carrier. Pharmaceutically acceptable carriers that are useful, include, but are not limited to, glycerol, water, saline, ethanol and other pharmaceutically acceptable salt solutions such as phosphates and salts of organic acids. Examples of these and other pharmaceutically acceptable carriers are described in Remington’s Pharmaceutical Sciences (1991, Mack Publication Co., New Jersey).

The carrier may be a solvent or dispersion medium containing, for example, water, ethanol, polyol (for example, glycerol, propylene glycol, and liquid polyethylene glycol, and the like), suitable mixtures thereof, and vegetable oils. The proper fluidity may be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersion and by the use of surfactants. Prevention of the action of microorganisms may be achieved by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, ascorbic acid, thimerosal, and the like. In many cases, it will be preferable to include isotonic agents, for example, sugars, sodium chloride, or poly alcohols such as mannitol and sorbitol, in the composition. Prolonged absorption of the injectable compositions may be brought about by including in the composition an agent that delays absorption, for example, aluminum monostearate or gelatin. In one embodiment, the pharmaceutically acceptable carrier is not DMSO alone.

Formulations may be employed in admixtures with conventional excipients, i.e., pharmaceutically acceptable organic or inorganic carrier substances suitable for oral, vaginal, parenteral, nasal, intravenous, subcutaneous, enteral, or any other suitable mode of administration, known to the art. The pharmaceutical preparations may be sterilized and if desired mixed with auxiliary agents, e.g., lubricants, preservatives, stabilizers, wetting agents, emulsifiers, salts for influencing osmotic pressure buffers, coloring, flavoring and/or aromatic substances and the like. They may also be combined where desired with other active agents, e.g., other analgesic agents.

As used herein, “additional ingredients” include, but are not limited to, one or more of the following: excipients; surface active agents; dispersing agents; inert diluents; granulating and disintegrating agents; binding agents; lubricating agents; sweetening agents; flavoring agents; coloring agents; preservatives; physiologically degradable compositions such as gelatin; aqueous vehicles and solvents; oily vehicles and solvents; suspending agents; dispersing or wetting agents; emulsifying agents, demulcents; buffers; salts; thickening agents; fillers; emulsifying agents; antioxidants; antibiotics; antifungal agents; stabilizing agents; and pharmaceutically acceptable polymeric or hydrophobic materials. Other “additional ingredients” that may be included in the pharmaceutical compositions of the invention are known in the art and described, for example in Genaro, ed. (1985, Remington’s Pharmaceutical Sciences, Mack Publishing Co., Easton, PA), which is incorporated herein by reference.

The composition of the invention may comprise a preservative from about 0.005% to 2.0% by total weight of the composition. The preservative is used to prevent spoilage in the case of exposure to contaminants in the environment.

Examples of preservatives useful in accordance with the invention included but are not limited to those selected from the group consisting of benzyl alcohol, sorbic acid, parabens, imidurea and combinations thereof. A particularly preferred preservative is a combination of about 0.5% to 2.0% benzyl alcohol and 0.05% to 0.5% sorbic acid.

The composition may include an anti-oxidant and a chelating agent that inhibits the degradation of the compound. Preferred antioxidants for some compounds are BHT, BHA, alpha-tocopherol and ascorbic acid in the preferred range of about 0.01% to 0.3% and more preferably BHT in the range of 0.03% to 0.1% by weight by total weight of the composition. Preferably, the chelating agent is present in an amount of from 0.01% to 0.5% by weight by total weight of the composition. Particularly preferred chelating agents include edetate salts (e.g. disodium edetate) and citric acid in the weight range of about 0.01% to 0.20% and more preferably in the range of 0.02% to 0.10% by weight by total weight of the composition. The chelating agent is useful for chelating metal ions in the composition that may be detrimental to the shelf life of the formulation. While BHT and disodium edetate are the particularly preferred antioxidant and chelating agent respectively for some compounds, other suitable and equivalent antioxidants and chelating agents may be substituted therefore as would be known to those skilled in the art.

The pharmaceutical composition may comprise any form known to a person of skill in the art. In one embodiment, the pharmaceutical composition comprises a liquid suspension of one of more of the active ingredients in an aqueous or oily vehicle. Aqueous vehicles include, for example, water, and isotonic saline. Oily vehicles include, for example, almond oil, oily esters, ethyl alcohol, vegetable oils such as arachis, olive, sesame, or coconut oil, fractionated vegetable oils, and mineral oils such as liquid paraffin. Liquid suspensions may further comprise one or more additional ingredients including, but not limited to, suspending agents, dispersing or wetting agents, emulsifying agents, demulcents, preservatives, buffers, salts, flavorings, coloring agents, and sweetening agents. Oily suspensions may further comprise a thickening agent. Known suspending agents include, but are not limited to, sorbitol syrup, hydrogenated edible fats, sodium alginate, polyvinylpyrrolidone, gum tragacanth, gum acacia, and cellulose derivatives such as sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose. Known dispersing or wetting agents include, but are not limited to, naturally-occurring phosphatides such as lecithin, condensation products of an alkylene oxide with a fatty acid, with a long chain aliphatic alcohol, with a partial ester derived from a fatty acid and a hexitol, or with a partial ester derived from a fatty acid and a hexitol anhydride (e.g., polyoxyethylene stearate, heptadecaethyleneoxycetanol, polyoxyethylene sorbitol monooleate, and polyoxyethylene sorbitan monooleate, respectively). Known emulsifying agents include, but are not limited to, lecithin, and acacia. Known preservatives include, but are not limited to, methyl, ethyl, or n-propyl-para- hydroxybenzoates, ascorbic acid, and sorbic acid. Known sweetening agents include, for example, glycerol, propylene glycol, sorbitol, sucrose, and saccharin. Known thickening agents for oily suspensions include, for example, beeswax, hard paraffin, and cetyl alcohol.

In one embodiment, the pharmaceutical composition comprises a liquid solution of the one or more active ingredients in aqueous or oily solvents, the primary difference being that the active ingredient is dissolved, rather than suspended in the solvent. As used herein, an “oily” liquid is one which comprises a carbon- containing liquid molecule and which exhibits a less polar character than water.

Liquid solutions of the pharmaceutical composition of the invention may comprise each of the components described with regard to liquid suspensions, it being understood that suspending agents will not necessarily aid dissolution of the active ingredient in the solvent. Aqueous solvents include, for example, water, and isotonic saline. Oily solvents include, for example, almond oil, oily esters, ethyl alcohol, vegetable oils such as arachis, olive, sesame, or coconut oil, fractionated vegetable oils, and mineral oils such as liquid paraffin.

In one embodiment, the pharmaceutical composition comprises a powdered or granular formulation of the one or more active ingredients. Such formulations may be administered directly to a subject, used, for example, to form tablets, to fill capsules, or to prepare an aqueous or oily suspension or solution by addition of an aqueous or oily vehicle thereto. Each of these formulations may further comprise one or more of dispersing or wetting agent, a suspending agent, and a preservative. Additional excipients, such as fillers and sweetening, flavoring, or coloring agents, may also be included in these formulations.

In one embodiment, the pharmaceutical composition of the invention may be in the form of oil-in-water emulsion or a water-in-oil emulsion. The oily phase may be a vegetable oil such as olive or arachis oil, a mineral oil such as liquid paraffin, or a combination of these. Such compositions may further comprise one or more emulsifying agents such as naturally occurring gums such as gum acacia or gum tragacanth, naturally-occurring phosphatides such as soybean or lecithin phosphatide, esters or partial esters derived from combinations of fatty acids and hexitol anhydrides such as sorbitan monooleate, and condensation products of such partial esters with ethylene oxide such as polyoxyethylene sorbitan monooleate. These emulsions may also contain additional ingredients including, for example, sweetening or flavoring agents. Methods for impregnating or coating a material with a chemical composition are known in the art, and include, but are not limited to methods of depositing or binding a chemical composition onto a surface, methods of incorporating a chemical composition into the structure of a material during the synthesis of the material (i.e., such as with a physiologically degradable material), and methods of absorbing an aqueous or oily solution or suspension into an absorbent material, with or without subsequent drying.

In an embodiment, the pharmaceutical compositions may be administered to deliver a dose of between 1 ng/kg/day and 100 mg/kg/day. In another embodiment, the pharmaceutical compositions useful for practicing the invention may be administered to deliver a dose of between 1 ng/kg/day and 500 mg/kg/day.

Pharmaceutical compositions that are useful in the methods of the invention may be suitably developed for oral, rectal, vaginal, parenteral, topical, pulmonary, intranasal, buccal, ophthalmic, intravenous, or another route of administration. A composition useful within the methods of the invention may be directly administered to the skin, or any other tissue of a mammal. Other contemplated formulations include liposomal preparations, resealed erythrocytes containing the active ingredient, and immunologically-based formulations. The route(s) of administration will be readily apparent to the skilled artisan and will depend upon any number of factors including the type and severity of the disease being treated, the type and age of the veterinary or human subject being treated, and the like.

The formulations of the pharmaceutical compositions described herein may be prepared by any method known or hereafter developed in the art of pharmacology. In general, such preparatory methods include the step of bringing the active ingredient into association with a carrier or one or more other accessory ingredients, and then, if necessary or desirable, shaping or packaging the product into a desired single- or multi-dose unit.

As used herein, a “unit dose” is a discrete amount of the pharmaceutical composition comprising a predetermined amount of the active ingredient. The amount of the active ingredient is generally equal to the dosage of the active ingredient that would be administered to a subject or a convenient fraction of such a dosage such as, for example, one-half or one-third of such a dosage. The unit dosage form may be for a single daily dose or one of multiple daily doses (e.g., about 1 to 4 or more times per day). When multiple daily doses are used, the unit dosage form may be the same or different for each dose.

The regimen of administration may affect what constitutes an effective amount. The therapeutic formulations may be administered to the subject either prior to or after a diagnosis of disease. Further, several divided dosages, as well as staggered dosages may be administered daily or sequentially, or the dose may be continuously infused, or may be a bolus injection. Further, the dosages of the therapeutic formulations may be proportionally increased or decreased as indicated by the exigencies of the therapeutic or prophylactic situation.

Administration of the compositions of the present invention to a subject, preferably a mammal, more preferably a human, may be carried out using known procedures, at dosages and for periods of time effective to prevent or treat disease. An effective amount of the therapeutic compound necessary to achieve a therapeutic effect may vary according to factors such as the activity of the particular compound employed; the time of administration; the rate of excretion of the compound; the duration of the treatment; other drugs, compounds or materials used in combination with the compound; the state of the disease or disorder, age, sex, weight, condition, general health and prior medical history of the subject being treated, and like factors well-known in the medical arts. Dosage regimens may be adjusted to provide the optimum therapeutic response. For example, several divided doses may be administered daily or the dose may be proportionally reduced as indicated by the exigencies of the therapeutic situation. A non-limiting example of an effective dose range for a therapeutic compound of the invention is from about 1 and 5,000 mg/kg of body weight/per day. One of ordinary skill in the art would be able to study the relevant factors and make the determination regarding the effective amount of the therapeutic compound without undue experimentation.

The compound may be administered to a subject as frequently as several times daily, or it may be administered less frequently, such as once a day, once a week, once every two weeks, once a month, or even less frequently, such as once every several months or even once a year or less. It is understood that the amount of compound dosed per day may be administered, in non-limiting examples, every day, every other day, every 2 days, every 3 days, every 4 days, or every 5 days. For example, with every other day administration, a 5 mg per day dose may be initiated on Monday with a first subsequent 5 mg per day dose administered on Wednesday, a second subsequent 5 mg per day dose administered on Friday, and so on. The frequency of the dose will be readily apparent to the skilled artisan and will depend upon any number of factors, such as, but not limited to, the type and severity of the disease being treated, the type and age of the animal, etc.

Actual dosage levels of the active ingredients in the pharmaceutical compositions of this invention may be varied so as to obtain an amount of the active ingredient that is effective to achieve the desired therapeutic response for a particular subject, composition, and mode of administration, without being toxic to the subject.

A medical doctor, e.g., physician or veterinarian, having ordinary skill in the art may readily determine and prescribe the effective amount of the pharmaceutical composition required. For example, the physician or veterinarian could start doses of the compounds of the invention employed in the pharmaceutical composition at levels lower than that required in order to achieve the desired therapeutic effect and gradually increase the dosage until the desired effect is achieved.

In particular embodiments, it is especially advantageous to formulate the compound in dosage unit form for ease of administration and uniformity of dosage. Dosage unit form as used herein refers to physically discrete units suited as unitary dosages for the subjects to be treated; each unit containing a predetermined quantity of therapeutic compound calculated to produce the desired therapeutic effect in association with the required pharmaceutical vehicle. The dosage unit forms of the invention are dictated by and directly dependent on (a) the unique characteristics of the therapeutic compound and the particular therapeutic effect to be achieved, and (b) the limitations inherent in the art of compounding/formulating such a therapeutic compound for the treatment of a disease in a subject.

In one embodiment, the compositions of the invention are administered to the subject in dosages that range from one to five times per day or more. In another embodiment, the compositions of the invention are administered to the subject in range of dosages that include, but are not limited to, once every day, every two, days, every three days to once a week, and once every two weeks. It will be readily apparent to one skilled in the art that the frequency of administration of the various combination compositions of the invention will vary from subject to subject depending on many factors including, but not limited to, age, disease or disorder to be treated, gender, overall health, and other factors. Thus, the invention should not be construed to be limited to any particular dosage regime and the precise dosage and composition to be administered to any subject will be determined by the attending physical taking all other factors about the subject into account.

Compounds of the invention for administration may be in the range of from about 1 mg to about 10,000 mg, about 20 mg to about 9,500 mg, about 40 mg to about 9,000 mg, about 75 mg to about 8,500 mg, about 150 mg to about 7,500 mg, about 200 mg to about 7,000 mg, about 3,050 mg to about 6,000 mg, about 500 mg to about 5,000 mg, about 750 mg to about 4,000 mg, about 1 mg to about 3,000 mg, about 10 mg to about 2,500 mg, about 20 mg to about 2,000 mg, about 25 mg to about 1,500 mg, about 50 mg to about 1,000 mg, about 75 mg to about 900 mg, about 100 mg to about 800 mg, about 250 mg to about 750 mg, about 300 mg to about 600 mg, about 400 mg to about 500 mg, and any and all whole or partial increments there between.

In some embodiments, the dose of a compound of the invention is from about 1 mg and about 2,500 mg. In some embodiments, a dose of a compound of the invention used in compositions described herein is less than about 10,000 mg, or less than about 8,000 mg, or less than about 6,000 mg, or less than about 5,000 mg, or less than about 3,000 mg, or less than about 2,000 mg, or less than about 1,000 mg, or less than about 500 mg, or less than about 200 mg, or less than about 50 mg. Similarly, in some embodiments, a dose of a second compound (i.e., a drug used for treating the same or another disease as that treated by the compositions of the invention) as described herein is less than about 1,000 mg, or less than about 800 mg, or less than about 600 mg, or less than about 500 mg, or less than about 400 mg, or less than about 300 mg, or less than about 200 mg, or less than about 100 mg, or less than about 50 mg, or less than about 40 mg, or less than about 30 mg, or less than about 25 mg, or less than about 20 mg, or less than about 15 mg, or less than about 10 mg, or less than about 5 mg, or less than about 2 mg, or less than about 1 mg, or less than about 0.5 mg, and any and all whole or partial increments thereof.

In one embodiment, the present invention is directed to a packaged pharmaceutical composition comprising a container holding a therapeutically effective amount of a compound or conjugate of the invention, alone or in combination with a second pharmaceutical agent; and instructions for using the compound or conjugate to treat, prevent, or reduce one or more symptoms of a disease in a subject. The term “container” includes any receptacle for holding the pharmaceutical composition. For example, in one embodiment, the container is the packaging that contains the pharmaceutical composition. In other embodiments, the container is not the packaging that contains the pharmaceutical composition, i.e., the container is a receptacle, such as a box or vial that contains the packaged pharmaceutical composition or unpackaged pharmaceutical composition and the instructions for use of the pharmaceutical composition. Moreover, packaging techniques are well known in the art. It should be understood that the instructions for use of the pharmaceutical composition may be contained on the packaging containing the pharmaceutical composition, and as such the instructions form an increased functional relationship to the packaged product. However, it should be understood that the instructions may contain information pertaining to the compound’s ability to perform its intended function, e.g., treating or preventing a disease in a subject, or delivering an imaging or diagnostic agent to a subject. Routes of administration of any of the compositions of the invention include oral, nasal, parenteral, sublingual, transdermal, transmucosal (e.g., sublingual, lingual, (trans)buccal, and (intra)nasal.). intravesical, intraduodenal, intragastrical, rectal, intra-peritoneal, subcutaneous, intramuscular, intradermal, intra-arterial, intravenous, or combinations of one or more types of administration.

EXPERIMENTAL EXAMPLES The invention is further described in detail by reference to the following experimental examples. These examples are provided for purposes of illustration only, and are not intended to be limiting unless otherwise specified. Thus, the invention should in no way be construed as being limited to the following examples, but rather should be construed to encompass any and all variations which become evident as a result of the teaching provided herein.

Without further description, it is believed that one of ordinary skill in the art can, using the preceding description and the following illustrative examples, make and utilize the present invention and practice the claimed methods. The following working examples therefore are not to be construed as limiting in any way the remainder of the disclosure.

Example 1 Materials and Methods

Concentration of stock solutions: Propofol and ketamine stock solutions are each 10 mg/mL. The concentrations of the non-opioid analgesic stock solutions vary depending on the analgesic selected. The concentration of the stock solution of the non-opioid analgesic etomidate is 2 mg/mL.

Preparation of the pharmaceutical composition: In a 10 mL syringe, 6 mL of propofol, 2 mL of ketamine, and 2 mL of etomidate are added, forming a 6-2-2 mixture known as KE6-2-2. The solution is mixed well.

Administration of the pharmaceutical composition: Before nerve blocks are performed, a bolus of the mixture is delivered by infusion pump or hand push approximately over 2-5 seconds. The dose of the mixture is based on patient’s weight and age. Usually, patient will reach OAA/S (Observer’s Assessment of Alertness/Sedation) score 3 level of sedation (slow verbal response to verbal stimulation, facial relaxation, and eyes close spontaneously) in less than one minute and is then ready for nerve blocks (retrobulbar block, ankle blocks, or injection of local anesthetics). The efficacy of painlessness is 90% or higher. Most of the patients are still be able to respond to verbal stimulation and breathe in response to demand without apnea or oxygen desaturation. Although some patients can still respond to verbal stimulation, most of them will not recall the blocks. The incidence of recall of injection is <10%.

Results and Discussion

The common practice of intravenous sedation for surgery is to administer several medications in different syringes to reduce anxiety (anxielytics), prevent pain associated with surgery (narcotics), provide continuous sedation (propofol), and prevent pain caused by propofol (lidocaine). It is very cumbersome to titrate all these medications contained in different syringes simultaneously and the sedative effects on the patients are often unpredictable. There is no standard dose for each of the medications. This type of technique is not only difficult and time consuming, but also unsafe since it is prone to oversedation or undersedation, leading to airway complications or injury if patients move during surgery, e.g. during retrobulbar blocks.

Previously, an opioid 6-2-2 sedative mixture was developed containing 6 mL of 10 mg/mL propofol, 2 mL of 10 mg/mL ketamine, and 2 mL of an opioid analgesic such as fentanyl, alfentanil, hydromorphone, remifentanil, sufentanil, or morphine. The concentration of opioid analgesic in this 6-2-2 mixture is dependent upon the concentration of the opioid stock solution (for example, 0.5 mg/mL for alfentanil and hydromorphone stock solutions and 0.05 mg/mL for fentanyl and remifentanil stock solutions). The opioid-containing 6-2-2 mixture represented a novel way to conduct intravenous sedation in a quantitatively controllable and predictable fashion in terms of its efficacy, timing, and incidence of complications. Compared to conventional sedation techniques, the time to sedation was < 1 min compared to 10 to 20 minutes, 90% patients without pain compared to unpredictable pain control, and 2% or less compared to 20-40% patients requiring intervention for airway complications. The mixture was very easy to use since only one syringe is required for the preparation. In addition, the sedation and analgesic results could be reproduced in the majority of patients. More importantly, the predetermined bolus dose based on patient’s age and weight met about 90% of patients’ needs adequately. The 6-2-2 mixtures can be made as a compound and delivered by infusion pump. Therefore, the technique can potentially become a commercial product and be used broadly in the clinical practice of MAC (intravenous sedation).

Opioids have been a very important portion of anesthesia practice for the prevention of pain during and immediately after surgery. The use of opioids definitely improves the quality of contemporary anesthesia. However, the current crisis of opioid associated addiction and death forces medical professionals to change their thinking and practice regarding the use of opioids. Although opioids are still administered to patients every day in operating rooms and hospitals, medical professionals, especially anesthesia providers, are under pressure to find an alternative non-opioid formula or technique. Without opioids, any sedation technique faces the crucial challenge of whether it is capable of providing adequate analgesia to prevent pain associated with regional blocks and surgery.

The present invention is a new non-opioid pharmaceutical composition for MAC (monitored anesthesia care, or intravenous sedation) that is both efficacious and safe wherein the composition is a 6-2-2 mixture of ketamine, propofol, and etomidate known as the KE6-2-2 mixture. In detail, in a 10 mL syringe, 6 mL of propofol (10 mg/mL), 2 mL of ketamine (10 mg/mL) and 2 mL of etomidate (2 mg/mL) are mixed together to form the KE6-2-2 mixture. 10 mL of the KE6-2-2 mixture is usually sufficient to provide sedation for procedures lasting about 30 minutes. For longer surgeries, the volume of the KE6- 2-2 mixture administered to the patient can be increased (for example, to 25 mL to cover one hour and 50 mL to cover three hours, depending on the patient’s age and weight), noting that if the volume administered is increased the ratio of the volume for each of the sedatives should remain 6:2:2, including 15 mL of propofol, 5 mL of ketamine, and 5 mL of etomidate. During surgery, the KE6-2-2 mixture is infused continuously by an infusion pump at a rate of 12 mL/hr, 24 mL/hr or 36 mL/hr, depending on the patient’s age and weight.

The determination of the bolus dose in volume (mL) is based on the patient’s age and weight. In detail, the dosage for patients between 40 and 60 years of age with normal ideal body weight is 1 mL per 10 kg body weight. The dose will increase 20% if the patient is younger than 40, leading to a dosage of 1.2 mL per 10 kg body weight. The dose will decrease 20% from the dosage for patients 40-60 years old if patient’s age is between 60 and 70, leading to a dosage of 0.8 mL per 10 kg.

The dose will decrease 40% from the dosage for patients 40-60 years old if the patient is 71 to 85 years of age, leading to a dosage of 0.6 mL per 10 kg. The dose will decrease 50% from the dosage for patients 40-60 years old if the patient is older than 85 years of age, leading to a dosage of 0.5 mL per 10 kg. For example, for a 55-year- old man or woman, with a normal weight of 70 kg, the bolus dose should be 7 mL. If he or she becomes 65 years old, the bolus dose would be 5.6 mL. And he or she becomes 75 in age, the bolus dose would be 4.2 mL. If the patient is overweight or obese with Body Mass Index (BMI) higher than 25, the weight for dosing should be calculated according to the following formula:

AWFD (Adjusted Weight For Dosing) = IBW + 30% (actual weight - IBW).

The KE6-2-2 mixture has been successfully used in glaucoma surgery, retinal surgery, comeal transplantation, pterygium surgery, cataract surgery, colonoscopy, etc. The data of approximately 100 patients who were administered the KE6-2-2 mixture and underwent surgical or diagnostic procedures has demonstrated the usefulness of the mixture. Specifically, the onset (the time required to reach the target level of moderate sedation) was about one minute or less, the efficacy (painlessness during regional blocks) was about 90% or higher, and there was a very low risk (2% or less) of complications, including head or body movement, apnea, hypoxia, and the requirement of airway intervention. Additionally, the effects of the non-opioid KE6-2-2 mixture were very compatible in every respect of MAC with opioid-containing 6-2-2 mixtures such as the KF6-2-2 mixture of propofol, ketamine, and fentanyl and other 6-2-2 mixtures containing opioids. One of the most striking features of the KE6-2-2 mixture was its great analgesia comparable with opioids, which was likely due to additive and synergistic effects from the combination of propofol, ketamine, and etomidate. In addition, the requirement of opioids for pain (morphine equivalent) after surgery was much less than patients receiving an opioid-based 6-2-2 mixture indicating the analgesia effect from the KE6-2-2 mixture was still effective in the postoperative recovery period (at least for several hours). Second, the incidence of postoperative nausea and vomiting (PONV) was very low even in patients receiving no prophylactic antiemetic drugs (ondansetron, metoclopramide, etc.) during surgery. Third, patients receiving the KE6-2-2 mixture usually had very stable hemodynamic function, such as blood pressure (BP), heart rate (HR), and oxygenation. Fourth, most of the patients receiving the KE6-2-2 mixture had very a positive experience. The patients stated that they were calm and very comfortable as well as without pain or anxiety while semi-awake during the procedures, even in patients who were super anxious before surgery and requested “to be out and hearing nothing.”

The inventive non-opioid KE6-2-2 mixture can potentially change the landscape of MAC practice in that it can be used to standardize and commercialize the MAC technique. Literature publications, including those from the Food and Drug Administration (FDA), have concluded that human error is a major contributing factor for patient injury and death during surgery and hospitalization. The lack of standardization of sedation technique MAC could be another contributing factor for patient injury associated with MAC. Therefore, the new KE6-2-2 technique has a great potential in the improvement of patient safety. The inventive non-opioid KE6- 2-2 mixture stands out as a novel technique to overcome the challenges associated with non-opioid MAC and to meet the need for adequate sedation and analgesia. Additionally, the non-opioid KE6-2-2 mixture demonstrates a quick onset and a profound safety profile. More importantly, a bolus dose for administration of the mixture can be precisely calculated based on patient’s age and weight and can be safely delivered intravenously either by infusion pump or even hand push over 2 seconds, which has never been demonstrated before. Whether this novel MAC technique will have a clinically significant impact in the fight against the opioid epidemic and opioid associated death remains to be seen and contested.

Example 2

Introduction

The American Society of Anesthesiologists (ASA) has been one of the driving forces behind the urgent fight of the opioid epidemic promoting multimodal approaches to perioperative care. The main challenge of the opioid-sparing anesthesia is that the results of the alternatives are either not as effective for pain control, too sedating, or limited by hemodynamic sequelae. Based on routinely used opioid anesthetic mixtures for ophthalmic surgery, an approach was designed with three anesthetics (propofol, ketamine, etomidate) in the 6-2-2 format, which provides moderate sedation with exquisite analgesia. However, the new combination is superior in onset of readiness for ophthalmic block, airway patency, and hemodynamic stability.

Methods

Approved by Institutional Review Board, anesthesia records of ophthalmic surgery at Jules Stein Eye Institute were reviewed, 629 pooled patients received opioid-based 6:2:2 mixture (Pooled 622), and 107 patients received the non opioid mixtures (KE622). The opioid-based anesthetic mixtures contained propofol (6 mL), narcotics (alfentanil [A622 group], fentanyl, or hydromorphone) (2 mL), and 2 mL lidocaine or ketamine, creating a ratio of 6:2:2 in volume used for sedation during ophthalmic block and surgery. These mixtures are compared with anon-opioid mixture (KE622) of propofol (6 mL), ketamine (2 mL), and etomidate (2 mL). Regardless of the mixture administered, the bolus dose was determined by the patient’s age and weight: < 60 yr, 1 ml/10 kg; 60-70 yr, 0.8 ml/10 kg; 71 -84 yr, 0.6 ml/10 kg; >85 yr, 0.5 ml/10 kg. For patients with BMI >25, adjusted weight for dosing (AWFD) calculated as:

AWFD = IBW + 30% (Actual weight - IBW)

The KE622 group received an additional lOmg of ketamine immediately after a mixture bolus. Parameters measured include mean time to reach an OAA/S (Observer's Assessment of Alertness/Sedation) of 3 or less as patient’s readiness for ocular block, incidence of pain, head movement, apnea, 02 desaturation, requirement of airway support, Mean Arterial Pressure (MAP) before and after bolus and block, recall of block, and use of pain or nausea medications in Post- Anesthesia Care Unit (PACU).

Results The mean age for the KE622 group was 64±15.3 compared to 75±9.3 in the A622 group and 66±15.3 in the pooled group, respectively (see Table 1 below). The BMI of the KE622 group of 28±5.5 was higher than the A622 and the pooled group. 98% of patients administered the KE622 mixture experienced no pain during the block, compared to 98% in the A622 group and 95% in the pooled group. The mean time to reach readiness for block was 36±15 seconds in the KE622 group; in comparison, the mean time to readiness was 51±20 seconds in the A622 group and 49±18 seconds in the pooled 622 group. None of the patients displayed involuntary head movement. There was a minimal difference in MAP before or after bolus and block with the KE622 group while the A622 group showed a 10 mm Hg decrease in MAP and the pooled group had a 7 mm Hg decrease after block. While all three groups showed similar absence of apnea, 97.2% patients in the KE622 group had no oxygen desaturation after the bolus compared to 87.5% in the A622 group, and 88.4% in the pooled group due to hypoventilation without need for mask ventilation or intubation. 94 to 99% of patients had no recall of the block in all three groups. 92% of patients received no post-operative nausea and vomiting (PONV) medications, and only 19% of patients required pain medications in the PACU.

Table 1. Comparison of opioid-based and non-opioid 6:2:2 anesthetic mixtures.

Conclusion The novel non-opioid multimodal single syringe 6:2:2 mixture with propofol, ketamine and etomidate was superior to the opioid-based 6:2:2 mixtures with an average of 36 seconds for patient readiness for ocular block and a 98% painless response without head movement, while maintaining airway patency and hemodynamic stability for ophthalmic surgery. While not being bound by scientific theory, it is believed that this mixture can be used in other surgical and diagnostic procedures under MAC.

The disclosures of each and every patent, patent application, and publication cited herein are hereby incorporated herein by reference in their entirety. While this invention has been disclosed with reference to specific embodiments, it is apparent that other embodiments and variations of this invention may be devised by others skilled in the art without departing from the true spirit and scope of the invention. The appended claims are intended to be construed to include all such embodiments and equivalent variations.

Claims

CLAIMS What is claimed is:

1. A pharmaceutical composition comprising a solution of propofol, ketamine, and a non-opioid analgesic wherein the concentration of propofol is 1 mg/mL - 10 mg/mL, the concentration of ketamine is 1 mg/mL - 10 mg/mL, and the concentration of non-opioid analgesic is 0.1 mg/mL - 2 mg/mL.

2. The pharmaceutical composition of claim 1, wherein the non-opioid analgesic is selected from the group consisting of: ketorolac, clonidine, lidocaine, magnesium sulfate, methylprednisolone, acetaminophen, aminobenzoate potassium, aminobenzoate sodium, phenacetin, etomidate, ibuprofen, fenoprofen, aspirin, indomethacin, naproxen, oxyphenbutazone, phenylbutazone, allopurinol, cholchicine, carbamazepine, methyl sergide, methotrimeprazine, propoxyphene, probenecid, salsalate, sulfinpyrazone, antipyrine, ethoheptazine, amodiaquine, diflunisal, dihydroergotamine, ergotamine, meclofenamate, mefenamic acid, piroxican, sulindac, tolmetin, benoxaprofen, benzydamine, bicifadine decibuprofen, flurbiprofen, ibufenac, indoprofen, ketoprofen, naproxen, naproxol, salicylamide, sodium salicylate, salicylate potassium, and combinations thereof.

3. The pharmaceutical composition of claim 1, wherein the analgesic is etomidate.

4. The pharmaceutical composition of claim 1, wherein the concentration of propofol is 5 mg/mL - 7 mg/mL, the concentration of ketamine is 1 mg/mL - 3 mg/mL, and the concentration of non-opioid analgesic is 0.1 mg/mL - 2 mg/mL.

5. The pharmaceutical composition of claim 1, wherein the solution comprises a sterile medium selected from the group consisting of water, deionized water, distilled water, sterilized water, saline solution, dextrose in water solution, Ringer’s lactate solution, soybean oil, egg lecithin, propylene glycol, disodium, and combinations thereof.

6. The pharmaceutical composition of claim 1, wherein the volume ratio of propofol: ketamine: non-opioid analgesic is 6:2:2.

7. A method of providing sedation to a subject in need thereof, the method comprising the step of administering to the subject a pharmaceutical composition comprising a solution of propofol, ketamine, and a non-opioid analgesic wherein the concentration of propofol is 1 mg/mL - 10 mg/mL, the concentration of ketamine is 1 mg/mL - 10 mg/mL, and the concentration of non-opioid analgesic is 0.1 mg/mL - 2 mg/mL; and wherein the composition is administered in a dosage based on the weight and age of the subject.

8. The method of claim 7, wherein the step of administering a pharmaceutical composition further comprises the step of intravenously administering the composition.

9. The method of claim 7, wherein when the subject is younger than 60 years of age, the dosage is 6 mg propofol per 10 kg body weight, 2 mg ketamine per 10 kg body weight, and 0.4 mg non-opioid analgesic per 10 kg body weight; when the subject is between 60 and 70 years of age, the dosage is 4.8 mg propofol per 10 kg body weight, 1.6 mg ketamine per 10 kg body weight, and 0.32 mg non-opioid analgesic per 10 kg body weight; and when the subject is over 70 years of age, the dosage is 3.6 mg propofol per 10 kg body weight, 1.2 mg ketamine per 10 kg body weight, and 0.24 mg non-opioid analgesic per 10 kg body weight.

10. The method of claim 9 wherein when the patient is obese, the dosage is adjusted using the formula:

11. The method of claim 7, wherein when the subject is younger than 40 years of age, the dosage is 7.2 mg of propofol per 10 kg body weight, 2.4 mg of ketamine per 10 kg body weight, and 0.48 mg of etomidate per 10 kg body weight; and when the subject is older than 85 years of age, the dosage is 3 mg of propofol per 10 kg body weight, 1 mg of ketamine per 10 kg body weight, and 0.2 mg of etomidate per 10 kg body weight.

12. The method of claim 11 wherein when the patient is obese, the dosage is adjusted using the formula:

13. The method of claim 7, wherein the step of administering a pharmaceutical composition further comprises the step of mixing a solution of propofol with a solution of ketamine and a solution of non-opioid analgesic to form a mixture.

14. The method of claim 7, wherein the non-opioid analgesic selected from the group consisting of: ketorolac, clonidine, lidocaine, magnesium sulfate, methylprednisolone, acetaminophen, aminobenzoate potassium, aminobenzoate sodium, phenacetin, etomidate, ibuprofen, fenoprofen, aspirin, indomethacin, naproxen, oxyphenbutazone, phenylbutazone, allopurinol, cholchicine, carbamazepine, methyl sergide, methotrimeprazine, propoxyphene, probenecid, salsalate, sulfinpyrazone, antipyrine, ethoheptazine, amodiaquine, diflunisal, dihydroergotamine, ergotamine, meclofenamate, mefenamic acid, piroxican, sulindac, tolmetin, benoxaprofen, benzydamine, bicifadine decibuprofen, flurbiprofen, ibufenac, indoprofen, ketoprofen, naproxen, naproxol, salicylamide, sodium salicylate, salicylate potassium, and combinations thereof.

15. The method of claim 7, wherein the non-opioid analgesic is etomidate.

16. The method of claim 7, wherein the of administering a pharmaceutical composition further comprises the step of administering a solution of propofol when a maximum dosage of ketamine or non-opioid analgesic is reached.

17. The method of claim 7, wherein the volume ratio of propofol: ketamine: non opioid analgesic is 6:2:2.